U.S. patent application number 17/326717 was filed with the patent office on 2022-04-28 for antibodies targeting cdh19 for melanoma.
The applicant listed for this patent is AMGEN INC.. Invention is credited to Brian Mingtung Chan, M. Shawn Jeffries, Chadwick Terence King, Zheng Pan, Dineli Wickramasinghe, Shouhua Xiao.
Application Number | 20220127354 17/326717 |
Document ID | / |
Family ID | 1000006078522 |
Filed Date | 2022-04-28 |
View All Diagrams
United States Patent
Application |
20220127354 |
Kind Code |
A1 |
Xiao; Shouhua ; et
al. |
April 28, 2022 |
ANTIBODIES TARGETING CDH19 FOR MELANOMA
Abstract
The present disclosure provides a human antibody or antigen
binding fragment thereof or an antibody construct comprising a
human binding domain or antigen binding fragment thereof capable of
binding to human CDH19 on the surface of a target cell. The
disclosure relates to a nucleic acid sequence encoding the antibody
or antigen binding fragment thereof contained in the antibody
construct, a vector comprising the nucleic acid sequence and a host
cell transformed or transfected with the vector. Furthermore, the
disclosure relates to a process for the production of the antibody
construct of the disclosure, a medical use or a method of treatment
using the antibody construct and a kit comprising the antibody or
antigen binding fragment thereof or the antibody construct.
Inventors: |
Xiao; Shouhua; (Foster City,
CA) ; Pan; Zheng; (Fremont, CA) ;
Wickramasinghe; Dineli; (San Francisco, CA) ;
Jeffries; M. Shawn; (Indianapolis, IN) ; King;
Chadwick Terence; (North Vancouver, CA) ; Chan; Brian
Mingtung; (Port Coquitlam, CA) |
|
Applicant: |
Name |
City |
State |
Country |
Type |
AMGEN INC. |
Thousand Oaks |
CA |
US |
|
|
Family ID: |
1000006078522 |
Appl. No.: |
17/326717 |
Filed: |
May 21, 2021 |
Related U.S. Patent Documents
|
|
|
|
|
|
Application
Number |
Filing Date |
Patent Number |
|
|
15878047 |
Jan 23, 2018 |
11053311 |
|
|
17326717 |
|
|
|
|
14762053 |
Jul 20, 2015 |
9920121 |
|
|
PCT/EP2014/051551 |
Jan 27, 2014 |
|
|
|
15878047 |
|
|
|
|
61756977 |
Jan 25, 2013 |
|
|
|
61785119 |
Mar 14, 2013 |
|
|
|
Current U.S.
Class: |
1/1 |
Current CPC
Class: |
C07K 16/3053 20130101;
A61K 47/6803 20170801; A61K 47/6849 20170801; C07K 16/28 20130101;
C07K 2317/34 20130101; C07K 2317/33 20130101; C07K 2317/92
20130101; C07K 2317/21 20130101; C07K 2317/73 20130101; C07K
2317/77 20130101; A61K 2039/505 20130101; A61K 47/6865 20170801;
C07K 2317/55 20130101 |
International
Class: |
C07K 16/28 20060101
C07K016/28; A61K 47/68 20060101 A61K047/68; C07K 16/30 20060101
C07K016/30 |
Claims
1. An isolated human antibody or antigen binding fragment thereof
capable of binding to human cadherin 19 (CDH19) on the surface of a
target cell, comprising a VH region comprising CDR-H1, CDR-H2 and
CDR-H3 and a VL region comprising CDR-L1, CDR-L2 and CDR-L3
selected from the group consisting of: (a) a VH region comprising
CDR-H1 as set forth in SEQ ID NO: 94, CDR-H2 as set forth in SEQ ID
NO: 95, CDR-H3 as set forth in SEQ ID NO: 96, and a VL region
comprising CDR-L1 as set forth in SEQ ID NO: 262, CDR-L2 as set
forth in SEQ ID NO: 263 and CDR-L3 as set forth in SEQ ID NO: 264,
(b) a VH region comprising CDR-H1 as set forth in CDR-H1 as set
forth in SEQ ID NO: 100, CDR-H2 as set forth in SEQ ID NO: 101,
CDR-H3 as set forth in SEQ ID NO: 102, and a VL region comprising
CDR-L1 as set forth in SEQ ID NO: 268, CDR-L2 as set forth in SEQ
ID NO: 269 and CDR-L3 as set forth in SEQ ID NO: 270, (c) a VH
region comprising CDR-H1 as set forth in CDR-H1 as set forth in SEQ
ID NO: 118, CDR-H2 as set forth in SEQ ID NO: 119, CDR-H3 as set
forth in SEQ ID NO: 120, and a VL region comprising CDR-L1 as set
forth in SEQ ID NO: 286, CDR-L2 as set forth in SEQ ID NO: 287 and
CDR-L3 as set forth in SEQ ID NO: 288, (d) a VH region comprising
CDR-H1 as set forth in CDR-H1 as set forth in SEQ ID NO: 154,
CDR-H2 as set forth in SEQ ID NO: 155, CDR-H3 as set forth in SEQ
ID NO: 156, and a VL region comprising CDR-L1 as set forth in SEQ
ID NO: 322, CDR-L2 as set forth in SEQ ID NO: 323 and CDR-L3 as set
forth in SEQ ID NO: 324, (e) a VH region comprising CDR-H1 as set
forth in CDR-H1 as set forth in SEQ ID NO: 100, CDR-H2 as set forth
in SEQ ID NO: 101, CDR-H3 as set forth in SEQ ID NO: 912, and a VL
region comprising CDR-L1 as set forth in SEQ ID NO: 268, CDR-L2 as
set forth in SEQ ID NO: 269 and CDR-L3 as set forth in SEQ ID NO:
270, (f) a VH region comprising CDR-H1 as set forth in CDR-H1 as
set forth in SEQ ID NO: 100, CDR-H2 as set forth in SEQ ID NO: 101,
CDR-H3 as set forth in SEQ ID NO: 913, and a VL region comprising
CDR-L1 as set forth in SEQ ID NO: 268, CDR-L2 as set forth in SEQ
ID NO: 269 and CDR-L3 as set forth in SEQ ID NO: 270, (g) a VH
region comprising CDR-H1 as set forth in CDR-H1 as set forth in SEQ
ID NO: 94, CDR-H2 as set forth in SEQ ID NO: 95, CDR-H3 as set
forth in SEQ ID NO: 910, and a VL region comprising CDR-L1 as set
forth in SEQ ID NO: 262, CDR-L2 as set forth in SEQ ID NO: 263 and
CDR-L3 as set forth in SEQ ID NO: 264, (h) a VH region comprising
CDR-H1 as set forth in CDR-H1 as set forth in SEQ ID NO: 94, CDR-H2
as set forth in SEQ ID NO: 95, CDR-H3 as set forth in SEQ ID NO:
911, and a VL region comprising CDR-L1 as set forth in SEQ ID NO:
262, CDR-L2 as set forth in SEQ ID NO: 263 and CDR-L3 as set forth
in SEQ ID NO: 264, (i) a VH region comprising CDR-H1 as set forth
in CDR-H1 as set forth in SEQ ID NO: 118, CDR-H2 as set forth in
SEQ ID NO: 119, CDR-H3 as set forth in SEQ ID NO: 120, and a VL
region comprising CDR-L1 as set forth in SEQ ID NO: 286, CDR-L2 as
set forth in SEQ ID NO: 287 and CDR-L3 as set forth in SEQ ID NO:
288, (j) a VH region comprising CDR-H1 as set forth in CDR-H1 as
set forth in SEQ ID NO: 118, CDR-H2 as set forth in SEQ ID NO: 914,
CDR-H3 as set forth in SEQ ID NO: 120, and a VL region comprising
CDR-L1 as set forth in SEQ ID NO: 286, CDR-L2 as set forth in SEQ
ID NO: 287 and CDR-L3 as set forth in SEQ ID NO: 288, and (k) a VH
region comprising CDR-H1 as set forth in CDR-H1 as set forth in SEQ
ID NO: 154, CDR-H2 as set forth in SEQ ID NO: 155, CDR-H3 as set
forth in SEQ ID NO: 920, and a VL region comprising CDR-L1 as set
forth in SEQ ID NO: 322, CDR-L2 as set forth in SEQ ID NO: 323 and
CDR-L3 as set forth in SEQ ID NO: 324.
2. The human antibody or antigen binding fragment thereof according
to claim 1, wherein the antibody or antigen binding fragment
thereof is a monoclonal antibody or a fragment thereof.
3. (canceled)
4. The human antibody or antigen binding fragment thereof according
to claim 1, comprising a VH region comprising the amino acid
sequence selected from the group consisting of: SEQ ID NO: 338, SEQ
ID NO: 354, SEQ ID NO: 378, SEQ ID NO: 356, SEQ ID NO: 476, SEQ ID
NO: 477, SEQ ID NO: 478, SEQ ID NO: 479, SEQ ID NO: 480, SEQ ID NO:
481, SEQ ID NO: 482, SEQ ID NO: 483, SEQ ID NO: 484, SEQ ID NO:
501, SEQ ID NO: 502, SEQ ID NO: 503, SEQ ID NO: 504, SEQ ID NO:
505, SEQ ID NO: 506, SEQ ID NO: 517, and SEQ ID NO: 518.
5. The human antibody or antigen binding fragment thereof according
to claim 1, comprising a VL region comprising the amino acid
sequence selected from the group consisting of: SEQ ID NO: 394, SEQ
ID NO: 410, SEQ ID NO: 434, SEQ ID NO: 412, SEQ ID NO: 571, SEQ ID
NO: 572, SEQ ID NO: 573, SEQ ID NO: 574, SEQ ID NO: 575, SEQ ID NO:
576, SEQ ID NO: 577, SEQ ID NO: 578, SEQ ID NO: 579, SEQ ID NO:
596, SEQ ID NO: 597, SEQ ID NO: 598, SEQ ID NO: 599, SEQ ID NO:
600, SEQ ID NO: 601, SEQ ID NO: 612, and SEQ ID NO: 613.
6. The human antibody or antigen binding fragment thereof according
to claim 1, comprising a VH region and a VL region comprising a
pair of amino acid sequences selected from the group consisting of:
SEQ ID NOs: 338 and 394, SEQ ID NOs: 354 and 410, SEQ ID NOs: 378
and 434, SEQ ID NOs: 356 and 412, SEQ ID NOs: 476 and 571, SEQ ID
NOs: 477 and 572, SEQ ID NOs: 478 and 573, SEQ ID NOs: 479 and 574,
SEQ ID NOs: 480 and 575, SEQ ID NOs: 481 and 576, SEQ ID NOs: 482
and 577, SEQ ID NOs: 483 and 578, SEQ ID NOs: 484 and 579, SEQ ID
NOs: 501 and 596, SEQ ID NOs; 502 and 597, SEQ ID NOs: 503 and 598,
SEQ ID NOs: 504 and 599, SEQ ID NOs: 505 and 600, SEQ ID NOs: 506
and 601, SEQ ID NOs: 517 and 612, and SEQ ID NOs: 518 and 613.
7. The human antibody or antigen binding fragment thereof according
to claim 6, wherein the human binding domain or antigen binding
fragment thereof comprising a heavy and light chain amino acid
sequence selected from the group consisting of: SEQ ID NOs: 656 and
692, SEQ ID NOs: 654 and 690, SEQ ID NOs: 664 and 700, SEQ ID NOs:
670 and 706, SEQ ID NOs: 738 and 833, SEQ ID NOs: 739 and 834, SEQ
ID NOs: 740 and 835, SEQ ID NOs: 741 and 836, SEQ ID NOs: 742 and
837, SEQ ID NOs: 743 and 838, SEQ ID NOs: 744 and 839, SEQ ID NOs:
745 and 840, SEQ ID NOs: 746 and 841, SEQ ID NOs: 763 and 858, SEQ
ID NOs: 764 and 859, SEQ ID NOs: 765 and 860, SEQ ID NOs: 766 and
861, SEQ ID NOs: 767 and 862, SEQ ID NOs: 768 and 863, SEQ ID NOs:
779 and 874, and SEQ ID NOs: 780 and 875.
8. An antibody construct comprising the human antibody or antigen
binding fragment thereof according to claim 1 conjugated to a
chemotherapeutic agent.
9. The antibody construct according to claim 8, further comprising
a linker, wherein the linker conjugates the chemotherapeutic agent
to the human antibody or antigen binding fragment thereof.
10. The antibody construct according to claim 9, wherein the linker
is a non-cleavable linker.
11. The antibody construct according to claim 10, wherein the
linker comprises N-succinimidyl 4-(N-maleimidomethyl) cyclohexane-1
carboxylate (MCC).
12. The antibody construct of claim 8, wherein the chemotherapeutic
agent is conjugated to one or more lysines contained in the human
antibody or antigen binding fragment thereof.
13. The antibody construct of claim 8, wherein the chemotherapeutic
agent is maytansinoid (DM1).
14. The antibody construct of claim 13, wherein the average number
of DM1 molecules per antibody construct is between 1 and 10.
15. The antibody construct of claim 13, wherein the average number
of DM1 molecules per antibody construct is between 3 and 7.
16. The antibody construct of claim 13, wherein the average number
of DM1 molecules per antibody construct is between 4 and 6.
17. The antibody construct of claim 13, wherein the average number
of DM1 molecules per antibody construct is about 4.0, about 4.1,
about 4.2, about 4.3, about 4.4, about 4.5, about 4.6, about 4.7,
about 4.8, about 4.9, about 5.0, about 5.1, about 5.2, about 5.3,
about 5.4, about 5.5, about 5.6, about 5.7, about 5.8, about 5.9,
or about 6.0.
18. An isolated nucleic acid molecule encoding the human antibody
or antigen binding fragment thereof of claim 1.
19. A vector comprising the nucleic acid molecule of claim 18.
20. A host cell transformed or transfected with the nucleic acid
molecule of claim 18.
21. A process for producing a human antibody or antigen binding
fragment thereof, said process comprising culturing the host cell
of claim 16 under conditions allowing the expression of the
antibody or antigen binding fragment thereof.
22. The process of claim 21 further comprising recovering the
produced antibody or antigen binding fragment thereof, and
conjugating a chemotherapeutic agent to the recovered antibody or
antigen binding fragment thereof to produce an antibody
conjugate.
23. A composition comprising the human antibody or antigen binding
fragment thereof according to claim 1 and a pharmaceutically
acceptable carrier.
24-25. (canceled)
26. A method for treating or ameliorating a melanoma disease or
metastatic melanoma disease, comprising administering to a subject
in need thereof the antibody or antigen binding fragment thereof of
claim 1.
27. The method according to claim 26, wherein the melanoma disease
or metastatic melanoma disease is selected from the group
consisting of superficial spreading melanoma, lentigo maligna,
lentigo maligna melanoma, acral lentiginous melanoma and nodular
melanoma.
28. A kit comprising the antibody or antigen binding fragment
thereof of claim 1 in a vial or a syringe.
Description
RELATED APPLICATIONS
[0001] This application is related to a U.S. provisional
application entitled "Antibody constructs for CDH19 and CD3," filed
on Mar. 15, 2013, the same day as the present application is filed.
This related application is incorporated in its entirety by
reference.
FIELD OF THE INVENTION
[0002] The present invention relates to compositions of antigen
binding proteins including antibodies capable of binding to human
CDH19 on the surface of a target cell, as well as related methods.
Moreover, the invention provides a nucleic acid sequence encoding
the antibody construct, a vector comprising the nucleic acid
sequence and a host cell transformed or transfected with the
nucleic acid sequence or a vector comprising the nucleic acid
sequence. Furthermore, the invention provides a process for the
production of the antibody of the invention, a method of treatment
using the antibody and a kit comprising the antibody.
BACKGROUND OF THE INVENTION
[0003] Melanoma is a skin cancer that is caused by the oncogenic
transformation of melanocytes, which are pigment producing skin
cells. As of 2009, Melanoma had a prevalence of more than 870,000
cases in the US alone (US National Institutes of Health). Each
year, over 75,000 new cases of melanoma are diagnosed in the US,
and approximately 25% of patients have advanced disease at the time
of diagnosis. Despite the fact that cases of primary melanoma can
be cured by surgery if they are detected early enough, melanoma is
the leading cause of death from skin disease in the US, responsible
for about 10,000 deaths per year in the US. Once the disease has
spread and became metastatic, the prognosis is poor, with a 5 year
relative survival of 15%.
[0004] There are four basic types of melanomas. Three types are
found in the top layers of the skin and the fourth one is invasive
and has penetrated deeper into the skin and may have spread to
other areas of the body.
[0005] Superficial spreading melanoma is the most common type of
melanoma which accounts for about 70% of all cases. It grows along
the top layer of the skin for a fairly long time before penetrating
more deeply. It first appears as a flat or slightly raised
discolored patch that has irregular borders and may be somewhat
asymmetrical in form. The color varies, and you may see areas of
tan, brown, black, red, blue or white. This type of melanoma can
occur in a previously benign mole and is found most often in young
people.
[0006] Lentigo maligna is similar to the superficial spreading
type, as it also remains close to the skin surface for quite a
while, and usually appears as a flat or mildly elevated mottled
tan, brown or dark brown discoloration. It is found most often in
the elderly. When this cancer becomes invasive, it is referred to
as lentigo maligna melanoma.
[0007] Acral lentiginous melanoma also spreads superficially before
penetrating more deeply. It is quite different from the others,
though, as it usually appears as a black or brown discoloration
under the nails or on the soles of the feet or palms of the hands.
This type of melanoma is sometimes found on dark-skinned people,
and can often advance more quickly than superficial spreading
melanoma and lentigo maligna.
[0008] Nodular melanoma is usually invasive at the time it is first
diagnosed. The malignancy is recognized when it becomes a bump. It
is usually black, but occasionally is blue, gray, white, brown,
tan, red or skin tone. This is the most aggressive of the
melanomas, and is found in 10 to 15 percent of cases.
[0009] Common treatments for metastatic melanoma include
chemotherapy, targeted therapies for eligible patients (e.g. BRAF
inhibitor treatment for patients with BRAF mutations) and
immunotherapy. Metastatic melanoma is a tumor type where
immunotherapy has been demonstrated to not only slow disease
progression, but to lead to cures in late stage patients.
Interleukin-2 was approved for the use in metastatic melanoma in
1998, and in 2011 an antibody targeting CTLA4, a member of a new
generation of immune checkpoint inhibitors, gained approval by the
FDA.
[0010] CDH19 is a type II cadherin transmembrane protein of unknown
function. The human gene was cloned in 2000 based on its sequence
similarity to CDH7 (Kools, P. et al. Genomics. 2000). Expressed
Sequence Tags (ESTs) for CDH19 were isolated from melanocyte cDNA
libraries, indicating that expression of CDH19 may be limited to
cells of neural crest origin (Kools, P. et al. Genomics. 2000). In
support of this notion, rat CDH19 was found to be expressed
primarily in nerve ganglia and in Schwann cells during rat
embryonic development (Takahashi, M. and Osumi, O. Devl Dynamics.
2005).
[0011] Diagnostic antibodies detecting CDH19 in Western Blot,
immunohistochemitstry or flow cytometry are known in the art and
commercially available. Those antibodies comprise poly- and
monoclonal antibodies generated in animal hosts.
SUMMARY OF THE INVENTION
[0012] The present invention provides an isolated human antibody or
antigen binding fragment thereof capable of binding to human CDH19
on the surface of a target cell. In a preferred embodiment the
antibody or antigen binding fragment thereof comprises a monoclonal
antibody or a fragment thereof.
[0013] In one embodiment the human antibody or antigen binding
fragment thereof of the invention comprises a human binding domain
or antigen binding fragment thereof comprising a VH region
comprising CDR-H1, CDR-H2 and CDR-H3 and a VL region comprising
CDR-L1, CDR-L2 and CDR-L3 selected from the group consisting of:
[0014] (a) CDR-H1 as depicted in SEQ ID NO: 52, CDR-H2 as depicted
in SEQ ID NO: 53, CDR-H3 as depicted in SEQ ID NO: 54, CDR-L1 as
depicted in SEQ ID NO: 220, CDR-L2 as depicted in SEQ ID NO: 221
and CDR-L3 as depicted in SEQ ID NO: 222, CDR-H1 as depicted in SEQ
ID NO: 82, CDR-H2 as depicted in SEQ ID NO: 83, CDR-H3 as depicted
in SEQ ID NO: 84, CDR-L1 as depicted in SEQ ID NO: 250, CDR-L2 as
depicted in SEQ ID NO: 251 and CDR-L3 as depicted in SEQ ID NO:
252, CDR-H1 as depicted in SEQ ID NO: 82, CDR-H2 as depicted in SEQ
ID NO: 83, CDR-H3 as depicted in SEQ ID NO: 84, CDR-L1 as depicted
in SEQ ID NO: 250, CDR-L2 as depicted in SEQ ID NO: 251 and CDR-L3
as depicted in SEQ ID NO: 927, CDR-H1 as depicted in SEQ ID NO: 82,
CDR-H2 as depicted in SEQ ID NO: 83, CDR-H3 as depicted in SEQ ID
NO: 909, CDR-L1 as depicted in SEQ ID NO: 250, CDR-L2 as depicted
in SEQ ID NO: 251 and CDR-L3 as depicted in SEQ ID NO: 927, CDR-H1
as depicted in SEQ ID NO: 52, CDR-H2 as depicted in SEQ ID NO: 53,
CDR-H3 as depicted in SEQ ID NO: 54, CDR-L1 as depicted in SEQ ID
NO: 220, CDR-L2 as depicted in SEQ ID NO: 221 and CDR-L3 as
depicted in SEQ ID NO: 926, and CDR-H1 as depicted in SEQ ID NO:
52, CDR-H2 as depicted in SEQ ID NO: 53, CDR-H3 as depicted in SEQ
ID NO: 904, CDR-L1 as depicted in SEQ ID NO: 220, CDR-L2 as
depicted in SEQ ID NO: 221 and CDR-L3 as depicted in SEQ ID NO:
926; [0015] (b) CDR-H1 as depicted in SEQ ID NO: 124, CDR-H2 as
depicted in SEQ ID NO: 125, CDR-H3 as depicted in SEQ ID NO: 126,
CDR-L1 as depicted in SEQ ID NO: 292, CDR-L2 as depicted in SEQ ID
NO: 293 and CDR-L3 as depicted in SEQ ID NO: 294, CDR-H1 as
depicted in SEQ ID NO: 130, CDR-H2 as depicted in SEQ ID NO: 131,
CDR-H3 as depicted in SEQ ID NO: 132, CDR-L1 as depicted in SEQ ID
NO: 298, CDR-L2 as depicted in SEQ ID NO: 299 and CDR-L3 as
depicted in SEQ ID NO: 300, CDR-H1 as depicted in SEQ ID NO: 136,
CDR-H2 as depicted in SEQ ID NO: 137, CDR-H3 as depicted in SEQ ID
NO: 138, CDR-L1 as depicted in SEQ ID NO: 304, CDR-L2 as depicted
in SEQ ID NO: 305 and CDR-L3 as depicted in SEQ ID NO: 306, CDR-H1
as depicted in SEQ ID NO: 142, CDR-H2 as depicted in SEQ ID NO:
143, CDR-H3 as depicted in SEQ ID NO: 144, CDR-L1 as depicted in
SEQ ID NO: 310, CDR-L2 as depicted in SEQ ID NO: 311 and CDR-L3 as
depicted in SEQ ID NO: 312, CDR-H1 as depicted in SEQ ID NO: 148,
CDR-H2 as depicted in SEQ ID NO: 149, CDR-H3 as depicted in SEQ ID
NO: 150, CDR-L1 as depicted in SEQ ID NO: 316, CDR-L2 as depicted
in SEQ ID NO: 317 and CDR-L3 as depicted in SEQ ID NO: 318, CDR-H1
as depicted in SEQ ID NO: 166, CDR-H2 as depicted in SEQ ID NO:
167, CDR-H3 as depicted in SEQ ID NO: 168, CDR-L1 as depicted in
SEQ ID NO: 334, CDR-L2 as depicted in SEQ ID NO: 335 and CDR-L3 as
depicted in SEQ ID NO: 336, CDR-H1 as depicted in SEQ ID NO: 124,
CDR-H2 as depicted in SEQ ID NO: 125, CDR-H3 as depicted in SEQ ID
NO: 915, CDR-L1 as depicted in SEQ ID NO: 292, CDR-L2 as depicted
in SEQ ID NO: 293 and CDR-L3 as depicted in SEQ ID NO: 294, CDR-H1
as depicted in SEQ ID NO: 124, CDR-H2 as depicted in SEQ ID NO:
125, CDR-H3 as depicted in SEQ ID NO: 915, CDR-L1 as depicted in
SEQ ID NO: 292, CDR-L2 as depicted in SEQ ID NO: 293 and CDR-L3 as
depicted in SEQ ID NO: 928, CDR-H1 as depicted in SEQ ID NO: 124,
CDR-H2 as depicted in SEQ ID NO: 125, CDR-H3 as depicted in SEQ ID
NO: 915, CDR-L1 as depicted in SEQ ID NO: 292, CDR-L2 as depicted
in SEQ ID NO: 293 and CDR-L3 as depicted in SEQ ID NO: 929, CDR-H1
as depicted in SEQ ID NO: 166, CDR-H2 as depicted in SEQ ID NO:
167, CDR-H3 as depicted in SEQ ID NO: 168, CDR-L1 as depicted in
SEQ ID NO: 334, CDR-L2 as depicted in SEQ ID NO: 335 and CDR-L3 as
depicted in SEQ ID NO: 336, CDR-H1 as depicted in SEQ ID NO: 166,
CDR-H2 as depicted in SEQ ID NO: 167, CDR-H3 as depicted in SEQ ID
NO: 168, CDR-L1 as depicted in SEQ ID NO: 334, CDR-L2 as depicted
in SEQ ID NO: 335 and CDR-L3 as depicted in SEQ ID NO: 942, CDR-H1
as depicted in SEQ ID NO: 166, CDR-H2 as depicted in SEQ ID NO:
167, CDR-H3 as depicted in SEQ ID NO: 168, CDR-L1 as depicted in
SEQ ID NO: 334, CDR-L2 as depicted in SEQ ID NO: 335 and CDR-L3 as
depicted in SEQ ID NO: 943, CDR-H1 as depicted in SEQ ID NO: 148,
CDR-H2 as depicted in SEQ ID NO: 149, CDR-H3 as depicted in SEQ ID
NO: 150, CDR-L1 as depicted in SEQ ID NO: 316, CDR-L2 as depicted
in SEQ ID NO: 317 and CDR-L3 as depicted in SEQ ID NO: 318, CDR-H1
as depicted in SEQ ID NO: 148, CDR-H2 as depicted in SEQ ID NO:
149, CDR-H3 as depicted in SEQ ID NO: 150, CDR-L1 as depicted in
SEQ ID NO: 316, CDR-L2 as depicted in SEQ ID NO: 317 and CDR-L3 as
depicted in SEQ ID NO: 937, CDR-H1 as depicted in SEQ ID NO: 148,
CDR-H2 as depicted in SEQ ID NO: 149, CDR-H3 as depicted in SEQ ID
NO: 150, CDR-L1 as depicted in SEQ ID NO: 316, CDR-L2 as depicted
in SEQ ID NO: 317 and CDR-L3 as depicted in SEQ ID NO: 938, CDR-H1
as depicted in SEQ ID NO: 148, CDR-H2 as depicted in SEQ ID NO:
149, CDR-H3 as depicted in SEQ ID NO: 919, CDR-L1 as depicted in
SEQ ID NO: 316, CDR-L2 as depicted in SEQ ID NO: 317 and CDR-L3 as
depicted in SEQ ID NO: 938, CDR-H1 as depicted in SEQ ID NO: 142,
CDR-H2 as depicted in SEQ ID NO: 143, CDR-H3 as depicted in SEQ ID
NO: 144, CDR-L1 as depicted in SEQ ID NO: 310, CDR-L2 as depicted
in SEQ ID NO: 311 and CDR-L3 as depicted in SEQ ID NO: 935, CDR-H1
as depicted in SEQ ID NO: 142, CDR-H2 as depicted in SEQ ID NO:
143, CDR-H3 as depicted in SEQ ID NO: 918, CDR-L1 as depicted in
SEQ ID NO: 310, CDR-L2 as depicted in SEQ ID NO: 311 and CDR-L3 as
depicted in SEQ ID NO: 935, CDR-H1 as depicted in SEQ ID NO: 142,
CDR-H2 as depicted in SEQ ID NO: 143, CDR-H3 as depicted in SEQ ID
NO: 918, CDR-L1 as depicted in SEQ ID NO: 310, CDR-L2 as depicted
in SEQ ID NO: 311 and CDR-L3 as depicted in SEQ ID NO: 936, CDR-H1
as depicted in SEQ ID NO: 136, CDR-H2 as depicted in SEQ ID NO:
137, CDR-H3 as depicted in SEQ ID NO: 138, CDR-L1 as depicted in
SEQ ID NO: 304, CDR-L2 as depicted in SEQ ID NO: 305 and CDR-L3 as
depicted in SEQ ID NO: 933, CDR-H1 as depicted in SEQ ID NO: 136,
CDR-H2 as depicted in SEQ ID NO: 137, CDR-H3 as depicted in SEQ ID
NO: 917, CDR-L1 as depicted in SEQ ID NO: 304, CDR-L2 as depicted
in SEQ ID NO: 305 and CDR-L3 as depicted in SEQ ID NO: 934, CDR-H1
as depicted in SEQ ID NO: 130, CDR-H2 as depicted in SEQ ID NO:
131, CDR-H3 as depicted in SEQ ID NO: 132, CDR-L1 as depicted in
SEQ ID NO: 298, CDR-L2 as depicted in SEQ ID NO: 299 and CDR-L3 as
depicted in SEQ ID NO: 930, CDR-H1 as depicted in SEQ ID NO: 130,
CDR-H2 as depicted in SEQ ID NO: 131, CDR-H3 as depicted in SEQ ID
NO: 916, CDR-L1 as depicted in SEQ ID NO: 298, CDR-L2 as depicted
in SEQ ID NO: 299 and CDR-L3 as depicted in SEQ ID NO: 931, and
CDR-H1 as depicted in SEQ ID NO: 130, CDR-H2 as depicted in SEQ ID
NO: 131, CDR-H3 as depicted in SEQ ID NO: 916, CDR-L1 as depicted
in SEQ ID NO: 298, CDR-L2 as depicted in SEQ ID NO: 299 and CDR-L3
as depicted in SEQ ID NO: 932; [0016] (c) CDR-H1 as depicted in SEQ
ID NO: 94, CDR-H2 as depicted in SEQ ID NO: 95, CDR-H3 as depicted
in SEQ ID NO: 96, CDR-L1 as depicted in SEQ ID NO: 262, CDR-L2 as
depicted in SEQ ID NO: 263 and CDR-L3 as depicted in SEQ ID NO:
264, CDR-H1 as depicted in SEQ ID NO: 100, CDR-H2 as depicted in
SEQ ID NO: 101, CDR-H3 as depicted in SEQ ID NO: 102, CDR-L1 as
depicted in SEQ ID NO: 268, CDR-L2 as depicted in SEQ ID NO: 269
and CDR-L3 as depicted in SEQ ID NO: 270, CDR-H1 as depicted in SEQ
ID NO: 118, CDR-H2 as depicted in SEQ ID NO: 119, CDR-H3 as
depicted in SEQ ID NO: 120, CDR-L1 as depicted in SEQ ID NO: 286,
CDR-L2 as depicted in SEQ ID NO: 287 and CDR-L3 as depicted in SEQ
ID NO: 288, CDR-H1 as depicted in SEQ ID NO: 154, CDR-H2 as
depicted in SEQ ID NO: 155, CDR-H3 as depicted in SEQ ID NO: 156,
CDR-L1 as depicted in SEQ ID NO: 322, CDR-L2 as depicted in SEQ ID
NO: 323 and CDR-L3 as depicted in SEQ ID NO: 324, CDR-H1 as
depicted in SEQ ID NO: 100, CDR-H2 as depicted in SEQ ID NO: 101,
CDR-H3 as depicted in SEQ ID NO: 912, CDR-L1 as depicted in SEQ ID
NO: 268, CDR-L2 as depicted in SEQ ID NO: 269 and CDR-L3 as
depicted in SEQ ID NO: 270, CDR-H1 as depicted in SEQ ID NO: 100,
CDR-H2 as depicted in SEQ ID NO: 101, CDR-H3 as depicted in SEQ ID
NO: 913, CDR-L1 as depicted in SEQ ID NO: 268, CDR-L2 as depicted
in SEQ ID NO: 269 and CDR-L3 as depicted in SEQ ID NO: 270, CDR-H1
as depicted in SEQ ID NO: 94, CDR-H2 as depicted in SEQ ID NO: 95,
CDR-H3 as depicted in SEQ ID NO: 910, CDR-L1 as depicted in SEQ ID
NO: 262, CDR-L2 as depicted in SEQ ID NO: 263 and CDR-L3 as
depicted in SEQ ID NO: 264, CDR-H1 as depicted in SEQ ID NO: 94,
CDR-H2 as depicted in SEQ ID NO: 95, CDR-H3 as depicted in SEQ ID
NO: 911, CDR-L1 as depicted in SEQ ID NO: 262, CDR-L2 as depicted
in SEQ ID NO: 263 and CDR-L3 as depicted in SEQ ID NO: 264, CDR-H1
as depicted in SEQ ID NO: 118, CDR-H2 as depicted in SEQ ID NO:
119, CDR-H3 as depicted in SEQ ID NO: 120, CDR-L1 as depicted in
SEQ ID NO: 286, CDR-L2 as depicted in SEQ ID NO: 287 and CDR-L3 as
depicted in SEQ ID NO: 288, CDR-H1 as depicted in SEQ ID NO: 118,
CDR-H2 as depicted in SEQ ID NO: 914, CDR-H3 as depicted in SEQ ID
NO: 120, CDR-L1 as depicted in SEQ ID NO: 286, CDR-L2 as depicted
in SEQ ID NO: 287 and CDR-L3 as depicted in SEQ ID NO: 288, and
CDR-H1 as depicted in SEQ ID NO: 154, CDR-H2 as depicted in SEQ ID
NO: 155, CDR-H3 as depicted in SEQ ID NO: 920, CDR-L1 as depicted
in SEQ ID NO: 322, CDR-L2 as depicted in SEQ ID NO: 323 and CDR-L3
as depicted in SEQ ID NO: 324; [0017] (d) CDR-H1 as depicted in SEQ
ID NO: 4, CDR-H2 as depicted in SEQ ID NO: 5, CDR-H3 as depicted in
SEQ ID NO: 6, CDR-L1 as depicted in SEQ ID NO: 172, CDR-L2 as
depicted in SEQ ID NO: 173 and CDR-L3 as depicted in SEQ ID NO:
174, CDR-H1 as depicted in SEQ ID NO: 10, CDR-H2 as depicted in SEQ
ID NO: 11, CDR-H3 as depicted in SEQ ID NO: 12, CDR-L1 as depicted
in SEQ ID NO: 178, CDR-L2 as depicted in SEQ ID NO: 179 and CDR-L3
as depicted in SEQ ID NO: 180, CDR-H1 as depicted in SEQ ID NO: 28,
CDR-H2 as depicted in SEQ ID NO: 29, CDR-H3 as depicted in SEQ ID
NO: 30, CDR-L1 as depicted in SEQ ID NO: 196, CDR-L2 as depicted in
SEQ ID NO: 197 and CDR-L3 as depicted in SEQ ID NO: 198, CDR-H1 as
depicted in SEQ ID NO: 34, CDR-H2 as depicted in SEQ ID NO: 35,
CDR-H3 as depicted in SEQ ID NO: 36, CDR-L1 as depicted in SEQ ID
NO: 202, CDR-L2 as depicted in SEQ ID NO: 203 and CDR-L3 as
depicted in SEQ ID NO: 204, CDR-H1 as depicted in SEQ ID NO: 46,
CDR-H2 as depicted in SEQ ID NO: 47, CDR-H3 as depicted in SEQ ID
NO: 48, CDR-L1 as depicted in SEQ ID NO: 214, CDR-L2 as depicted in
SEQ ID NO: 215 and CDR-L3 as depicted in SEQ ID NO: 216, CDR-H1 as
depicted in SEQ ID NO: 58, CDR-H2 as depicted in SEQ ID NO: 59,
CDR-H3 as depicted in SEQ ID NO: 60, CDR-L1 as depicted in SEQ ID
NO: 226, CDR-L2 as depicted in SEQ ID NO: 227 and CDR-L3 as
depicted in SEQ ID NO: 228, CDR-H1 as depicted in SEQ ID NO: 64,
CDR-H2 as depicted in SEQ ID NO: 65, CDR-H3 as depicted in SEQ ID
NO: 66, CDR-L1 as depicted in SEQ ID NO: 232, CDR-L2 as depicted in
SEQ ID NO: 233 and CDR-L3 as depicted in SEQ ID NO: 234, CDR-H1 as
depicted in SEQ ID NO: 70, CDR-H2 as depicted in SEQ ID NO: 71,
CDR-H3 as depicted in SEQ ID NO: 72, CDR-L1 as depicted in SEQ ID
NO: 238, CDR-L2 as depicted in SEQ ID NO: 239 and CDR-L3 as
depicted in SEQ ID NO: 240, CDR-H1 as depicted in SEQ ID NO: 160,
CDR-H2 as depicted in SEQ ID NO: 161, CDR-H3 as depicted in SEQ ID
NO: 162, CDR-L1 as depicted in SEQ ID NO: 328, CDR-L2 as depicted
in SEQ ID NO: 329 and CDR-L3 as depicted in SEQ ID NO: 330, CDR-H1
as depicted in SEQ ID NO: 46, CDR-H2 as depicted in SEQ ID NO: 47,
CDR-H3 as depicted in SEQ ID NO: 48, CDR-L1 as depicted in SEQ ID
NO: 924, CDR-L2 as depicted in SEQ ID NO: 215 and CDR-L3 as
depicted in SEQ ID NO: 216, CDR-H1 as depicted in SEQ ID NO: 46,
CDR-H2 as depicted in SEQ ID NO: 47, CDR-H3 as depicted in SEQ ID
NO: 902, CDR-L1 as depicted in SEQ ID NO: 924, CDR-L2 as depicted
in SEQ ID NO: 215 and CDR-L3 as depicted in SEQ ID NO: 216, CDR-H1
as depicted in SEQ ID NO: 46, CDR-H2 as depicted in SEQ ID NO: 47,
CDR-H3 as depicted in SEQ ID NO: 903, CDR-L1 as depicted in SEQ ID
NO: 924, CDR-L2 as depicted in SEQ ID NO: 215 and CDR-L3 as
depicted in SEQ ID NO: 216, CDR-H1 as depicted in SEQ ID NO: 46,
CDR-H2 as depicted in SEQ ID NO: 47, CDR-H3 as depicted in SEQ ID
NO: 48, CDR-L1 as depicted in SEQ ID NO: 925, CDR-L2 as depicted in
SEQ ID NO: 215 and CDR-L3 as depicted in SEQ ID NO: 216, CDR-H1 as
depicted in SEQ ID NO: 70, CDR-H2 as depicted in SEQ ID NO: 907,
CDR-H3 as depicted in SEQ ID NO: 72, CDR-L1 as depicted in SEQ ID
NO: 238, CDR-L2 as depicted in SEQ ID NO: 239 and CDR-L3 as
depicted in SEQ ID NO: 240, CDR-H1 as depicted in SEQ ID NO: 70,
CDR-H2 as depicted in SEQ ID NO: 907, CDR-H3 as depicted in SEQ ID
NO: 908, CDR-L1 as depicted in SEQ ID NO: 238, CDR-L2 as depicted
in SEQ ID NO: 239 and CDR-L3 as depicted in SEQ ID NO: 240, CDR-H1
as depicted in SEQ ID NO: 28, CDR-H2 as depicted in SEQ ID NO: 901,
CDR-H3 as depicted in SEQ ID NO: 30, CDR-L1 as depicted in SEQ ID
NO: 922, CDR-L2 as depicted in SEQ ID NO: 197 and CDR-L3 as
depicted in SEQ ID NO: 923, CDR-H1 as depicted in SEQ ID NO: 58,
CDR-H2 as depicted in SEQ ID NO: 905, CDR-H3 as depicted in SEQ ID
NO: 906, CDR-L1 as depicted in SEQ ID NO: 226, CDR-L2 as depicted
in SEQ ID NO: 227 and CDR-L3 as depicted in SEQ ID NO: 228, CDR-H1
as depicted in SEQ ID NO: 58, CDR-H2 as depicted in SEQ ID NO: 905,
CDR-H3 as depicted in SEQ ID NO: 60, CDR-L1 as depicted in SEQ ID
NO: 226, CDR-L2 as depicted in SEQ ID NO: 227 and CDR-L3 as
depicted in SEQ ID NO: 228, CDR-H1 as depicted in SEQ ID NO: 160,
CDR-H2 as depicted in SEQ ID NO: 161, CDR-H3 as depicted in SEQ ID
NO: 162, CDR-L1 as depicted in SEQ ID NO: 939, CDR-L2 as depicted
in SEQ ID NO: 329 and CDR-L3 as depicted in SEQ ID NO: 330, CDR-H1
as depicted in SEQ ID NO: 160, CDR-H2 as depicted in SEQ ID NO:
921, CDR-H3 as depicted in SEQ ID NO: 162, CDR-L1 as depicted in
SEQ ID NO: 939, CDR-L2 as depicted in SEQ ID NO: 329 and CDR-L3 as
depicted in SEQ ID NO: 940, CDR-H1 as depicted in SEQ ID NO: 160,
CDR-H2 as depicted in SEQ ID NO: 161, CDR-H3 as depicted in SEQ ID
NO: 162, CDR-L1 as depicted in SEQ ID NO: 941, CDR-L2 as depicted
in SEQ ID NO: 329 and CDR-L3 as depicted in SEQ ID NO: 330, CDR-H1
as depicted in SEQ ID NO: 28, CDR-H2 as depicted in SEQ ID NO: 29,
CDR-H3 as depicted in SEQ ID NO: 30, CDR-L1 as depicted in SEQ ID
NO: 196, CDR-L2 as depicted in SEQ ID NO: 197 and CDR-L3 as
depicted in SEQ ID NO: 923, CDR-H1 as depicted in SEQ ID NO: 28,
CDR-H2 as depicted in SEQ ID NO: 29, CDR-H3 as depicted in SEQ ID
NO: 30, CDR-L1 as depicted in SEQ ID NO: 922, CDR-L2 as depicted in
SEQ ID NO: 197 and CDR-L3 as depicted in SEQ ID NO: 923, CDR-H1 as
depicted in SEQ ID NO: 28, CDR-H2 as depicted in SEQ ID NO: 901,
CDR-H3 as depicted in SEQ ID NO: 30, CDR-L1 as depicted in SEQ ID
NO: 922, CDR-L2 as depicted in SEQ ID NO: 197 and CDR-L3 as
depicted in SEQ ID NO: 923, and CDR-H1 as depicted in SEQ ID NO:
28, CDR-H2 as depicted in SEQ ID NO: 29, CDR-H3 as depicted in SEQ
ID NO: 30, CDR-L1 as depicted in SEQ ID NO: 939, CDR-L2 as depicted
in SEQ ID NO: 329 and CDR-L3 as depicted in SEQ ID NO: 330; and
[0018] (e) CDR-H1 as depicted in SEQ ID NO: 76, CDR-H2 as depicted
in SEQ ID NO: 77, CDR-H3 as depicted in SEQ ID NO: 78, CDR-L1 as
depicted in SEQ ID NO: 244, CDR-L2 as depicted in SEQ ID NO: 245
and CDR-L3 as depicted in SEQ ID NO: 246, CDR-H1 as depicted in SEQ
ID NO: 88, CDR-H2 as depicted in SEQ ID NO: 89, CDR-H3 as depicted
in SEQ ID NO: 90, CDR-L1 as depicted in SEQ ID NO: 256, CDR-L2 as
depicted in SEQ ID NO: 257 and CDR-L3 as depicted in SEQ ID NO:
258, CDR-H1 as depicted in SEQ ID NO: 106, CDR-H2 as depicted in
SEQ ID NO: 107, CDR-H3 as depicted in SEQ ID NO: 108, CDR-L1 as
depicted in SEQ ID NO: 274, CDR-L2 as depicted in SEQ ID NO: 275
and CDR-L3 as depicted in SEQ ID NO: 276, CDR-H1 as depicted in SEQ
ID NO: 112, CDR-H2 as depicted in SEQ ID NO: 113, CDR-H3 as
depicted in SEQ ID NO: 114, CDR-L1 as depicted in SEQ ID NO: 280,
CDR-L2 as depicted in SEQ ID NO: 281 and CDR-L3 as depicted in SEQ
ID NO: 282, and CDR-H1 as depicted in SEQ ID NO: 106, CDR-H2 as
depicted in SEQ ID NO: 107, CDR-H3 as depicted in SEQ ID NO: 108,
CDR-L1 as depicted in SEQ ID NO: 274, CDR-L2 as depicted in SEQ ID
NO: 275 and CDR-L3 as depicted in SEQ ID NO: 276.
[0019] In a further embodiment of the human antibody or antigen
binding fragment thereof of the invention the human binding domain
or antigen binding fragment thereof comprises a VH region selected
from the group consisting of VH regions [0020] (a) as depicted in
SEQ ID NO: 362, SEQ ID NO: 364, SEQ ID NO: 485, SEQ ID NO: 486, SEQ
ID NO: 487, SEQ ID NO: 492, SEQ ID NO: 493, SEQ ID NO: 494, and SEQ
ID NO: 495; [0021] (b) as depicted in SEQ ID NO: 342, SEQ ID NO:
366, SEQ ID NO: 370, SEQ ID NO: 344, SEQ ID NO: 372, SEQ ID NO:
368, SEQ ID NO: 496, SEQ ID NO: 497, SEQ ID NO: 498, SEQ ID NO:
499, SEQ ID NO: 500, SEQ ID NO: 508, SEQ ID NO: 509, SEQ ID NO:
510, SEQ ID NO: 511, SEQ ID NO: 512, SEQ ID NO: 519, SEQ ID NO:
520, SEQ ID NO: 521, SEQ ID NO: 522, SEQ ID NO: 523, SEQ ID NO:
524, SEQ ID NO: 525, SEQ ID NO: 526, SEQ ID NO: 527, SEQ ID NO:
528, SEQ ID NO: 529, SEQ ID NO: 530, SEQ ID NO: 531, SEQ ID NO:
532, SEQ ID NO: 533, SEQ ID NO: 534, SEQ ID NO: 535, SEQ ID NO:
536, SEQ ID NO: 537, and SEQ ID NO: 538; [0022] (c) as depicted in
SEQ ID NO: 338, SEQ ID NO: 354, SEQ ID NO: 378, SEQ ID NO: 356, SEQ
ID NO: 476, SEQ ID NO: 477, SEQ ID NO: 478, SEQ ID NO: 479, SEQ ID
NO: 480, SEQ ID NO: 481, SEQ ID NO: 482, SEQ ID NO: 483, SEQ ID NO:
484, SEQ ID NO: 501, SEQ ID NO: 502, SEQ ID NO: 503, SEQ ID NO:
504, SEQ ID NO: 505, SEQ ID NO: 506, SEQ ID NO: 517, and SEQ ID NO:
518; [0023] (d) as depicted in SEQ ID NO: 352, SEQ ID NO: 360, SEQ
ID NO: 388, SEQ ID NO: 386, SEQ ID NO: 340, SEQ ID NO: 346, SEQ ID
NO: 374, SEQ ID NO: 348, SEQ ID NO: 390, SEQ ID NO: 463, SEQ ID NO:
464, SEQ ID NO: 465, SEQ ID NO: 466, SEQ ID NO: 467, SEQ ID NO:
468, SEQ ID NO: 469, SEQ ID NO: 470, SEQ ID NO: 471, SEQ ID NO:
472, SEQ ID NO: 473, SEQ ID NO: 474, SEQ ID NO: 475, SEQ ID NO:
488, SEQ ID NO: 489, SEQ ID NO: 490, SEQ ID NO: 491, SEQ ID NO:
513, SEQ ID NO: 514, SEQ ID NO: 515, SEQ ID NO: 516, SEQ ID NO:
540, SEQ ID NO: 541, SEQ ID NO: 542, and SEQ ID NO: 543; and [0024]
(e) as depicted in SEQ ID NO: 376, SEQ ID NO: 392, SEQ ID NO: 358,
SEQ ID NO: 350, and SEQ ID NO: 507.
[0025] In another embodiment the human antibody or antigen binding
fragment thereof of the invention comprises the human binding
domain or antigen binding fragment thereof comprising a VL region
selected from the group consisting of VL regions [0026] (a) as
depicted in SEQ ID NO: 418, SEQ ID NO: 420, SEQ ID NO: 580, SEQ ID
NO: 581, SEQ ID NO: 582, SEQ ID NO: 587, SEQ ID NO: 588, SEQ ID NO:
589, and SEQ ID NO: 590; [0027] (b) as depicted in SEQ ID NO: 398,
SEQ ID NO: 422, SEQ ID NO: 426, SEQ ID NO: 400, SEQ ID NO: 428, SEQ
ID NO: 424, SEQ ID NO: 591, SEQ ID NO: 592, SEQ ID NO: 593, SEQ ID
NO: 594, SEQ ID NO: 595, SEQ ID NO: 603, SEQ ID NO: 604, SEQ ID NO:
605, SEQ ID NO: 606, SEQ ID NO: 607, SEQ ID NO: 614, SEQ ID NO:
615, SEQ ID NO: 616, SEQ ID NO: 617, SEQ ID NO: 618, SEQ ID NO:
619, SEQ ID NO: 620, SEQ ID NO: 621, SEQ ID NO: 622, SEQ ID NO:
623, SEQ ID NO: 624, SEQ ID NO: 625, SEQ ID NO: 626, SEQ ID NO:
627, SEQ ID NO: 628, SEQ ID NO: 629, SEQ ID NO: 630, SEQ ID NO:
631, SEQ ID NO: 632, and SEQ ID NO: 633; [0028] (c) as depicted in
SEQ ID NO: 394, SEQ ID NO: 410, SEQ ID NO: 434, SEQ ID NO: 412, SEQ
ID NO: 571, SEQ ID NO: 572, SEQ ID NO: 573, SEQ ID NO: 574, SEQ ID
NO: 575, SEQ ID NO: 576, SEQ ID NO: 577, SEQ ID NO: 578, SEQ ID NO:
579, SEQ ID NO: 596, SEQ ID NO: 597, SEQ ID NO: 598, SEQ ID NO:
599, SEQ ID NO: 600, SEQ ID NO: 601, SEQ ID NO: 612, and SEQ ID NO:
613; [0029] (d) as depicted in SEQ ID NO: 408, SEQ ID NO: 416, SEQ
ID NO: 444, SEQ ID NO: 442, SEQ ID NO: 396, SEQ ID NO: 402, SEQ ID
NO: 430, SEQ ID NO: 404, SEQ ID NO: 446, SEQ ID NO: 558, SEQ ID NO:
559, SEQ ID NO: 560, SEQ ID NO: 561, SEQ ID NO: 562, SEQ ID NO:
563, SEQ ID NO: 564, SEQ ID NO: 565, SEQ ID NO: 566, SEQ ID NO:
567, SEQ ID NO: 568, SEQ ID NO: 569, SEQ ID NO: 570, SEQ ID NO:
583, SEQ ID NO: 584, SEQ ID NO: 585, SEQ ID NO: 586, SEQ ID NO:
608, SEQ ID NO: 609, SEQ ID NO: 610, SEQ ID NO: 611, SEQ ID NO:
635, SEQ ID NO: 636, SEQ ID NO: 637, and SEQ ID NO: 638; and [0030]
(e) as depicted in SEQ ID NO: 432, SEQ ID NO: 448, SEQ ID NO: 414,
SEQ ID NO: 406, and SEQ ID NO: 602.
[0031] The invention further provides an embodiment of the human
antibody or antigen binding fragment thereof of the invention,
wherein the human binding domain or antigen binding fragment
thereof comprises a VH region and a VL region selected from the
group consisting of: [0032] (1) pairs of a VH region and a VL
region as depicted in SEQ ID NOs: 362+418, SEQ ID NOs: 364+420, SEQ
ID NOs: 485+580, SEQ ID NOs: 486+581, SEQ ID NOs: 487+582, SEQ ID
NOs: 492+587, SEQ ID NOs: 493+588, SEQ ID NOs: 494+589, and SEQ ID
NOs: 495+590; [0033] (2) pairs of a VH region and a VL region as
depicted in SEQ ID NOs: 342+398, SEQ ID NOs: 366+422, SEQ ID NOs:
370+426, SEQ ID NOs: 344+400, SEQ ID NOs: 372+428, SEQ ID NOs:
368+424, SEQ ID NOs: 496+591, SEQ ID NOs: 497+592, SEQ ID NOs:
498+593, SEQ ID NOs: 499+594, SEQ ID NOs: 500+595, SEQ ID NOs:
508+603, SEQ ID NOs: 509+604, SEQ ID NOs: 510+605, SEQ ID NOs:
511+606, SEQ ID NOs: 512+607, SEQ ID NOs: 519+614, SEQ ID NOs:
520+615, SEQ ID NOs: 521+616, SEQ ID NOs: 522+617, SEQ ID NOs:
523+618, SEQ ID NOs: 524+619, SEQ ID NOs: 525+620, SEQ ID NOs:
526+621, SEQ ID NOs: 527+622, SEQ ID NOs: 528+623, SEQ ID NOs:
529+624, SEQ ID NOs: 530+625, SEQ ID NOs: 531+626, SEQ ID NOs:
532+627, SEQ ID NOs: 533+628, SEQ ID NOs: 534+629, SEQ ID NOs:
535+630, SEQ ID NOs: 536+631, SEQ ID NOs: 537+632, and SEQ ID NOs:
538+633; [0034] (3) pairs of a VH region and a VL region as
depicted in SEQ ID NOs: 338+394, SEQ ID NOs: 354+410, SEQ ID NOs:
378+434, SEQ ID NOs: 356+412, SEQ ID NOs: 476+571, SEQ ID NOs:
477+572, SEQ ID NOs: 478+573, SEQ ID NOs: 479+574, SEQ ID NOs:
480+575, SEQ ID NOs: 481+576, SEQ ID NOs: 482+577, SEQ ID NOs:
483+578, SEQ ID NOs: 484+579, SEQ ID NOs: 501+596, SEQ ID NOs:
502+597, SEQ ID NOs: 503+598, SEQ ID NOs: 504+599, SEQ ID NOs:
505+600, SEQ ID NOs: 506+601, SEQ ID NOs: 517+612, and SEQ ID NOs:
518+613; [0035] (4) pairs of a VH region and a VL region as
depicted in SEQ ID NOs: 352+408, SEQ ID NOs: 360+416, SEQ ID NOs:
388+444, SEQ ID NOs: 386+442, SEQ ID NOs: 340+396, SEQ ID NOs:
346+402, SEQ ID NOs: 374+430, SEQ ID NOs: 348+404, SEQ ID NOs:
390+446, SEQ ID NOs: 463+558, SEQ ID NOs: 464+559, SEQ ID NOs:
465+560, SEQ ID NOs: 466+561, SEQ ID NOs: 467+562, SEQ ID NOs:
468+563, SEQ ID NOs: 469+564, SEQ ID NOs: 470+565, SEQ ID NOs:
471+566, SEQ ID NOs: 472+567, SEQ ID NOs: 473+568, SEQ ID NOs:
474+569, SEQ ID NOs: 475+570, SEQ ID NOs: 488+583, SEQ ID NOs:
489+584, SEQ ID NOs: 490+585, SEQ ID NOs: 491+586, SEQ ID NOs:
513+608, SEQ ID NOs: 514+609, SEQ ID NOs: 515+610, SEQ ID NOs:
516+611, SEQ ID NOs: 540+635, SEQ ID NOs: 541+636, SEQ ID NOs:
542+637, and SEQ ID NOs: 543+638; and [0036] (5) pairs of a VH
region and a VL region as depicted in SEQ ID NOs: 376+432, SEQ ID
NOs: 392+448, SEQ ID NOs: 358+414, SEQ ID NOs: 350+406, and SEQ ID
NOs: 507+602.
[0037] In a further embodiment the human binding domain or antigen
binding fragment thereof comprises the groups of heavy and light
chains having an amino acid sequence selected from the group
consisting of [0038] (1) a heavy and light chain as depicted in SEQ
ID NOs: 644+680, SEQ ID NOs: 650+686, SEQ ID NOs: 747+842, SEQ ID
NOs: 748+843, SEQ ID NOs: 749+844, SEQ ID NOs: 754+849, SEQ ID NOs:
755+850, SEQ ID NOs: 756+851, and SEQ ID NOs: 757+852; [0039] (2) a
heavy and light chain as depicted in SEQ ID NOs: 660+696, SEQ ID
NOs: 662+698, SEQ ID NOs: 668+704, SEQ ID NOs: 674+710, SEQ ID NOs:
672+708, SEQ ID NOs: 658+694, SEQ ID NOs: 758+853, SEQ ID NOs:
759+854, SEQ ID NOs: 760+855, SEQ ID NOs: 761+856, SEQ ID NOs:
762+857, SEQ ID NOs: 770+865, SEQ ID NOs: 771+866, SEQ ID NOs:
772+867, SEQ ID NOs: 773+868, SEQ ID NOs: 774+869, SEQ ID NOs:
781+876, SEQ ID NOs: 782+877, SEQ ID NOs: 783+878, SEQ ID NOs:
784+879, SEQ ID NOs: 785+880, SEQ ID NOs: 786+881, SEQ ID NOs:
787+882, SEQ ID NOs: 788+883, SEQ ID NOs: 789+884, SEQ ID NOs:
790+885, SEQ ID NOs: 791+886, SEQ ID NOs: 792+887, SEQ ID NOs:
793+888, SEQ ID NOs: 794+889, SEQ ID NOs: 795+890, SEQ ID NOs:
796+891, SEQ ID NOs: 797+892, SEQ ID NOs: 798+893, SEQ ID NOs:
799+894, and SEQ ID NOs: 800+895; [0040] (3) a heavy and light
chain as depicted in SEQ ID NOs: 656+692, SEQ ID NOs: 654+690, SEQ
ID NOs: 664+700, SEQ ID NOs: 670+706, SEQ ID NOs: 738+833, SEQ ID
NOs: 739+834, SEQ ID NOs: 740+835, SEQ ID NOs: 741+836, SEQ ID NOs:
742+837, SEQ ID NOs: 743+838, SEQ ID NOs: 744+839, SEQ ID NOs:
745+840, SEQ ID NOs: 746+841, SEQ ID NOs: 763+858, SEQ ID NOs:
764+859, SEQ ID NOs: 765+860, SEQ ID NOs: 766+861, SEQ ID NOs:
767+862, SEQ ID NOs: 768+863, SEQ ID NOs: 779+874, and SEQ ID NOs:
780+875; [0041] (4) a heavy and light chain as depicted in SEQ ID
NOs: 640+676, SEQ ID NOs: 642+678, SEQ ID NOs: 646+682, SEQ ID NOs:
648+684, SEQ ID NOs: 666+702, SEQ ID NOs: 725+820, SEQ ID NOs:
726+821, SEQ ID NOs: 727+822, SEQ ID NOs: 728+823, SEQ ID NOs:
729+824, SEQ ID NOs: 730+825, SEQ ID NOs: 731+826, SEQ ID NOs:
732+827, SEQ ID NOs: 733+828, SEQ ID NOs: 734+829, SEQ ID NOs:
735+830, SEQ ID NOs: 736+831, SEQ ID NOs: 737+832, SEQ ID NOs:
750+845, SEQ ID NOs: 751+846, SEQ ID NOs: 752+847, SEQ ID NOs:
753+848, SEQ ID NOs: 775+870, SEQ ID NOs: 776+871, SEQ ID NOs:
777+872, SEQ ID NOs: 778+873, SEQ ID NOs: 802+897, SEQ ID NOs:
803+898, SEQ ID NOs: 804+899, and SEQ ID NOs: 805+900; and [0042]
(5) a heavy and light chain as depicted in SEQ ID NOs: 652+688, and
SEQ ID NOs: 769+864.
[0043] In another embodiment the invention is directed to an
antibody construct comprising the human antibody or antigen binding
fragment thereof capable of binding to human CDH19 on the surface
of a target cell as described above that is conjugated to a
chemotherapeutic agent.
[0044] In one embodiment of the antibody construct of the invention
a linker conjugates the chemotherapeutic agent to the human
antibody or antigen binding fragment thereof.
[0045] In a preferred embodiment of the antibody construct of the
invention the linker is a non-cleavable linker.
[0046] It is also preferred that the linker in the antibody
construct of the invention comprises MCC.
[0047] In a further embodiment of the antibody construct of the
invention the chemotherapeutic agent is conjugated to one or more
lysines contained in the human antibody or antigen binding fragment
thereof.
[0048] In one embodiment of the antibody construct of the invention
the chemotherapeutic agent is DM1.
[0049] In a preferred embodiment of the antibody construct of the
invention the average number of DM1 molecules per antibody
construct is between 1 and 10.
[0050] It is also preferred for the antibody construct of the
invention that the average number of DM1 molecules per antibody
construct is between 3 and 7.
[0051] Moreover, it is preferred for the antibody construct of the
invention that the average number of DM1 molecules per antibody
construct is between 4 and 6.
[0052] In a further alternative embodiment of the antibody
construct of the invention the average number of DM1 molecules per
antibody construct is about 4.0, about 4.1, about 4.2, about 4.3,
about 4.4, about 4.5, about 4.6, about 4.7, about 4.8, about 4.9,
about 5.0, about 5.1, about 5.2, about 5.3, about 5.4, about 5.5,
about 5.6, about 5.7, about 5.8, about 5.9, or about 6.0.
[0053] The invention further provides an isolated nucleic acid
molecule or sequence encoding a human antibody or antigen binding
fragment thereof of the invention.
[0054] Furthermore, the invention provides a vector comprising a
nucleic acid sequence of the invention. Moreover, the invention
provides a host cell transformed or transfected with the nucleic
acid sequence of the invention or with a vector comprising the
nucleic acid molecule.
[0055] In a further embodiment the invention provides a process for
the production of a human antibody or an antigen binding fragment
thereof of the invention, said process comprising culturing a host
cell of the invention under conditions allowing the expression of
the human antibody or antigen binding fragment thereof of the
invention and recovering the produced antibody or antigen binding
fragment thereof from the culture.
[0056] In a further embodiment the invention provides a process for
the production of an antibody construct comprising a human antibody
or an antigen binding fragment thereof of the invention, said
process comprising culturing a host cell of the invention under
conditions allowing the expression of the human antibody or antigen
binding fragment thereof of the invention and recovering the
produced antibody or antigen binding fragment thereof from the
culture, and conjugating a chemotherapeutic agent to the recovered
antibody or antigen binding fragment thereof to produce the
antibody conjugate.
[0057] Moreover, the invention provides a pharmaceutical
composition comprising a human antibody or antigen binding fragment
thereof of the invention or an antibody construct of the invention
or produced according to the process of the invention in admixture
with a pharmaceutically acceptable carrier thereof.
[0058] In one embodiment the invention provides the human antibody
or antigen binding fragment thereof of the invention, the antibody
construct of the invention, or produced according to the process of
the invention for use in the prevention, treatment or amelioration
of a melanoma disease or metastatic melanoma disease. Preferably,
the melanoma disease or metastatic melanoma disease is selected
from the group consisting of superficial spreading melanoma,
lentigo maligna, lentigo maligna melanoma, acral lentiginous
melanoma and nodular melanoma.
[0059] The invention also provides a method for the treatment or
amelioration of a melanoma disease or metastatic melanoma disease,
comprising the step of administering to a subject in need thereof
the antibody or antigen binding fragment thereof of the invention,
the antibody construct of the invention, an antibody or antigen
binding fragment thereof of the invention or the antibody construct
of the invention produced according to the process of the invention
or a pharmaceutical composition of the invention.
[0060] In a preferred embodiment method the invention the melanoma
disease or metastatic melanoma disease is selected from the group
consisting of superficial spreading melanoma, lentigo maligna,
lentigo maligna melanoma, acral lentiginous melanoma and nodular
melanoma.
[0061] In a further embodiment, the invention provides a kit
comprising an antibody or antigen binding fragment thereof of the
invention, an antibody construct of the invention, an antibody or
antigen binding fragment thereof of the invention or the antibody
construct produced according to the process of the invention, a
vector of the invention, and/or a host cell of the invention.
BRIEF DESCRIPTION OF THE DRAWINGS
[0062] FIG. 1 depicts cell viability data of Colo-699 cells that
have been treated with fully human anti-CDH19 antibodies and a high
concentration of a goat anti-human Fc monovalent Fab conjugated
with DM1 (DM1-Fab) at a drug-antibody ratio (DAR) (.about.1.3).
[0063] FIG. 2 depicts the average cell viability data from a CHL-1
assay plotted against the average cell viability data from the
Colo-699 assay.
[0064] FIG. 3 shows the relative expression of CDH19 mRNA in
metastatic and primary melanoma samples.
[0065] FIG. 4 shows the expression of CDH19 protein in human tumor
samples by IHC.
[0066] FIG. 5 shows the results of the analysis of tumor cell lines
by flow cytometry and IHC to identify model systems with CDH19
expression similar to human tumors based on the number of CDH19
receptors present on the cell surface.
[0067] FIG. 6 shows in vitro activity of a CDH19 ADC against the
model tumor cell lines.
[0068] FIG. 7 shows in vitro activity of a CDH19 ADC in model tumor
cell lines at varying DAR ratios.
[0069] FIG. 8 shows in vivo activity of CDH19 ADCs in a xenograft
mouse model as compared to naked CDH19 antibodies.
[0070] FIG. 9 shows in vivo activity of CDH19 ADCs in a xenograft
mouse model. 4B10-DM1 Moderately Inhibited Tumor Growth at 182
.mu.g/kg DM1 in CHL-1 Xenografts
[0071] FIG. 10 shows in vivo activity of CDH19 ADCs in a xenograft
mouse model. Increasing the DAR Did Not Increase Tumor Growth
Inhibition in CHL-1 Xenografts
[0072] FIG. 11 shows in vivo activity of CDH19 ADCs in a xenograft
mouse model. Anti-CDH19 ADCs Moderately Inhibited Tumor Growth in
COLO699 Xenografts
DETAILED DESCRIPTION OF THE INVENTION
Definitions
[0073] It must be noted that as used herein, the singular forms
"a", "an", and "the", include plural references unless the context
clearly indicates otherwise. Thus, for example, reference to "a
reagent" includes one or more of such different reagents and
reference to "the method" includes reference to equivalent steps
and methods known to those of ordinary skill in the art that could
be modified or substituted for the methods described herein.
[0074] Unless otherwise indicated, the term "at least" preceding a
series of elements is to be understood to refer to every element in
the series. Those skilled in the art will recognize, or be able to
ascertain using no more than routine experimentation, many
equivalents to the specific embodiments of the invention described
herein. Such equivalents are intended to be encompassed by the
present invention.
[0075] The term "and/or" wherever used herein includes the meaning
of "and", "or" and "all or any other combination of the elements
connected by said term".
[0076] The term "about" or "approximately" as used herein means
within .+-.20%, preferably within .+-.15%, more preferably within
.+-.10%, and most preferably within .+-.5% of a given value or
range.
[0077] Throughout this specification and the claims which follow,
unless the context requires otherwise, the word "comprise", and
variations such as "comprises" and "comprising", will be understood
to imply the inclusion of a stated integer or step or group of
integers or steps but not the exclusion of any other integer or
step or group of integer or step. When used herein the term
"comprising" can be substituted with the term "containing" or
"including" or sometimes when used herein with the term
"having".
[0078] When used herein "consisting of" excludes any element, step,
or ingredient not specified in the claim element. When used herein,
"consisting essentially of" does not exclude materials or steps
that do not materially affect the basic and novel characteristics
of the claim.
[0079] In each instance herein any of the terms "comprising",
"consisting essentially of" and "consisting of" may be replaced
with either of the other two terms.
[0080] The definition of the term "antibody" includes embodiments
such as monoclonal, chimeric, single chain, humanized and human
antibodies, as well as antibody fragments, like, inter alia, Fab
fragments. Antibody fragments or derivatives further comprise
F(ab').sub.2, Fv, scFv fragments or single domain antibodies such
as domain antibodies or nanobodies, single variable domain
antibodies or immunoglobulin single variable domain comprising
merely one variable domain, which might be VHH, VH or VL, that
specifically bind an antigen or epitope independently of other V
regions or domains; see, for example, Harlow and Lane (1988) and
(1999), loc. cit.; Kontermann and Dubel, Antibody Engineering,
Springer, 2nd ed. 2010 and Little, Recombinant Antibodies for
Immunotherapy, Cambridge University Press 2009. Such immunoglobulin
single variable domain encompasses not only an isolated antibody
single variable domain polypeptide, but also larger polypeptides
that comprise one or more monomers of an antibody single variable
domain polypeptide sequence.
[0081] In line with this definition all above described embodiments
of the term antibody can be subsumed under the term "antibody
construct". Said term also includes diabodies or Dual-Affinity
Re-Targeting (DART) antibodies. Further envisaged are (bispecific)
single chain diabodies, tandem diabodies (Tandab's), "minibodies"
exemplified by a structure which is as follows: (VH-VL-CH3).sub.2,
(scFv-CH3).sub.2 or (scFv-CH3-scFv).sub.2, "Fc DART" antibodies and
"IgG DART" antibodies, and multibodies such as triabodies.
Immunoglobulin single variable domains encompass not only an
isolated antibody single variable domain polypeptide, but also
larger polypeptides that comprise one or more monomers of an
antibody single variable domain polypeptide sequence.
[0082] Various procedures are known in the art and may be used for
the production of such antibody constructs (antibodies and/or
fragments). Thus, (antibody) derivatives can be produced by
peptidomimetics. Further, techniques described for the production
of single chain antibodies (see, inter alia, U.S. Pat. No.
4,946,778, Kontermann and Dubel (2010), loc. cit. and Little
(2009), loc. cit.) can be adapted to produce single chain
antibodies specific for elected polypeptide(s). Also, transgenic
animals may be used to express humanized antibodies specific for
polypeptides and fusion proteins of this invention. For the
preparation of monoclonal antibodies, any technique, providing
antibodies produced by continuous cell line cultures can be used.
Examples for such techniques include the hybridoma technique
(Kohler and Milstein Nature 256 (1975), 495-497), the trioma
technique, the human B-cell hybridoma technique (Kozbor, Immunology
Today 4 (1983), 72) and the EBV-hybridoma technique to produce
human monoclonal antibodies (Cole et al., Monoclonal Antibodies and
Cancer Therapy, Alan R. Liss, Inc. (1985), 77-96). Surface plasmon
resonance as employed in the BIAcore system can be used to increase
the efficiency of phage antibodies which bind to an epitope of a
target polypeptide, such as CDH19 (Schier, Human Antibodies
Hybridomas 7 (1996), 97-105; Malmborg, J. Immunol. Methods 183
(1995), 7-13). It is also envisaged in the context of this
invention that the term "antibody" comprises antibody constructs,
which may be expressed in a host as described herein below, e.g.
antibody constructs which may be transfected and/or transduced via,
inter alia, viruses or plasmid vectors.
[0083] Furthermore, the term "antibody" as employed in the
invention also relates to derivatives or variants of the antibodies
described herein which display the same specificity as the
described antibodies. Accordingly, the term "antibody" also
subsumes antibody constructs such as different types of fragments
of antibodies, which still are characterized by the feature of
specific binding for CDH19.
[0084] The terms "antigen-binding domain", "antigen-binding
fragment" and "antibody binding region" when used herein refer to a
part of an antibody molecule that comprises amino acids responsible
for the specific binding between antibody and antigen. The part of
the antigen that is specifically recognized and bound by the
antibody is referred to as the "epitope" as described herein above.
As mentioned above, an antigen-binding domain may typically
comprise an antibody light chain variable region (VL) and an
antibody heavy chain variable region (VH); however, it does not
have to comprise both. Fd fragments, for example, have two VH
regions and often retain some antigen-binding function of the
intact antigen-binding domain. Examples of antigen-binding
fragments of an antibody include (1) a Fab fragment, a monovalent
fragment having the VL, VH, CL and CH1 domains; (2) a F(ab')2
fragment, a bivalent fragment having two Fab fragments linked by a
disulfide bridge at the hinge region; (3) a Fd fragment having the
two VH and CH1 domains; (4) a Fv fragment having the VL and VH
domains of a single arm of an antibody, (5) a dAb fragment (Ward et
al., (1989) Nature 341:544-546), which has a VH domain; (6) an
isolated complementarity determining region (CDR), and (7) a single
chain Fv (scFv). Although the two domains of the Fv fragment, VL
and VH are coded for by separate genes, they can be joined, using
recombinant methods, by a synthetic linker that enables them to be
made as a single protein chain in which the VL and VH regions pair
to form monovalent molecules (known as single chain Fv (scFv); see
e.g., Huston et al. (1988) Proc. Natl. Acad. Sci USA 85:5879-5883).
These antibody fragments are obtained using conventional techniques
known to those with skill in the art, and the fragments are
evaluated for function in the same manner as are intact
antibodies.
[0085] The term "monoclonal antibody" as used herein refers to an
antibody obtained from a population of substantially homogeneous
antibodies, i.e., the individual antibodies comprising the
population are identical except for possible naturally occurring
mutations and/or post-translation modifications (e.g.,
isomerizations, amidations) that may be present in minor amounts.
Monoclonal antibodies are highly specific, being directed against a
single antigenic site. Furthermore, in contrast to conventional
(polyclonal) antibody preparations which typically include
different antibodies directed against different determinants
(epitopes), each monoclonal antibody is directed against a single
determinant on the antigen. In addition to their specificity, the
monoclonal antibodies are advantageous in that they are synthesized
by the hybridoma culture, uncontaminated by other immunoglobulins.
The modifier "monoclonal" indicates the character of the antibody
as being obtained from a substantially homogeneous population of
antibodies, and is not to be construed as requiring production of
the antibody by any particular method. For example, the monoclonal
antibodies to be used in accordance with the present invention may
be made by the hybridoma method first described by Kohler et al.,
Nature, 256: 495 (1975), or may be made by recombinant DNA methods
(see, e.g., U.S. Pat. No. 4,816,567). The "monoclonal antibodies"
may also be isolated from phage antibody libraries using the
techniques described in Clackson et al., Nature, 352: 624-628
(1991) and Marks et al., J. Mol. Biol., 222: 581-597 (1991), for
example.
[0086] The term "human antibody" includes antibodies having
variable and constant regions corresponding substantially to human
germline immunoglobulin sequences known in the art, including, for
example, those described by Kabat et al. (See Kabat et al. (1991)
loc. cit.). The human antibodies of the invention may include amino
acid residues not encoded by human germline immunoglobulin
sequences (e.g., mutations introduced by random or site-specific
mutagenesis in vitro or by somatic mutation in vivo), for example
in the CDRs, and in particular, CDR3. The human antibody can have
at least one, two, three, four, five, or more positions replaced
with an amino acid residue that is not encoded by the human
germline immunoglobulin sequence. It is emphasized that the
definition of human antibodies as used herein also contemplates
fully human antibodies, which include only non-artificially and/or
genetically altered human sequences of antibodies as those can be
derived by technologies using systems such as the Xenomice.
[0087] Examples of "antibody variants" include humanized variants
of non-human antibodies, "affinity matured" antibodies (see, e.g.
Hawkins et al. J. Mol. Biol. 254, 889-896 (1992) and Lowman et al.,
Biochemistry 30, 10832-10837 (1991)) and antibody mutants with
altered effector function (s) (see, e.g., U.S. Pat. No. 5,648,260,
Kontermann and Dubel (2010), loc. cit. and Little (2009), loc.
cit.).
[0088] As used herein, "in vitro generated antibody" refers to an
antibody where all or part of the variable region (e.g., at least
one CDR) is generated in a non-immune cell selection (e.g., an in
vitro phage display, protein chip or any other method in which
candidate sequences can be tested for their ability to bind to an
antigen). This term thus preferably excludes sequences generated by
genomic rearrangement in an immune cell.
[0089] The pairing of a VH and VL together forms a single
antigen-binding site. The CH domain most proximal to VH is
designated as CH1. Each L chain is linked to an H chain by one
covalent disulfide bond, while the two H chains are linked to each
other by one or more disulfide bonds depending on the H chain
isotype. The VH and VL domains consist of four regions of
relatively conserved sequences called framework regions (FR1, FR2,
FR3, and FR4), which form a scaffold for three regions of
hypervariable sequences (complementarity determining regions,
CDRs). The CDRs contain most of the residues responsible for
specific interactions of the antibody with the antigen. CDRs are
referred to as CDR 1, CDR2, and CDR3. Accordingly, CDR constituents
on the heavy chain are referred to as H1, H2, and H3, while CDR
constituents on the light chain are referred to as L1, L2, and
L3.
[0090] The term "variable" refers to the portions of the
immunoglobulin domains that exhibit variability in their sequence
and that are involved in determining the specificity and binding
affinity of a particular antibody (i.e., the "variable domain(s)").
Variability is not evenly distributed throughout the variable
domains of antibodies; it is concentrated in sub-domains of each of
the heavy and light chain variable regions. These sub-domains are
called "hypervariable" regions or "complementarity determining
regions" (CDRs). The more conserved (i.e., non-hypervariable)
portions of the variable domains are called the "framework" regions
(FRM). The variable domains of naturally occurring heavy and light
chains each comprise four FRM regions, largely adopting a
.beta.-sheet configuration, connected by three hypervariable
regions, which form loops connecting, and in some cases forming
part of, the .beta.-sheet structure. The hypervariable regions in
each chain are held together in close proximity by the FRM and,
with the hypervariable regions from the other chain, contribute to
the formation of the antigen-binding site (see Kabat et al., loc.
cit.). The constant domains are not directly involved in antigen
binding, but exhibit various effector functions, such as, for
example, antibody-dependent, cell-mediated cytotoxicity and
complement activation.
[0091] The terms "CDR", and its plural "CDRs", refer to a
complementarity determining region (CDR) of which three make up the
binding character of a light chain variable region (CDRL1, CDRL2
and CDRL3) and three make up the binding character of a heavy chain
variable region (CDRH1, CDRH2 and CDRH3). CDRs contribute to the
functional activity of an antibody molecule and are separated by
amino acid sequences that comprise scaffolding or framework
regions. The exact definitional CDR boundaries and lengths are
subject to different classification and numbering systems. CDRs may
therefore be referred to by Kabat, Chothia, contact or any other
boundary definitions, including the numbering system described
herein. Despite differing boundaries, each of these systems has
some degree of overlap in what constitutes the so called
"hypervariable regions" within the variable sequences. CDR
definitions according to these systems may therefore differ in
length and boundary areas with respect to the adjacent framework
region. See for example Kabat, Chothia, and/or MacCallum (Kabat et
al., loc. cit.; Chothia et al., J. Mol. Biol, 1987, 196: 901; and
MacCallum et al., J. Mol. Biol, 1996, 262: 732). However, the
numbering in accordance with the so-called Kabat system is
preferred. The CDR3 of the light chain and, particularly, CDR3 of
the heavy chain may constitute the most important determinants in
antigen binding within the light and heavy chain variable regions.
In some antibodies, the heavy chain CDR3 appears to constitute the
major area of contact between the antigen and the antibody. In
vitro selection schemes in which CDR3 alone is varied can be used
to vary the binding properties of an antibody or determine which
residues contribute to the binding of an antigen.
[0092] In one embodiment, the antibody of the invention may
comprise from one to six of the exemplary CDRs described herein.
The antibodies of the invention may be of any type including IgM,
IgG (including IgG1, IgG2, IgG3, IgG4), IgD, IgA, or IgE antibody.
In a specific embodiment the antigen binding protein is an IgG type
antibody, e.g., a IgG1 antibody.
[0093] In one embodiment, the antibody of the invention may be a
mutlispecific antibody, and notably a bispecfic antibody, also
sometimes referred to as "diabodies." These are antibodies that
bind to two or more different antigens or different epitopes on a
single antigen. In certain embodiments, a bispecific antibody binds
CDH19 and an antigen on a human effector cell (e.g., T cell). Such
antibodies are useful in targeting an effector cell response
against a CDH19 expressing cells, such as a tumor cell. In
preferred embodiments, the human effector cell antigen is CD3 (see
corresponding formats e.g. in WO 2008/119567. Methods of making
bispecific antibodies are known in the art. One such method
involves engineering the Fc portion of the heavy chains such as to
create "knobs" and "holes" which facilitate heterodimer formation
of the heavy chains when co-expressed in a cell. U.S. Pat. No.
7,695,963. Another method also involves engineering the Fc portion
of the heavy chain but uses electrostatic steering to encourage
heterodimer formation while discouraging homodimer formation of the
heavy chains when co-expressed in a cell. WO 2009/089004, which is
incorporated herein by reference in its entirety.
[0094] In one embodiment, antibody of the invention is a minibody.
Minibodies are minimized antibody-like proteins comprising a scFv
joined to a CH3 domain. Hu et al., 1996, Cancer Res.
56:3055-3061.
[0095] In one embodiment, the antibody of the invention is a domain
antibody; see, for example U.S. Pat. No. 6,248,516. Domain
antibodies (dAbs) are functional binding domains of antibodies,
corresponding to the variable regions of either the heavy (VH) or
light (VL) chains of human antibodies. dABs have a molecular weight
of approximately 13 kDa, or less than one-tenth the size of a full
antibody. dABs are well expressed in a variety of hosts including
bacterial, yeast, and mammalian cell systems. In addition, dAbs are
highly stable and retain activity even after being subjected to
harsh conditions, such as freeze-drying or heat denaturation. See,
for example, U.S. Pat. Nos. 6,291,158; 6,582,915; 6,593,081;
6,172,197; US Serial No. 2004/0110941; European Patent 0368684;
U.S. Pat. No. 6,696,245, WO04/058821, WO04/003019 and
WO03/002609.
[0096] In one embodiment, the antibody of the invention is an
antibody fragment, that is a fragment of any of the antibodies
outlined herein that retain binding specificity to CDH19. In
various embodiments, the antibody binding proteins comprise, but
are not limited to, a F(ab), F(ab'), F(ab')2, Fv, or a single chain
Fv fragments. At a minimum, an antibody, as meant herein, comprises
a polypeptide that can bind specifically to CDH19 comprising all or
part of a light or heavy chain variable region, such as one or more
CDRs.
[0097] Naturally occurring antibodies typically include a signal
sequence, which directs the antibody into the cellular pathway for
protein secretion and which is typically not present in the mature
antibody. A polynucleotide encoding an antibody of the invention
may encode a naturally occurring a signal sequence or a
heterologous signal sequence as described below.
[0098] "Consisting essentially of" means that the amino acid
sequence can vary by about 1, 2, 3, 4, 5, 6, 7, 8, 9, 10, 11, 12,
13, 14, or 15% relative to the recited SEQ ID NO: sequence and
still retain biological activity, as described herein.
[0099] In some embodiments, the antibodies of the invention are
isolated proteins or substantially pure proteins. An "isolated"
protein is unaccompanied by at least some of the material with
which it is normally associated in its natural state, for example
constituting at least about 5%, or at least about 50% by weight of
the total protein in a given sample. It is understood that the
isolated protein may constitute from 5 to 99.9% by weight of the
total protein content depending on the circumstances. For example,
the protein may be made at a significantly higher concentration
through the use of an inducible promoter or high expression
promoter, such that the protein is made at increased concentration
levels. The definition includes the production of an antigen
binding protein in a wide variety of organisms and/or host cells
that are known in the art.
[0100] For amino acid sequences, sequence identity and/or
similarity is determined by using standard techniques known in the
art, including, but not limited to, the local sequence identity
algorithm of Smith and Waterman, 1981, Adv. Appl. Math. 2:482, the
sequence identity alignment algorithm of Needleman and Wunsch,
1970, J. Mol. Biol. 48:443, the search for similarity method of
Pearson and Lipman, 1988, Proc. Nat. Acad. Sci. U.S.A. 85:2444,
computerized implementations of these algorithms (GAP, BESTFIT,
FASTA, and TFASTA in the Wisconsin Genetics Software Package,
Genetics Computer Group, 575 Science Drive, Madison, Wis.), the
Best Fit sequence program described by Devereux et al., 1984, Nucl.
Acid Res. 12:387-395, preferably using the default settings, or by
inspection. Preferably, percent identity is calculated by FastDB
based upon the following parameters: mismatch penalty of 1; gap
penalty of 1; gap size penalty of 0.33; and joining penalty of 30,
"Current Methods in Sequence Comparison and Analysis,"
Macromolecule Sequencing and Synthesis, Selected Methods and
Applications, pp 127-149 (1988), Alan R. Liss, Inc.
[0101] An example of a useful algorithm is PILEUP. PILEUP creates a
multiple sequence alignment from a group of related sequences using
progressive, pairwise alignments. It can also plot a tree showing
the clustering relationships used to create the alignment. PILEUP
uses a simplification of the progressive alignment method of Feng
& Doolittle, 1987, J. Mol. Evol. 35:351-360; the method is
similar to that described by Higgins and Sharp, 1989, CABIOS
5:151-153. Useful PILEUP parameters including a default gap weight
of 3.00, a default gap length weight of 0.10, and weighted end
gaps.
[0102] Another example of a useful algorithm is the BLAST
algorithm, described in: Altschul et al., 1990, J. Mol. Biol.
215:403-410; Altschul et al., 1997, Nucleic Acids Res.
25:3389-3402; and Karin et al., 1993, Proc. Natl. Acad. Sci. U.S.A.
90:5873-5787. A particularly useful BLAST program is the WU-BLAST-2
program which was obtained from Altschul et al., 1996, Methods in
Enzymology 266:460-480. WU-BLAST-2 uses several search parameters,
most of which are set to the default values. The adjustable
parameters are set with the following values: overlap span=1,
overlap fraction=0.125, word threshold (T)=II. The HSP S and HSP S2
parameters are dynamic values and are established by the program
itself depending upon the composition of the particular sequence
and composition of the particular database against which the
sequence of interest is being searched; however, the values may be
adjusted to increase sensitivity.
[0103] An additional useful algorithm is gapped BLAST as reported
by Altschul et al., 1993, Nucl. Acids Res. 25:3389-3402. Gapped
BLAST uses BLOSUM-62 substitution scores; threshold T parameter set
to 9; the two-hit method to trigger ungapped extensions, charges
gap lengths of k a cost of 10+k; Xu set to 16, and Xg set to 40 for
database search stage and to 67 for the output stage of the
algorithms. Gapped alignments are triggered by a score
corresponding to about 22 bits.
[0104] Generally, the amino acid homology, similarity, or identity
between individual variant CDRs are at least 80% to the sequences
depicted herein, and more typically with preferably increasing
homologies or identities of at least 85%, 90%, 91%, 92%, 93%, 94%,
95%, 96%, 97%, 98%, 99%, and almost 100%. In a similar manner,
"percent (%) nucleic acid sequence identity" with respect to the
nucleic acid sequence of the binding proteins identified herein is
defined as the percentage of nucleotide residues in a candidate
sequence that are identical with the nucleotide residues in the
coding sequence of the antigen binding protein. A specific method
utilizes the BLASTN module of WU-BLAST-2 set to the default
parameters, with overlap span and overlap fraction set to 1 and
0.125, respectively.
[0105] Generally, the nucleic acid sequence homology, similarity,
or identity between the nucleotide sequences encoding individual
variant CDRs and the nucleotide sequences depicted herein are at
least 80%, and more typically with preferably increasing homologies
or identities of at least 80%, 81%, 82%, 83%, 84%, 85%, 86%, 87%,
88%, 89%, 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98%, or 99%, and
almost 100%.
[0106] Thus, a "variant CDR" is one with the specified homology,
similarity, or identity to the parent CDR of the invention, and
shares biological function, including, but not limited to, at least
80%, 81%, 82%, 83%, 84%, 85%, 86%, 87%, 88%, 89%, 90%, 91%, 92%,
93%, 94%, 95%, 96%, 97%, 98%, or 99% of the specificity and/or
activity of the parent CDR.
[0107] While the site or region for introducing an amino acid
sequence variation is predetermined, the mutation per se need not
be predetermined. For example, in order to optimize the performance
of a mutation at a given site, random mutagenesis may be conducted
at the target codon or region and the expressed antigen binding
protein CDR variants screened for the optimal combination of
desired activity. Techniques for making substitution mutations at
predetermined sites in DNA having a known sequence are well known,
for example, M13 primer mutagenesis and PCR mutagenesis. Screening
of the mutants is done using assays of antigen binding protein
activities, such as CDH19 binding.
[0108] The term "amino acid" or "amino acid residue" typically
refers to an amino acid having its art recognized definition such
as an amino acid selected from the group consisting of: alanine
(Ala or A); arginine (Arg or R); asparagine (Asn or N); aspartic
acid (Asp or D); cysteine (Cys or C); glutamine (Gln or Q);
glutamic acid (Glu or E); glycine (Gly or G); histidine (His or H);
isoleucine (He or I): leucine (Leu or L); lysine (Lys or K);
methionine (Met or M); phenylalanine (Phe or F); pro line (Pro or
P); serine (Ser or S); threonine (Thr or T); tryptophan (Trp or W);
tyrosine (Tyr or Y); and valine (Val or V), although modified,
synthetic, or rare amino acids may be used as desired. Generally,
amino acids can be grouped as having a nonpolar side chain (e.g.,
Ala, Cys, He, Leu, Met, Phe, Pro, Val); a negatively charged side
chain (e.g., Asp, Glu); a positively charged sidechain (e.g., Arg,
His, Lys); or an uncharged polar side chain (e.g., Asn, Cys, Gln,
Gly, His, Met, Phe, Ser, Thr, Trp, and Tyr).
[0109] The term "hypervariable region" (also known as
"complementarity determining regions" or CDRs) when used herein
refers to the amino acid residues of an antibody which are (usually
three or four short regions of extreme sequence variability) within
the V-region domain of an immunoglobulin which form the
antigen-binding site and are the main determinants of antigen
specificity. There are at least two methods for identifying the CDR
residues: (1) An approach based on cross-species sequence
variability (i. e., Kabat et al., loc. cit.); and (2) An approach
based on crystallographic studies of antigen-antibody complexes
(Chothia, C. et al., J. Mol. Biol. 196: 901-917 (1987)). However,
to the extent that two residue identification techniques define
regions of overlapping, but not identical regions, they can be
combined to define a hybrid CDR. However, in general, the CDR
residues are preferably identified in accordance with the so-called
Kabat (numbering) system.
[0110] The term "framework region" refers to the art-recognized
portions of an antibody variable region that exist between the more
divergent (i.e., hypervariable) CDRs. Such framework regions are
typically referred to as frameworks 1 through 4 (FR1, FR2, FR3, and
FR4) and provide a scaffold for the presentation of the six CDRs
(three from the heavy chain and three from the light chain) in
three dimensional space, to form an antigen-binding surface.
[0111] Typically, CDRs form a loop structure that can be classified
as a canonical structure. The term "canonical structure" refers to
the main chain conformation that is adopted by the antigen binding
(CDR) loops. From comparative structural studies, it has been found
that five of the six antigen binding loops have only a limited
repertoire of available conformations. Each canonical structure can
be characterized by the torsion angles of the polypeptide backbone.
Correspondent loops between antibodies may, therefore, have very
similar three dimensional structures, despite high amino acid
sequence variability in most parts of the loops (Chothia and Lesk,
J. Mol. Biol., 1987, 196: 901; Chothia et al., Nature, 1989, 342:
877; Martin and Thornton, J. Mol. Biol, 1996, 263: 800, each of
which is incorporated by reference in its entirety). Furthermore,
there is a relationship between the adopted loop structure and the
amino acid sequences surrounding it. The conformation of a
particular canonical class is determined by the length of the loop
and the amino acid residues residing at key positions within the
loop, as well as within the conserved framework (i.e., outside of
the loop). Assignment to a particular canonical class can therefore
be made based on the presence of these key amino acid residues. The
term "canonical structure" may also include considerations as to
the linear sequence of the antibody, for example, as catalogued by
Kabat (Kabat et al., loc. cit.). The Kabat numbering scheme
(system) is a widely adopted standard for numbering the amino acid
residues of an antibody variable domain in a consistent manner and
is the preferred scheme applied in the present invention as also
mentioned elsewhere herein. Additional structural considerations
can also be used to determine the canonical structure of an
antibody. For example, those differences not fully reflected by
Kabat numbering can be described by the numbering system of Chothia
et al and/or revealed by other techniques, for example,
crystallography and two or three-dimensional computational
modeling. Accordingly, a given antibody sequence may be placed into
a canonical class which allows for, among other things, identifying
appropriate chassis sequences (e.g., based on a desire to include a
variety of canonical structures in a library). Kabat numbering of
antibody amino acid sequences and structural considerations as
described by Chothia et al., loc. cit. and their implications for
construing canonical aspects of antibody structure, are described
in the literature.
[0112] CDR3 is typically the greatest source of molecular diversity
within the antibody-binding site. H3, for example, can be as short
as two amino acid residues or greater than 26 amino acids. The
subunit structures and three-dimensional configurations of
different classes of immunoglobulins are well known in the art. For
a review of the antibody structure, see Antibodies: A Laboratory
Manual, Cold Spring Harbor Laboratory, eds. Harlow et al., 1988.
One of skill in the art will recognize that each subunit structure,
e.g., a CH, VH, CL, VL, CDR, FR structure, comprises active
fragments, e.g., the portion of the VH, VL, or CDR subunit the
binds to the antigen, i.e., the antigen-binding fragment, or, e.g.,
the portion of the CH subunit that binds to and/or activates, e.g.,
an Fc receptor and/or complement. The CDRs typically refer to the
Kabat CDRs, as described in Sequences of Proteins of immunological
Interest, US Department of Health and Human Services (1991), eds.
Kabat et al. Another standard for characterizing the antigen
binding site is to refer to the hypervariable loops as described by
Chothia. See, e.g., Chothia, et al. (1987; J. Mol. Biol.
227:799-817); and Tomlinson et al. (1995) EMBO J. 14: 4628-4638.
Still another standard is the AbM definition used by Oxford
Molecular's AbM antibody modeling software. See, generally, e.g.,
Protein Sequence and Structure Analysis of Antibody Variable
Domains. In: Antibody Engineering Lab Manual (Ed.: Duebel, S. and
Kontermann, R., Springer-Verlag, Heidelberg). Embodiments described
with respect to Kabat CDRs can alternatively be implemented using
similar described relationships with respect to Chothia
hypervariable loops or to the AbM-defined loops.
[0113] The sequence of antibody genes after assembly and somatic
mutation is highly varied, and these varied genes are estimated to
encode 10.sup.10 different antibody molecules (Immunoglobulin
Genes, 2.sup.nd ed., eds. Jonio et al., Academic Press, San Diego,
Calif., 1995). Accordingly, the immune system provides a repertoire
of immunoglobulins. The term "repertoire" refers to at least one
nucleotide sequence derived wholly or partially from at least one
sequence encoding at least one immunoglobulin. The sequence(s) may
be generated by rearrangement in vivo of the V, D, and J segments
of heavy chains, and the V and J segments of light chains.
Alternatively, the sequence(s) can be generated from a cell in
response to which rearrangement occurs, e.g., in vitro stimulation.
Alternatively, part or all of the sequence(s) may be obtained by
DNA splicing, nucleotide synthesis, mutagenesis, and other methods,
see, e.g., U.S. Pat. No. 5,565,332. A repertoire may include only
one sequence or may include a plurality of sequences, including
ones in a genetically diverse collection.
[0114] The term "binding molecule" or "antibody construct" in the
sense of the present disclosure indicates any molecule capable of
(specifically) binding to, interacting with or recognizing the
target molecule CDH19. Such molecules or constructs may include
proteinaceous parts and non-proteinaceous parts (e.g. chemical
linkers or chemical cross-linking agents such as
glutaraldehyde).
[0115] The term "multispecific" as used herein refers to a binding
molecule which is an antibody construct and comprises at least a
first and a second binding domain, wherein the first binding domain
is capable of binding to one antigen or target, and the second
binding domain is capable of binding to another antigen or target.
Accordingly, antibody constructs according to the invention
comprise at least a specificity for CDH19. The "antibody construct"
of the invention also comprises multispecific binding molecules
such as e.g. trispecific binding molecules, the latter ones
including three binding domains.
[0116] It is also envisaged that the antibody construct of the
invention has, in addition to its function to bind to the target
molecules CDH19 and CD3, a further function. In this format, the
antibody construct is a bi-, tri- or multifunctional antibody
construct by targeting plasma cells through binding to CDH19,
mediating cytotoxic T cell activity through CD3 binding and
providing a further function such as a fully functional Fc constant
domain mediating antibody-dependent cellular cytotoxicity through
recruitment of effector cells like NK cells, a label (fluorescent
etc.), a therapeutic agent such as, e.g. a toxin or radionuclide,
and/or means to enhance serum half-life, etc.
[0117] The term "binding domain" characterizes in connection with
the present invention a domain which is capable of specifically
binding to/interacting with a given target epitope or a given
target site on the target molecule CDH19.
[0118] Binding domains can be derived from a binding domain donor
such as for example an antibody. It is envisaged that a binding
domain of the present invention comprises at least said part of any
of the aforementioned binding domains that is required for binding
to/interacting with a given target epitope or a given target site
on the target molecule CDH19.
[0119] It is envisaged that the binding domain of the
aforementioned binding domain donors is characterized by that part
of these donors that is responsible for binding the respective
target, i.e. when that part is removed from the binding domain
donor, said donor loses its binding capability. "Loses" means a
reduction of at least 50% of the binding capability when compared
with the binding donor. Methods to map these binding sites are well
known in the art--it is therefore within the standard knowledge of
the skilled person to locate/map the binding site of a binding
domain donor and, thereby, to "derive" said binding domain from the
respective binding domain donors.
[0120] The term "epitope" refers to a site on an antigen to which a
binding domain, such as an antibody or immunoglobulin or derivative
or fragment of an antibody or of an immunoglobulin, specifically
binds. An "epitope" is antigenic and thus the term epitope is
sometimes also referred to herein as "antigenic structure" or
"antigenic determinant". Thus, the binding domain is an
"antigen-interaction-site". Said binding/interaction is also
understood to define a "specific recognition". In one example, said
binding domain which (specifically) binds to/interacts with a given
target epitope or a given target site on the target molecule CDH19
is an antibody or immunoglobulin, and said binding domain is a VH
and/or VL region of an antibody or of an immunoglobulin.
[0121] "Epitopes" can be formed both by contiguous amino acids or
non-contiguous amino acids juxtaposed by tertiary folding of a
protein. A "linear epitope" is an epitope where an amino acid
primary sequence comprises the recognized epitope. A linear epitope
typically includes at least 3 or at least 4, and more usually, at
least 5 or at least 6 or at least 7, for example, about 8 to about
10 amino acids in a unique sequence.
[0122] A "conformational epitope", in contrast to a linear epitope,
is an epitope wherein the primary sequence of the amino acids
comprising the epitope is not the sole defining component of the
epitope recognized (e.g., an epitope wherein the primary sequence
of amino acids is not necessarily recognized by the binding
domain). Typically a conformational epitope comprises an increased
number of amino acids relative to a linear epitope. With regard to
recognition of conformational epitopes, the binding domain
recognizes a three-dimensional structure of the antigen, preferably
a peptide or protein or fragment thereof (in the context of the
present invention, the antigen for one of the binding domains is
comprised within the CDH19 protein). For example, when a protein
molecule folds to form a three-dimensional structure, certain amino
acids and/or the polypeptide backbone forming the conformational
epitope become juxtaposed enabling the antibody to recognize the
epitope. Methods of determining the conformation of epitopes
include, but are not limited to, x-ray crystallography,
two-dimensional nuclear magnetic resonance (2D-NMR) spectroscopy
and site-directed spin labelling and electron paramagnetic
resonance (EPR) spectroscopy. Moreover, the provided examples
describe a further method to characterize a given binding domain by
way of binning, which includes a test whether the given binding
domain binds to one or more epitope cluster(s) of a given protein,
in particular CDH19.
[0123] As used herein, the term "epitope cluster" denotes the
entirety of epitopes lying in a defined contiguous stretch of an
antigen. An epitope cluster can comprise one, two or more epitopes.
The concept of epitope cluster is also used in the characterization
of the features of the antibody or antigen binding fragment thereof
of the invention.
[0124] The terms "(capable of) binding to", "specifically
recognizing", "directed to" and "reacting with" mean in accordance
with this invention that a binding domain is capable of
specifically interacting with one or more, preferably at least two,
more preferably at least three and most preferably at least four
amino acids of an epitope.
[0125] As used herein, the terms "specifically interacting",
"specifically binding" or "specifically bind(s)" mean that a
binding domain exhibits appreciable affinity for a particular
protein or antigen and, generally, does not exhibit significant
reactivity with proteins or antigens other than CDH19. "Appreciable
affinity" includes binding with an affinity of about 10.sup.-6M
(KD) or stronger. Preferably, binding is considered specific when
binding affinity is about 10.sup.-12 to 10.sup.-8 M, 10.sup.-12 to
10.sup.-9 M, 10.sup.-12 to 10.sup.-10 M, 10.sup.-11 to 10.sup.-8 M,
preferably of about 10.sup.-11 to 10.sup.-9 M. Whether a binding
domain specifically reacts with or binds to a target can be tested
readily by, inter alia, comparing the reaction of said binding
domain with a target protein or antigen with the reaction of said
binding domain with proteins or antigens other than CDH19.
Preferably, a binding domain of the invention does not essentially
bind or is not capable of binding to proteins or antigens other
than CDH19.
[0126] The term "does not essentially bind", or "is not capable of
binding" means that a binding domain of the present invention does
not bind another protein or antigen other than CDH19, i.e., does
not show reactivity of more than 30%, preferably not more than 20%,
more preferably not more than 10%, particularly preferably not more
than 9%, 8%, 7%, 6% or 5% with proteins or antigens other than
CDH19, whereby binding to CDH19, respectively, is set to be
100%.
[0127] Specific binding is believed to be effected by specific
motifs in the amino acid sequence of the binding domain and the
antigen. Thus, binding is achieved as a result of their primary,
secondary and/or tertiary structure as well as the result of
secondary modifications of said structures. The specific
interaction of the antigen-interaction-site with its specific
antigen may result in a simple binding of said site to the antigen.
Moreover, the specific interaction of the antigen-interaction-site
with its specific antigen may alternatively or additionally result
in the initiation of a signal, e.g. due to the induction of a
change of the conformation of the antigen, an oligomerization of
the antigen, etc.
[0128] Proteins (including fragments thereof, preferably
biologically active fragments, and peptides, usually having less
than 30 amino acids) comprise one or more amino acids coupled to
each other via a covalent peptide bond (resulting in a chain of
amino acids). The term "polypeptide" as used herein describes a
group of molecules, which consist of more than 30 amino acids.
Polypeptides may further form multimers such as dimers, trimers and
higher oligomers, i.e. consisting of more than one polypeptide
molecule. Polypeptide molecules forming such dimers, trimers etc.
may be identical or non-identical. The corresponding higher order
structures of such multimers are, consequently, termed homo- or
heterodimers, homo- or heterotrimers etc. An example for a
hereteromultimer is an antibody molecule, which, in its naturally
occurring form, consists of two identical light polypeptide chains
and two identical heavy polypeptide chains. The terms "polypeptide"
and "protein" also refer to naturally modified
polypeptides/proteins wherein the modification is effected e.g. by
post-translational modifications like glycosylation, acetylation,
phosphorylation and the like. A "polypeptide" when referred to
herein may also be chemically modified such as pegylated. Such
modifications are well known in the art.
[0129] "Isolated" when used to describe the antibody or antigen
binding fragment thereof or antibody construct disclosed herein,
refers to the antibody or antigen binding fragment thereof or
antibody construct disclosed herein that has been identified,
separated and/or recovered from a component of its production
environment. Preferably, the isolated the antibody or antigen
binding fragment thereof or antibody construct disclosed herein is
free of association with all other components from its production
environment. Contaminant components of its production environment,
such as that resulting from recombinant transfected cells, are
materials that would typically interfere with diagnostic or
therapeutic uses for the polypeptide, and may include enzymes,
hormones, and other proteinaceous or non-proteinaceous solutes. In
preferred embodiments, the the antibody or antigen binding fragment
thereof or antibody construct will be purified (1) to a degree
sufficient to obtain at least 15 residues of N-terminal or internal
amino acid sequence by use of a spinning cup sequenator, or (2) to
homogeneity by SDS-PAGE under non-reducing or reducing conditions
using Coomassie blue or, preferably, silver stain. Ordinarily,
however, an isolated antibody will be prepared by at least one
purification step.
[0130] Amino acid sequence modifications of the the antibody or
antigen binding fragment thereof or antibody construct described
herein are contemplated. For example, it may be desirable to
improve the binding affinity and/or other biological properties of
the antibody. Amino acid sequence variants of the the antibody or
antigen binding fragment thereof or antibody construct disclosed
herein are prepared by introducing appropriate nucleotide changes
into the the antibody or antigen binding fragment thereof or
antibody construct nucleic acid, or by peptide synthesis.
[0131] Such modifications include, for example, deletions from,
and/or insertions into, and/or substitutions of, residues within
the amino acid sequences of the the antibody or antigen binding
fragment thereof or antibody construct disclosed herein. Any
combination of deletion, insertion, and substitution is made to
arrive at the final construct, provided that the final construct
possesses the desired characteristics. The amino acid changes also
may alter post-translational processes of the the antibody or
antigen binding fragment thereof or antibody construct disclosed
herein, such as changing the number or position of glycosylation
sites. Preferably, 1, 2, 3, 4, 5, 6, 7, 8, 9, or 10 amino acids may
be substituted in a CDR, while 1, 2, 3, 4, 5, 6, 7, 8, 9, 10, 11,
12, 13, 14, 15, 16, 17, 18, 19, 20, or 25 amino acids may be
substituted in the framework regions (FRs). The substitutions are
preferably conservative substitutions as described herein.
Additionally or alternatively, 1, 2, 3, 4, 5, or 6 amino acids may
be inserted or deleted in each of the CDRs (of course, dependent on
their length), while 1, 2, 3, 4, 5, 6, 7, 8, 9, 10, 11, 12, 13, 14,
15, 16, 17, 18, 19, 20, or 25 amino acids may be inserted or
deleted in each of the FRs.
[0132] A useful method for identification of certain residues or
regions of the the antibody or antigen binding fragment thereof or
antibody construct disclosed herein that are preferred locations
for mutagenesis is called "alanine scanning mutagenesis" as
described by Cunningham and Wells in Science, 244: 1081-1085
(1989). Here, a residue or group of target residues within the the
antibody or antigen binding fragment thereof or antibody construct
disclosed herein is/are identified (e.g. charged residues such as
arg, asp, his, lys, and glu) and replaced by a neutral or
negatively charged amino acid (most preferably alanine or
polyalanine) to affect the interaction of the amino acids with the
epitope.
[0133] Those amino acid locations demonstrating functional
sensitivity to the substitutions then are refined by introducing
further or other variants at, or for, the sites of substitution.
Thus, while the site for introducing an amino acid sequence
variation is predetermined, the nature of the mutation per se needs
not to be predetermined. For example, to analyze the performance of
a mutation at a given site, ala scanning or random mutagenesis is
conducted at a target codon or region and the expressed the
antibody or antigen binding fragment thereof or antibody construct
disclosed herein variants are screened for the desired
activity.
[0134] Preferably, amino acid sequence insertions include amino-
and/or carboxyl-terminal fusions ranging in length from 1, 2, 3, 4,
5, 6, 7, 8, 9 or 10 residues to polypeptides containing a hundred
or more residues, as well as intrasequence insertions of single or
multiple amino acid residues. An insertional variant of the the
antibody or antigen binding fragment thereof or antibody construct
disclosed herein includes the fusion to the N- or C-terminus of the
antibody to an enzyme or a fusion to a polypeptide which increases
the serum half-life of the antibody.
[0135] Another type of variant is an amino acid substitution
variant. These variants have preferably at least 1, 2, 3, 4, 5, 6,
7, 8, 9 or 10 amino acid residues in the the antibody or antigen
binding fragment thereof or antibody construct disclosed herein
replaced by a different residue. The sites of greatest interest for
substitutional mutagenesis include the CDRs of the heavy and/or
light chain, in particular the hypervariable regions, but FR
alterations in the heavy and/or light chain are also
contemplated.
[0136] For example, if a CDR sequence encompasses 6 amino acids, it
is envisaged that one, two or three of these amino acids are
substituted. Similarly, if a CDR sequence encompasses 15 amino
acids it is envisaged that one, two, three, four, five or six of
these amino acids are substituted.
[0137] Generally, if amino acids are substituted in one or more or
all of the CDRs of the heavy and/or light chain, it is preferred
that the then-obtained "substituted" sequence is at least 60%, more
preferably 65%, even more preferably 70%, particularly preferably
75%, more particularly preferably 80% identical to the "original"
CDR sequence. This means that it is dependent of the length of the
CDR to which degree it is identical to the "substituted" sequence.
For example, a CDR having 5 amino acids is preferably 80% identical
to its substituted sequence in order to have at least one amino
acid substituted. Accordingly, the CDRs of the the antibody or
antigen binding fragment thereof or antibody construct disclosed
herein may have different degrees of identity to their substituted
sequences, e.g., CDRL1 may have 80%, while CDRL3 may have 90%.
[0138] Preferred substitutions (or replacements) are conservative
substitutions. However, any substitution (including
non-conservative substitution or one or more from the "exemplary
substitutions" listed in Table 1, below) is envisaged as long as
the the antibody or antigen binding fragment thereof or antibody
construct retains its capability to bind to CDH19 v and/or its CDRs
have an identity to the then substituted sequence (at least 60%,
more preferably 65%, even more preferably 70%, particularly
preferably 75%, more particularly preferably 80% identical to the
"original" CDR sequence).
[0139] Conservative substitutions are shown in Table 1 under the
heading of "preferred substitutions". If such substitutions result
in a change in biological activity, then more substantial changes,
denominated "exemplary substitutions" in Table 1, or as further
described below in reference to amino acid classes, may be
introduced and the products screened for a desired
characteristic.
TABLE-US-00001 TABLE 1 Amino Acid Substitutions Preferred Original
Exemplary Substitutions Substitutions Ala (A) val, leu, ile val Arg
(R) lys, gin, asn lys Asn (N) gin, his, asp, lys, arg gin Asp (D)
glu, asn glu Cys (C) ser, ala ser Gln (Q) asn, glu asn Glu (E) asp,
gin Asp Gly (G) ala Ala His (H) asn, gin, lys, arg Arg Ile (I) leu,
val, met, ala, phe Leu Leu (L) norleucine, ile, val, met, ala Ile
Lys (K) arg, gin, asn Arg Met (M) leu, phe, ile Leu Phe (F) leu,
val, ile, ala, tyr Tyr Pro (P) ala Ala Ser (S) thr Thr Thr (T) ser
Ser Trp (W) tyr, phe Tyr Tyr (Y) trp, phe, thr, ser Phe Val (V)
ile, leu, met, phe, ala Leu
[0140] Substantial modifications in the biological properties of
the the antibody or antigen binding fragment thereof or antibody
construct of the present invention are accomplished by selecting
substitutions that differ significantly in their effect on
maintaining (a) the structure of the polypeptide backbone in the
area of the substitution, for example, as a sheet or helical
conformation, (b) the charge or hydrophobicity of the molecule at
the target site, or (c) the bulk of the side chain. Naturally
occurring residues are divided into groups based on common
side-chain properties: (1) hydrophobic: norleucine, met, ala, val,
leu, ile; (2) neutral hydrophilic: cys, ser, thr; (3) acidic: asp,
glu; (4) basic: asn, gin, his, lys, arg; (5) residues that
influence chain orientation: gly, pro; and (6) aromatic: trp, tyr,
phe.
[0141] Non-conservative substitutions will entail exchanging a
member of one of these classes for another class. Any cysteine
residue not involved in maintaining the proper conformation of the
the antibody or antigen binding fragment thereof or antibody
construct may be substituted, generally with serine, to improve the
oxidative stability of the molecule and prevent aberrant
crosslinking. Conversely, cysteine bond(s) may be added to the
antibody to improve its stability (particularly where the antibody
is an antibody fragment such as an Fv fragment).
[0142] A particularly preferred type of substitutional variant
involves substituting one or more hypervariable region residues of
a parent antibody (e. g. a humanized or human antibody). Generally,
the resulting variant(s) selected for further development will have
improved biological properties relative to the parent antibody from
which they are generated. A convenient way for generating such
substitutional variants involves affinity maturation using phage
display. Briefly, several hypervariable region sites (e. g. 6-7
sites) are mutated to generate all possible amino acid
substitutions at each site. The antibody variants thus generated
are displayed in a monovalent fashion from filamentous phage
particles as fusions to the gene III product of M13 packaged within
each particle. The phage-displayed variants are then screened for
their biological activity (e. g. binding affinity) as herein
disclosed. In order to identify candidate hypervariable region
sites for modification, alanine scanning mutagenesis can be
performed to identify hypervariable region residues contributing
significantly to antigen binding. Alternatively, or additionally,
it may be beneficial to analyze a crystal structure of the
antigen-antibody complex to identify contact points between the
binding domain and, e.g., human CDH19. Such contact residues and
neighbouring residues are candidates for substitution according to
the techniques elaborated herein. Once such variants are generated,
the panel of variants is subjected to screening as described herein
and antibodies with superior properties in one or more relevant
assays may be selected for further development.
[0143] Other modifications of the the antibody or antigen binding
fragment thereof or antibody construct are contemplated herein. For
example, the the antibody or antigen binding fragment thereof or
antibody construct may be linked to one of a variety of
non-proteinaceous polymers, e.g., polyethylene glycol,
polypropylene glycol, polyoxyalkylenes, or copolymers of
polyethylene glycol and polypropylene glycol. The the antibody or
antigen binding fragment thereof or antibody construct may also be
entrapped in microcapsules prepared, for example, by coacervation
techniques or by interfacial polymerization (for example,
hydroxymethylcellulose or gelatine-microcapsules and poly
(methylmethacylate) microcapsules, respectively), in colloidal drug
delivery systems (for example, liposomes, albumin microspheres,
microemulsions, nanoparticles and nanocapsules), or in
macroemulsions. Such techniques are disclosed in Remington's
Pharmaceutical Sciences, 16th edition, Oslo, A., Ed., (1980).
[0144] The the antibody or antigen binding fragment thereof or
antibody construct disclosed herein may also be formulated as
immuno-liposomes. A "liposome" is a small vesicle composed of
various types of lipids, phospholipids and/or surfactant which is
useful for delivery of a drug to a mammal. The components of the
liposome are commonly arranged in a bilayer formation, similar to
the lipid arrangement of biological membranes. Liposomes containing
the antibody are prepared by methods known in the art, such as
described in Epstein et al., Proc. Natl. Acad. Sci. USA, 82: 3688
(1985); Hwang et al., Proc. Natl Acad. Sci. USA, 77: 4030 (1980);
U.S. Pat. Nos. 4,485,045 and 4,544,545; and WO 97/38731 published
Oct. 23, 1997. Liposomes with enhanced circulation time are
disclosed in U.S. Pat. No. 5,013,556. Particularly useful liposomes
can be generated by the reverse phase evaporation method with a
lipid composition comprising phosphatidylcholine, cholesterol and
PEG-derivatized phosphatidylethanolamine (PEG-PE). Liposomes are
extruded through filters of defined pore size to yield liposomes
with the desired diameter. Fab' fragments of the antibody of the
present invention can be conjugated to the liposomes as described
in Martin et al. J. Biol. Chem. 257: 286-288 (1982) via a disulfide
interchange reaction. A chemotherapeutic agent is optionally
contained within the liposome. See Gabizon et al. J. National
Cancer Inst. 81 (19) 1484 (1989).
[0145] When using recombinant techniques, the antibody, antigen
binding fragment thereof or antibody construct can be produced
intracellularly, in the periplasmic space, or directly secreted
into the medium. If the antibody, antigen binding fragment thereof
or antibody construct is produced intracellularly, as a first step,
the particulate debris, either host cells or lysed fragments, are
removed, for example, by centrifugation or ultrafiltration. Carter
et al., Bio/Technology 10: 163-167 (1992) describe a procedure for
isolating antibodies which are secreted to the periplasmic space of
E. coli.
[0146] The antibody, antigen binding fragment thereof or antibody
construct composition prepared from the cells can be purified
using, for example, hydroxylapatite chromatography, gel
electrophoresis, dialysis, and affinity chromatography, with
affinity chromatography being the preferred purification
technique.
[0147] The term "agent" is used herein to denote a chemical
compound, a mixture of chemical compounds, a biological
macromolecule, or an extract made from biological materials.
[0148] The term "nucleic acid" is well known to the skilled person
and encompasses DNA (such as cDNA) and RNA (such as mRNA). The
nucleic acid can be double stranded and single stranded, linear and
circular. Said nucleic acid molecule is preferably comprised in a
vector which is preferably comprised in a host cell. Said host cell
is, e.g. after transformation or transfection with the nucleic acid
sequence of the invention, capable of expressing the the antibody
or antigen binding fragment thereof or antibody construct disclosed
herein. For that purpose the nucleic acid molecule is operatively
linked with control sequences.
[0149] A vector is a nucleic acid molecule used as a vehicle to
transfer (foreign) genetic material into a cell. The term "vector"
encompasses--but is not restricted to--plasmids, viruses, cosmids
and artificial chromosomes. In general, engineered vectors comprise
an origin of replication, a multicloning site and a selectable
marker. The vector itself is generally a nucleotide sequence,
commonly a DNA sequence, that comprises an insert (transgene) and a
larger sequence that serves as the "backbone" of the vector. Modern
vectors may encompass additional features besides the transgene
insert and a backbone: promoter, genetic marker, antibiotic
resistance, reporter gene, targeting sequence, protein purification
tag. Vectors called expression vectors (expression constructs)
specifically are for the expression of the transgene in the target
cell, and generally have control sequences such as a promoter
sequence that drives expression of the transgene. Insertion of a
vector into the target cell is usually called "transformation" for
bacteria, "transfection" for eukaryotic cells, although insertion
of a viral vector is also called "transduction".
[0150] As used herein, the term "host cell" is intended to refer to
a cell into which a nucleic acid encoding the the antibody or
antigen binding fragment thereof or antibody construct of the
invention is introduced by way of transformation, transfection and
the like. It should be understood that such terms refer not only to
the particular subject cell but to the progeny or potential progeny
of such a cell. Because certain modifications may occur in
succeeding generations due to either mutation or environmental
influences, such progeny may not, in fact, be identical to the
parent cell, but are still included within the scope of the term as
used herein.
[0151] As used herein, the term "expression" includes any step
involved in the production of a the antibody or antigen binding
fragment thereof or antibody construct of the invention including,
but not limited to, transcription, post-transcriptional
modification, translation, post-translational modification, and
secretion.
[0152] The term "control sequences" refers to DNA sequences
necessary for the expression of an operably linked coding sequence
in a particular host organism. The control sequences that are
suitable for prokaryotes, for example, include a promoter,
optionally an operator sequence, and a ribosome binding site.
Eukaryotic cells are known to utilize promoters, polyadenylation
signals, and enhancers.
[0153] A nucleic acid is "operably linked" when it is placed into a
functional relationship with another nucleic acid sequence. For
example, DNA for a presequence or secretory leader is operably
linked to DNA for a polypeptide if it is expressed as a preprotein
that participates in the secretion of the polypeptide; a promoter
or enhancer is operably linked to a coding sequence if it affects
the transcription of the sequence; or a ribosome binding site is
operably linked to a coding sequence if it is positioned so as to
facilitate translation. Generally, "operably linked" means that the
DNA sequences being linked are contiguous, and, in the case of a
secretory leader, contiguous and in reading phase. However,
enhancers do not have to be contiguous. Linking is accomplished by
ligation at convenient restriction sites. If such sites do not
exist, the synthetic oligonucleotide adaptors or linkers are used
in accordance with conventional practice.
[0154] The terms "host cell," "target cell" or "recipient cell" are
intended to include any individual cell or cell culture that can be
or has/have been recipients for vectors or the incorporation of
exogenous nucleic acid molecules, polynucleotides and/or proteins.
It also is intended to include progeny of a single cell, and the
progeny may not necessarily be completely identical (in morphology
or in genomic or total DNA complement) to the original parent cell
due to natural, accidental, or deliberate mutation. The cells may
be prokaryotic or eukaryotic, and include but are not limited to
bacteria, yeast cells, animal cells, and mammalian cells, e.g.,
murine, rat, macaque or human.
[0155] Suitable host cells include prokaryotes and eukaryotic host
cells including yeasts, fungi, insect cells and mammalian
cells.
[0156] The the antibody or antigen binding fragment thereof or
antibody construct of the invention can be produced in bacteria.
After expression, the the antibody or antigen binding fragment
thereof or antibody construct of the invention, preferably the the
antibody or antigen binding fragment thereof or antibody construct
is isolated from the E. coli cell paste in a soluble fraction and
can be purified through, e.g., affinity chromatography and/or size
exclusion. Final purification can be carried out similar to the
process for purifying antibody expressed e. g, in CHO cells.
[0157] In addition to prokaryotes, eukaryotic microbes such as
filamentous fungi or yeast are suitable cloning or expression hosts
for the the antibody or antigen binding fragment thereof or
antibody construct of the invention. Saccharomyces cerevisiae, or
common baker's yeast, is the most commonly used among lower
eukaryotic host microorganisms. However, a number of other genera,
species, and strains are commonly available and useful herein, such
as Schizosaccharomyces pombe, Kluyveromyces hosts such as, e.g., K.
lactis, K. fragilis (ATCC 12424), K. bulgaricus (ATCC 16045), K.
wickeramii (ATCC 24178), K. waltii (ATCC 56500), K. drosophilarum
(ATCC 36906), K. thermotolerans, and K. marxianus; yarrowia (EP 402
226); Pichia pastoris (EP 183 070); Candida; Trichoderma reesia (EP
244 234); Neurospora crassa; Schwanniomyces such as Schwanniomyces
occidentalis; and filamentous fungi such as, e.g., Neurospora,
Penicillium, Tolypocladium, and Aspergillus hosts such as A.
nidulans and A. niger.
[0158] Suitable host cells for the expression of glycosylated the
antibody or antigen binding fragment thereof or antibody construct
of the invention, preferably antibody derived antibody constructs
are derived from multicellular organisms. Examples of invertebrate
cells include plant and insect cells. Numerous baculoviral strains
and variants and corresponding permissive insect host cells from
hosts such as Spodoptera frugiperda (caterpillar), Aedes aegypti
(mosquito), Aedes albopictus (mosquito), Drosophila melanogaster
(fruit fly), and Bombyx mori have been identified. A variety of
viral strains for transfection are publicly available, e. g., the
L-1 variant of Autographa californica NPV and the Bm-5 strain of
Bombyx mori NPV, and such viruses may be used as the virus herein
according to the present invention, particularly for transfection
of Spodoptera frugiperda cells.
[0159] Plant cell cultures of cotton, corn, potato, soybean,
petunia, tomato, Arabidopsis and tobacco can also be utilized as
hosts. Cloning and expression vectors useful in the production of
proteins in plant cell culture are known to those of skill in the
art. See e.g. Hiatt et al., Nature (1989) 342: 76-78, Owen et al.
(1992) Bio/Technology 10: 790-794, Artsaenko et al. (1995) The
Plant J 8: 745-750, and Fecker et al. (1996) Plant Mol Biol 32:
979-986.
[0160] However, interest has been greatest in vertebrate cells, and
propagation of vertebrate cells in culture (tissue culture) has
become a routine procedure. Examples of useful mammalian host cell
lines are monkey kidney CV1 line transformed by SV40 (COS-7, ATCC
CRL 1651); human embryonic kidney line (293 or 293 cells subcloned
for growth in suspension culture, Graham et al., J. Gen Virol. 36:
59 (1977)); baby hamster kidney cells (BHK, ATCC CCL 10); Chinese
hamster ovary cells/-DHFR (CHO, Urlaub et al., Proc. Natl. Acad.
Sci. USA 77: 4216 (1980)); mouse sertoli cells (TM4, Mather, Biol.
Reprod. 23: 243-251 (1980)); monkey kidney cells (CVI ATCC CCL 70);
African green monkey kidney cells (VERO-76, ATCC CRL1587); human
cervical carcinoma cells (HELA, ATCC CCL 2); canine kidney cells
(MDCK, ATCC CCL 34); buffalo rat liver cells (BRL 3A, ATCC CRL
1442); human lung cells (W138, ATCC CCL 75); human liver cells (Hep
G2,1413 8065); mouse mammary tumor (MMT 060562, ATCC CCLS 1); TRI
cells (Mather et al., Annals N. Y Acad. Sci. 383: 44-68 (1982));
MRC 5 cells; FS4 cells; and a human hepatoma line (Hep G2).
[0161] When using recombinant techniques, the antibody or antigen
binding fragment thereof or antibody construct of the invention can
be produced intracellularly, in the periplasmic space, or directly
secreted into the medium. If the the antibody or antigen binding
fragment thereof or antibody construct is produced intracellularly,
as a first step, the particulate debris, either host cells or lysed
fragments, are removed, for example, by centrifugation or
ultrafiltration. Carter et al., Bio/Technology 10: 163-167 (1992)
describe a procedure for isolating antibodies which are secreted to
the periplasmic space of E. coli. Briefly, cell paste is thawed in
the presence of sodium acetate (pH 3.5), EDTA, and
phenylmethylsulfonylfluoride (PMSF) over about 30 min. Cell debris
can be removed by centrifugation. Where the antibody is secreted
into the medium, supernatants from such expression systems are
generally first concentrated using a commercially available protein
concentration filter, for example, an Amicon or Millipore Pellicon
ultrafiltration unit. A protease inhibitor such as PMSF may be
included in any of the foregoing steps to inhibit proteolysis and
antibiotics may be included to prevent the growth of adventitious
contaminants.
[0162] The the antibody or antigen binding fragment thereof or
antibody construct of the invention prepared from the host cells
can be purified using, for example, hydroxylapatite chromatography,
gel electrophoresis, dialysis, and affinity chromatography, with
affinity chromatography being the preferred purification
technique.
[0163] The matrix to which the affinity ligand is attached is most
often agarose, but other matrices are available. Mechanically
stable matrices such as controlled pore glass or poly
(styrenedivinyl) benzene allow for faster flow rates and shorter
processing times than can be achieved with agarose. Where the
antibody or antigen binding fragment thereof or antibody construct
of the invention comprises a CH3 domain, the Bakerbond ABXMresin
(J. T. Baker, Phillipsburg, N.J.) is useful for purification. Other
techniques for protein purification such as fractionation on an
ion-exchange column, ethanol precipitation, Reverse Phase HPLC,
chromatography on silica, chromatography on heparin SEPHAROSE.TM.
chromatography on an anion or cation exchange resin (such as a
polyaspartic acid column), chromato-focusing, SDS-PAGE, and
ammonium sulfate precipitation are also available depending on the
antibody to be recovered.
[0164] The term "culturing" refers to the in vitro maintenance,
differentiation, growth, proliferation and/or propagation of cells
under suitable conditions in a medium.
[0165] As used herein, the term "pharmaceutical composition"
relates to a composition for administration to a patient,
preferably a human patient. The particular preferred pharmaceutical
composition of this invention comprises the antibody or antigen
binding fragment thereof or antibody construct of the invention.
Preferably, the pharmaceutical composition comprises suitable
formulations of carriers, stabilizers and/or excipients. In a
preferred embodiment, the pharmaceutical composition comprises a
composition for parenteral, transdermal, intraluminal,
intraarterial, intrathecal and/or intranasal administration or by
direct injection into tissue. It is in particular envisaged that
said composition is administered to a patient via infusion or
injection. Administration of the suitable compositions may be
effected by different ways, e.g., by intravenous, intraperitoneal,
subcutaneous, intramuscular, topical or intradermal administration.
In particular, the present invention provides for an uninterrupted
administration of the suitable composition. As a non-limiting
example, uninterrupted, i.e. continuous administration may be
realized by a small pump system worn by the patient for metering
the influx of therapeutic agent into the body of the patient. The
pharmaceutical composition comprising the antibody or antigen
binding fragment thereof or antibody construct of the invention can
be administered by using said pump systems. Such pump systems are
generally known in the art, and commonly rely on periodic exchange
of cartridges containing the therapeutic agent to be infused. When
exchanging the cartridge in such a pump system, a temporary
interruption of the otherwise uninterrupted flow of therapeutic
agent into the body of the patient may ensue. In such a case, the
phase of administration prior to cartridge replacement and the
phase of administration following cartridge replacement would still
be considered within the meaning of the pharmaceutical means and
methods of the invention together make up one "uninterrupted
administration" of such therapeutic agent.
[0166] The continuous or uninterrupted administration of these
antibody or antigen binding fragment thereof or antibody constructs
of the invention may be intravenous or subcutaneous by way of a
fluid delivery device or small pump system including a fluid
driving mechanism for driving fluid out of a reservoir and an
actuating mechanism for actuating the driving mechanism. Pump
systems for subcutaneous administration may include a needle or a
cannula for penetrating the skin of a patient and delivering the
suitable composition into the patient's body. Said pump systems may
be directly fixed or attached to the skin of the patient
independently of a vein, artery or blood vessel, thereby allowing a
direct contact between the pump system and the skin of the patient.
The pump system can be attached to the skin of the patient for 24
hours up to several days. The pump system may be of small size with
a reservoir for small volumes. As a non-limiting example, the
volume of the reservoir for the suitable pharmaceutical composition
to be administered can be between 0.1 and 50 ml.
[0167] The continuous administration may be transdermal by way of a
patch worn on the skin and replaced at intervals. One of skill in
the art is aware of patch systems for drug delivery suitable for
this purpose. It is of note that transdermal administration is
especially amenable to uninterrupted administration, as exchange of
a first exhausted patch can advantageously be accomplished
simultaneously with the placement of a new, second patch, for
example on the surface of the skin immediately adjacent to the
first exhausted patch and immediately prior to removal of the first
exhausted patch. Issues of flow interruption or power cell failure
do not arise.
[0168] The inventive compositions may further comprise a
pharmaceutically acceptable carrier. Examples of suitable
pharmaceutical carriers are well known in the art and include
solutions, e.g. phosphate buffered saline solutions, water,
emulsions, such as oil/water emulsions, various types of wetting
agents, sterile solutions, liposomes, etc. Compositions comprising
such carriers can be formulated by well known conventional methods.
Formulations can comprise carbohydrates, buffer solutions, amino
acids and/or surfactants. Carbohydrates may be non-reducing sugars,
preferably trehalose, sucrose, octasulfate, sorbitol or xylitol. In
general, as used herein, "pharmaceutically acceptable carrier"
means any and all solvents, dispersion media, coatings,
antibacterial and antifungal agents, isotonic and absorption
delaying agents, compatible with pharmaceutical administration. The
use of such media and agents for pharmaceutically active substances
is well known in the art. Acceptable carriers, excipients, or
stabilizers are nontoxic to recipients at the dosages and
concentrations employed and include: additional buffering agents;
preservatives; co-solvents; antioxidants, including ascorbic acid
and methionine; chelating agents such as EDTA; metal complexes
(e.g., Zn-protein complexes); biodegradable polymers, such as
polyesters; salt-forming counter-ions, such as sodium, polyhydric
sugar alcohols; amino acids, such as alanine, glycine, asparagine,
2-phenylalanine, and threonine; sugars or sugar alcohols, such as
trehalose, sucrose, octasulfate, sorbitol or xylitol stachyose,
mannose, sorbose, xylose, ribose, myoinisitose, galactose,
lactitol, ribitol, myoinisitol, galactitol, glycerol, cyclitols
(e.g., inositol), polyethylene glycol; sulfur containing reducing
agents, such as glutathione, thioctic acid, sodium thioglycolate,
thioglycerol, [alpha]-monothioglycerol, and sodium thio sulfate;
low molecular weight proteins, such as human serum albumin, bovine
serum albumin, gelatin, or other immunoglobulins; and hydrophilic
polymers, such as polyvinylpyrrolidone. Such formulations may be
used for continuous administrations which may be intravenous or
subcutaneous with and/or without pump systems. Amino acids may be
charged amino acids, preferably lysine, lysine acetate, arginine,
glutamate and/or histidine. Surfactants may be detergents,
preferably with a molecular weight of >1.2 KD and/or a
polyether, preferably with a molecular weight of >3 KD.
Non-limiting examples for preferred detergents are Tween 20, Tween
40, Tween 60, Tween 80 or Tween 85. Non-limiting examples for
preferred polyethers are PEG 3000, PEG 3350, PEG 4000 or PEG 5000.
Buffer systems used in the present invention can have a preferred
pH of 5-9 and may comprise citrate, succinate, phosphate, histidine
and acetate.
[0169] The compositions of the present invention can be
administered to the subject at a suitable dose which can be
determined e.g. by dose escalating studies by administration of
increasing doses of the polypeptide of the invention exhibiting
cross-species specificity described herein to non-chimpanzee
primates, for instance macaques. As set forth above, the antibody
or antigen binding fragment thereof or antibody construct of the
invention exhibiting cross-species specificity described herein can
be advantageously used in identical form in preclinical testing in
non-chimpanzee primates and as drug in humans. These compositions
can also be administered in combination with other proteinaceous
and non-proteinaceous drugs. These drugs may be administered
simultaneously with the composition comprising the polypeptide of
the invention as defined herein or separately before or after
administration of said polypeptide in timely defined intervals and
doses. The dosage regimen will be determined by the attending
physician and clinical factors. As is well known in the medical
arts, dosages for any one patient depend upon many factors,
including the patient's size, body surface area, age, the
particular compound to be administered, sex, time and route of
administration, general health, and other drugs being administered
concurrently.
[0170] Preparations for parenteral administration include sterile
aqueous or non-aqueous solutions, suspensions, and emulsions.
Examples of non-aqueous solvents are propylene glycol, polyethylene
glycol, vegetable oils such as olive oil, and injectable organic
esters such as ethyl oleate. Aqueous carriers include water,
alcoholic/aqueous solutions, emulsions or suspensions, including
saline and buffered media. Parenteral vehicles include sodium
chloride solution, Ringer's dextrose, dextrose and sodium chloride,
lactated Ringer's, or fixed oils. Intravenous vehicles include
fluid and nutrient replenishers, electrolyte replenishers (such as
those based on Ringer's dextrose), and the like. Preservatives and
other additives may also be present such as, for example,
antimicrobials, anti-oxidants, chelating agents, inert gases and
the like. In addition, the composition of the present invention
might comprise proteinaceous carriers, like, e.g., serum albumin or
immunoglobulin, preferably of human origin. It is envisaged that
the composition of the invention might comprise, in addition to the
polypeptide of the invention defined herein, further biologically
active agents, depending on the intended use of the composition.
Such agents might be drugs acting on the gastro-intestinal system,
drugs acting as cytostatica, drugs preventing hyperurikemia, drugs
inhibiting immunoreactions (e.g. corticosteroids), drugs modulating
the inflammatory response, drugs acting on the circulatory system
and/or agents such as cytokines known in the art. It is also
envisaged that the antibody or antigen binding fragment thereof or
antibody construct of the present invention is applied in a
co-therapy, i.e., in combination with another anti-cancer
medicament.
[0171] The biological activity of the pharmaceutical composition
defined herein can be determined for instance by cytotoxicity
assays, as described in the following examples, in WO 99/54440 or
by Schlereth et al. (Cancer Immunol. Immunother. 20 (2005), 1-12).
"Efficacy" or "in vivo efficacy" as used herein refers to the
response to therapy by the pharmaceutical composition of the
invention, using e.g. standardized NCI response criteria. The
success or in vivo efficacy of the therapy using a pharmaceutical
composition of the invention refers to the effectiveness of the
composition for its intended purpose, i.e. the ability of the
composition to cause its desired effect, i.e. depletion of
pathologic cells, e.g. tumor cells. The in vivo efficacy may be
monitored by established standard methods for the respective
disease entities including, but not limited to white blood cell
counts, differentials, Fluorescence Activated Cell Sorting, bone
marrow aspiration. In addition, various disease specific clinical
chemistry parameters and other established standard methods may be
used. Furthermore, computer-aided tomography, X-ray, nuclear
magnetic resonance tomography (e.g. for National Cancer
Institute-criteria based response assessment [Cheson B D, Horning S
J, Coiffier B, Shipp M A, Fisher R I, Connors J M, Lister T A, Vose
J, Grillo-Lopez A, Hagenbeek A, Cabanillas F, Klippensten D,
Hiddemann W, Castellino R, Harris N L, Armitage J O, Carter W,
Hoppe R, Canellos G P. Report of an international workshop to
standardize response criteria for non-Hodgkin's lymphomas. NCI
Sponsored International Working Group. J Clin Oncol. 1999 April;
17(4):1244]), positron-emission tomography scanning, white blood
cell counts, differentials, Fluorescence Activated Cell Sorting,
bone marrow aspiration, lymph node biopsies/histologies, and
various lymphoma specific clinical chemistry parameters (e.g.
lactate dehydrogenase) and other established standard methods may
be used.
[0172] Another major challenge in the development of drugs such as
the pharmaceutical composition of the invention is the predictable
modulation of pharmacokinetic properties. To this end, a
pharmacokinetic profile of the drug candidate, i.e. a profile of
the pharmacokinetic parameters that affect the ability of a
particular drug to treat a given condition, can be established.
Pharmacokinetic parameters of the drug influencing the ability of a
drug for treating a certain disease entity include, but are not
limited to: half-life, volume of distribution, hepatic first-pass
metabolism and the degree of blood serum binding. The efficacy of a
given drug agent can be influenced by each of the parameters
mentioned above.
[0173] "Half-life" means the time where 50% of an administered drug
are eliminated through biological processes, e.g. metabolism,
excretion, etc.
[0174] By "hepatic first-pass metabolism" is meant the propensity
of a drug to be metabolized upon first contact with the liver, i.e.
during its first pass through the liver.
[0175] "Volume of distribution" means the degree of retention of a
drug throughout the various compartments of the body, like e.g.
intracellular and extracellular spaces, tissues and organs, etc.
and the distribution of the drug within these compartments.
[0176] "Degree of blood serum binding" means the propensity of a
drug to interact with and bind to blood serum proteins, such as
albumin, leading to a reduction or loss of biological activity of
the drug.
[0177] Pharmacokinetic parameters also include bioavailability, lag
time (Tlag), Tmax, absorption rates, more onset and/or Cmax for a
given amount of drug administered. "Bioavailability" means the
amount of a drug in the blood compartment. "Lag time" means the
time delay between the administration of the drug and its detection
and measurability in blood or plasma.
[0178] "Tmax" is the time after which maximal blood concentration
of the drug is reached, and "Cmax" is the blood concentration
maximally obtained with a given drug. The time to reach a blood or
tissue concentration of the drug which is required for its
biological effect is influenced by all parameters. Pharmacokinetic
parameters of bispecific single chain antibodies exhibiting
cross-species specificity, which may be determined in preclinical
animal testing in non-chimpanzee primates as outlined above, are
also set forth e.g. in the publication by Schlereth et al. (Cancer
Immunol. Immunother. 20 (2005), 1-12).
[0179] The term "toxicity" as used herein refers to the toxic
effects of a drug manifested in adverse events or severe adverse
events. These side events might refer to a lack of tolerability of
the drug in general and/or a lack of local tolerance after
administration. Toxicity could also include teratogenic or
carcinogenic effects caused by the drug.
[0180] The term "safety", "in vivo safety" or "tolerability" as
used herein defines the administration of a drug without inducing
severe adverse events directly after administration (local
tolerance) and during a longer period of application of the drug.
"Safety", "in vivo safety" or "tolerability" can be evaluated e.g.
at regular intervals during the treatment and follow-up period.
Measurements include clinical evaluation, e.g. organ
manifestations, and screening of laboratory abnormalities. Clinical
evaluation may be carried out and deviations to normal findings
recorded/coded according to NCI-CTC and/or MedDRA standards. Organ
manifestations may include criteria such as allergy/immunology,
blood/bone marrow, cardiac arrhythmia, coagulation and the like, as
set forth e.g. in the Common Terminology Criteria for adverse
events v3.0 (CTCAE). Laboratory parameters which may be tested
include for instance hematology, clinical chemistry, coagulation
profile and urine analysis and examination of other body fluids
such as serum, plasma, lymphoid or spinal fluid, liquor and the
like. Safety can thus be assessed e.g. by physical examination,
imaging techniques (i.e. ultrasound, x-ray, CT scans, Magnetic
Resonance Imaging (MRI), other measures with technical devices
(i.e. electrocardiogram), vital signs, by measuring laboratory
parameters and recording adverse events. For example, adverse
events in non-chimpanzee primates in the uses and methods according
to the invention may be examined by histopathological and/or
histochemical methods.
[0181] The term "effective dose" or "effective dosage" is defined
as an amount sufficient to achieve or at least partially achieve
the desired effect. The term "therapeutically effective dose" is
defined as an amount sufficient to cure or at least partially
arrest the disease and its complications in a patient already
suffering from the disease. Amounts effective for this use will
depend upon the severity of the infection and the general state of
the subject's own immune system. The term "patient" includes human
and other mammalian subjects that receive either prophylactic or
therapeutic treatment.
[0182] The term "effective and non-toxic dose" as used herein
refers to a tolerable dose of an inventive antibody or antigen
binding fragment thereof or antibody construct which is high enough
to cause depletion of pathologic cells, tumor elimination, tumor
shrinkage or stabilization of disease without or essentially
without major toxic effects. Such effective and non-toxic doses may
be determined e.g. by dose escalation studies described in the art
and should be below the dose inducing severe adverse side events
(dose limiting toxicity, DLT).
[0183] The above terms are also referred to e.g. in the Preclinical
safety evaluation of biotechnology-derived pharmaceuticals S6; ICH
Harmonised Tripartite Guideline; ICH Steering Committee meeting on
Jul. 16, 1997.
[0184] The appropriate dosage, or therapeutically effective amount,
of the antibody or antigen binding fragment thereof or antibody
construct of the invention will depend on the condition to be
treated, the severity of the condition, prior therapy, and the
patient's clinical history and response to the therapeutic agent.
The proper dose can be adjusted according to the judgment of the
attending physician such that it can be administered to the patient
one time or over a series of administrations. The pharmaceutical
composition can be administered as a sole therapeutic or in
combination with additional therapies such as anti-cancer therapies
as needed.
[0185] The pharmaceutical compositions of this invention are
particularly useful for parenteral administration, i.e.,
subcutaneously, intramuscularly, intravenously, intra-articular
and/or intra-synovial. Parenteral administration can be by bolus
injection or continuous infusion.
[0186] If the pharmaceutical composition has been lyophilized, the
lyophilized material is first reconstituted in an appropriate
liquid prior to administration. The lyophilized material may be
reconstituted in, e.g., bacteriostatic water for injection (BWFI),
physiological saline, phosphate buffered saline (PBS), or the same
formulation the protein had been in prior to lyophilization.
[0187] In an internal analysis of proprietary mRNA expression data
it has been surprisingly found that CDH19 expression is elevated in
both primary and metastatic melanoma tumors compared to normal,
untransformed tissues. Internal analysis also confirmed that
expression of CDH19 in normal tissues is limited to neural crest
derived peripheral nerve ganglia and nerve fibers. The differential
CDH19 expression in normal and tumor tissues makes this protein
attractive for cell-surface targeting therapeutics. Although CDH 19
was discussed as one marker as part of long lists of markers
associated with some cancer types (see e.g. WO2009/055937) or
Parkinson's disease (see e.g. WO2005/067391) CDH19 was never
discussed as a prognostic marker or a drug target in connection
with melanoma tumors.
[0188] As stated above, the present invention provides an isolated
human antibody or antigen binding fragment thereof capable of
binding to human CDH19 on the surface of a target cell. In a
preferred embodiment the antibody or antigen binding fragment
thereof comprises a monoclonal antibody or a fragment thereof.
[0189] The "CDH19 extracellular domain" or "CDH19 ECD" refers to a
form of CDH19 which is essentially free of transmembrane and
cytoplasmic domains of CDH19. It will be understood by the skilled
artisan that the transmembrane domain identified for the CDH19
polypeptide of the present invention is identified pursuant to
criteria routinely employed in the art for identifying that type of
hydrophobic domain. The exact boundaries of a transmembrane domain
may vary but most likely by no more than about 5 amino acids at
either end of the domain specifically mentioned herein. A preferred
human CDH19 ECD is shown in SEQ ID NO: 948 (aa residues 44-596). In
this context it is understood that the CDH19 ECD represents the
part of CDH19 on the surface of a target cell.
[0190] The affinity of the antibody or fragment thereof for human
CDH19 is preferably .ltoreq.15 nM, more preferably .ltoreq.10 nM,
even more preferably .ltoreq.5 nM, even more preferably .ltoreq.1
nM, even more preferably .ltoreq.0.5 nM, even more preferably
.ltoreq.0.1 nM, and most preferably .ltoreq.0.05 nM. The affinity
of the first binding domain for macaque CDH19 is preferably
.ltoreq.15 nM, more preferably .ltoreq.10 nM, even more preferably
.ltoreq.5 nM, even more preferably .ltoreq.1 nM, even more
preferably .ltoreq.0.5 nM, even more preferably .ltoreq.0.1 nM, and
most preferably .ltoreq.0.05 nM or even .ltoreq.0.01 nM. The
affinity can be measured for example in a Biacore assay or in a
Scatchard assay, e.g. as described in the Examples. The affinity
gap for binding to macaque CDH19 versus human CDH19 is preferably
[1:10-1:5] or [5:1-10:1], more preferably [1:5-5:1], and most
preferably [1:2-3:1] or even [1:1-3:1]. Other methods of
determining the affinity are well-known to the skilled person.
[0191] Human antibodies avoid some of the problems associated with
antibodies that possess murine or rat variable and/or constant
regions. The presence of such murine or rat derived proteins can
lead to the rapid clearance of the antibodies or can lead to the
generation of an immune response against the antibody by a patient.
In order to avoid the utilization of murine or rat derived
antibodies, human or fully human antibodies can be generated
through the introduction of human antibody function into a rodent
so that the rodent produces fully human antibodies.
[0192] The ability to clone and reconstruct megabase-sized human
loci in YACs and to introduce them into the mouse germline provides
a powerful approach to elucidating the functional components of
very large or crudely mapped loci as well as generating useful
models of human disease. Furthermore, the utilization of such
technology for substitution of mouse loci with their human
equivalents could provide unique insights into the expression and
regulation of human gene products during development, their
communication with other systems, and their involvement in disease
induction and progression.
[0193] An important practical application of such a strategy is the
"humanization" of the mouse humoral immune system. Introduction of
human immunoglobulin (Ig) loci into mice in which the endogenous Ig
genes have been inactivated offers the opportunity to study the
mechanisms underlying programmed expression and assembly of
antibodies as well as their role in B-cell development.
Furthermore, such a strategy could provide an ideal source for
production of fully human monoclonal antibodies (mAbs)--an
important milestone towards fulfilling the promise of antibody
therapy in human disease. Fully human antibodies are expected to
minimize the immunogenic and allergic responses intrinsic to mouse
or mouse-derivatized mAbs and thus to increase the efficacy and
safety of the administered antibodies. The use of fully human
antibodies can be expected to provide a substantial advantage in
the treatment of chronic and recurring human diseases, such as
inflammation, autoimmunity, and cancer, which require repeated
antibody administrations.
[0194] One approach towards this goal was to engineer mouse strains
deficient in mouse antibody production with large fragments of the
human Ig loci in anticipation that such mice would produce a large
repertoire of human antibodies in the absence of mouse antibodies.
Large human Ig fragments would preserve the large variable gene
diversity as well as the proper regulation of antibody production
and expression. By exploiting the mouse machinery for antibody
diversification and selection and the lack of immunological
tolerance to human proteins, the reproduced human antibody
repertoire in these mouse strains should yield high affinity
antibodies against any antigen of interest, including human
antigens. Using the hybridoma technology, antigen-specific human
mAbs with the desired specificity could be readily produced and
selected. This general strategy was demonstrated in connection with
our generation of the first XenoMouse mouse strains, as published
in 1994. (See Green et al. Nature Genetics 7:13-21 (1994)) The
XenoMouse strains were engineered with yeast artificial chromosomes
(YACs) containing 245 kb and 190 kb-sized germline configuration
fragments of the human heavy chain locus and kappa light chain
locus, respectively, which contained core variable and constant
region sequences. Id. The human Ig containing YACs proved to be
compatible with the mouse system for both rearrangement and
expression of antibodies and were capable of substituting for the
inactivated mouse Ig genes. This was demonstrated by their ability
to induce B-cell development, to produce an adult-like human
repertoire of fully human antibodies, and to generate
antigen-specific human mAbs. These results also suggested that
introduction of larger portions of the human Ig loci containing
greater numbers of V genes, additional regulatory elements, and
human Ig constant regions might recapitulate substantially the full
repertoire that is characteristic of the human humoral response to
infection and immunization. The work of Green et al. was recently
extended to the introduction of greater than approximately 80% of
the human antibody repertoire through introduction of megabase
sized, germline configuration YAC fragments of the human heavy
chain loci and kappa light chain loci, respectively. See Mendez et
al. Nature Genetics 15:146-156 (1997) and U.S. patent application
Ser. No. 08/759,620, filed Dec. 3, 1996, the disclosures of which
are hereby incorporated by reference.
[0195] The production of the XenoMouse mice is further discussed
and delineated in U.S. patent application Ser. No. 07/466,008,
filed Jan. 12, 1990, Ser. No. 07/610,515, filed Nov. 8, 1990, Ser.
No. 07/919,297, filed Jul. 24, 1992, Ser. No. 07/922,649, filed
Jul. 30, 1992, filed Ser. No. 08/031,801, filed Mar. 15, 1993, Ser.
No. 08/112,848, filed Aug. 27, 1993, Ser. No. 08/234,145, filed
Apr. 28, 1994, Ser. No. 08/376,279, filed Jan. 20, 1995, Ser. No.
08/430,938, Apr. 27, 1995, Ser. No. 08/464,584, filed Jun. 5, 1995,
Ser. No. 08/464,582, filed Jun. 5, 1995, Ser. No. 08/463,191, filed
Jun. 5, 1995, Ser. No. 08/462,837, filed Jun. 5, 1995, Ser. No.
08/486,853, filed Jun. 5, 1995, Ser. No. 08/486,857, filed Jun. 5,
1995, Ser. No. 08/486,859, filed Jun. 5, 1995, Ser. No. 08/462,513,
filed Jun. 5, 1995, Ser. No. 08/724,752, filed Oct. 2, 1996, and
Ser. No. 08/759,620, filed Dec. 3, 1996 and U.S. Pat. Nos.
6,162,963, 6,150,584, 6,114,598, 6,075,181, and 5,939,598 and
Japanese Patent Nos. 3 068 180 B2, 3 068 506 B2, and 3 068 507 B2.
See also Mendez et al. Nature Genetics 15:146-156 (1997) and Green
and Jakobovits J. Exp. Med. 188:483-495 (1998). See also European
Patent No., EP 0 463151 B1, grant published Jun. 12, 1996,
International Patent Application No., WO 94/02602, published Feb.
3, 1994, International Patent Application No., WO 96/34096,
published Oct. 31, 1996, WO 98/24893, published Jun. 11, 1998, WO
00/76310, published Dec. 21, 2000, WO 03/47336. The disclosures of
each of the above-cited patents, applications, and references are
hereby incorporated by reference in their entirety.
[0196] In an alternative approach, others, including GenPharm
International, Inc., have utilized a "minilocus" approach. In the
minilocus approach, an exogenous Ig locus is mimicked through the
inclusion of pieces (individual genes) from the Ig locus. Thus, one
or more V.sub.H genes, one or more D.sub.H genes, one or more
J.sub.H genes, a mu constant region, and a second constant region
(preferably a gamma constant region) are formed into a construct
for insertion into an animal. This approach is described in U.S.
Pat. No. 5,545,807 to Surani et al. and U.S. Pat. Nos. 5,545,806,
5,625,825, 5,625,126, 5,633,425, 5,661,016, 5,770,429, 5,789,650,
5,814,318, 5,877,397, 5,874,299, and 6,255,458 each to Lonberg and
Kay, U.S. Pat. Nos. 5,591,669 and 6,023.010 to Krimpenfort and
Berns, U.S. Pat. Nos. 5,612,205, 5,721,367, and 5,789,215 to Berns
et al., and U.S. Pat. No. 5,643,763 to Choi and Dunn, and GenPharm
International U.S. patent application Ser. No. 07/574,748, filed
Aug. 29, 1990, Ser. No. 07/575,962, filed Aug. 31, 1990, Ser. No.
07/810,279, filed Dec. 17, 1991, Ser. No. 07/853,408, filed Mar.
18, 1992, Ser. No. 07/904,068, filed Jun. 23, 1992, Ser. No.
07/990,860, filed Dec. 16, 1992, Ser. No. 08/053,131, filed Apr.
26, 1993, Ser. No. 08/096,762, filed Jul. 22, 1993, Ser. No.
08/155,301, filed Nov. 18, 1993, Ser. No. 08/161,739, filed Dec. 3,
1993, Ser. No. 08/165,699, filed Dec. 10, 1993, Ser. No.
08/209,741, filed Mar. 9, 1994, the disclosures of which are hereby
incorporated by reference. See also European Patent No. 0 546 073 B
1, International Patent Application Nos. WO 92/03918, WO 92/22645,
WO 92/22647, WO 92/22670, WO 93/12227, WO 94/00569, WO 94/25585, WO
96/14436, WO 97/13852, and WO 98/24884 and U.S. Pat. No. 5,981,175,
the disclosures of which are hereby incorporated by reference in
their entirety. See further Taylor et al., 1992, Chen et al., 1993,
Tuaillon et al., 1993, Choi et al., 1993, Lonberg et al., (1994),
Taylor et al., (1994), and Tuaillon et al., (1995), Fishwild et
al., (1996), the disclosures of which are hereby incorporated by
reference in their entirety.
[0197] Kirin has also demonstrated the generation of human
antibodies from mice in which, through microcell fusion, large
pieces of chromosomes, or entire chromosomes, have been introduced.
See European Patent Application Nos. 773 288 and 843 961, the
disclosures of which are hereby incorporated by reference. Xenerex
Biosciences is developing a technology for the potential generation
of human antibodies. In this technology, SCID mice are
reconstituted with human lymphatic cells, e.g., B and/or T cells.
Mice are then immunized with an antigen and can generate an immune
response against the antigen. See U.S. Pat. Nos. 5,476,996,
5,698,767, and 5,958,765.
[0198] Human anti-mouse antibody (HAMA) responses have led the
industry to prepare chimeric or otherwise humanized antibodies.
While chimeric antibodies have a human constant region and a murine
variable region, it is expected that certain human anti-chimeric
antibody (HACA) responses will be observed, particularly in chronic
or multi-dose utilizations of the antibody. Thus, it would be
desirable to provide fully human antibodies against EGFRvIII in
order to vitiate concerns and/or effects of HAMA or HACA
response.
[0199] According to one embodiment the antibody of the present
invention is a dimer comprising two fusion proteins created by
fusing a CDH19 binding fragment of a CDH19 antibody to the Fc
region of an antibody. The dimer can be made by, for example,
inserting a gene fusion encoding the fusion protein into an
appropriate expression vector, expressing the gene fusion in host
cells transformed with the recombinant expression vector, and
allowing the expressed fusion protein to assemble much like
antibody molecules, whereupon interchain disulfide bonds form
between the Fc moieties to yield the dimer.
[0200] The term "Fc polypeptide" as used herein includes native and
mutein forms of polypeptides derived from the Fc region of an
antibody. Truncated forms of such polypeptides containing the hinge
region that promotes dimerization also are included. Fusion
proteins comprising Fc moieties (and oligomers formed therefrom)
offer the advantage of facile purification by affinity
chromatography over Protein A or Protein G columns.
[0201] One suitable Fc polypeptide, described in PCT application WO
93/10151 (hereby incorporated by reference), is a single chain
polypeptide extending from the N-terminal hinge region to the
native C-terminus of the Fc region of a human IgG antibody. Another
useful Fc polypeptide is the Fc mutein described in U.S. Pat. No.
5,457,035 and in Baum et al., 1994, EMBO J. 13:3992-4001. The amino
acid sequence of this mutein is identical to that of the native Fc
sequence presented in WO 93/10151, except that amino acid 19 has
been changed from Leu to Ala, amino acid 20 has been changed from
Leu to Glu, and amino acid 22 has been changed from Gly to Ala. The
mutein exhibits reduced affinity for Fc receptors.
[0202] Alternatively, the antibody of the invention is a fusion
protein comprising multiple CDH19 antibody polypeptides, with or
without peptide linkers (spacer peptides). Among the suitable
peptide linkers are those described in U.S. Pat. Nos. 4,751,180 and
4,935,233 or WO 88/09344.
[0203] Another method for preparing oligomeric CDH19 antibody
derivatives involves use of a leucine zipper. Leucine zipper
domains are peptides that promote oligomerization of the proteins
in which they are found. Leucine zippers were originally identified
in several DNA-binding proteins (Landschulz et al., 1988, Science
240:1759), and have since been found in a variety of different
proteins. Among the known leucine zippers are naturally occurring
peptides and derivatives thereof that dimerize or trimerize.
Examples of leucine zipper domains suitable for producing soluble
oligomeric proteins are described in PCT application WO 94/10308,
and the leucine zipper derived from lung surfactant protein D (SPD)
described in Hoppe et al., 1994, FEBS Letters 344:191, hereby
incorporated by reference. The use of a modified leucine zipper
that allows for stable trimerization of a heterologous protein
fused thereto is described in Fanslow et al., 1994, Semin. Immunol.
6:267-78. In one approach, recombinant fusion proteins comprising
CDH19 antibody fragment or derivative fused to a leucine zipper
peptide are expressed in suitable host cells, and the soluble
oligomeric CDH19 antibody fragments or derivatives that form are
recovered from the culture supernatant.
[0204] Covalent modifications of antigen binding proteins are
included within the scope of this invention, and are generally, but
not always, done post-translationally. For example, several types
of covalent modifications of the antigen binding protein are
introduced into the molecule by reacting specific amino acid
residues of the antigen binding protein with an organic
derivatizing agent that is capable of reacting with selected side
chains or the N- or C-terminal residues.
[0205] Cysteinyl residues most commonly are reacted with
.alpha.-haloacetates (and corresponding amines), such as
chloroacetic acid or chloroacetamide, to give carboxymethyl or
carboxyamidomethyl derivatives. Cysteinyl residues also are
derivatized by reaction with bromotrifluoroacetone,
.alpha.-bromo-.beta.-(5-imidozoyl)propionic acid, chloroacetyl
phosphate, N-alkylmaleimides, 3-nitro-2-pyridyl disulfide, methyl
2-pyridyl disulfide, p-chloromercuribenzoate,
2-chloromercuri-4-nitrophenol, or
chloro-7-nitrobenzo-2-oxa-1,3-diazole.
[0206] Histidyl residues are derivatized by reaction with
diethylpyrocarbonate at pH 5.5-7.0 because this agent is relatively
specific for the histidyl side chain. Para-bromophenacyl bromide
also is useful; the reaction is preferably performed in 0.1 M
sodium cacodylate at pH 6.0.
[0207] Lysinyl and amino terminal residues are reacted with
succinic or other carboxylic acid anhydrides. Derivatization with
these agents has the effect of reversing the charge of the lysinyl
residues. Other suitable reagents for derivatizing
alpha-amino-containing residues include imidoesters such as methyl
picolinimidate; pyridoxal phosphate; pyridoxal; chloroborohydride;
trinitrobenzenesulfonic acid; O-methylisourea; 2,4-pentanedione;
and transaminase-catalyzed reaction with glyoxylate.
[0208] Arginyl residues are modified by reaction with one or
several conventional reagents, among them phenylglyoxal,
2,3-butanedione, 1,2-cyclohexanedione, and ninhydrin.
Derivatization of arginine residues requires that the reaction be
performed in alkaline conditions because of the high pKa of the
guanidine functional group. Furthermore, these reagents may react
with the groups of lysine as well as the arginine epsilon-amino
group.
[0209] The specific modification of tyrosyl residues may be made,
with particular interest in introducing spectral labels into
tyrosyl residues by reaction with aromatic diazonium compounds or
tetranitromethane. Most commonly, N-acetylimidizole and
tetranitromethane are used to form O-acetyl tyrosyl species and
3-nitro derivatives, respectively. Tyrosyl residues are iodinated
using .sup.125I or .sup.131I to prepare labeled proteins for use in
radioimmunoassay, the chloramine T method described above being
suitable.
[0210] Carboxyl side groups (aspartyl or glutamyl) are selectively
modified by reaction with carbodiimides (R'--N.dbd.C.dbd.N--R'),
where R and R' are optionally different alkyl groups, such as
1-cyclohexyl-3-(2-morpholinyl-4-ethyl) carbodiimide or
1-ethyl-3-(4-azonia-4,4-dimethylpentyl) carbodiimide. Furthermore,
aspartyl and glutamyl residues are converted to asparaginyl and
glutaminyl residues by reaction with ammonium ions.
[0211] Derivatization with bifunctional agents is useful for
crosslinking antigen binding proteins to a water-insoluble support
matrix or surface for use in a variety of methods. Commonly used
crosslinking agents include, e.g.,
1,1-bis(diazoacetyl)-2-phenylethane, glutaraldehyde,
N-hydroxysuccinimide esters, for example, esters with
4-azidosalicylic acid, homobifunctional imidoesters, including
disuccinimidyl esters such as
3,3'-dithiobis(succinimidylpropionate), and bifunctional maleimides
such as bis-N-maleimido-1,8-octane. Derivatizing agents such as
methyl-3-[(p-azidophenyl)dithio]propioimidate yield
photoactivatable intermediates that are capable of forming
crosslinks in the presence of light. Alternatively, reactive
water-insoluble matrices such as cyanogen bromide-activated
carbohydrates and the reactive substrates described in U.S. Pat.
Nos. 3,969,287; 3,691,016; 4,195,128; 4,247,642; 4,229,537; and
4,330,440 are employed for protein immobilization.
[0212] Glutaminyl and asparaginyl residues are frequently
deamidated to the corresponding glutamyl and aspartyl residues,
respectively. Alternatively, these residues are deamidated under
mildly acidic conditions. Either form of these residues falls
within the scope of this invention.
[0213] Other modifications include hydroxylation of proline and
lysine, phosphorylation of hydroxyl groups of seryl or threonyl
residues, methylation of the .alpha.-amino groups of lysine,
arginine, and histidine side chains (T. E. Creighton, Proteins:
Structure and Molecular Properties, W. H. Freeman & Co., San
Francisco, 1983, pp. 79-86), acetylation of the N-terminal amine,
and amidation of any C-terminal carboxyl group.
[0214] Another type of covalent modification of the antigen binding
protein included within the scope of this invention comprises
altering the glycosylation pattern of the protein. As is known in
the art, glycosylation patterns can depend on both the sequence of
the protein (e.g., the presence or absence of particular
glycosylation amino acid residues, discussed below), or the host
cell or organism in which the protein is produced. Particular
expression systems are discussed below.
[0215] Glycosylation of polypeptides is typically either N-linked
or O-linked. N-linked refers to the attachment of the carbohydrate
moiety to the side chain of an asparagine residue. The tri-peptide
sequences asparagine-X-serine and asparagine-X-threonine, where X
is any amino acid except proline, are the recognition sequences for
enzymatic attachment of the carbohydrate moiety to the asparagine
side chain. Thus, the presence of either of these tri-peptide
sequences in a polypeptide creates a potential glycosylation site.
O-linked glycosylation refers to the attachment of one of the
sugars N-acetylgalactosamine, galactose, or xylose, to a
hydroxyamino acid, most commonly serine or threonine, although
5-hydroxyproline or 5-hydroxylysine may also be used.
[0216] Addition of glycosylation sites to the antigen binding
protein is conveniently accomplished by altering the amino acid
sequence such that it contains one or more of the above-described
tri-peptide sequences (for N-linked glycosylation sites). The
alteration may also be made by the addition of, or substitution by,
one or more serine or threonine residues to the starting sequence
(for O-linked glycosylation sites). For ease, the antigen binding
protein amino acid sequence is preferably altered through changes
at the DNA level, particularly by mutating the DNA encoding the
target polypeptide at preselected bases such that codons are
generated that will translate into the desired amino acids.
[0217] Another means of increasing the number of carbohydrate
moieties on the antigen binding protein is by chemical or enzymatic
coupling of glycosides to the protein. These procedures are
advantageous in that they do not require production of the protein
in a host cell that has glycosylation capabilities for N- and
O-linked glycosylation. Depending on the coupling mode used, the
sugar(s) may be attached to (a) arginine and histidine, (b) free
carboxyl groups, (c) free sulfhydryl groups such as those of
cysteine, (d) free hydroxyl groups such as those of serine,
threonine, or hydroxyproline, (e) aromatic residues such as those
of phenylalanine, tyrosine, or tryptophan, or (f) the amide group
of glutamine. These methods are described in WO 87/05330 published
Sep. 11, 1987, and in Aplin and Wriston, 1981, CRC Crit. Rev.
Biochem., pp. 259-306.
[0218] Removal of carbohydrate moieties present on the starting
antigen binding protein may be accomplished chemically or
enzymatically. Chemical deglycosylation requires exposure of the
protein to the compound trifluoromethanesulfonic acid, or an
equivalent compound. This treatment results in the cleavage of most
or all sugars except the linking sugar (N-acetylglucosamine or
N-acetylgalactosamine), while leaving the polypeptide intact.
Chemical deglycosylation is described by Hakimuddin et al., 1987,
Arch. Biochem. Biophys. 259:52 and by Edge et al., 1981, Anal.
Biochem. 118:131. Enzymatic cleavage of carbohydrate moieties on
polypeptides can be achieved by the use of a variety of endo- and
exo-glycosidases as described by Thotakura et al., 1987, Meth.
Enzymol. 138:350. Glycosylation at potential glycosylation sites
may be prevented by the use of the compound tunicamycin as
described by Duskin et al., 1982, J. Biol. Chem. 257:3105.
Tunicamycin blocks the formation of protein-N-glycoside
linkages.
[0219] Another type of covalent modification of the antigen binding
protein comprises linking the antigen binding protein to various
non-proteinaceous polymers, including, but not limited to, various
polyols such as polyethylene glycol, polypropylene glycol or
polyoxyalkylenes, in the manner set forth in U.S. Pat. Nos.
4,640,835; 4,496,689; 4,301,144; 4,670,417; 4,791,192 or 4,179,337.
In addition, as is known in the art, amino acid substitutions may
be made in various positions within the antigen binding protein to
facilitate the addition of polymers such as PEG.
[0220] In some embodiments, the covalent modification of the
antigen binding proteins of the invention comprises the addition of
one or more labels.
[0221] The term "labelling group" means any detectable label.
Examples of suitable labelling groups include, but are not limited
to, the following: radioisotopes or radionuclides (e.g., .sup.3H,
.sup.14C, .sup.15N, .sup.35S, .sup.90Y, .sup.99Tc, .sup.111In,
.sup.125I, .sup.131I), fluorescent groups (e.g., FITC, rhodamine,
lanthanide phosphors), enzymatic groups (e.g., horseradish
peroxidase, .beta.-galactosidase, luciferase, alkaline
phosphatase), chemiluminescent groups, biotinyl groups, or
predetermined polypeptide epitopes recognized by a secondary
reporter (e.g., leucine zipper pair sequences, binding sites for
secondary antibodies, metal binding domains, epitope tags). In some
embodiments, the labelling group is coupled to the antigen binding
protein via spacer arms of various lengths to reduce potential
steric hindrance. Various methods for labelling proteins are known
in the art and may be used in performing the present invention.
[0222] In general, labels fall into a variety of classes, depending
on the assay in which they are to be detected: a) isotopic labels,
which may be radioactive or heavy isotopes; b) magnetic labels
(e.g., magnetic particles); c) redox active moieties; d) optical
dyes; enzymatic groups (e.g. horseradish peroxidase,
.beta.-galactosidase, luciferase, alkaline phosphatase); e)
biotinylated groups; and f) predetermined polypeptide epitopes
recognized by a secondary reporter (e.g., leucine zipper pair
sequences, binding sites for secondary antibodies, metal binding
domains, epitope tags, etc.). In some embodiments, the labelling
group is coupled to the antigen binding protein via spacer arms of
various lengths to reduce potential steric hindrance. Various
methods for labelling proteins are known in the art and may be used
in performing the present invention.
[0223] Specific labels include optical dyes, including, but not
limited to, chromophores, phosphors and fluorophores, with the
latter being specific in many instances. Fluorophores can be either
"small molecule" fluores, or proteinaceous fluores.
[0224] By "fluorescent label" is meant any molecule that may be
detected via its inherent fluorescent properties. Suitable
fluorescent labels include, but are not limited to, fluorescein,
rhodamine, tetramethylrhodamine, eosin, erythrosin, coumarin,
methyl-coumarins, pyrene, Malacite green, stilbene, Lucifer Yellow,
Cascade BlueJ, Texas Red, IAEDANS, EDANS, BODIPY FL, LC Red 640, Cy
5, Cy 5.5, LC Red 705, Oregon green, the Alexa-Fluor dyes (Alexa
Fluor 350, Alexa Fluor 430, Alexa Fluor 488, Alexa Fluor 546, Alexa
Fluor 568, Alexa Fluor 594, Alexa Fluor 633, Alexa Fluor 660, Alexa
Fluor 680), Cascade Blue, Cascade Yellow and R-phycoerythrin (PE)
(Molecular Probes, Eugene, Oreg.), FITC, Rhodamine, and Texas Red
(Pierce, Rockford, Ill.), Cy5, Cy5.5, Cy7 (Amersham Life Science,
Pittsburgh, Pa.). Suitable optical dyes, including fluorophores,
are described in Molecular Probes Handbook by Richard P. Haugland,
hereby expressly incorporated by reference.
[0225] Suitable proteinaceous fluorescent labels also include, but
are not limited to, green fluorescent protein, including a Renilla,
Ptilosarcus, or Aequorea species of GFP (Chalfie et al., 1994,
Science 263:802-805), EGFP (Clontech Laboratories, Inc., Genbank
Accession Number U55762), blue fluorescent protein (BFP, Quantum
Biotechnologies, Inc. 1801 de Maisonneuve Blvd. West, 8th Floor,
Montreal, Quebec, Canada H3H 1J9; Stauber, 1998, Biotechniques
24:462-471; Heim et al., 1996, Curr. Biol. 6:178-182), enhanced
yellow fluorescent protein (EYFP, Clontech Laboratories, Inc.),
luciferase (Ichiki et al., 1993, J. Immunol. 150:5408-5417), .beta.
galactosidase (Nolan et al., 1988, Proc. Natl. Acad. Sci. U.S.A.
85:2603-2607) and Renilla (WO92/15673, WO95/07463, WO98/14605,
WO98/26277, WO99/49019, U.S. Pat. Nos. 5,292,658, 5,418,155,
5,683,888, 5,741,668, 5,777,079, 5,804,387, 5,874,304, 5,876,995,
5,925,558). All of the above-cited references are expressly
incorporated herein by reference.
[0226] As described in appended example 2 a broad number of CDH19
specific binder has been characterized with respect to identified
binding characteristics and those binders were grouped into five
different bins, which refers to five different subgroups of CDH19
specific binding domains. Accordingly, in one embodiment the human
antibody or antigen binding fragment thereof of the invention
comprises a human binding domain or antigen binding fragment
thereof comprising a VH region comprising CDR-H1, CDR-H2 and CDR-H3
and a VL region comprising CDR-L1, CDR-L2 and CDR-L3 selected from
the group consisting of: [0227] (a) CDR-H1 as depicted in SEQ ID
NO: 52, CDR-H2 as depicted in SEQ ID NO: 53, CDR-H3 as depicted in
SEQ ID NO: 54, CDR-L1 as depicted in SEQ ID NO: 220, CDR-L2 as
depicted in SEQ ID NO: 221 and CDR-L3 as depicted in SEQ ID NO:
222, CDR-H1 as depicted in SEQ ID NO: 82, CDR-H2 as depicted in SEQ
ID NO: 83, CDR-H3 as depicted in SEQ ID NO: 84, CDR-L1 as depicted
in SEQ ID NO: 250, CDR-L2 as depicted in SEQ ID NO: 251 and CDR-L3
as depicted in SEQ ID NO: 252, CDR-H1 as depicted in SEQ ID NO: 82,
CDR-H2 as depicted in SEQ ID NO: 83, CDR-H3 as depicted in SEQ ID
NO: 84, CDR-L1 as depicted in SEQ ID NO: 250, CDR-L2 as depicted in
SEQ ID NO: 251 and CDR-L3 as depicted in SEQ ID NO: 927, CDR-H1 as
depicted in SEQ ID NO: 82, CDR-H2 as depicted in SEQ ID NO: 83,
CDR-H3 as depicted in SEQ ID NO: 909, CDR-L1 as depicted in SEQ ID
NO: 250, CDR-L2 as depicted in SEQ ID NO: 251 and CDR-L3 as
depicted in SEQ ID NO: 927, CDR-H1 as depicted in SEQ ID NO: 52,
CDR-H2 as depicted in SEQ ID NO: 53, CDR-H3 as depicted in SEQ ID
NO: 54, CDR-L1 as depicted in SEQ ID NO: 220, CDR-L2 as depicted in
SEQ ID NO: 221 and CDR-L3 as depicted in SEQ ID NO: 926, and CDR-H1
as depicted in SEQ ID NO: 52, CDR-H2 as depicted in SEQ ID NO: 53,
CDR-H3 as depicted in SEQ ID NO: 904, CDR-L1 as depicted in SEQ ID
NO: 220, CDR-L2 as depicted in SEQ ID NO: 221 and CDR-L3 as
depicted in SEQ ID NO: 926; which all characterize binding domains
for CDH19 grouped into bin 1; [0228] (b) CDR-H1 as depicted in SEQ
ID NO: 124, CDR-H2 as depicted in SEQ ID NO: 125, CDR-H3 as
depicted in SEQ ID NO: 126, CDR-L1 as depicted in SEQ ID NO: 292,
CDR-L2 as depicted in SEQ ID NO: 293 and CDR-L3 as depicted in SEQ
ID NO: 294, CDR-H1 as depicted in SEQ ID NO: 130, CDR-H2 as
depicted in SEQ ID NO: 131, CDR-H3 as depicted in SEQ ID NO: 132,
CDR-L1 as depicted in SEQ ID NO: 298, CDR-L2 as depicted in SEQ ID
NO: 299 and CDR-L3 as depicted in SEQ ID NO: 300, CDR-H1 as
depicted in SEQ ID NO: 136, CDR-H2 as depicted in SEQ ID NO: 137,
CDR-H3 as depicted in SEQ ID NO: 138, CDR-L1 as depicted in SEQ ID
NO: 304, CDR-L2 as depicted in SEQ ID NO: 305 and CDR-L3 as
depicted in SEQ ID NO: 306, CDR-H1 as depicted in SEQ ID NO: 142,
CDR-H2 as depicted in SEQ ID NO: 143, CDR-H3 as depicted in SEQ ID
NO: 144, CDR-L1 as depicted in SEQ ID NO: 310, CDR-L2 as depicted
in SEQ ID NO: 311 and CDR-L3 as depicted in SEQ ID NO: 312, CDR-H1
as depicted in SEQ ID NO: 148, CDR-H2 as depicted in SEQ ID NO:
149, CDR-H3 as depicted in SEQ ID NO: 150, CDR-L1 as depicted in
SEQ ID NO: 316, CDR-L2 as depicted in SEQ ID NO: 317 and CDR-L3 as
depicted in SEQ ID NO: 318, CDR-H1 as depicted in SEQ ID NO: 166,
CDR-H2 as depicted in SEQ ID NO: 167, CDR-H3 as depicted in SEQ ID
NO: 168, CDR-L1 as depicted in SEQ ID NO: 334, CDR-L2 as depicted
in SEQ ID NO: 335 and CDR-L3 as depicted in SEQ ID NO: 336, CDR-H1
as depicted in SEQ ID NO: 124, CDR-H2 as depicted in SEQ ID NO:
125, CDR-H3 as depicted in SEQ ID NO: 915, CDR-L1 as depicted in
SEQ ID NO: 292, CDR-L2 as depicted in SEQ ID NO: 293 and CDR-L3 as
depicted in SEQ ID NO: 294, CDR-H1 as depicted in SEQ ID NO: 124,
CDR-H2 as depicted in SEQ ID NO: 125, CDR-H3 as depicted in SEQ ID
NO: 915, CDR-L1 as depicted in SEQ ID NO: 292, CDR-L2 as depicted
in SEQ ID NO: 293 and CDR-L3 as depicted in SEQ ID NO: 928, CDR-H1
as depicted in SEQ ID NO: 124, CDR-H2 as depicted in SEQ ID NO:
125, CDR-H3 as depicted in SEQ ID NO: 915, CDR-L1 as depicted in
SEQ ID NO: 292, CDR-L2 as depicted in SEQ ID NO: 293 and CDR-L3 as
depicted in SEQ ID NO: 929, CDR-H1 as depicted in SEQ ID NO: 166,
CDR-H2 as depicted in SEQ ID NO: 167, CDR-H3 as depicted in SEQ ID
NO: 168, CDR-L1 as depicted in SEQ ID NO: 334, CDR-L2 as depicted
in SEQ ID NO: 335 and CDR-L3 as depicted in SEQ ID NO: 336, CDR-H1
as depicted in SEQ ID NO: 166, CDR-H2 as depicted in SEQ ID NO:
167, CDR-H3 as depicted in SEQ ID NO: 168, CDR-L1 as depicted in
SEQ ID NO: 334, CDR-L2 as depicted in SEQ ID NO: 335 and CDR-L3 as
depicted in SEQ ID NO: 942, CDR-H1 as depicted in SEQ ID NO: 166,
CDR-H2 as depicted in SEQ ID NO: 167, CDR-H3 as depicted in SEQ ID
NO: 168, CDR-L1 as depicted in SEQ ID NO: 334, CDR-L2 as depicted
in SEQ ID NO: 335 and CDR-L3 as depicted in SEQ ID NO: 943, CDR-H1
as depicted in SEQ ID NO: 148, CDR-H2 as depicted in SEQ ID NO:
149, CDR-H3 as depicted in SEQ ID NO: 150, CDR-L1 as depicted in
SEQ ID NO: 316, CDR-L2 as depicted in SEQ ID NO: 317 and CDR-L3 as
depicted in SEQ ID NO: 318, CDR-H1 as depicted in SEQ ID NO: 148,
CDR-H2 as depicted in SEQ ID NO: 149, CDR-H3 as depicted in SEQ ID
NO: 150, CDR-L1 as depicted in SEQ ID NO: 316, CDR-L2 as depicted
in SEQ ID NO: 317 and CDR-L3 as depicted in SEQ ID NO: 937, CDR-H1
as depicted in SEQ ID NO: 148, CDR-H2 as depicted in SEQ ID NO:
149, CDR-H3 as depicted in SEQ ID NO: 150, CDR-L1 as depicted in
SEQ ID NO: 316, CDR-L2 as depicted in SEQ ID NO: 317 and CDR-L3 as
depicted in SEQ ID NO: 938, CDR-H1 as depicted in SEQ ID NO: 148,
CDR-H2 as depicted in SEQ ID NO: 149, CDR-H3 as depicted in SEQ ID
NO: 919, CDR-L1 as depicted in SEQ ID NO: 316, CDR-L2 as depicted
in SEQ ID NO: 317 and CDR-L3 as depicted in SEQ ID NO: 938, CDR-H1
as depicted in SEQ ID NO: 142, CDR-H2 as depicted in SEQ ID NO:
143, CDR-H3 as depicted in SEQ ID NO: 144, CDR-L1 as depicted in
SEQ ID NO: 310, CDR-L2 as depicted in SEQ ID NO: 311 and CDR-L3 as
depicted in SEQ ID NO: 935, CDR-H1 as depicted in SEQ ID NO: 142,
CDR-H2 as depicted in SEQ ID NO: 143, CDR-H3 as depicted in SEQ ID
NO: 918, CDR-L1 as depicted in SEQ ID NO: 310, CDR-L2 as depicted
in SEQ ID NO: 311 and CDR-L3 as depicted in SEQ ID NO: 935, CDR-H1
as depicted in SEQ ID NO: 142, CDR-H2 as depicted in SEQ ID NO:
143, CDR-H3 as depicted in SEQ ID NO: 918, CDR-L1 as depicted in
SEQ ID NO: 310, CDR-L2 as depicted in SEQ ID NO: 311 and CDR-L3 as
depicted in SEQ ID NO: 936, CDR-H1 as depicted in SEQ ID NO: 136,
CDR-H2 as depicted in SEQ ID NO: 137, CDR-H3 as depicted in SEQ ID
NO: 138, CDR-L1 as depicted in SEQ ID NO: 304, CDR-L2 as depicted
in SEQ ID NO: 305 and CDR-L3 as depicted in SEQ ID NO: 933, CDR-H1
as depicted in SEQ ID NO: 136, CDR-H2 as depicted in SEQ ID NO:
137, CDR-H3 as depicted in SEQ ID NO: 917, CDR-L1 as depicted in
SEQ ID NO: 304, CDR-L2 as depicted in SEQ ID NO: 305 and CDR-L3 as
depicted in SEQ ID NO: 934, CDR-H1 as depicted in SEQ ID NO: 130,
CDR-H2 as depicted in SEQ ID NO: 131, CDR-H3 as depicted in SEQ ID
NO: 132, CDR-L1 as depicted in SEQ ID NO: 298, CDR-L2 as depicted
in SEQ ID NO: 299 and CDR-L3 as depicted in SEQ ID NO: 930, CDR-H1
as depicted in SEQ ID NO: 130, CDR-H2 as depicted in SEQ ID NO:
131, CDR-H3 as depicted in SEQ ID NO: 916, CDR-L1 as depicted in
SEQ ID NO: 298, CDR-L2 as depicted in SEQ ID NO: 299 and CDR-L3 as
depicted in SEQ ID NO: 931, and CDR-H1 as depicted in SEQ ID NO:
130, CDR-H2 as depicted in SEQ ID NO: 131, CDR-H3 as depicted in
SEQ ID NO: 916, CDR-L1 as depicted in SEQ ID NO: 298, CDR-L2 as
depicted in SEQ ID NO: 299 and CDR-L3 as depicted in SEQ ID NO:
932; which all characterize binding domains for CDH19 grouped into
bin 2; [0229] (c) CDR-H1 as depicted in SEQ ID NO: 94, CDR-H2 as
depicted in SEQ ID NO: 95, CDR-H3 as depicted in SEQ ID NO: 96,
CDR-L1 as depicted in SEQ ID NO: 262, CDR-L2 as depicted in SEQ ID
NO: 263 and CDR-L3 as depicted in SEQ ID NO: 264, CDR-H1 as
depicted in SEQ ID NO: 100, CDR-H2 as depicted in SEQ ID NO: 101,
CDR-H3 as depicted in SEQ ID NO: 102, CDR-L1 as depicted in SEQ ID
NO: 268, CDR-L2 as depicted in SEQ ID NO: 269 and CDR-L3 as
depicted in SEQ ID NO: 270, CDR-H1 as depicted in SEQ ID NO: 118,
CDR-H2 as depicted in SEQ ID NO: 119, CDR-H3 as depicted in SEQ ID
NO: 120, CDR-L1 as depicted in SEQ ID NO: 286, CDR-L2 as depicted
in SEQ ID NO: 287 and CDR-L3 as depicted in SEQ ID NO: 288, CDR-H1
as depicted in SEQ ID NO: 154, CDR-H2 as depicted in SEQ ID NO:
155, CDR-H3 as depicted in SEQ ID NO: 156, CDR-L1 as depicted in
SEQ ID NO: 322, CDR-L2 as depicted in SEQ ID NO: 323 and CDR-L3 as
depicted in SEQ ID NO: 324, CDR-H1 as depicted in SEQ ID NO: 100,
CDR-H2 as depicted in SEQ ID NO: 101, CDR-H3 as depicted in SEQ ID
NO: 912, CDR-L1 as depicted in SEQ ID NO: 268, CDR-L2 as depicted
in SEQ ID NO: 269 and CDR-L3 as depicted in SEQ ID NO: 270, CDR-H1
as depicted in SEQ ID NO: 100, CDR-H2 as depicted in SEQ ID NO:
101, CDR-H3 as depicted in SEQ ID NO: 913, CDR-L1 as depicted in
SEQ ID NO: 268, CDR-L2 as depicted in SEQ ID NO: 269 and CDR-L3 as
depicted in SEQ ID NO: 270, CDR-H1 as depicted in SEQ ID NO: 94,
CDR-H2 as depicted in SEQ ID NO: 95, CDR-H3 as depicted in SEQ ID
NO: 910, CDR-L1 as depicted in SEQ ID NO: 262, CDR-L2 as depicted
in SEQ ID NO: 263 and CDR-L3 as depicted in SEQ ID NO: 264, CDR-H1
as depicted in SEQ ID NO: 94, CDR-H2 as depicted in SEQ ID NO: 95,
CDR-H3 as depicted in SEQ ID NO: 911, CDR-L1 as depicted in SEQ ID
NO: 262, CDR-L2 as depicted in SEQ ID NO: 263 and CDR-L3 as
depicted in SEQ ID NO: 264, CDR-H1 as depicted in SEQ ID NO: 118,
CDR-H2 as depicted in SEQ ID NO: 119, CDR-H3 as depicted in SEQ ID
NO: 120, CDR-L1 as depicted in SEQ ID NO: 286, CDR-L2 as depicted
in SEQ ID NO: 287 and CDR-L3 as depicted in SEQ ID NO: 288, CDR-H1
as depicted in SEQ ID NO: 118, CDR-H2 as depicted in SEQ ID NO:
914, CDR-H3 as depicted in SEQ ID NO: 120, CDR-L1 as depicted in
SEQ ID NO: 286, CDR-L2 as depicted in SEQ ID NO: 287 and CDR-L3 as
depicted in SEQ ID NO: 288, and CDR-H1 as depicted in SEQ ID NO:
154, CDR-H2 as depicted in SEQ ID NO: 155, CDR-H3 as depicted in
SEQ ID NO: 920, CDR-L1 as depicted in SEQ ID NO: 322, CDR-L2 as
depicted in SEQ ID NO: 323 and CDR-L3 as depicted in SEQ ID NO:
324; which all characterize binding domains for CDH19 grouped into
bin 3; [0230] (d) CDR-H1 as depicted in SEQ ID NO: 4, CDR-H2 as
depicted in SEQ ID NO: 5, CDR-H3 as depicted in SEQ ID NO: 6,
CDR-L1 as depicted in SEQ ID NO: 172, CDR-L2 as depicted in SEQ ID
NO: 173 and CDR-L3 as depicted in SEQ ID NO: 174, CDR-H1 as
depicted in SEQ ID NO: 10, CDR-H2 as depicted in SEQ ID NO: 11,
CDR-H3 as depicted in SEQ ID NO: 12, CDR-L1 as depicted in SEQ ID
NO: 178, CDR-L2 as depicted in SEQ ID NO: 179 and CDR-L3 as
depicted in SEQ ID NO: 180, CDR-H1 as depicted in SEQ ID NO: 28,
CDR-H2 as depicted in SEQ ID NO: 29, CDR-H3 as depicted in SEQ ID
NO: 30, CDR-L1 as depicted in SEQ ID NO: 196, CDR-L2 as depicted in
SEQ ID NO: 197 and CDR-L3 as depicted in SEQ ID NO: 198, CDR-H1 as
depicted in SEQ ID NO: 34, CDR-H2 as depicted in SEQ ID NO: 35,
CDR-H3 as depicted in SEQ ID NO: 36, CDR-L1 as depicted in SEQ ID
NO: 202, CDR-L2 as depicted in SEQ ID NO: 203 and CDR-L3 as
depicted in SEQ ID NO: 204, CDR-H1 as depicted in SEQ ID NO: 46,
CDR-H2 as depicted in SEQ ID NO: 47, CDR-H3 as depicted in SEQ ID
NO: 48, CDR-L1 as depicted in SEQ ID NO: 214, CDR-L2 as depicted in
SEQ ID NO: 215 and CDR-L3 as depicted in SEQ ID NO: 216, CDR-H1 as
depicted in SEQ ID NO: 58, CDR-H2 as depicted in SEQ ID NO: 59,
CDR-H3 as depicted in SEQ ID NO: 60, CDR-L1 as depicted in SEQ ID
NO: 226, CDR-L2 as depicted in SEQ ID NO: 227 and CDR-L3 as
depicted in SEQ ID NO: 228, CDR-H1 as depicted in SEQ ID NO: 64,
CDR-H2 as depicted in SEQ ID NO: 65, CDR-H3 as depicted in SEQ ID
NO: 66, CDR-L1 as depicted in SEQ ID NO: 232, CDR-L2 as depicted in
SEQ ID NO: 233 and CDR-L3 as depicted in SEQ ID NO: 234, CDR-H1 as
depicted in SEQ ID NO: 70, CDR-H2 as depicted in SEQ ID NO: 71,
CDR-H3 as depicted in SEQ ID NO: 72, CDR-L1 as depicted in SEQ ID
NO: 238, CDR-L2 as depicted in SEQ ID NO: 239 and CDR-L3 as
depicted in SEQ ID NO: 240, CDR-H1 as depicted in SEQ ID NO: 160,
CDR-H2 as depicted in SEQ ID NO: 161, CDR-H3 as depicted in SEQ ID
NO: 162, CDR-L1 as depicted in SEQ ID NO: 328, CDR-L2 as depicted
in SEQ ID NO: 329 and CDR-L3 as depicted in SEQ ID NO: 330, CDR-H1
as depicted in SEQ ID NO: 46, CDR-H2 as depicted in SEQ ID NO: 47,
CDR-H3 as depicted in SEQ ID NO: 48, CDR-L1 as depicted in SEQ ID
NO: 924, CDR-L2 as depicted in SEQ ID NO: 215 and CDR-L3 as
depicted in SEQ ID NO: 216, CDR-H1 as depicted in SEQ ID NO: 46,
CDR-H2 as depicted in SEQ ID NO: 47, CDR-H3 as depicted in SEQ ID
NO: 902, CDR-L1 as depicted in SEQ ID NO: 924, CDR-L2 as depicted
in SEQ ID NO: 215 and CDR-L3 as depicted in SEQ ID NO: 216, CDR-H1
as depicted in SEQ ID NO: 46, CDR-H2 as depicted in SEQ ID NO: 47,
CDR-H3 as depicted in SEQ ID NO: 903, CDR-L1 as depicted in SEQ ID
NO: 924, CDR-L2 as depicted in SEQ ID NO: 215 and CDR-L3 as
depicted in SEQ ID NO: 216, CDR-H1 as depicted in SEQ ID NO: 46,
CDR-H2 as depicted in SEQ ID NO: 47, CDR-H3 as depicted in SEQ ID
NO: 48, CDR-L1 as depicted in SEQ ID NO: 925, CDR-L2 as depicted in
SEQ ID NO: 215 and CDR-L3 as depicted in SEQ ID NO: 216, CDR-H1 as
depicted in SEQ ID NO: 70, CDR-H2 as depicted in SEQ ID NO: 907,
CDR-H3 as depicted in SEQ ID NO: 72, CDR-L1 as depicted in SEQ ID
NO: 238, CDR-L2 as depicted in SEQ ID NO: 239 and CDR-L3 as
depicted in SEQ ID NO: 240, CDR-H1 as depicted in SEQ ID NO: 70,
CDR-H2 as depicted in SEQ ID NO: 907, CDR-H3 as depicted in SEQ ID
NO: 908, CDR-L1 as depicted in SEQ ID NO: 238, CDR-L2 as depicted
in SEQ ID NO: 239 and CDR-L3 as depicted in SEQ ID NO: 240, CDR-H1
as depicted in SEQ ID NO: 28, CDR-H2 as depicted in SEQ ID NO: 901,
CDR-H3 as depicted in SEQ ID NO: 30, CDR-L1 as depicted in SEQ ID
NO: 922, CDR-L2 as depicted in SEQ ID NO: 197 and CDR-L3 as
depicted in SEQ ID NO: 923, CDR-H1 as depicted in SEQ ID NO: 58,
CDR-H2 as depicted in SEQ ID NO: 905, CDR-H3 as depicted in SEQ ID
NO: 906, CDR-L1 as depicted in SEQ ID NO: 226, CDR-L2 as depicted
in SEQ ID NO: 227 and CDR-L3 as depicted in SEQ ID NO: 228, CDR-H1
as depicted in SEQ ID NO: 58, CDR-H2 as depicted in SEQ ID NO: 905,
CDR-H3 as depicted in SEQ ID NO: 60, CDR-L1 as depicted in SEQ ID
NO: 226, CDR-L2 as depicted in SEQ ID NO: 227 and CDR-L3 as
depicted in SEQ ID NO: 228, CDR-H1 as depicted in SEQ ID NO: 160,
CDR-H2 as depicted in SEQ ID NO: 161, CDR-H3 as depicted in SEQ ID
NO: 162, CDR-L1 as depicted in SEQ ID NO: 939, CDR-L2 as depicted
in SEQ ID NO: 329 and CDR-L3 as depicted in SEQ ID NO: 330, CDR-H1
as depicted in SEQ ID NO: 160, CDR-H2 as depicted in SEQ ID NO:
921, CDR-H3 as depicted in SEQ ID NO: 162, CDR-L1 as depicted in
SEQ ID NO: 939, CDR-L2 as depicted in SEQ ID NO: 329 and CDR-L3 as
depicted in SEQ ID NO: 940, CDR-H1 as depicted in SEQ ID NO: 160,
CDR-H2 as depicted in SEQ ID NO: 161, CDR-H3 as depicted in SEQ ID
NO: 162, CDR-L1 as depicted in SEQ ID NO: 941, CDR-L2 as depicted
in SEQ ID NO: 329 and CDR-L3 as depicted in SEQ ID NO: 330, CDR-H1
as depicted in SEQ ID NO: 28, CDR-H2 as depicted in SEQ ID NO: 29,
CDR-H3 as depicted in SEQ ID NO: 30, CDR-L1 as depicted in SEQ ID
NO: 196, CDR-L2 as depicted in SEQ ID NO: 197 and CDR-L3 as
depicted in SEQ ID NO: 923, CDR-H1 as depicted in SEQ ID NO: 28,
CDR-H2 as depicted in SEQ ID NO: 29, CDR-H3 as depicted in SEQ ID
NO: 30, CDR-L1 as depicted in SEQ ID NO: 922, CDR-L2 as depicted in
SEQ ID NO: 197 and CDR-L3 as depicted in SEQ ID NO: 923, CDR-H1 as
depicted in SEQ ID NO: 28, CDR-H2 as depicted in SEQ ID NO: 901,
CDR-H3 as depicted in SEQ ID NO: 30, CDR-L1 as depicted in SEQ ID
NO: 922, CDR-L2 as depicted in SEQ ID NO: 197 and CDR-L3 as
depicted in SEQ ID NO: 923, and
CDR-H1 as depicted in SEQ ID NO: 28, CDR-H2 as depicted in SEQ ID
NO: 29, CDR-H3 as depicted in SEQ ID NO: 30, CDR-L1 as depicted in
SEQ ID NO: 939, CDR-L2 as depicted in SEQ ID NO: 329 and CDR-L3 as
depicted in SEQ ID NO: 330; which all characterize binding domains
for CDH19 grouped into bin 4; and [0231] (e) CDR-H1 as depicted in
SEQ ID NO: 76, CDR-H2 as depicted in SEQ ID NO: 77, CDR-H3 as
depicted in SEQ ID NO: 78, CDR-L1 as depicted in SEQ ID NO: 244,
CDR-L2 as depicted in SEQ ID NO: 245 and CDR-L3 as depicted in SEQ
ID NO: 246, CDR-H1 as depicted in SEQ ID NO: 88, CDR-H2 as depicted
in SEQ ID NO: 89, CDR-H3 as depicted in SEQ ID NO: 90, CDR-L1 as
depicted in SEQ ID NO: 256, CDR-L2 as depicted in SEQ ID NO: 257
and CDR-L3 as depicted in SEQ ID NO: 258, CDR-H1 as depicted in SEQ
ID NO: 106, CDR-H2 as depicted in SEQ ID NO: 107, CDR-H3 as
depicted in SEQ ID NO: 108, CDR-L1 as depicted in SEQ ID NO: 274,
CDR-L2 as depicted in SEQ ID NO: 275 and CDR-L3 as depicted in SEQ
ID NO: 276, CDR-H1 as depicted in SEQ ID NO: 112, CDR-H2 as
depicted in SEQ ID NO: 113, CDR-H3 as depicted in SEQ ID NO: 114,
CDR-L1 as depicted in SEQ ID NO: 280, CDR-L2 as depicted in SEQ ID
NO: 281 and CDR-L3 as depicted in SEQ ID NO: 282, and CDR-H1 as
depicted in SEQ ID NO: 106, CDR-H2 as depicted in SEQ ID NO: 107,
CDR-H3 as depicted in SEQ ID NO: 108, CDR-L1 as depicted in SEQ ID
NO: 274, CDR-L2 as depicted in SEQ ID NO: 275 and CDR-L3 as
depicted in SEQ ID NO: 276 which all characterize binding domains
for CDH19 grouped into bin 5;
[0232] In a further embodiment of the human antibody or antigen
binding fragment thereof of the invention the human binding domain
or antigen binding fragment thereof comprises a VH region selected
from the group consisting of VH regions [0233] (a) as depicted in
SEQ ID NO: 362, SEQ ID NO: 364, SEQ ID NO: 485, SEQ ID NO: 486, SEQ
ID NO: 487, SEQ ID NO: 492, SEQ ID NO: 493, SEQ ID NO: 494, and SEQ
ID NO: 495; [0234] which all characterize binding domains for CDH19
grouped into bin 1; [0235] (b) as depicted in SEQ ID NO: 342, SEQ
ID NO: 366, SEQ ID NO: 370, SEQ ID NO: 344, SEQ ID NO: 372, SEQ ID
NO: 368, SEQ ID NO: 496, SEQ ID NO: 497, SEQ ID NO: 498, SEQ ID NO:
499, SEQ ID NO: 500, SEQ ID NO: 508, SEQ ID NO: 509, SEQ ID NO:
510, SEQ ID NO: 511, SEQ ID NO: 512, SEQ ID NO: 519, SEQ ID NO:
520, SEQ ID NO: 521, SEQ ID NO: 522, SEQ ID NO: 523, SEQ ID NO:
524, SEQ ID NO: 525, SEQ ID NO: 526, SEQ ID NO: 527, SEQ ID NO:
528, SEQ ID NO: 529, SEQ ID NO: 530, SEQ ID NO: 531, SEQ ID NO:
532, SEQ ID NO: 533, SEQ ID NO: 534, SEQ ID NO: 535, SEQ ID NO:
536, SEQ ID NO: 537, and SEQ ID NO: 538; [0236] which all
characterize binding domains for CDH19 grouped into bin 2; [0237]
(c) as depicted in SEQ ID NO: 338, SEQ ID NO: 354, SEQ ID NO: 378,
SEQ ID NO: 356, SEQ ID NO: 476, SEQ ID NO: 477, SEQ ID NO: 478, SEQ
ID NO: 479, SEQ ID NO: 480, SEQ ID NO: 481, SEQ ID NO: 482, SEQ ID
NO: 483, SEQ ID NO: 484, SEQ ID NO: 501, SEQ ID NO: 502, SEQ ID NO:
503, SEQ ID NO: 504, SEQ ID NO: 505, SEQ ID NO: 506, SEQ ID NO:
517, and SEQ ID NO: 518; [0238] which all characterize binding
domains for CDH19 grouped into bin 3; [0239] (d) as depicted in SEQ
ID NO: 352, SEQ ID NO: 360, SEQ ID NO: 388, SEQ ID NO: 386, SEQ ID
NO: 340, SEQ ID NO: 346, SEQ ID NO: 374, SEQ ID NO: 348, SEQ ID NO:
390, SEQ ID NO: 463, SEQ ID NO: 464, SEQ ID NO: 465, SEQ ID NO:
466, SEQ ID NO: 467, SEQ ID NO: 468, SEQ ID NO: 469, SEQ ID NO:
470, SEQ ID NO: 471, SEQ ID NO: 472, SEQ ID NO: 473, SEQ ID NO:
474, SEQ ID NO: 475, SEQ ID NO: 488, SEQ ID NO: 489, SEQ ID NO:
490, SEQ ID NO: 491, SEQ ID NO: 513, SEQ ID NO: 514, SEQ ID NO:
515, SEQ ID NO: 516, SEQ ID NO: 540, SEQ ID NO: 541, SEQ ID NO:
542, and SEQ ID NO: 543; [0240] which all characterize binding
domains for CDH19 grouped into bin 4; and [0241] (e) as depicted in
SEQ ID NO: 376, SEQ ID NO: 392, SEQ ID NO: 358, SEQ ID NO: 350, and
SEQ ID NO: 507; [0242] which all characterize binding domains for
CDH19 grouped into bin 5.
[0243] In another embodiment the human antibody or antigen binding
fragment thereof of the invention comprises the human binding
domain or antigen binding fragment thereof comprising a VL region
selected from the group consisting of VL regions [0244] (a) as
depicted in SEQ ID NO: 418, SEQ ID NO: 420, SEQ ID NO: 580, SEQ ID
NO: 581, SEQ ID NO: 582, SEQ ID NO: 587, SEQ ID NO: 588, SEQ ID NO:
589, and SEQ ID NO: 590; [0245] which all characterize binding
domains for CDH19 grouped into bin 1; [0246] (b) as depicted in SEQ
ID NO: 398, SEQ ID NO: 422, SEQ ID NO: 426, SEQ ID NO: 400, SEQ ID
NO: 428, SEQ ID NO: 424, SEQ ID NO: 591, SEQ ID NO: 592, SEQ ID NO:
593, SEQ ID NO: 594, SEQ ID NO: 595, SEQ ID NO: 603, SEQ ID NO:
604, SEQ ID NO: 605, SEQ ID NO: 606, SEQ ID NO: 607, SEQ ID NO:
614, SEQ ID NO: 615, SEQ ID NO: 616, SEQ ID NO: 617, SEQ ID NO:
618, SEQ ID NO: 619, SEQ ID NO: 620, SEQ ID NO: 621, SEQ ID NO:
622, SEQ ID NO: 623, SEQ ID NO: 624, SEQ ID NO: 625, SEQ ID NO:
626, SEQ ID NO: 627, SEQ ID NO: 628, SEQ ID NO: 629, SEQ ID NO:
630, SEQ ID NO: 631, SEQ ID NO: 632, and SEQ ID NO: 633; [0247]
which all characterize binding domains for CDH19 grouped into bin
2; [0248] (c) as depicted in SEQ ID NO: 394, SEQ ID NO: 410, SEQ ID
NO: 434, SEQ ID NO: 412, SEQ ID NO: 571, SEQ ID NO: 572, SEQ ID NO:
573, SEQ ID NO: 574, SEQ ID NO: 575, SEQ ID NO: 576, SEQ ID NO:
577, SEQ ID NO: 578, SEQ ID NO: 579, SEQ ID NO: 596, SEQ ID NO:
597, SEQ ID NO: 598, SEQ ID NO: 599, SEQ ID NO: 600, SEQ ID NO:
601, SEQ ID NO: 612, and SEQ ID NO: 613; [0249] which all
characterize binding domains for CDH19 grouped into bin 3; [0250]
(d) as depicted in SEQ ID NO: 408, SEQ ID NO: 416, SEQ ID NO: 444,
SEQ ID NO: 442, SEQ ID NO: 396, SEQ ID NO: 402, SEQ ID NO: 430, SEQ
ID NO: 404, SEQ ID NO: 446, SEQ ID NO: 558, SEQ ID NO: 559, SEQ ID
NO: 560, SEQ ID NO: 561, SEQ ID NO: 562, SEQ ID NO: 563, SEQ ID NO:
564, SEQ ID NO: 565, SEQ ID NO: 566, SEQ ID NO: 567, SEQ ID NO:
568, SEQ ID NO: 569, SEQ ID NO: 570, SEQ ID NO: 583, SEQ ID NO:
584, SEQ ID NO: 585, SEQ ID NO: 586, SEQ ID NO: 608, SEQ ID NO:
609, SEQ ID NO: 610, SEQ ID NO: 611, SEQ ID NO: 635, SEQ ID NO:
636, SEQ ID NO: 637, and SEQ ID NO: 638; [0251] which all
characterize binding domains for CDH19 grouped into bin 4; and
[0252] (e) as depicted in SEQ ID NO: 432, SEQ ID NO: 448, SEQ ID
NO: 414, SEQ ID NO: 406, and SEQ ID NO: 602; [0253] which all
characterize binding domains for CDH19 grouped into bin 5.
[0254] The invention further provides an embodiment of the human
antibody or antigen binding fragment thereof of the invention,
wherein the human binding domain or antigen binding fragment
thereof comprises a VH region and a VL region selected from the
group consisting of: [0255] (1) pairs of a VH region and a VL
region as depicted in SEQ ID NOs: 362+418, SEQ ID NOs: 364+420, SEQ
ID NOs: 485+580, SEQ ID NOs: 486+581, SEQ ID NOs: 487+582, SEQ ID
NOs: 492+587, SEQ ID NOs: 493+588, SEQ ID NOs: 494+589, and SEQ ID
NOs: 495+590; [0256] all pairs grouped into bin 1; [0257] (2) pairs
of a VH region and a VL region as depicted in SEQ ID NOs: 342+398,
SEQ ID NOs: 366+422, SEQ ID NOs: 370+426, SEQ ID NOs: 344+400, SEQ
ID NOs: 372+428, SEQ ID NOs: 368+424, SEQ ID NOs: 496+591, SEQ ID
NOs: 497+592, SEQ ID NOs: 498+593, SEQ ID NOs: 499+594, SEQ ID NOs:
500+595, SEQ ID NOs: 508+603, SEQ ID NOs: 509+604, SEQ ID NOs:
510+605, SEQ ID NOs: 511+606, SEQ ID NOs: 512+607, SEQ ID NOs:
519+614, SEQ ID NOs: 520+615, SEQ ID NOs: 521+616, SEQ ID NOs:
522+617, SEQ ID NOs: 523+618, SEQ ID NOs: 524+619, SEQ ID NOs:
525+620, SEQ ID NOs: 526+621, SEQ ID NOs: 527+622, SEQ ID NOs:
528+623, SEQ ID NOs: 529+624, SEQ ID NOs: 530+625, SEQ ID NOs:
531+626, SEQ ID NOs: 532+627, SEQ ID NOs: 533+628, SEQ ID NOs:
534+629, SEQ ID NOs: 535+630, SEQ ID NOs: 536+631, SEQ ID NOs:
537+632, and SEQ ID NOs: 538+633; [0258] all pairs grouped into bin
2; [0259] (3) pairs of a VH region and a VL region as depicted in
SEQ ID NOs: 338+394, SEQ ID NOs: 354+410, SEQ ID NOs: 378+434, SEQ
ID NOs: 356+412, SEQ ID NOs: 476+571, SEQ ID NOs: 477+572, SEQ ID
NOs: 478+573, SEQ ID NOs: 479+574, SEQ ID NOs: 480+575, SEQ ID NOs:
481+576, SEQ ID NOs: 482+577, SEQ ID NOs: 483+578, SEQ ID NOs:
484+579, SEQ ID NOs: 501+596, SEQ ID NOs: 502+597, SEQ ID NOs:
503+598, SEQ ID NOs: 504+599, SEQ ID NOs: 505+600, SEQ ID NOs:
506+601, SEQ ID NOs: 517+612, and SEQ ID NOs: 518+613; [0260] all
pairs grouped into bin 3; [0261] (4) pairs of a VH region and a VL
region as depicted in SEQ ID NOs: 352+408, SEQ ID NOs: 360+416, SEQ
ID NOs: 388+444, SEQ ID NOs: 386+442, SEQ ID NOs: 340+396, SEQ ID
NOs: 346+402, SEQ ID NOs: 374+430, SEQ ID NOs: 348+404, SEQ ID NOs:
390+446, SEQ ID NOs: 463+558, SEQ ID NOs: 464+559, SEQ ID NOs:
465+560, SEQ ID NOs: 466+561, SEQ ID NOs: 467+562, SEQ ID NOs:
468+563, SEQ ID NOs: 469+564, SEQ ID NOs: 470+565, SEQ ID NOs:
471+566, SEQ ID NOs: 472+567, SEQ ID NOs: 473+568, SEQ ID NOs:
474+569, SEQ ID NOs: 475+570, SEQ ID NOs: 488+583, SEQ ID NOs:
489+584, SEQ ID NOs: 490+585, SEQ ID NOs: 491+586, SEQ ID NOs:
513+608, SEQ ID NOs: 514+609, SEQ ID NOs: 515+610, SEQ ID NOs:
516+611, SEQ ID NOs: 540+635, SEQ ID NOs: 541+636, SEQ ID NOs:
542+637, and SEQ ID NOs: 543+638; [0262] all pairs grouped into bin
4; and [0263] (5) pairs of a VH region and a VL region as depicted
in SEQ ID NOs: 376+432, SEQ ID NOs: 392+448, SEQ ID NOs: 358+414,
SEQ ID NOs: 350+406, and SEQ ID NOs: 507+602; [0264] all pairs
grouped into bin 5.
[0265] In a further embodiment the human binding domain or antigen
binding fragment thereof comprises the groups of heavy and light
chains having an amino acid sequence selected from the group
consisting of [0266] (1) a heavy and light chain as depicted in SEQ
ID NOs: 644+680, SEQ ID NOs: 650+686, SEQ ID NOs: 747+842, SEQ ID
NOs: 748+843, SEQ ID NOs: 749+844, SEQ ID NOs: 754+849, SEQ ID NOs:
755+850, SEQ ID NOs: 756+851, and SEQ ID NOs: 757+852; [0267] all
pairs grouped into bin 1; [0268] (2) a heavy and light chain as
depicted in SEQ ID NOs: 660+696, SEQ ID NOs: 662+698, SEQ ID NOs:
668+704, SEQ ID NOs: 674+710, SEQ ID NOs: 672+708, SEQ ID NOs:
658+694, SEQ ID NOs: 758+853, SEQ ID NOs: 759+854, SEQ ID NOs:
760+855, SEQ ID NOs: 761+856, SEQ ID NOs: 762+857, SEQ ID NOs:
770+865, SEQ ID NOs: 771+866, SEQ ID NOs: 772+867, SEQ ID NOs:
773+868, SEQ ID NOs: 774+869, SEQ ID NOs: 781+876, SEQ ID NOs:
782+877, SEQ ID NOs: 783+878, SEQ ID NOs: 784+879, SEQ ID NOs:
785+880, SEQ ID NOs: 786+881, SEQ ID NOs: 787+882, SEQ ID NOs:
788+883, SEQ ID NOs: 789+884, SEQ ID NOs: 790+885, SEQ ID NOs:
791+886, SEQ ID NOs: 792+887, SEQ ID NOs: 793+888, SEQ ID NOs:
794+889, SEQ ID NOs: 795+890, SEQ ID NOs: 796+891, SEQ ID NOs:
797+892, SEQ ID NOs: 798+893, SEQ ID NOs: 799+894, and SEQ ID NOs:
800+895; [0269] all pairs grouped into bin 2; [0270] (3) a a heavy
and light chain as depicted in SEQ ID NOs: 656+692, SEQ ID NOs:
654+690, SEQ ID NOs: 664+700, SEQ ID NOs: 670+706, SEQ ID NOs:
738+833, SEQ ID NOs: 739+834, SEQ ID NOs: 740+835, SEQ ID NOs:
741+836, SEQ ID NOs: 742+837, SEQ ID NOs: 743+838, SEQ ID NOs:
744+839, SEQ ID NOs: 745+840, SEQ ID NOs: 746+841, SEQ ID NOs:
763+858, SEQ ID NOs: 764+859, SEQ ID NOs: 765+860, SEQ ID NOs:
766+861, SEQ ID NOs: 767+862, SEQ ID NOs: 768+863, SEQ ID NOs:
779+874, and SEQ ID NOs: 780+875; [0271] all pairs grouped into bin
3; [0272] (4) a heavy and light chain as depicted in SEQ ID NOs:
640+676, SEQ ID NOs: 642+678, SEQ ID NOs: 646+682, SEQ ID NOs:
648+684, SEQ ID NOs: 666+702, SEQ ID NOs: 725+820, SEQ ID NOs:
726+821, SEQ ID NOs: 727+822, SEQ ID NOs: 728+823, SEQ ID NOs:
729+824, SEQ ID NOs: 730+825, SEQ ID NOs: 731+826, SEQ ID NOs:
732+827, SEQ ID NOs: 733+828, SEQ ID NOs: 734+829, SEQ ID NOs:
735+830, SEQ ID NOs: 736+831, SEQ ID NOs: 737+832, SEQ ID NOs:
750+845, SEQ ID NOs: 751+846, SEQ ID NOs: 752+847, SEQ ID NOs:
753+848, SEQ ID NOs: 775+870, SEQ ID NOs: 776+871, SEQ ID NOs:
777+872, SEQ ID NOs: 778+873, SEQ ID NOs: 802+897, SEQ ID NOs:
803+898, SEQ ID NOs: 804+899, and SEQ ID NOs: 805+900; [0273] all
pairs grouped into bin 4; and [0274] (5) a heavy and light chain as
depicted in SEQ ID NOs: 652+688, and SEQ ID NOs: 769+864 all pairs
grouped into bin 5.
[0275] In another embodiment the invention is directed to an
antibody construct comprising the human antibody or antigen binding
fragment thereof capable of binding to human CDH19 on the surface
of a target cell as described above that is conjugated to a
chemotherapeutic agent.
[0276] In one embodiment of the antibody construct of the invention
a linker conjugates the chemotherapeutic agent to the human
antibody or antigen binding fragment thereof. Accordingly,
embodiments of the antibody construct comprising of the invention
include antibody drug conjugates (ADCs). Generally the antibody
construct comprising of the invention comprises an antibody
conjugated to a chemotherapeutic agent, e.g., a cytotoxic agent, a
cytostatic agent, a toxin, or a radioactive agent. A linker
molecule can be used to conjugate the drug to the antibody. A wide
variety of linkers and drugs useful e.g. in ADC technology are
known in the art and may be used in embodiments of the present
invention. (See US20090028856; US2009/0274713; US2007/0031402;
WO2005/084390; WO2009/099728; U.S. Pat. Nos. 5,208,020; 5,416,064;
5,475,092; 5,585,499; 6,436,931; 6,372,738; and 6,340,701, all
incorporated herein by reference).
[0277] In certain embodiments, the antibody construct comprising of
the invention comprises a linker made up of one or more linker
components. Exemplary linker components include 6-maleimidocaproyl,
maleimidopropanoyl, valine-citrulline, alanine-phenylalanine,
p-aminobenzyloxycarbonyl, and those resulting from conjugation with
linker reagents, including, but not limited to, N-succinimidyl
4-(2-pyridylthio) pentanoate ("SPP"), N-succinimidyl
4-(N-maleimidomethyl) cyclohexane-1 carboxylate ("SMCC," also
referred to herein also as "MCC"), and N-succinimidyl
(4-iodo-acetyl) aminobenzoate ("SIAB"). Linkers may be a
"cleavable" linker or a "non-cleavable" linker (Ducry and Stump,
Bioconjugate Chem. 2010, 21, 5-13; incorporated herein by reference
in its entirety) Cleavable linkers are designed to release the drug
when subjected to certain environment factors, e.g., when
internalized into the target cell. Cleavable linkers include acid
labile linkers, protease sensitive linkers, photolabile linkers,
dimethyl linker or disulfide-containing linkers. Non-cleavable
linkers tend to remain covalently associated with at least one
amino acid of the antibody and the drug upon internalization by and
degradation within the target cell. An exemplary non-cleavable
linker is MCC.
[0278] In a preferred embodiment of the antibody construct of the
invention the linker is a non-cleavable linker.
[0279] It is also preferred that the linker in the antibody
construct of the invention comprises MCC.
[0280] In a further embodiment of the antibody construct of the
invention the chemotherapeutic agent is conjugated to one or more
lysines contained in the human antibody or antigen binding fragment
thereof.
[0281] In certain embodiments, the antibody of the invention is
conjugated to a chemotherapeutic agent. Examples of
chemotherapeutic agents include alkylating agents, such as thiotepa
and cyclophosphamide (CYTOXAN.TM.); alkyl sulfonates such as
busulfan, improsulfan and piposulfan; aziridines, such as
benzodopa, carboquone, meturedopa, and uredopa; ethylenimines and
methylamelamines including altretamine, triethylenemelamine,
trietylenephosphoramide, triethylenethiophosphaoramide and
trimethylolomelamine; acetogenins (especially bullatacin and
bullatacinone); a camptothecin (including the synthetic analogue
topotecan); bryostatin; callystatin; CC-1065 (including its
adozelesin, carzelesin and bizelesin synthetic analogues);
cryptophycins (particularly cryptophycin 1 and cryptophycin 8);
dolastatin; duocarmycin (including the synthetic analogues, KW-2189
and CBI-TMI); eleutherobin; pancratistatin; a sarcodictyin;
spongistatin; nitrogen mustards such as chlorambucil,
chlomaphazine, cholophosphamide, estramustine, ifosfamide,
mechlorethamine, mechlorethamine oxide hydrochloride, melphalan,
novembichin, phenesterine, prednimustine, trofosfamide, uracil
mustard; nitrosureas such as carmustine, chlorozotocin,
fotemustine, lomustine, nimustine, ranimustine; antibiotics, such
as the enediyne antibiotics (e.g. calicheamicin, especially
calicheamicin .gammal and calicheamicin theta I, see, e.g., Angew
Chem. Intl. Ed. Engl. 33:183-186 (1994); dynemicin, including
dynemicin A; an esperamicin; as well as neocarzinostatin
chromophore and related chromoprotein enediyne antiobiotic
chromomophores), aclacinomysins, actinomycin, authramycin,
azaserine, bleomycins, cactinomycin, carabicin, caminomycin,
carzinophilin; chromomycins, dactinomycin, daunorubicin,
detorubicin, 6-diazo-5-oxo-L-norleucine, doxorubicin (including
morpholino-doxorubicin, cyanomorpholino-doxorubicin,
2-pyrrolino-doxorubicin and deoxydoxorubicin), epirubicin,
esorubicin, idarubicin, marcellomycin, nitomycins, mycophenolic
acid, nogalamycin, olivomycins, peplomycin, potfiromycin,
puromycin, quelamycin, rodorubicin, streptonigrin, streptozocin,
tubercidin, ubenimex, zinostatin, zorubicin; anti-metabolites, such
as methotrexate and 5-fluorouracil (5-FU); folic acid analogues,
such as denopterin, methotrexate, pteropterin, trimetrexate; purine
analogs, such as fludarabine, 6-mercaptopurine, thiamiprine,
thioguanine; pyrimidine analogs such as, ancitabine, azacitidine,
6-azauridine, carmofur, cytarabine, dideoxyuridine, doxifluridine,
enocitabine, floxuridine, 5-FU; androgens, such as calusterone,
dromostanolone propionate, epitiostanol, mepitiostane,
testolactone; anti-adrenals, such as aminoglutethimide, mitotane,
trilostane; folic acid replenisher, such as frolinic acid;
aceglatone; aldophosphamide glycoside; aminolevulinic acid;
amsacrine; bestrabucil; bisantrene; edatraxate; defofamine;
demecolcine; diaziquone; elfomithine; elliptinium acetate; an
epothilone; etoglucid; gallium nitrate; hydroxyurea; lentinan;
lonidamine; maytansinoids, such as maytansine and ansamitocins;
mitoguazone; mitoxantrone; mopidamol; nitracrine; pentostatin;
phenamet; pirarubicin; podophyllinic acid; 2-ethylhydrazide;
procarbazine; PSK.RTM.; razoxane; rhizoxin; sizofuran;
spirogermanium; tenuazonic acid; triaziquone;
2,2',2''-trichlorotriethylamine; trichothecenes (especially T-2
toxin, verracurin A, roridin A and anguidine); urethan; vindesine;
dacarbazine; mannomustine; mitobronitol; mitolactol; pipobroman;
gacytosine; arabinoside ("Ara-C"); cyclophosphamide; thiotepa;
taxoids, e.g. paclitaxel (TAXOL.TM., Bristol-Myers Squibb Oncology,
Princeton, N.J.) and doxetaxel (TAXOTERE.RTM., Rhone-Poulenc Rorer,
Antony, France); chlorambucil; gemcitabine; 6-thioguanine;
mercaptopurine; methotrexate; platinum analogs such as cisplatin
and carboplatin; vinblastine; platinum; etoposide (VP-16);
ifosfamide; mitomycin C; mitoxantrone; vincristine; vinorelbine;
navelbine; novantrone; teniposide; 65 daunomycin; aminopterin;
xeloda; ibandronate; CPT-11; topoisomerase inhibitor RFS 2000;
difluoromethylomithine (DMFO); retinoic acid; capecitabine; and
pharmaceutically acceptable salts, acids or derivatives of any of
the above. Also included in this definition are anti-hormonal
agents that act to regulate or inhibit hormone action on tumors,
such as anti-estrogens including for example tamoxifen, raloxifene,
aromatase inhibiting 4(5)-imidazoles, 4-hydroxytamoxifen,
trioxifene, keoxifene, LY117018, onapristone, and toremifene
(Fareston); and anti-androgens, such as flutamide, nilutamide,
bicalutamide, leuprolide, and goserelin; siRNA and pharmaceutically
acceptable salts, acids or derivatives of any of the above. Other
chemotherapeutic agents that can be used with the present invention
are disclosed in US Publication No. 20080171040 or US Publication
No. 20080305044 and are incorporated in their entirety by
reference.
[0282] It is contemplated that an antibody may be conjugated to two
or more different chemotherapeutic agents or a pharmaceutical
composition may comprise a mixture of antibodies wherein the
antibody component is identical except for being conjugated to a
different chemotherapeutic agent. Such embodiments may be useful
for targeting multiple biological pathways with a target cell.
[0283] In preferred embodiments, the antibody construct comprising
of the invention comprises an antibody conjugated to one or more
maytansinoid molecules, which are mitotic inhibitors that act by
inhibiting tubulin polymerization. Maytansinoids, including various
modifications, are described in U.S. Pat. Nos. 3,896,111;
4,151,042; 4,137,230; 4,248,870; 4,256,746; 4,260,608; 4,265,814;
4,294,757; 4,307,016; 4,308,268; 4,309,428; 4,313,946; 4,315,929;
4,317,821; 4,322,348; 4331598; 4361650; 4364866; 4424219; 4450254;
4362663; 4371533; and WO 2009/099728. Maytansinoid drug moieties
may be isolated from natural sources, produced using recombinant
technology, or prepared synthetically. Exemplary maytansinoids
include C-19-dechloro (U.S. Pat. No. 4,256,746), C-20-hydroxy (or
C-20-demethyl) +/-C-19-dechloro (U.S. Pat. Nos. 4,307,016 and
4,361,650), C-20-demethoxy (or C-20-acyloxy (--OCOR), +/-dechrolo
(U.S. Pat. No. 4,294,757), C-9-SH (U.S. Pat. No. 4,424,219),
C-14-alkoxymethyl (demethoxy/CH2OR) (U.S. Pat. No. 4,331,598),
C-14-hydroxymethyl or acyloxymethyl (CH2OH or CH2OAc) (U.S. Pat.
No. 4,450,254), C-15-hydroxy/acyloxy (U.S. Pat. No. 4,364,866),
C-15-methoxy (U.S. Pat. Nos. 4,313,946 and 4,315,929),
C-18-N-demethyl (U.S. Pat. Nos. 4,362,663 and 4,322,348), and
4,5-deoxy (U.S. Pat. No. 4,371,533).
[0284] Various positions on maytansinoid compounds may be used as
the linkage position, depending upon the type of link desired. For
example, for forming an ester linkage, the C-3 position having a
hydroxyl group, the C-14 position modified with hydrozymethyl, the
C-15 position modified with a hydroxyl a group, and the C-20
position having a hydroxyl group are all suitable (U.S. Pat. Nos.
5,208,020, RE39,151, and 6,913,748; US Patent Appl. Pub. Nos.
20060167245 and 20070037972, and WO 2009099728).
[0285] Preferred maytansinoids include those known in the art as
DM1, DM3, and DM4 (US Pat. Appl. Pub. Nos. 2009030924 and
20050276812, incorporated herein by reference). In one embodiment
of the antibody construct of the invention the chemotherapeutic
agent is DM1. Accordingly, in a preferred embodiment the antibody
construct of the invention is an the human antibody or antigen
binding fragment thereof conjugated to one or more DM1
molecules.
[0286] ADCs containing maytansinoids, methods of making such ADCs,
and their therapeutic use are disclosed in U.S. Pat. Nos. 5,208,020
and 5,416,064, US Pat. Appl. Pub. No. 20050276812, and WO
2009099728 (all incorporated by reference herein). Linkers that are
useful for making maytansinoid ADCs are know in the art (U.S. Pat.
No. 5,208,020 and US Pat. Appl. Pub. Nos. 2005016993 and
20090274713; all incorporated herein by reference). Maytansinoid
ADCs comprising an SMCC linker may be prepared as disclosed in US
Pat. Publ. No. 2005/0276812.
[0287] In certain embodiments, the antibody construct comprising of
the invention comprises an antibody conjugated to DM1 with an SMCC
linker.
[0288] An antibody construct comprising of the invention may have 1
to 20 chemotherapeutic agents per antibody. Compositions of ADCs
may be characterized by the average number of drug moieties per
antibody molecule in the composition. The average number of drug
moieties may be determined by conventional means such as mass
spectrometry, immunoassay, and HPLC. In some instances, a
homogeneous ADC population may be separated and purified by means
of reverse phase HPLC or electrophoresis. Thus, pharmaceutical ADC
compositions may contain a heterogeneous or homogeneous population
of antibodies linked to 1, 2, 3, 4, 5, 6, 7 or more drug
moieties.
[0289] Thus, in a preferred embodiment of the antibody construct of
the invention the average number of DM1 molecules per antibody
construct is between 1 and 10.
[0290] It is also preferred for the antibody construct of the
invention that the average number of DM1 molecules per antibody
construct is between 3 and 7.
[0291] Moreover, it is preferred for the antibody construct of the
invention that the average number of DM1 molecules per antibody
construct is between 4 and 6.
[0292] Embodiments of the invention include antibody constructs
comprising an average of about 1, about 2, about 3, about 4, about
5, about 6, about 7, about 8, about 9, about 10, about 11, about
12, about 13, about 14, about 15, about 16, about 17, about 18,
about 19, or about 20 DM1 molecules per antibody.
[0293] In a further alternative embodiment of the antibody
construct of the invention the average number of DM1 molecules per
antibody construct is about 4.0, about 4.1, about 4.2, about 4.3,
about 4.4, about 4.5, about 4.6, about 4.7, about 4.8, about 4.9,
about 5.0, about 5.1, about 5.2, about 5.3, about 5.4, about 5.5,
about 5.6, about 5.7, about 5.8, about 5.9, or about 6.0.
[0294] In one embodiment the antibody respectively the antibody
construct of the invention comprises an effector function-enhanced
antibody. One of the functions of the Fc portion of an antibody is
to communicate to the immune system when the antibody binds its
target. This is considered "effector function". Communication leads
to antibody-dependent cellular cytotoxicity (ADCC),
antibody-dependent cellular phagocytosis (ADCP), and/or complement
dependent cytotoxicity (CDC). ADCC and ADCP are mediated through
the binding of the Fc to Fc receptors on the surface of cells of
the immune system. CDC is mediated through the binding of the Fc
with proteins of the complement system, e.g., C1q.
[0295] The IgG subclasses vary in their ability to mediate effector
functions. For example IgG1 is much superior to IgG2 and IgG4 at
mediating ADCC and CDC. Thus, in embodiments wherein a cell
expressing CDH19 is targeted for destruction, an anti-CDH19 IgG1
antibody would be preferred.
[0296] The effector function of an antibody can be increased, or
decreased, by introducing one or more mutations into the Fc.
Embodiments of the invention include antigen binding proteins,
e.g., antibodies, having an Fc engineered to increase effector
function (U.S. Pat. No. 7,317,091 and Strohl, Curr. Opin. Biotech.,
20:685-691, 2009; both incorporated herein by reference in its
entirety). Exemplary IgG1 Fc molecules having increased effector
function include (based on the Kabat numbering scheme) those have
the following substitutions:
[0297] S239D/I332E
[0298] S239D/A330S/I332E
[0299] S239D/A330L/I332E
[0300] S298A/D333A/K334A
[0301] P247I/A339D
[0302] P247I/A339Q
[0303] D280H/K290S
[0304] D280H/K290S/S298D
[0305] D280H/K290S/S298V
[0306] F243L/R292P/Y300L
[0307] F243L/R292P/Y300L/P396L
[0308] F243L/R292P/Y300L/V3051/P396L
[0309] G236A/S239D/I332E
[0310] K326A/E333A
[0311] K326W/E333S
[0312] K290E/S298G/T299A
[0313] K290N/S298G/T299A
[0314] K290E/5298G/T299A/K326E
[0315] K290N/S298G/T299A/K326E
[0316] Further embodiments of the invention include antibodies,
having an Fc engineered to decrease effector function. Exemplary Fc
molecules having decreased effector function include (based on the
Kabat numbering scheme) those have the following substitutions:
[0317] N297A (IgG1)
[0318] L234A/L235A (IgG1)
[0319] V234A/G237A (IgG2)
[0320] L235A/G237A/E318A (IgG4)
[0321] H2680/V309L/A330S/A331S (IgG2)
[0322] C220S/C226S/C229S/P238S (IgG1)
[0323] C226S/C229S/E233P/L234V/L235A (IgG1)
[0324] L234F/L235E/P331S (IgG1)
[0325] S267E/L328F (IgG1)
[0326] Another method of increasing effector function of IgG
Fc-containing proteins is by reducing the fucosylation of the Fc.
Removal of the core fucose from the biantennary complex-type
oligosachharides attached to the Fc greatly increased ADCC effector
function without altering antigen binding or CDC effector function.
Several ways are known for reducing or abolishing fucosylation of
Fc-containing molecules, e.g., antibodies. These include
recombinant expression in certain mammalian cell lines including a
FUT8 knockout cell line, variant CHO line Lec13, rat hybridoma cell
line YB2/0, a cell line comprising a small interfering RNA
specifically against the FUT8 gene, and a cell line coexpressing
B-1,4-N-acetylglucosaminyltransferase III and Golgi
.alpha.-mannosidase II. Alternatively, the Fc-containing molecule
may be expressed in a non-mammalian cell such as a plant cell,
yeast, or prokaryotic cell, e.g., E. coli. Thus, in certain
embodiments of the invention, a composition comprises an antibody,
e.g., Ab1, Ab2, Ab3, Ab4, Ab5, Ab6, Ab7, or Ab8, having reduced
fucosylation or lacking fucosylation altogether.
[0327] The invention further provides an isolated nucleic acid
molecule or sequence encoding a human antibody or antigen binding
fragment thereof of the invention.
[0328] Furthermore, the invention provides a vector comprising a
nucleic acid sequence of the invention. Moreover, the invention
provides a host cell transformed or transfected with the nucleic
acid sequence of the invention or with a vector comprising the
nucleic acid molecule.
[0329] In a further embodiment the invention provides a process for
the production of a human antibody or an antigen binding fragment
thereof of the invention, said process comprising culturing a host
cell of the invention under conditions allowing the expression of
the human antibody or antigen binding fragment thereof of the
invention and recovering the produced antibody or antigen binding
fragment thereof from the culture.
[0330] In a further embodiment the invention provides a process for
the production of an antibody construct comprising a human antibody
or an antigen binding fragment thereof of the invention, said
process comprising culturing a host cell of the invention under
conditions allowing the expression of the human antibody or antigen
binding fragment thereof of the invention and recovering the
produced antibody or antigen binding fragment thereof from the
culture, and conjugating a chemotherapeutic agent to the recovered
antibody or antigen binding fragment thereof to produce the
antibody conjugate.
[0331] Moreover, the invention provides a pharmaceutical
composition comprising a human antibody or antigen binding fragment
thereof of the invention or an antibody construct of the invention
or produced according to the process of the invention in admixture
with a pharmaceutically acceptable carrier thereof.
[0332] The formulations described herein are useful as
pharmaceutical compositions in the treatment, amelioration and/or
prevention of the pathological medical condition as described
herein in a patient in need thereof. The term "treatment" refers to
both therapeutic treatment and prophylactic or preventative
measures. Treatment includes the application or administration of
the formulation to the body, an isolated tissue, or cell from a
patient who has a disease/disorder, a symptom of a
disease/disorder, or a predisposition toward a disease/disorder,
with the purpose to cure, heal, alleviate, relieve, alter, remedy,
ameliorate, improve, or affect the disease, the symptom of the
disease, or the predisposition toward the disease.
[0333] Those "in need of treatment" include those already with the
disorder, as well as those in which the disorder is to be
prevented. The term "disease" is any condition that would benefit
from treatment with the protein formulation described herein. This
includes chronic and acute disorders or diseases including those
pathological conditions that predispose the mammal to the disease
in question. Non-limiting examples of diseases/disorders to be
treated herein include proliferative disease, a tumorous disease,
or an immunological disorder.
[0334] In some embodiments, the invention provides a pharmaceutical
composition comprising a therapeutically effective amount of one or
a plurality of the a human antibody or antigen binding fragment
thereof of the invention or an antibody construct of the invention
together with a pharmaceutically effective diluents, carrier,
solubilizer, emulsifier, preservative, and/or adjuvant. In certain
embodiments, the antigen binding protein is an antibody, including
a drug-conjugated antibody or a bispecific antibody. Pharmaceutical
compositions of the invention include, but are not limited to,
liquid, frozen, and lyophilized compositions.
[0335] Preferably, formulation materials are nontoxic to recipients
at the dosages and concentrations employed. In specific
embodiments, pharmaceutical compositions comprising a
therapeutically effective amount of a human antibody or antigen
binding fragment thereof of the invention or an antibody construct
of the invention.
[0336] In certain embodiments, the pharmaceutical composition may
contain formulation materials for modifying, maintaining or
preserving, for example, the pH, osmolarity, viscosity, clarity,
color, isotonicity, odor, sterility, stability, rate of dissolution
or release, adsorption or penetration of the composition. In such
embodiments, suitable formulation materials include, but are not
limited to, amino acids (such as glycine, glutamine, asparagine,
arginine, proline, or lysine); antimicrobials; antioxidants (such
as ascorbic acid, sodium sulfite or sodium hydrogen-sulfite);
buffers (such as borate, bicarbonate, Tris-HCl, citrates,
phosphates or other organic acids); bulking agents (such as
mannitol or glycine); chelating agents (such as ethylenediamine
tetraacetic acid (EDTA)); complexing agents (such as caffeine,
polyvinylpyrrolidone, beta-cyclodextrin or
hydroxypropyl-beta-cyclodextrin); fillers; monosaccharides;
disaccharides; and other carbohydrates (such as glucose, mannose or
dextrins); proteins (such as serum albumin, gelatin or
immunoglobulins); coloring, flavoring and diluting agents;
emulsifying agents; hydrophilic polymers (such as
polyvinylpyrrolidone); low molecular weight polypeptides;
salt-forming counterions (such as sodium); preservatives (such as
benzalkonium chloride, benzoic acid, salicylic acid, thimerosal,
phenethyl alcohol, methylparaben, propylparaben, chlorhexidine,
sorbic acid or hydrogen peroxide); solvents (such as glycerin,
propylene glycol or polyethylene glycol); sugar alcohols (such as
mannitol or sorbitol); suspending agents; surfactants or wetting
agents (such as pluronics, PEG, sorbitan esters, polysorbates such
as polysorbate 20, polysorbate, triton, tromethamine, lecithin,
cholesterol, tyloxapal); stability enhancing agents (such as
sucrose or sorbitol); tonicity enhancing agents (such as alkali
metal halides, preferably sodium or potassium chloride, mannitol
sorbitol); delivery vehicles; diluents; excipients and/or
pharmaceutical adjuvants. See, REMINGTON'S PHARMACEUTICAL SCIENCES,
18'' Edition, (A. R. Genrmo, ed.), 1990, Mack Publishing
Company.
[0337] In certain embodiments, the optimal pharmaceutical
composition will be determined by one skilled in the art depending
upon, for example, the intended route of administration, delivery
format and desired dosage. See, for example, REMINGTON'S
PHARMACEUTICAL SCIENCES, supra. In certain embodiments, such
compositions may influence the physical state, stability, rate of
in vivo release and rate of in vivo clearance of the antigen
binding proteins of the invention. In certain embodiments, the
primary vehicle or carrier in a pharmaceutical composition may be
either aqueous or non-aqueous in nature. For example, a suitable
vehicle or carrier may be water for injection, physiological saline
solution or artificial cerebrospinal fluid, possibly supplemented
with other materials common in compositions for parenteral
administration. Neutral buffered saline or saline mixed with serum
albumin are further exemplary vehicles. In specific embodiments,
pharmaceutical compositions comprise Tris buffer of about pH
7.0-8.5, or acetate buffer of about pH 4.0-5.5, and may further
include sorbitol or a suitable substitute therefore. In certain
embodiments of the invention, human antibody or antigen binding
fragment thereof of the invention or the antibody construct of the
invention compositions may be prepared for storage by mixing the
selected composition having the desired degree of purity with
optional formulation agents (REMINGTON'S PHARMACEUTICAL SCIENCES,
supra) in the form of a lyophilized cake or an aqueous solution.
Further, in certain embodiments, the human antibody or antigen
binding fragment thereof of the invention or the antibody construct
of the invention may be formulated as a lyophilizate using
appropriate excipients such as sucrose.
[0338] The pharmaceutical compositions of the invention can be
selected for parenteral delivery. Alternatively, the compositions
may be selected for inhalation or for delivery through the
digestive tract, such as orally. Preparation of such
pharmaceutically acceptable compositions is within the skill of the
art. The formulation components are present preferably in
concentrations that are acceptable to the site of administration.
In certain embodiments, buffers are used to maintain the
composition at physiological pH or at a slightly lower pH,
typically within a pH range of from about 5 to about 8.
[0339] When parenteral administration is contemplated, the
therapeutic compositions for use in this invention may be provided
in the form of a pyrogen-free, parenterally acceptable aqueous
solution comprising the desired human antibody or antigen binding
fragment thereof of the invention or the antibody construct of the
invention in a pharmaceutically acceptable vehicle. A particularly
suitable vehicle for parenteral injection is sterile distilled
water in which the human antibody or antigen binding fragment
thereof of the invention or the antibody construct of the invention
is formulated as a sterile, isotonic solution, properly preserved.
In certain embodiments, the preparation can involve the formulation
of the desired molecule with an agent, such as injectable
microspheres, bio-erodible particles, polymeric compounds (such as
polylactic acid or polyglycolic acid), beads or liposomes, that may
provide controlled or sustained release of the product which can be
delivered via depot injection. In certain embodiments, hyaluronic
acid may also be used, having the effect of promoting sustained
duration in the circulation. In certain embodiments, implantable
drug delivery devices may be used to introduce the desired antigen
binding protein.
[0340] Additional pharmaceutical compositions will be evident to
those skilled in the art, including formulations involving human
antibody or antigen binding fragment thereof of the invention or
the antibody construct of the invention in sustained- or
controlled-delivery formulations. Techniques for formulating a
variety of other sustained- or controlled-delivery means, such as
liposome carriers, bio-erodible microparticles or porous beads and
depot injections, are also known to those skilled in the art. See,
for example, International Patent Application No. PCT/US93/00829,
which is incorporated by reference and describes controlled release
of porous polymeric microparticles for delivery of pharmaceutical
compositions. Sustained-release preparations may include
semipermeable polymer matrices in the form of shaped articles,
e.g., films, or microcapsules. Sustained release matrices may
include polyesters, hydrogels, polylactides (as disclosed in U.S.
Pat. No. 3,773,919 and European Patent Application Publication No.
EP 058481, each of which is incorporated by reference), copolymers
of L-glutamic acid and gamma ethyl-L-glutamate (Sidman et al.,
1983, Biopolymers 2:547-556), poly (2-hydroxyethyl-methacrylate)
(Langer et al., 1981, J. Biomed. Mater. Res. 15:167-277 and Langer,
1982, Chem. Tech. 12:98-105), ethylene vinyl acetate (Langer et
al., 1981, supra) or poly-D(-)-3-hydroxybutyric acid (European
Patent Application Publication No. EP 133,988). Sustained release
compositions may also include liposomes that can be prepared by any
of several methods known in the art. See, e.g., Eppstein et al.,
1985, Proc. Natl. Acad. Sci. U.S.A. 82:3688-3692; European Patent
Application Publication Nos. EP 036,676; EP 088,046 and EP 143,949,
incorporated by reference.
[0341] Pharmaceutical compositions used for in vivo administration
are typically provided as sterile preparations. Sterilization can
be accomplished by filtration through sterile filtration membranes.
When the composition is lyophilized, sterilization using this
method may be conducted either prior to or following lyophilization
and reconstitution. Compositions for parenteral administration can
be stored in lyophilized form or in a solution. Parenteral
compositions generally are placed into a container having a sterile
access port, for example, an intravenous solution bag or vial
having a stopper pierceable by a hypodermic injection needle.
[0342] Aspects of the invention includes self-buffering human
antibody or antigen binding fragment thereof of the invention or
the antibody construct of the invention formulations, which can be
used as pharmaceutical compositions, as described in international
patent application WO 06138181A2 (PCT/US2006/022599), which is
incorporated by reference in its entirety herein.
[0343] As discussed above, certain embodiments provide human
antibody or antigen binding fragment thereof of the invention or
the antibody construct of the invention protein compositions,
particularly pharmaceutical compositions of the invention, that
comprise, in addition to the human antibody or antigen binding
fragment thereof of the invention or the antibody construct of the
invention, one or more excipients such as those illustratively
described in this section and elsewhere herein. Excipients can be
used in the invention in this regard for a wide variety of
purposes, such as adjusting physical, chemical, or biological
properties of formulations, such as adjustment of viscosity, and or
processes of the invention to improve effectiveness and or to
stabilize such formulations and processes against degradation and
spoilage due to, for instance, stresses that occur during
manufacturing, shipping, storage, pre-use preparation,
administration, and thereafter.
[0344] A variety of expositions are available on protein
stabilization and formulation materials and methods useful in this
regard, such as Arakawa et al., "Solvent interactions in
pharmaceutical formulations," Pharm Res. 8(3): 285-91 (1991);
Kendrick et al., "Physical stabilization of proteins in aqueous
solution," in: RATIONAL DESIGN OF STABLE PROTEIN FORMULATIONS:
THEORY AND PRACTICE, Carpenter and Manning, eds. Pharmaceutical
Biotechnology. 13: 61-84 (2002), and Randolph et al.,
"Surfactant-protein interactions," Pharm Biotechnol. 13: 159-75
(2002), each of which is herein incorporated by reference in its
entirety, particularly in parts pertinent to excipients and
processes of the same for self-buffering protein formulations in
accordance with the current invention, especially as to protein
pharmaceutical products and processes for veterinary and/or human
medical uses.
[0345] Salts may be used in accordance with certain embodiments of
the invention to, for example, adjust the ionic strength and/or the
isotonicity of a formulation and/or to improve the solubility
and/or physical stability of a protein or other ingredient of a
composition in accordance with the invention.
[0346] As is well known, ions can stabilize the native state of
proteins by binding to charged residues on the protein's surface
and by shielding charged and polar groups in the protein and
reducing the strength of their electrostatic interactions,
attractive, and repulsive interactions. Ions also can stabilize the
denatured state of a protein by binding to, in particular, the
denatured peptide linkages (--CONH) of the protein. Furthermore,
ionic interaction with charged and polar groups in a protein also
can reduce intermolecular electrostatic interactions and, thereby,
prevent or reduce protein aggregation and insolubility.
[0347] Ionic species differ significantly in their effects on
proteins. A number of categorical rankings of ions and their
effects on proteins have been developed that can be used in
formulating pharmaceutical compositions in accordance with the
invention. One example is the Hofmeister series, which ranks ionic
and polar non-ionic solutes by their effect on the conformational
stability of proteins in solution. Stabilizing solutes are referred
to as "kosmotropic." Destabilizing solutes are referred to as
"chaotropic." Kosmotropes commonly are used at high concentrations
(e.g., >1 molar ammonium sulfate) to precipitate proteins from
solution ("salting-out"). Chaotropes commonly are used to denture
and/or to solubilize proteins ("salting-in"). The relative
effectiveness of ions to "salt-in" and "salt-out" defines their
position in the Hofmeister series.
[0348] Free amino acids can be used in human antibody or antigen
binding fragment thereof of the invention or the antibody construct
of the invention formulations in accordance with various
embodiments of the invention as bulking agents, stabilizers, and
antioxidants, as well as other standard uses. Lysine, proline,
serine, and alanine can be used for stabilizing proteins in a
formulation. Glycine is useful in lyophilization to ensure correct
cake structure and properties. Arginine may be useful to inhibit
protein aggregation, in both liquid and lyophilized formulations.
Methionine is useful as an antioxidant.
[0349] Polyols include sugars, e.g., mannitol, sucrose, and
sorbitol and polyhydric alcohols such as, for instance, glycerol
and propylene glycol, and, for purposes of discussion herein,
polyethylene glycol (PEG) and related substances. Polyols are
kosmotropic. They are useful stabilizing agents in both liquid and
lyophilized formulations to protect proteins from physical and
chemical degradation processes. Polyols also are useful for
adjusting the tonicity of formulations.
[0350] Among polyols useful in select embodiments of the invention
is mannitol, commonly used to ensure structural stability of the
cake in lyophilized formulations. It ensures structural stability
to the cake. It is generally used with a lyoprotectant, e.g.,
sucrose. Sorbitol and sucrose are among preferred agents for
adjusting tonicity and as stabilizers to protect against
freeze-thaw stresses during transport or the preparation of bulks
during the manufacturing process. Reducing sugars (which contain
free aldehyde or ketone groups), such as glucose and lactose, can
glycate surface lysine and arginine residues. Therefore, they
generally are not among preferred polyols for use in accordance
with the invention. In addition, sugars that form such reactive
species, such as sucrose, which is hydrolyzed to fructose and
glucose under acidic conditions, and consequently engenders
glycation, also is not among preferred polyols of the invention in
this regard. PEG is useful to stabilize proteins and as a
cryoprotectant and can be used in the invention in this regard.
[0351] Embodiments of the human antibody or antigen binding
fragment thereof of the invention or the antibody construct of the
invention formulations further comprise surfactants. Protein
molecules may be susceptible to adsorption on surfaces and to
denaturation and consequent aggregation at air-liquid,
solid-liquid, and liquid-liquid interfaces. These effects generally
scale inversely with protein concentration. These deleterious
interactions generally scale inversely with protein concentration
and typically are exacerbated by physical agitation, such as that
generated during the shipping and handling of a product.
[0352] Surfactants routinely are used to prevent, minimize, or
reduce surface adsorption. Useful surfactants in the invention in
this regard include polysorbate 20, polysorbate 80, other fatty
acid esters of sorbitan polyethoxylates, and poloxamer 188.
[0353] Surfactants also are commonly used to control protein
conformational stability. The use of surfactants in this regard is
protein-specific since, any given surfactant typically will
stabilize some proteins and destabilize others.
[0354] Polysorbates are susceptible to oxidative degradation and
often, as supplied, contain sufficient quantities of peroxides to
cause oxidation of protein residue side-chains, especially
methionine. Consequently, polysorbates should be used carefully,
and when used, should be employed at their lowest effective
concentration. In this regard, polysorbates exemplify the general
rule that excipients should be used in their lowest effective
concentrations.
[0355] Embodiments of human antibody or antigen binding fragment
thereof of the invention or the antibody construct of the invention
formulations further comprise one or more antioxidants. To some
extent deleterious oxidation of proteins can be prevented in
pharmaceutical formulations by maintaining proper levels of ambient
oxygen and temperature and by avoiding exposure to light.
Antioxidant excipients can be used as well to prevent oxidative
degradation of proteins. Among useful antioxidants in this regard
are reducing agents, oxygen/free-radical scavengers, and chelating
agents. Antioxidants for use in therapeutic protein formulations in
accordance with the invention preferably are water-soluble and
maintain their activity throughout the shelf life of a product.
EDTA is a preferred antioxidant in accordance with the invention in
this regard.
[0356] Antioxidants can damage proteins. For instance, reducing
agents, such as glutathione in particular, can disrupt
intramolecular disulfide linkages. Thus, antioxidants for use in
the invention are selected to, among other things, eliminate or
sufficiently reduce the possibility of themselves damaging proteins
in the formulation.
[0357] Formulations in accordance with the invention may include
metal ions that are protein co-factors and that are necessary to
form protein coordination complexes, such as zinc necessary to form
certain insulin suspensions. Metal ions also can inhibit some
processes that degrade proteins. However, metal ions also catalyze
physical and chemical processes that degrade proteins.
[0358] Magnesium ions (10-120 mM) can be used to inhibit
isomerization of aspartic acid to isoaspartic acid. Ca+2 ions (up
to 100 mM) can increase the stability of human deoxyribonuclease.
Mg+2, Mn+2, and Zn+2, however, can destabilize rhDNase. Similarly,
Ca+2 and Sr+2 can stabilize Factor VIII, it can be destabilized by
Mg+2, Mn+2 and Zn+2, Cu+2 and Fe+2, and its aggregation can be
increased by Al+3 ions.
[0359] Embodiments of the human antibody or antigen binding
fragment thereof of the invention or the antibody construct of the
invention formulations further comprise one or more preservatives.
Preservatives are necessary when developing multi-dose parenteral
formulations that involve more than one extraction from the same
container. Their primary function is to inhibit microbial growth
and ensure product sterility throughout the shelf-life or term of
use of the drug product. Commonly used preservatives include benzyl
alcohol, phenol and m-cresol. Although preservatives have a long
history of use with small-molecule parenterals, the development of
protein formulations that includes preservatives can be
challenging. Preservatives almost always have a destabilizing
effect (aggregation) on proteins, and this has become a major
factor in limiting their use in multi-dose protein formulations. To
date, most protein drugs have been formulated for single-use only.
However, when multi-dose formulations are possible, they have the
added advantage of enabling patient convenience, and increased
marketability. A good example is that of human growth hormone (hGH)
where the development of preserved formulations has led to
commercialization of more convenient, multi-use injection pen
presentations. At least four such pen devices containing preserved
formulations of hGH are currently available on the market.
Norditropin (liquid, Novo Nordisk), Nutropin AQ (liquid, Genentech)
& Genotropin (lyophilized--dual chamber cartridge, Pharmacia
& Upjohn) contain phenol while Somatrope (Eli Lilly) is
formulated with m-cresol. Several aspects need to be considered
during the formulation and development of preserved dosage forms.
The effective preservative concentration in the drug product must
be optimized. This requires testing a given preservative in the
dosage form with concentration ranges that confer anti-microbial
effectiveness without compromising protein stability.
[0360] As might be expected, development of liquid formulations
containing preservatives are more challenging than lyophilized
formulations. Freeze-dried products can be lyophilized without the
preservative and reconstituted with a preservative containing
diluent at the time of use. This shortens the time for which a
preservative is in contact with the protein, significantly
minimizing the associated stability risks. With liquid
formulations, preservative effectiveness and stability should be
maintained over the entire product shelf-life (about 18 to 24
months). An important point to note is that preservative
effectiveness should be demonstrated in the final formulation
containing the active drug and all excipient components.
[0361] Human antibody or antigen binding fragment thereof of the
invention or the antibody construct of the invention generally will
be designed for specific routes and methods of administration, for
specific administration dosages and frequencies of administration,
for specific treatments of specific diseases, with ranges of
bio-availability and persistence, among other things. Formulations
thus may be designed in accordance with the invention for delivery
by any suitable route, including but not limited to orally,
aurally, opthalmically, rectally, and vaginally, and by parenteral
routes, including intravenous and intraarterial injection,
intramuscular injection, and subcutaneous injection.
[0362] Once the pharmaceutical composition has been formulated, it
may be stored in sterile vials as a solution, suspension, gel,
emulsion, solid, crystal, or as a dehydrated or lyophilized powder.
Such formulations may be stored either in a ready-to-use form or in
a form (e.g., lyophilized) that is reconstituted prior to
administration. The invention also provides kits for producing a
single-dose administration unit. The kits of the invention may each
contain both a first container having a dried protein and a second
container having an aqueous formulation. In certain embodiments of
this invention, kits containing single and multi-chambered
pre-filled syringes (e.g., liquid syringes and lyosyringes) are
provided. The therapeutically effective amount of a human antibody
or antigen binding fragment thereof of the invention or the
antibody construct of the invention protein-containing
pharmaceutical composition to be employed will depend, for example,
upon the therapeutic context and objectives. One skilled in the art
will appreciate that the appropriate dosage levels for treatment
will vary depending, in part, upon the molecule delivered, the
indication for which the human antibody or antigen binding fragment
thereof of the invention or the antibody construct of the invention
is being used, the route of administration, and the size (body
weight, body surface or organ size) and/or condition (the age and
general health) of the patient. In certain embodiments, the
clinician may titer the dosage and modify the route of
administration to obtain the optimal therapeutic effect. A typical
dosage may range from about 0.1 .mu.g/kg to up to about 30 mg/kg or
more, depending on the factors mentioned above. In specific
embodiments, the dosage may range from 1.0 .mu.g/kg up to about 20
mg/kg, optionally from 10 .mu.g/kg up to about 10 mg/kg or from 100
.mu.g/kg up to about 5 mg/kg.
[0363] A therapeutic effective amount of a human antibody or
antigen binding fragment thereof of the invention or the antibody
construct of the invention preferably results in a decrease in
severity of disease symptoms, in increase in frequency or duration
of disease symptom-free periods or a prevention of impairment or
disability due to the disease affliction. For treating
CDH19-expressing tumors, a therapeutically effective amount of
human antibody or antigen binding fragment thereof of the invention
or the antibody construct of the invention, e.g. an anti-CDH19
antibody construct (ADC construct), preferably inhibits cell growth
or tumor growth by at least about 20%, at least about 40%, at least
about 50%, at least about 60%, at least about 70%, at least about
80%, or at least about 90% relative to untreated patients. The
ability of a compound to inhibit tumor growth may be evaluated in
an animal model predictive of efficacy in human tumors.
[0364] Pharmaceutical compositions may be administered using a
medical device. Examples of medical devices for administering
pharmaceutical compositions are described in U.S. Pat. Nos.
4,475,196; 4,439,196; 4,447,224; 4,447, 233; 4,486,194; 4,487,603;
4,596,556; 4,790,824; 4,941,880; 5,064,413; 5,312,335; 5,312,335;
5,383,851; and 5,399,163, all incorporated by reference herein.
[0365] In one embodiment the invention provides the human antibody
or antigen binding fragment thereof of the invention, the antibody
construct of the invention, or produced according to the process of
the invention for use in the prevention, treatment or amelioration
of a melanoma disease or metastatic melanoma disease. Preferably,
the melanoma disease or metastatic melanoma disease is selected
from the group consisting of superficial spreading melanoma,
lentigo maligna, lentigo maligna melanoma, acral lentiginous
melanoma and nodular melanoma.
[0366] The invention also provides a method for the treatment or
amelioration of a melanoma disease or metastatic melanoma disease,
comprising the step of administering to a subject in need thereof
the antibody or antigen binding fragment thereof of the invention,
the antibody construct of the invention, an antibody or antigen
binding fragment thereof of the invention or the antibody construct
of the invention produced according to the process of the invention
or a pharmaceutical composition of the invention.
[0367] In a preferred embodiment method the invention the melanoma
disease or metastatic melanoma disease is selected from the group
consisting of superficial spreading melanoma, lentigo maligna,
lentigo maligna melanoma, acral lentiginous melanoma and nodular
melanoma.
[0368] In a further embodiment, the invention provides a kit
comprising an antibody or antigen binding fragment thereof of the
invention, an antibody construct of the invention, an antibody or
antigen binding fragment thereof of the invention or the antibody
construct produced according to the process of the invention, a
vector of the invention, and/or a host cell of the invention.
[0369] It should be understood that the inventions herein are not
limited to particular methodology, protocols, or reagents, as such
can vary. The discussion and examples provided herein are presented
for the purpose of describing particular embodiments only and are
not intended to limit the scope of the present invention, which is
defined solely by the claims.
[0370] All publications and patents cited throughout the text of
this specification (including all patents, patent applications,
scientific publications, manufacturer's specifications,
instructions, etc.), whether supra or infra, are hereby
incorporated by reference in their entirety. Nothing herein is to
be construed as an admission that the invention is not entitled to
antedate such disclosure by virtue of prior invention. To the
extent the material incorporated by reference contradicts or is
inconsistent with this specification, the specification will
supersede any such material.
EXAMPLES
[0371] The following examples illustrate the invention. These
examples should not be construed as to limit the scope of this
invention. The examples are included for purposes of illustration,
and the present invention is limited only by the claims.
Example 1--Fully Human Monoclonal Antibodies Against CDH19
[0372] 1.1 Immunization:
[0373] Fully human antibodies to Cadherin-19 (CDH19) were generated
using XENOMOUSE.RTM. technology, transgenic mice engineered to
express diverse repertoires of fully human IgG.kappa. and
IgG.lamda. antibodies of the corresponding isotype. (U.S. Pat. Nos.
6,114,598; 6,162,963; 6,833,268; 7,049,426; 7,064,244, which are
incorporated herein by reference in their entirety; Green et al.,
1994, Nature Genetics 7:13-21; Mendez et al., 1997, Nature Genetics
15:146-156; Green and Jakobovitis, 1998, J. Ex. Med. 188:483-495;
Kellermann and Green, Current Opinion in Biotechnology 13, 593-597,
2002).
[0374] Mice were immunized with multiple forms of Cadherin-19
immunogen, including: (1) full length human and cynomologous
("cyno") monkey cadherin-19, (2) secreted Cadherin-19 ecto-domain
(amino acids 1-596), and (3) a truncated membrane bound form of
human cadherin-19 (amino acids 1-624). Mice were immunized over a
period of 8 to 10 weeks with a range of 16-18 boosts.
[0375] Sera were collected at approximately 5 and 9 weeks after the
first injection and specific titers were determined by FACs
staining of recombinant Cadherin-19 receptor transiently expressed
on CHO--S cells. A total of 37 animals were identified with
specific immune responses, these animals were pooled into 3 groups
and advanced to antibody generation.
[0376] 1.2 Preparation of Monoclonal Antibodies
[0377] Animals exhibiting suitable titers were identified, and
lymphocytes were obtained from draining lymph nodes and, if
necessary, pooled for each cohort. Lymphocytes were dissociated
from lymphoid tissue by grinding in a suitable medium (for example,
Dulbecco's Modified Eagle Medium (DMEM); obtainable from
Invitrogen, Carlsbad, Calif.) to release the cells from the
tissues, and suspended in DMEM. B cells were selected and/or
expanded using standard methods, and fused with suitable fusion
partner using techniques that were known in the art.
[0378] After several days of culture, the hybridoma supernatants
were collected and subjected to screening assays as detailed in the
examples below, including confirmation of binding to human and
cynomologous monkey as well as the ability to kill cell lines in
secondary antibody-drug conjugate Bioassays. Hybridoma lines that
were identified to have the binding and functional properties of
interest were then further selected and subjected to standard
cloning and subcloning techniques. Clonal lines were expanded in
vitro, and the secreted human antibodies obtained for analysis and
V gene sequencing was performed.
[0379] 1.3 Selection of Cadherin-19 Receptor Specific Binding
Antibodies by FMAT
[0380] After 14 days of culture, hybridoma supernatants were
screened for CDH19-specific monoclonal antibodies by Fluorometric
Microvolume Assay Technology (FMAT) (Applied Biosystems, Foster
City, Calif.). The supernatants were screened against adherent CHO
cells transiently transfected with human Cadherin-19 and counter
screened against CHO cells transiently transfected with the same
expression plasmid that did not contain the Cadherin-19 gene.
[0381] After multiple screening campaigns, a panel of 1570
anti-Cadherin-19 binding hybridoma lines were identified and
advanced to further characterization assays.
Example 2--Assessment of Fully Human Monoclonal Antibodies Against
CDH19
[0382] 2.1 Additional Binding Characterization by Flow Cytometry
(FACs)
[0383] FACS binding assays were performed to evaluate the binding
of the anti-Cadherin-19 receptor specific antibodies to endogenous
Cadherin-19 receptor expressed on the CHL-1 tumor cell lines. In
addition, cross-reactive binding to murine and cynomologous monkey
Cadherin-19 orthologues was also evaluated by FACs using
recombinant forms of the various receptors transiently expressed on
293T cells.
[0384] FACs assays were performed by incubating hybridoma
supernatants with 10,000 to 25,000 cells in PBS/2% Fetal bovine
serum/2 mM Calcium Chloride at 4.degree. C. for one hour followed
by two washes with PBS/2% Fetal bovine serum/2 mM Calcium Chloride.
Cells were then treated with florochrome-labeled secondary
antibodies at 4.degree. C. followed by one wash. The cells were
resuspended in 50 .mu.l of PBS/2% FBS and antibody binding was
analyzed using a FACSCalibur.TM. instrument.
[0385] 2.2 Antibody Drug Conjugate Screening of Fully Human
Antibodies Derived from XenoMouse.RTM. Hybridomas
[0386] Cell killing through antibody drug conjugates requires the
delivery of the conjugate into a cell through internalization and
the catabolism of the drug-conjugate into a form that it is toxic
to the cell. To identify antibodies with these properties,
CDH19-positive cell lines (Colo-699 or CHL-1) were seeded at low
cell densities and allowed to adhere overnight in a 384 well plate.
XENOMOUSE.RTM. hybridoma samples containing fully human anti-CDH19
antibodies were then added to these cells in the presence of a high
concentration of a goat anti-human Fc monovalent Fab conjugated
with DM1 (DM1-Fab) at a relatively low drug-antibody ratio (DAR)
(.about.1.3). The cells were incubated for 96 hours at 37.degree.
C. and 5% CO.sub.2 in the presence of the antibody samples and the
DM1-Fab. At the end of this time, the cell viability was assessed
using the CellTiter-Glo.RTM. Luminescent Cell Viability reagent
(Promega) according to manufacturer's recommendations.
[0387] An example of the cell viability data with the Colo-699
cells is shown in FIG. 1 and FIG. 2. The antibodies capable of
delivering the DM1-Fab to the cells and inhibiting the cell growth
read out with a lower luminescent signal (RLU). The top antibodies
of interest from this screen are observed in the lower left corner
of FIG. 1 and are denoted as open circles.
[0388] These antibodies were taken forward into a cell viability
assay on CHL-1 cells. The average cell viability data from the
CHL-1 assay is plotted against the average cell viability data from
the Colo-699 assay (FIG. 2). The antibodies that had activity on
both the Colo-699 and the CHL-1 cells are denoted as open circles
on the left-hand side of the FIG. 2.
[0389] This assay was run concurrently with the FACs antibody
binding assay above (2.2), and the results from these two studies
were used to select the antibodies for further characterization. In
total, 1570 antibodies were run through these cell based viability
assays and approximately 44 antibodies were selected on the bases
of in vitro cell killing and/or antibody binding for sub-cloning, V
gene sequencing and expressed in recombinant form for further
characterization assays as described below.
[0390] These 44 antibodies were again assayed as in Example 2 and
19 antibodies were selected that contained unique sequences. Of
these 19 antibodies, 18 antibodies were analyzed and their
properties characterized in Table 2 below. The data in this table
was generated using FACs binding on recombinant human and
cynomologous CDH-19, +/-Calcium (Ca.sup.+2) binding data on
293/CDH-19 transfectants, binding to endogenous CDH-19 on CHL-1 and
Colo699 tumor cells and competition with the antibody designated as
4A9 in the table. These experiments provided the further
characterizations for the grouping of these antibodies into 5
groups or bins.
TABLE-US-00002 TABLE 2 Binning of Lead panel using Antibody Binding
Information LMR Bin Sequence/ Clone ID Ab ID ID Bin Characteristics
1 13589 4A9 High Endogenous binding, Calcium 13591 4F7 insensitive,
sequence clustered, moderate cyno complete 4A9 competitor 2 13885
19B5 High Endogenous binding, Calcium 13880 25F8 insensitive,
sequence 13882 26D1 clustered, Good cyno, 13881 26F12 = partial 4A9
competitor 27B3 13878 16H2 = 20D3 = 23E7 13879 22D1 3 13877 22G10
High Endogenous binding, moderate 13874 17H8 = 293 binding, Calcium
insensitive, 23B6 = 2 sequence clusters, moderate 28D10 cyno,
partial 4A9 competitor, 13883 25G10 22G10 best binder in bin. 13875
16C1 4 13590 4610 Low Endogenous and 13586 4F3 recombinant binding,
13592 4A2 Calcium sensitive, sequence 13884 23A10 diverse group,
comparable 13588 2G6 cyno, No 4A9 competition 5 13876 16A4 Best
endogenous binder, moderate recombinant binder, calcium
insensitive, very weak cyno, No 4A9 competition.
[0391] Of these 18 antibodies. 8 antibodies were selected for
further analysis of their epitope binding as described below. At
least one representative antibody from each bin was selected for
further analysis.
Example 3--Epitope Prediction
[0392] Epitope Prediction by 4A9 Antibody Competition and by
Human/Mouse Cadherin-19 Chimeras
[0393] A 4A9 binding competition method was developed to identify
antibodies that compete with 4A9 binding. In 96-well V-bottom
plates (Sarstedt #82.1583.001), 50,000 transiently transfected 293T
cells were incubated with 5 ug/ml of purified anti-CDH19 antibodies
for 1 hr at 4.degree. C. followed by one wash with PBS/2% FBS. 25
.mu.l of 5 .mu.g/ml Alexa647-labelled 4A9 was then added to each
well and the plates incubated for 1 hour at 4.degree. C. Cells were
then washed two times and the amount of cell associated
Alexa647-labelled 4A9 was quantitated by flow cytometry.
[0394] The experiments included negative controls consisting of
PBS/2% FBS only. The average signal observed in these negative
control experiments was adopted as the maximum possible signal for
the assay. Antibodies were compared to this maximum signal and a
percent inhibition was calculated for each well (%
Inhibition=(1-(FL4 Geomean with the anti-CDH19 antibodies/Maximum
FL4 Geomean signal)).
[0395] Domain binding was determined by flow cytometry as above on
293T cells transiently transfected with plasmids consisting of
single or dual human CDH19 cadherin repeat domain replacements into
the mouse Cadherin19 backbone cloned into the pTT5 expression
vector immediately preceded by native human or murine CDH19 leader
sequences and a Flag tag (SEQ ID NO: 968). The experiment included
assaying the anti-CDH19 antibodies against mouse Cadherin19 to
determine suitability for binning on these human/mouse
chimeras.
[0396] The data from these experiments are presented in the Table
below entitled as follows:
TABLE-US-00003 TABLE 3 Calcium Sensitive Binding and Epitope
Prediction Summary Com- petes Hu Hu Hu Hu Mu Ca2+ with EC1- Hu EC1-
Hu EC2- Hu EC4- Hu EC1- Predicted Clone Ab Sensitive 4A9 5 EC1 2
EC2 3 EC3 5 EC5 5 Epitope ID ID Bin Binding (13589) A B C D E F G H
I Region 4A9 13589 1 No Yes + + + - - - - - - 44-141 14056 1 No Yes
+ + + - - - - - - 14057 1 No Yes + + + - - - - - - 25F8 13880 2 No
Yes + + + - - - - - - 14094 2 No Yes + + + - - - - - - 14096 2 No
Yes + + + - - - - - - 26D1 13882 2 No Yes + + + - - - - - - 14088 2
No Yes + + + - - - - - - 17H8 13874 3 No Yes + + + - - - - - -
14045 3 No Yes + + + - - - - - - 14048 3 No Yes + + + - - - - - -
4A2 13592 4 Yes No + - - - + + - - - 250-364 14026 4 Yes No + - - -
+ + - - - 4610 13590 4 Yes No + - - - + + - - - 14055 4 Yes No + -
- - + + - - - 14054 4 Yes No + - - - + + - - - 2G6 13588 4 Yes No +
+ + + + + + + + un- 14304 4 Yes No + + + + + + + + + assignable
14039 4 Yes No + + + + + + + + + 16A4 13876 5 No No + + + - - - - -
- Unassigned 14071 5 No No + + + - - - - - - complex epitope Rat
anti-FLAG + + + + + + + + + Legend Table 3 Human and/or murine
chimera constructs A = huCDH19(44-772) (see SEQ ID NO: 944) B =
huCDH19(44-141)::muCDH19(140-770) (see SEQ ID NO: 952) C =
huCDH19(44-249)::muCDH19(248-770) (see SEQ ID NO: 954) D =
muCDH19(44-139)::huCDH19(142-249)::muCDH19(248-770) (see SEQ ID NO:
956) E = muCDH19(44-139)::huCDH19(142-364)::muCDH19(363-770) (see
SEQ ID NO: 958) F =
muCDH19(44-247)::huCDH19(250-364)::muCDH19(363-770) (see SEQ ID NO:
960) G = muCDH19(44-362)::huCDH19(365-772) (see SEQ ID NO: 962) H =
muCDH19(44-461)::huCDH19(464-772) (see SEQ ID NO: 964) I =
muCDH19(44-770) (see SEQ ID NO: 966)
[0397] Epitope Prediction by Human/Chicken Cadherin-19 Chimeras
[0398] Domain binding was determined by flow cytometry on 293T
cells transiently transfected with plasmids consisting of single
human CDH19 cadherin repeat domain replacements into the chicken
Cadherin19 backbone cloned into the pTT5 expression vector
immediately preceded by native human or chicken CDH19 leader
sequences and a Flag tag. The experiment included assaying a subset
of anti-CDH19 antibodies against chicken Cadherin19 to determine
suitability for binning on these human/chicken chimeras.
[0399] The following binding assay was completed in presence of 2
mM CaCl.sub.2). In 96-well V-bottom plates (Costar 3897), 50,000
transiently transfected 293T cells were incubated with 5 ug/ml of
purified anti-CDH19 antibodies for 1 hr at 4.degree. C. followed by
two washes with PBS/2% FBS. 50 .mu.l of 5 .mu.g/ml
Alexa647-labelled anti-human IgG secondary antibody (Jackson Immuno
109-605-098) and 2 ug/ml 7AAD (Sigma A9400) was then added to each
well and the plates incubated for 15 minutes at 4.degree. C. Cells
were then washed one time and the amount of cell associated
Alexa647-labelled Ab was quantitated by flow cytometry. The
experiments included mock transfected controls. The data from these
experiments are presented in the Table below, n.d.=not
determined.
TABLE-US-00004 TABLE 4 Antibody Bin C Epitope Prediction Summary Hu
Ck Pre- EC1- Ed1- Hu Hu Hu Hu dicted Clone Ab. 5 5 EC1 EC2 EC3 EC5
Epitope ID ID Bin A J K L M O Region 4A9 13589 1 + - + - - - 44-141
26F12 13881 2 + - + - - - Bin A 25F8 14096 2 + - + - - - 26D1 13882
2 + - + - - - 17H8 13874 3 + - + - - - 16A4 14071 5 + - + - - - 4A2
13592 4 + - - - + - 250- 4B10 13590 4 + - - - + - 364 2G6 13588 4 +
- - - + - Bin B 23A10 14077 4 + - - - + - Rat anti-FLAG + + + + + +
control + Positive Binding - Negative Binding Legend Table 4 Human
and/or chicken chimera constructs A = huCDH19(44-772) (see SEQ ID
NO: 944) J = ckCDH19(44-776) (see SEQ ID NO: 970) K =
huCDH19(44-141)::ckCDH19(142-776) (see SEQ ID NO: 971) L =
ckCDH19(44-141)::huCDH19(142-249)::ckCDH19(250-776) (see SEQ ID NO:
972) M = ckCDH19(44-249)::huCDH19(250-364)::ckCDH19(365-776) (see
SEQ ID NO: 973) N =
ckCDH19(44-364)::huCDH19(365-463)::ckCDH19(469-776) (see SEQ ID NO:
974) O = ckCDH19(44-468)::huCDH19(464-772) (see SEQ ID NO: 975)
[0400] Epitope Prediction by Macaque/Dog or Rat/Macaque Cadherin-19
Chimeras
[0401] Domain binding was determined by flow cytometry on 293T
cells transiently transfected with plasmids consisting of rhesus
macaque CDH19 cadherin repeat domain 1 or segments domain 1
(designated EC1a, EC1b, EC1c) replacements into the dog Cadherin19
backbone, or rat CDH19 cadherin repeat domain 2 replacement into
the rhesus Cadherin19 backbone cloned into the pTT5 expression
vector immediately preceded by native rhesus or canine CDH19 leader
sequences and a Flag tag. The experiment included assaying a subset
of anti-CDH19 antibodies against dog, rat and macaque Cadherin19 to
determine suitability for binning on these macaque/dog and
rat/rhesus chimeras.
[0402] The following binding assay was completed in presence of 2
mM CaCl.sub.2). In 96-well V-bottom plates (Costar 3897), 50,000
transiently transfected 293T cells were incubated with 5 ug/ml of
purified anti-CDH19 antibodies for 1 hr at 4.degree. C. followed by
two washes with PBS/2% FBS. 50 .mu.l of 5 .mu.g/ml
Alexa647-labelled anti-human IgG secondary antibody (Jackson Immuno
109-605-098) and 2 ug/ml 7AAD (Sigma A9400) was then added to each
well and the plates incubated for 15 minutes at 4.degree. C. Cells
were then washed one time and the amount of cell associated
Alexa647-labelled Ab was quantitated by flow cytometry. The
experiments included mock transfected controls. The data from these
experiments are presented in the Table below, n.d.=not
determined.
TABLE-US-00005 TABLE 5 Antibody BinA Epitope prediction Summary Rh
Ca rh rh rh ra Ra Predicted EC1-5 EC1-5 EC1 EC1a EC1b EC2 EC1-5
Epitope Clone ID Ab. ID Bin P Q R S T V W Region 4A9 13589 1 + - +
- - - - 44-141 + + + Bin A.1 26F12 13881 2 + - + + + - - 44-141
25F8 14096 2 + - + + + - - Bin A.2 26D1 13882 2 + - + + + - - (44-
114) 17H8 13874 3 + - + + - - - 44-141 Bin A.3 16A4 14071 5 + - + +
- n.d. + (44-65) 4A2 13592 4 + - n.d. n.d. n.d. n.d. + 250- 4B10
13590 4 + + n.d. n.d. n.d. n.d. + 364 2G6 13588 4 + + n.d. n.d.
n.d. n.d. + Bin B 23A10 14077 4 + + n.d. n.d. n.d. n.d. + Rat
anti-FLAG + + + + + + + + Positive Binding - Negative Binding
(n.d.) Not Determined Legend Table 5 Rhesus macaque, dog, and/or
rat chimera constructs P = rhCDH19(44-772) (see SEQ ID NO: 976) Q =
caCDH19(44-770) (see SEQ ID NO: 977) R =
rhCDH19(44-141)::caCDH19(141-770) (see SEQ ID NO: 978) S =
rhCDH19(44-65)::caCDH19(65-770) (see SEQ ID NO: 979) T =
caCDH19(44-87)::rhCDH19(89-114)::caCDH19(115-770) (see SEQ ID NO:
980) U = caCDH19(44-120)::rhCDH19(122-137)::caCDH19(137-770) (see
SEQ ID NO: 981) V =
rhCDH19(44-141)::raCDH19(140-247)::rhCDH19(250-772) (see SEQ ID NO:
982) W = raCDH19(44-770) (see SEQ ID NO: 983)
[0403] The data summarized in table 5 allowed for segregating the
binder of Bin A 44-141 into the following subgroups:
[0404] Bin A.1 44-141
[0405] Bin A.2 44-141 (44-114)
[0406] Bin A.3 44-141 (44-65)
[0407] Epitope Prediction by Rat/Mouse or Human/Mouse Cadherin-19
Chimeras
[0408] Domain binding was determined by flow cytometry on 293T
cells transiently transfected with plasmids consisting of rat CDH19
cadherin repeat domain 3 substitutions (designated EC3a, EC3b) or
human CDH19 cadherin repeat domain 3 substitution (designated EC3c)
into the mouse Cadherin19 backbone cloned into the pTT5 expression
vector immediately preceded by native mouse CDH19 leader sequence
and a Flag tag. The experiment included assaying a subset of
anti-CDH19 antibodies against human, rat and mouse Cadherin19 to
determine suitability for binning on these rat/mouse and
human/mouse chimeras.
[0409] The following binding assay was completed in presence of 2
mM CaCl.sub.2). In 96-well V-bottom plates (Costar 3897), 50,000
transiently transfected 293T cells were incubated with 5 ug/ml of
purified anti-CDH19 antibodies for 1 hr at 4.degree. C. followed by
two washes with PBS/2% FBS. 50 .mu.l of 5 .mu.g/ml
Alexa647-labelled anti-human IgG secondary antibody (Jackson Immuno
109-605-098) and 2 ug/ml 7AAD (Sigma A9400) was then added to each
well and the plates incubated for 15 minutes at 4.degree. C. Cells
were then washed one time and the amount of cell associated
Alexa647-labelled Ab was quantitated by flow cytometry. The
experiments included mock transfected controls. The data from these
experiments are presented in the Table below, n.d.=not
determined.
TABLE-US-00006 TABLE 6 Antibody Bin B Epitope Prediction Summary Hu
Mo Ra Pre- EC1- EC1- EC1- Ra Ra Hu dicted Clone Ab. 5 5 5 EC3c EC3b
EC3a Epitope ID ID Bin A I W X Y Z Region 4A9 13589 1 + - - n.d.
n.d. n.d. 44-141 26F12 13881 2 + - - n.d. n.d. n.d. Bin A 25F8
14096 2 + - - n.d. n.d. n.d. 26D1 13882 2 + - - n.d. n.d. n.d. 17H8
13874 3 + - - n.d. n.d. n.d. 16A4 14071 5 + - + n.d. n.d. n.d. 4A2
13592 4 + - + + - - 250- 364 4B10 13590 4 + - + + - - (324- 327)
Bin B.2 2G6 13588 4 + + + + + + 250-364 23A10 14077 4 + + + n.d.
n.d. n.d. Bin B.1 Rat anti- + + + + + + control FLAG + Positive
Binding - Negative Binding (n.d.) Not Determined Legend Table 6
Rat/mouse or human/mouse chimera constructs A = huCDH19(44-772)
(see SEQ ID NO: 944) I = muCDH19(44-770) (see SEQ ID NO: 966) W =
raCDH19(44-770) (see SEQ ID NO: 983) X =
muCDH19(44-323)::raCDH19(324-327)::muCDH19(328-770) (see SEQ ID NO:
984) Y = muCDH19(44-770)::raCDH19(290, 299, 308) (see SEQ ID NO:
985) Z = muCDH19(44-770)::huCDH19(271) (see SEQ ID NO: 986)
[0410] The data summarized in table 4 allowed for segregating the
binder of Bin B 250-364 into the following subgroups:
[0411] Bin B.1 250-364
[0412] Bin B.2 250-364 (324-327) by rodent numeration as referenced
in table 6, corresponding to residues (326-329) within human and
macaque CDH19.
Example 4--Hotspot/Covariant Mutants
[0413] A total of 18 antibodies were analyzed for potential
hotspots and covariance violations. The designed variants (shown
below) outline amino acid substitutions capable of reducing and/or
avoiding isomerization, deamidation, oxidation, covariance
violations, and the like. The 80 engineered variants together with
the 15 parental antibodies, thus totaling 95 sequences, were taken
forward to the cloning, expression, and purification processes.
Site-directed mutagenesis was performed on the engineered variants
in a 96-well format. The parental antibodies and engineered
variants were expressed by high throughput transient transfection
in HEK 293-6E cells, purified using a modified AKTA auto-sampler
and assayed for activity and biophysical characteristics. The 3
parental antibodies that had either free (unpaired) Cys or
N-glycosylation site were not taken forward in this process. Those
were replaced with the engineered version of the parental
antibodies. The designed variants outline amino acid substitutions
capable of reducing and/or avoiding isomerization, deamidation,
oxidation, covariance violations, immunogenicity and the like. It
will be appreciated that these variant sequences are examples of
engineered antibodies within the meaning of the present application
but single point and/or multiple point mutations can be combined in
any combinatorial manner in order to arrive at a final desired
antigen binding molecule or antibody.
Example 5--CDH19 mRNA Expression Pattern
[0414] RNA was extracted from individual patient tissues
representing tumor (>70% tumor content by cell count) or normal
(0% tumor content by cell count). Individual tissues were
homogenized using TisssueLyzer (Qiagen, Valencia, Calif.) and total
RNA extracted and purified by the mirVana total RNA extraction kit
(Life Technologies, Foster City, Calif.). RNA quality and quantity
checked by NanoDrop (NanoDrop, Wilmington, Del.) spectrophotometer
readings and Bioanalyzer RNA profiling (Agilient Technologies,
Santa Clara, Calif.). RNA was DNAse treated with DNA-free kit (Life
Technologies, Foster City, Calif.) and reverse transcribed
according to manufacturer's specifications using random hexamers in
the High Capacity cDNA Reverse Transcription Kit (Life
Technologies, Foster City, Calif.). Quantitative Real Time
Polymerase Chain Reaction (qRT-PCR) was performed on cDNA using
primers to CDH19, probeset Hs00253534_m1, (Life Technologies,
Foster City, Calif.) or the housekeeping gene human ACTB (primers
CCT GGC ACC CAG CAC AA; GCC GAT CCA CAC GGA GTA CT; probe ATC AAG
ATC ATT GCT CCT CCT GAG CG). 10 .mu.L qRT-PCR reaction components;
1.0 ng/.mu.L cDNA, 2.times. Universal PCR Master Mix (Life
Technologies, Foster City, Calif.), gene expression assay (ACTB; 75
nM primers, 150 nM probe. EPOR; 300 nM primers, 250 nM probe)
Following the qRT-PCR amplification program: (1) activation at
50.degree. C. for 2 min; (2) denaturation at 95.degree. C. for 10
min; (3) amplification 40 cycles at 95.degree. C. for 15 s and
60.degree. C. for 1 min with fluorescence capture at each step (ABI
PRISM 7900HT Sequence Detection Systems, Applied Biosystems).
Threshold cycle values (C.sub.T) were determined, using Sequence
Detector software version 2.3 (Applied Biosystems) and transformed
to 2.sup.-.DELTA.CT for relative expression of CDH19 specific
transcript to ACTB. The results are shown in FIG. 3. Of 54 unique
metastatic and primary melanoma samples, the majority can be seen
to overexpress CDH19 mRNA relative to the expression in samples
from normal tissue.
Example 6--CDH19 Protein Expression
[0415] Expression of CDH19 protein was analyzed in human tumor
samples by IHC and the results are shown in FIG. 4. Samples were
fixed in 10% neutral buffered formalin for 24 hours, dehydrated and
paraffin embedded. 4 .mu.m sections were cut. Sections were
deparaffinized first and then heated in DIVA Decloaker solution
(Biocare) for 40 minutes for antigen retrieval. Remaining IHC steps
were performed at room temperature in a DAKO Autostainer. Sections
were incubated for 10 minutes with Peroxidazed 1 (Biocare) to block
endogenous peroxidase, followed by incubation for 10 minutes with
background sniper (Biocare) to reduce nonspecific background.
Section were incubated for 60 minutes with CDH19 antibody (Novo
Biologicals, Catalog #H00028513-B01P) at 5 .mu.g/ml, then incubated
for 30 minutes with Envision+HRP anti-mouse polymer (DAKO),
followed by DAB+(DAKO) for 5 minutes. Sections were counterstained
with hematoxylin (DAKO) approximately for 1 minute. CDH19
expression could be detected in 62% of tumors examined (staining
intensity .gtoreq.1+ in 101 of 162 samples). 51% of the tumor
samples demonstrated medium to high expression (staining intensity
of 2+ to 3+ in 83 of 162 samples). CDH19 showed dense and distinct
membrane staining in many samples, although in some tumors
heterogeneity was noted.
Example 7--Selection of Model Cell Lines
[0416] Tumor cell lines were analyzed by flow cytometry and IHC to
identify model systems with CDH19 expression similar to human
tumors. Human anti-huCDH19 IgG4 antibody 4A2 was purified directly
from hybridoma conditioned media. For flow cytometry,
2.times.10.sup.5 cells were incubated with 200 nM of the CDH19 4A2
antibody that was conjugated to PE at a 1:1 ratio. The incubation
and subsequent wash steps were performed in the presence of 1.2 mM
calcium. A tube of QuantiBRITE PE lyophilized beads with four
levels of PE (BD, cat #340495) was simultaneously prepared
according to the manufacturer's instructions. The beads were
analyzed by flow cytometry to generate a standard curve. The PE
median values obtained from the melanoma lines after FACS analysis
were then calibrated against the standard curve to calculate the
antibodies bound per cell (ABC), which provides an estimate of the
number of receptors on each cell. IHC was performed as described in
Example 6 and the results are provided in FIG. 5. The melanoma cell
line CHL-1 expresses about 10,000 CDH19 molecules on the cell
surface, while Colo699 cells express about 5,000 receptors. Both
cell lines represent tumors with medium to high expression levels
based on IHC. Expression in A2058 is very low, while LOX cells do
not express any detectable CDH19 protein.
Example 8--Preparation of Antibody Drug Conjugates
[0417] DNA sequences encoding the heavy chain and light chain
components of anti-CDH19 antibodies were subcloned into mammalian
expression vector pTT5 and transiently co-transfected into 293-6E
cells, as described in published US2005/0170450 which is
incorporated in its entirety by reference. Antibodies were purified
from conditioned media by protein A affinity and ion exchange
chromatography. Antibodies were incubated at 3 to 5 mg/ml with 4 to
13 equivalents of SMCC-DM1 in neutral to slightly basic buffered
solutions containing 50 mM sodium chloride, 2 mM EDTA, and from 5
to 15% dimethylacetamide at room temperature for up to 5 hours or
at 4.degree. C. for up to 18 hours. Conjugation to DM1 and DAR
determination for conjugates, is described in U.S. Pat. No.
7,368,565 and related U.S. Pat. No. 7,851,432, which are herein
incorporated in their entirety by reference. Resultant antibody
drug conjugates (ADCs) were purified from solutes and unconjugated
drug by gel permeation or ion exchange chromatography. UV
spectrophotometric measurements at 252 nm and 280 nm combined with
respective molar extinction coefficients of SMCC-DM1 and antibody
as defined by amino acid composition were used to algebraically
determine the concentration of drug (CD) and antibody (CAb)
components of ADC preparations which could be used to calculate a
drug to antibody ratio (DAR) as described in U.S. Pat. No.
7,368,565. DAR determinations of ADCs were more accurately made by
similar algebraic calculations based on integrated peaks measured
at 252 nm and 280 nm in analytical size exclusion chromatography.
Orthogonal LC/MS methods were also used to qualitatively assess
random drug distribution profiles by mass. The table below
describes ADCs used in the experiments for which the results are
provided in FIG. 6 (lots 1,2), FIG. 7 (lots 3-10), and FIG. 8 (lots
11-14), which are representative of typical ADC preparations.
TABLE-US-00007 Exam- ADC ple lot ID hu anti-huCDH19 IgG1 antibody
DAR Fig. 6 1 13590 4B10 3.6 Fig. 6 2 1462 anti-SA
(anti-streptavidin control) 4.5 Fig. 7 3 13590 4B10 2.5 Fig. 7 4
13590 4B10 4.1 Fig. 7 5 13590 4B10 5.1 Fig. 7 6 13590 4B10 5.8 Fig.
7 7 13590 4B10 5 Fig. 7 8 13590 4B10 6.3 Fig. 7 9 13590 4B10 7.4
Fig. 7 10 1462 anti-SA (anti-streptavidin control) 6.5 Fig. 8 11
14096 25F8.1 (K45Q,S102A,D111E) 5.6 VL + (F90Y) VH Fig. 8 12 14045
17H8.2 (G149R) VL 4.7 Fig. 8 13 14054 4B10 (H450,A90T) VL + 5.2
(R17G) VH Fig. 8 14 1462 anti-SA (anti-streptavidin control)
5.3
Example 9--Activity of CDH19 Targeting ADCs in Model Cell Lines
[0418] The CDH19 recognizing parental antibody 4B10 (Ab ID 13590)
was covalently coupled to the toxin DM1 as described in Example 8.
The tumor cells were plated in 384-well microtiter plates on Day 1,
and on Day 2, the ADC was titrated on the cells and incubated for
additional 72 h. Cell viability was determined at the end of the
experiment with CellTiterGlo reagent (Promega) according to the
manufacturer's instructions. Unconjugated, free DM1 served as a
positive control, and a streptavidin recognizing antibody/DM1
conjugate served as a negative control to detect non specific
binding. IC50s were determined with a non-linear, 4 parameter curve
fit and are shown in FIG. 6.
Example 10--Effect of Drug to Antibody Ratio (DAR) on ADC
Potency
[0419] In order to assess the effect of the drug antibody ratio on
the potency of the ADC molecule, the CDH19 recognizing parental
antibody 4B10 (Ab ID 13590) was coupled with different amounts of
DM1 as indicated in FIG. 7. The effect of DARs on ADC potency was
determined in cell viability assays as described in Example 9. An
increased DAR leads to increases in potency for a given DM1
concentration. This effect is more pronounced on tumor cells with
lower CDH19 expression.
Example 11--Efficacy of CDH19 Targeting ADCs In Vivo
[0420] Three CDH19 recognizing engineered variant antibodies (Ab
IDs 14096, 14045, 14054) were coupled to DM1 and tested in
xenograft experiments. CHL-1 cells were suspended in a solution of
50% serum free medium and 50% Matrigel, and implanted
subcutaneously in the flank of female athymic nude mice. Each mouse
received five million cells in a volume of 200 .mu.l. When tumors
reached approximately 200 mm.sup.3, mice were sorted into seven
groups of 10 mice each with equivalent mean and SD tumor size per
group, and dosed with test agents or controls. All treatments were
administered IV in a volume of 200 .mu.l. Tumors were measured two
times per week using calipers. Length, width and height
measurements were taken A repeated measures ANOVA with Dunnett's
post-hoc test was used to compare the difference in tumor volume
between each CDH19 targeting ADC and a non-specific control ADC
(anti-streptavidin coupled to DM1). The percentage of tumor growth
inhibition was calculated for each CDH19 targeting ADC compared to
the corresponding unconjugated antibody. All three reagents
demonstrate significant inhibition of tumor growth in mice as shown
in FIG. 8.
Example 12--Internalization of CDH19 Following ADC Binding
[0421] Human anti-huCDH19 IgG4 antibody 4A2 was purified directly
from hybridoma conditioned media and conjugated with SMCC-DM1 as
described in example 8. Because the exact sequence of parental 4A2
was unknown at the time, the DAR of this IgG4 ADC was estimated to
be 4.4 using a molecular weight of 150,000 Da and an extinction
coefficient of 225,000 at 280 nm. CHL-1 melanoma cells were
incubated with either unconjugated or DM1 conjugated CDH19
recognizing parental antibody 4A2 in complete medium at 4.degree.
C. or for 2 h at 37.degree. C. After a brief wash in PBS, cells
were fixed in 3% formaldehyde/PBS for 20 min. Fixed cells were
washed, blocked and permeabilized in TBST/1% BSA/5% normal donkey
serum/0.3% TX-100 and incubated with rabbit anti-EEA1 (CST #3288).
Following another wash step, the samples were incubated with donkey
anti mouse Alexa 488 and donkey anti rabbit Alexa 554. Images were
taken with a 63.times. oil lens on a Zeiss LSM 510 confocal
microscope. A review of the images demonstrate that both the
parental and DM1 conjugated antibody detect the membrane bound
CDH19 at 4.degree. C. but get quickly internalized and co-localize
with endosome markers at 37.degree. C. Thus, both the unconjugated
and DM1 conjugated CDH19 antibodies are internalized by melanoma
cells, and the conjugation of the drug does not appear to interfere
with the internalization of the CDH19 antibody.
Example 13--Efficacy of CDH19 Targeting ADCs In Vivo
[0422] 13.1: 4B10-DM1 Moderately Inhibited Tumor Growth at 182
.mu.g/kg DM1 in CHL-1 Xenografts
[0423] A study was conducted to examine the effect of the
anti-CDH19 ADC 4B10-DM1 administered once per week for two weeks in
CHL-1 xenografts. CHL-1 cells were suspended in a solution of 50%
serum free medium and 50% Matrigel, and implanted subcutaneously in
the flank of female athymic nude mice. Each mouse received five
million cells in a volume of 200 .mu.l. When tumors reached
approximately 150 mm3, mice were sorted into groups of 10 mice each
with equivalent mean and SD tumor size per group and dosed with
test agents or controls. All treatments were administered IV in a
volume of 200 .mu.l. Tumors were measured two times per week using
calipers (length, width and height measurement). Body weights were
recorded at each measurement. A repeated measures ANOVA with
Dunnett's post-hoc test was used to compare the difference in tumor
volume between mice treated with 4B10-DM1 and the ADC control. The
percentage of tumor growth inhibition was calculated against the
ADC control. The results are shown in FIG. 9.
[0424] 13.2: Increasing the DAR Did not Increase Tumor Growth
Inhibition in CHL-1 Xenografts
[0425] A study was conducted to examine the effect of drug:antibody
ratio (DAR) on efficacy of the anti-CDH19 ADC 4B10-DM1 administered
once per week for two weeks in CHL-1 xenografts. CHL-1 cells were
suspended in a solution of 50% serum free medium and 50% Matrigel,
and implanted subcutaneously in the flank of female athymic nude
mice. Each mouse received five million cells in a volume of 200
.mu.l. When tumors reached approximately 200 mm3, mice were sorted
into groups of 10 mice each with equivalent mean and SD tumor size
per group and dosed with test agents or controls. All treatments
were administered IV in a volume of 200 .mu.l. Tumors were measured
two times per week using calipers (length, width and height
measurement). Body weights were recorded at each measurement. A
repeated measures ANOVA with Dunnett's post-hoc test was used to
compare the difference in tumor volume between mice treated with
4B10-DM1 and the ADC control. The percentage of tumor growth
inhibition was calculated against the ADC control. The results are
shown in FIG. 10.
[0426] 13.3: Anti-CDH19 ADCs Moderately Inhibited Tumor Growth in
COLO699 Xenografts
[0427] A study was conducted to examine the effects of anti-CDH19
ADC 4B10-DM1 and an optimized variant administered once per week
for two weeks on COLO699 xenografts. COLO699 cells were suspended
in a solution of 50% serum free medium and 50% Matrigel, and
implanted subcutaneously in the flank of female athymic nude mice.
Each mouse received five million cells in a volume of 200 .mu.l.
When tumors reached approximately 200 mm3, mice were sorted into
groups of 10 mice each with equivalent mean and SD tumor size per
group, and dosed with test agents or controls. All treatments were
administered IV in a volume of 200 .mu.l. Tumors were measured two
times per week using calipers (length, width and height
measurement). Body weights were recorded at each measurement. A
repeated measures ANOVA with Dunnett's post-hoc test was used to
compare the difference in tumor volume between mice treated with
4B10-DM1 and the ADC control. The percentage of tumor growth
inhibition was calculated against the ADC control. A similar study
was conducted as described above (data not shown) that resulted in
the same trends for tumor growth inhibition, however, that study
did not reach statistical significance. The results are shown in
FIG. 11.
[0428] Sequence Table:
TABLE-US-00008 TABLE Ia HEAVY CHAIN CDRs Ab Type CDR 1 CDR 2 CDR 3
1D10 NA AGCTATGGCATGCAC GTTATATGGTATGATGGAAGT AGGGCCGGTATAATAGGAAC
2C12 AATAAATACTATGCAGACTCC TACAGGCTACTACTACGGTA GTGAAGGGC TGGACGTC
SEQ ID NO: 1 SEQ ID NO: 2 SEQ ID NO: 3 AA SYGMH VIWYDGSNKYYADSVKG
RAGIIGTTGYYYGMDV SEQ ID NO: 4 SEQ ID NO: 5 SEQ ID NO: 6 1F10 NA
AGTGGTGGTTACTACT TACATCTATTACAGTGGGAGC GATGGAAGCAGTGGCTGGTA GGAGC
ACCTACTACAACCCGTCCCTC CTTCCAGCAC ACGAGT SEQ ID NO: 7 SEQ ID NO: 8
SEQ ID NO: 9 AA SGGYYWS YIYYSGSTYYNPSLTS DGSSGWYFQH SEQ ID NO: 10
SEQ ID NO: 11 SEQ ID NO: 12 2C12_LC#1 NA AGCTATGGCATGCAC
GTTATATGGTATGATGGAAGT AGGGCCGGTATAATAGGAAC AATAAATACTATGCAGACTCC
TACAGGCTACTACTACGGTA GTGAAGGGC TGGACGTC SEQ ID NO: 13 SEQ ID NO: 14
SEQ ID NO: 15 AA SYGMH VIWYDGSNKYYADSVKG RAGIIGTTGYYYGMDV SEQ ID
NO: 16 SEQ ID NO: 17 SEQ ID NO: 18 2G6_LC#1 NA AGCTATGGCATGCAC
TTTATATGGTATGATGGAAGT AGGGCCGGTATAATAGGAAC AATAAATACTATGCAGACTCC
TATAGGCTACTACTACGGTA GTGAAGGAC TGGACGTC SEQ ID NO: 19 SEQ ID NO: 20
SEQ ID NO: 21 AA SYGMH FIWYDGSNKYYADSVKD RAGIIGTIGYYYGMDV SEQ ID
NO: 22 SEQ ID NO: 23 SEQ ID NO: 24 2G6 NA AGCTATGGCATGCAC
TTTATATGGTATGATGGAAGT AGGGCCGGTATAATAGGAAC AATAAATACTATGCAGACTCC
TATAGGCTACTACTACGGTA GTGAAGGAC TGGACGTC SEQ ID NO: 25 SEQ ID NO: 26
SEQ ID NO: 27 AA SYGMH FIWYDGSNKYYADSVKD RAGIIGTIGYYYGMDV SEQ ID
NO: 28 SEQ ID NO: 29 SEQ ID NO: 30 2H12 NA AGCTATGGCATGCAC
GTTATATGGTATGATGGAAGT AGGGCCGGTATAATAGGAAC AATAAATACTATACAGACTCC
TACAGGCTACTACTACGGTA GTGAAGGGC TGGACGTC SEQ ID NO: 31 SEQ ID NO: 32
SEQ ID NO: 33 AA SYGMH VIWYDGSNKYYTDSVKG RAGIIGTTGYYYGMDV SEQ ID
NO: 34 SEQ ID NO: 35 SEQ ID NO: 36 2H12_LC#2 NA AGCTATGGCATGCAC
GTTATATGGTATGATGGAAGT AGGGCCGGTATAATAGGAAC AATAAATACTATACAGACTCC
TACAGGCTACTACTACGGTA GTGAAGGGC TGGACGTC SEQ ID NO: 37 SEQ ID NO: 38
SEQ ID NO: 39 AA SYGMH VIWYDGSNKYYTDSVKG RAGIIGTTGYYYGMDV SEQ ID
NO: 40 SEQ ID NO: 41 SEQ ID NO: 42 4A2 NA AGTAGTGGTTACTACT
TACATCTATTACACTGGGAGC GATGGAAGCAGTGGCTGGTA 5B4 GGAGC
GCCTACTACAACCCGTCCCTC CTTCCAGTAT 5C5 AAGAGT SEQ ID NO: 43 SEQ ID
NO: 44 SEQ ID NO: 45 AA SSGYYWS YIYYTGSAYYNPSLKS DGSSGWYFQY SEQ ID
NO: 46 SEQ ID NO: 47 SEQ ID NO: 48 4A9 NA GGTTACTACTGGAGC
TATTTCTCTTACAGTGGGAGC AACTGGGCCTTCCACTTTGA ACCAACTACAACCCCTCCCTC
CTTC AAGAGT SEQ ID NO: 49 SEQ ID NO: 50 SEQ ID NO: 51 AA GYYWS
YFSYSGSTNYNPSLKS NWAFHFDF SEQ ID NO: 52 SEQ ID NO: 53 SEQ ID NO: 54
4B10 NA AGCTATGACATGCAC GTTATATCATATGATGGAACT GAACGATATTTTGACTGGTC
4C2 AATGAATACTATGCAGACTCC TTTTGACTAC GTGAAGGGC SEQ ID NO: 55 SEQ ID
NO: 56 SEQ ID NO: 57 AA SYDMH VISYDGTNEYYADSVKG ERYFDWSFDY SEQ ID
NO: 58 SEQ ID NO: 59 SEQ ID NO: 60 4D2 NA AGTTATGACATGCAC
GTTATATCATATGATGGAACT GAACGATATTTTGACTGGTC AATGAATACTATGCAGACTCC
TTTTGACTAC GTGAAGGGC SEQ ID NO: 61 SEQ ID NO: 62 SEQ ID NO: 63 AA
SYDMH VISYDGTNEYYADSVKG ERYFDWSFDY SEQ ID NO: 64 SEQ ID NO: 65 SEQ
ID NO: 66 4D3 NA AGCTATGACATGGAC GTTATATGGTATGATGGAAGT
GAAACTGGGGAGGgCTGGTA 4F3 AATAAAtacTATGCAGACTCC CTTCGAtctc GTGAGGGGC
SEQ ID NO: 67 SEQ ID NO: 68 SEQ ID NO: 69 AA SYDMD
VIWYDGSNKYYADSVRG ETGEGWYFDL SEQ ID NO: 70 SEQ ID NO: 71 SEQ ID NO:
72 4E10 NA AGCTATGACATGCAC GTTATATGGTATGATGGAAGT
GAGTATAGGTACAGCTGGTA AATAAATACTATGCAGACTCC CTTTGACTAC GTGAAGGGC SEQ
ID NO: 73 SEQ ID NO: 74 SEQ ID NO: 75 AA SYDMH VIWYDGSNKYYADSVKG
EYRYSWYFDY SEQ ID NO: 76 SEQ ID NO: 77 SEQ ID NO: 78 4F7 NA
AGTTACTCCTGGAGC TATATCTATTACAGTGGGAGC AACTGGGCCTTCCACTTTGA
ACCAACTACAACCCCTCCCTC CTAC AAGAGT SEQ ID NO: 79 SEQ ID NO: 80 SEQ
ID NO: 81 AA SYSWS YIYYSGSTNYNPSLKS NWAFHFDY SEQ ID NO: 82 SEQ ID
NO: 83 SEQ ID NO: 84 5E3 NA AGCTATAGCATGCAC TCCATTAGTAGTAGTAGTAGT
GGGGAAACTGGAACTAACTA TACATATACTACGCAGACTCA CTACTACTACGGTATGGACG
GTGAAGGGC TC SEQ ID NO: 85 SEQ ID NO: 86 SEQ ID NO: 87 AA SYSMH
SISSSSSYIYYADSVKG GETGTNYYYYGMDV SEQ ID NO: 88 SEQ ID NO: 89 SEQ ID
NO: 90 17H8 NA AGTTACTACTGGAGC TATATCTATTACATTGGGAGC
GATTCCCGGTATAGAAGTGG 23B6 ACCAACTACAACCCCTCCCTC
CTGGTACGATGCTTTTGATA 28D10 AAGAGT TC SEQ ID NO: 91 SEQ ID NO: 92
SEQ ID NO: 93 AA SYYWS YIYYIGSTNYNPSLKS DSRYRSGWYDAFDI SEQ ID NO:
94 SEQ ID NO: 95 SEQ ID NO: 96 16C1 NA GGTTACTACTGGAGC
TATATCTATTACATTGGGAGC GATGGGAGCAGTGGCTGGTA ACCAACTACAACCCCTCCCTC
CCGGTGGTTCGACCCC AAGAGT SEQ ID NO: 97 SEQ ID NO: 98 SEQ ID NO: 99
AA GYYWS YIYYIGSTNYNPSLKS DGSSGWYRWFDP SEQ ID NO: 100 SEQ ID NO:
101 SEQ ID NO: 102 16A4 NA AGTTACTACTGGAGC TATATCTATTACAGTGGGAGC
GATCAAAGGCGGATAGCAGC ACCAATTACAACCCCTCCCTC AGCTGGTACCCACTTCTACG
AAGAGT GTATGGACGTC SEQ ID NO: 103 SEQ ID NO: 104 SEQ ID NO: 105 AA
SYYWS YIYYSGSTNYNPSLKS DQRRIAAAGTHFYGMDV SEQ ID NO: 106 SEQ ID NO:
107 SEQ ID NO: 108 16E2 NA AGCTATGGCATGCAC GTGATATGGTATGATGGAAGT
GACGGGTGGGAGCTGTCCTT 17E10 AATAAATACTATGCAGACTCC TGACTAC 20B12
GTGAAGGGC SEQ ID NO: 109 SEQ ID NO: 110 SEQ ID NO: 111 AA SYGMH
VIWYDGSNKYYADSVKG DGWELSFDY SEQ ID NO: 112 SEQ ID NO: 113 SEQ ID
NO: 114 22G10 NA AGTTATGCCATGAAC ACTATTAGTGGTGGTGGTGCT
GGGGGAATGGGGGGATACTA AACACATACTACGCAGACTCC CTACGGTATGGACGTC
GTGAAGGGC SEQ ID NO: 115 SEQ ID NO: 116 SEQ ID NO: 117 AA SYAMN
TISGGGANTYYADSVKG GGMGGYYYGMDV SEQ ID NO: 118 SEQ ID NO: 119 SEQ ID
NO: 120 16H2 NA AGCTACTTTATTCAC ATAATCAACCCTATTAGTGTT
GGGGGGATACAGCTATGGTT 20D3 AGCACAAGCTACGCACAGAAG ACATTTTGACTAC 23E7
TTCCAGGGC SEQ ID NO: 121 SEQ ID NO: 122 SEQ ID NO: 123 AA SYFIH
IINPISVSTSYAQKFQG GGIQLWLHFDY SEQ ID NO: 124 SEQ ID NO: 125 SEQ ID
NO: 126 22D1 NA AGCTACTTTATTCAC ATAATCAACCCTATTAGTGTT
GGGGGGATACAGCTATGGTT AGCACAAGCTACGCACAGAAG ACATTTGGACTAC TTCCAGGGC
SEQ ID NO: 127 SEQ ID NO: 128 SEQ ID NO: 129 AA SYFIH
IINPISVSTSYAQKFQG GGIQLWLHLDY SEQ ID NO: 130 SEQ ID NO: 131 SEQ ID
NO: 132 25F8 NA AGCTACTATATTCAC ATAATCAACCCCAGTGGTGGT
GGGGGAATACAGCTATGGTT AGCACAAGGTACGCACAGAAG ACATTttGACTAC TTCCAGGGC
SEQ ID NO: 133 SEQ ID NO: 134 SEQ ID NO: 135 AA SYYIH
IINPSGGSTRYAQKFQG GGIQLWLHFDY SEQ ID NO: 136 SEQ ID NO: 137 SEQ ID
NO: 138 26F12 NA AACTACTATATGTCC ATAATCAACCCTAGTGGTGGT
GGGGGGATACAACTATGGTT 27B3 GACTCAACCTACGCACAGAAG ACATTTTGACTAC
TTCCAGGGC SEQ ID NO: 139 SEQ ID NO: 140 SEQ ID NO: 141 AA NYYMS
IINPSGGDSTYAQKFQG GGIQLWLHFDY SEQ ID NO: 142 SEQ ID NO: 143 SEQ ID
NO: 144 26D1 NA AGCTACTATATGTCC ATAATCCACCCTAGTGGTGGT
GGGGGGATAAAACTATGGTT GACACAACCTACGCACAGAAG ACATTTTGACTAT TTCCAGGGC
SEQ ID NO: 145 SEQ ID NO: 146 SEQ ID NO: 147 AA SYYMS
IIHPSGGDTTYAQKFQG GGIKLWLHFDY SEQ ID NO: 148 SEQ ID NO: 149 SEQ ID
NO: 150 25G10 NA GGTTACTACTGGAGC TATATCTATTACATTGGGAGC
GATGGGAGCAGTGGCTGGTA ACCAACTACAACCCCTCCCTC CCGGTGGTTCGACCCC AAGAGT
SEQ ID NO: 151 SEQ ID NO: 152 SEQ ID NO: 153 AA GYYWS
YIYYIGSTNYNPSLKS DGSSGWYRWFDP SEQ ID NO: 154 SEQ ID NO: 155 SEQ ID
NO: 156 23A10 NA CGCTATGGCATACAC GTTATATGGTATGATGGAAGT
AGGGCCGGTATACCTGGAAC AATAAATACTATGCAGACTCC TACGGGCTACTACTATGGTA
GTGAAGGGC TGGACGTC SEQ ID NO: 157 SEQ ID NO: 158 SEQ ID NO: 159 AA
RYGIH VIWYDGSNKYYADSVKG RAGIPGTTGYYYGMDV SEQ ID NO: 160 SEQ ID NO:
161 SEQ ID NO: 162 19B5 NA AGCTACTTTATTCAC ATTATCAACCCTATTAGTGTT
GGGGGGATACAGCTATGGTT AGCACAAGCTACGCACAGAAG ACATTTGGACTAC TTCCAGGGC
SEQ ID NO: 163 SEQ ID NO: 164 SEQ ID NO: 165 AA SYFIH
IINPISVSTSYAQKFQG GGIQLWLHLDY SEQ ID NO: 166 SEQ ID NO: 167 SEQ ID
NO: 168
TABLE-US-00009 TABLE Ib LIGHT CHAIN CDRs Ab Type CDR 1 CDR 2 CDR 3
1D10 NA TCTGGAGATAGATTGG CAAGATACCAAGCGGCCCTCA CAGGCGTGGGACAGCAGCAC
2C12 GGGAAAAATATACTTG TGTGGTA C SEQ ID NO: 169 SEQ ID NO: 170 SEQ
ID NO: 171 AA SGDRLGEKYTC QDTKRPS QAWDSSTVV SEQ ID NO: 172 SEQ ID
NO: 173 SEQ ID NO: 174 1F10 NA AGGGCCAGTCGGAGTA
GGTCCATCCAGCAGGGCCACT CAGCAGTATGGTAGCTCATT TTAGCAGCAGCTACTT CACT
AGCC SEQ ID NO: 175 SEQ ID NO: 176 SEQ ID NO: 177 AA RASRSISSSYLA
GPSSRAT QQYGSSFT SEQ ID NO: 178 SEQ ID NO: 179 SEQ ID NO: 180
2C12_LC#1 NA AGGtCTAGTCAAAGcc AAGGTTTCTAACTGGGactct
ATGCAAGGTATAGTGTGGCC tcgtaTACAGTGATGG GTGCAGT AAACAcctACTTGAAT SEQ
ID NO: 181 SEQ ID NO: 182 SEQ ID NO: 183 AA RSSQSLVYSDGNTYLN
KVSNWDS MQGIVWPCS SEQ ID NO: 184 SEQ ID NO: 185 SEQ ID NO: 186
2G6_LC#1 NA AGGTCTAGTCAAAGCC CAGGTTTCTAACTGGGACTCT
ATGCAAGATACACTGTGGCC TCGTATACAGTGATGG GTGCAGT AAACACCTACTTGAAT SEQ
ID NO: 187 SEQ ID NO: 188 SEQ ID NO: 189 AA RSSQSLVYSDGNTYLN
QVSNWDS MQDTLWPCS SEQ ID NO: 190 SEQ ID NO: 191 SEQ ID NO: 192 2G6
NA TCTGGAGATAGGTTGG CAAGATACCAAGCGGCCCTCA CAGGCGTGGGACAGCAGCAC
GGGAAAAATATACTTG TGTGGTA C SEQ ID NO: 193 SEQ ID NO: 194 SEQ ID NO:
195 AA SGDRLGEKYTC QDTKRPS QAWDSSTVV SEQ ID NO: 196 SEQ ID NO: 197
SEQ ID NO: 198 2H12 NA TCTGGAGATAGATTGG CAAGATACCAAGCGGCCCTCA
CAGGCGTGGGACAGCAGCAC GGGAAAAATATACTTG TGTGGTA C SEQ ID NO: 199 SEQ
ID NO: 200 SEQ ID NO: 201 AA SGDRLGEKYTC QDTKRPS QAWDSSTVV SEQ ID
NO: 202 SEQ ID NO: 203 SEQ ID NO: 204 2H12_LC#2 NA AGGTCTAGTCAAAGCC
AAGGTTTCTAACTGGGACTCT ATGCAAGATACACTGTGGCC TCGTATACAGTGATGG GTGCAGT
AAACACCTACTTGAAT SEQ ID NO: 205 SEQ ID NO: 206 SEQ ID NO: 207 AA
RSSQSLVYSDGNTYLN KVSNWDS MQDTLWPCS SEQ ID NO: 208 SEQ ID NO: 209
SEQ ID NO: 210 4A2 NA AGGgcCAGTCGGAATA GGTCCATCCAGCAGGGccaCT
CAGCAGTATGGtagctCATT 5B4 TTAGCAGCAGCTACtt CACT 5C5 aGCC SEQ ID NO:
211 SEQ ID NO: 212 SEQ ID NO: 213 AA RASRNISSSYLA GPSSRAT QQYGSSFT
SEQ ID NO: 214 SEQ ID NO: 215 SEQ ID NO: 216 4A9 NA
ACTGGGAGCAGCTCCA GGTAACAACAATCGGCCCTCA CAGTCCTATGACAGCagACT
ACATCGGGACAGGTTA GAGTGGTTGGGTG TGCTGTACAC SEQ ID NO: 217 SEQ ID NO:
218 SEQ ID NO: 219 AA TGSSSNIGTGYAVH GNNNRPS QSYDSRLSGWV SEQ ID NO:
220 SEQ ID NO: 221 SEQ ID NO: 222 4B10 NA AGGGCCAGTCAGAGTG
GGTGCATCCAGCAGGGCCACT CAGCAGTACAGTAACTCgtg 4C2 TTAGCAACACCTACTT
GACG AGCC SEQ ID NO: 223 SEQ ID NO: 224 SEQ ID NO: 225 AA
RASQSVSNTYLA GASSRAT QQYSNSWT SEQ ID NO: 226 SEQ ID NO: 227 SEQ ID
NO: 228 4D2 NA AGGGCCAGTCAGAGTG GGTGCATCCAGCAGGGCCGCT
CagcagTATAGTAacTcgtg TTAGCAACACCTACTT GACG AGCC SEQ ID NO: 229 SEQ
ID NO: 230 SEQ ID NO: 231 AA RASQSVSNTYLA GASSRAA QQYSNSWT SEQ ID
NO: 232 SEQ ID NO: 233 SEQ ID NO: 234 4D3 NA AGGGCCAGTCAGAGTG
GGTGCATCCAGCAGGGCCACT CAGCAGTATGGTAGCTCGTG 4F3 TTAGCAGCAGCTACTT
GACG AGCC SEQ ID NO: 235 SEQ ID NO: 236 SEQ ID NO: 237 AA
RASQSVSSSYLA GASSRAT QQYGSSWT SEQ ID NO: 238 SEQ ID NO: 239 SEQ ID
NO: 240 4E10 NA AGGGCCAGTCAGAGTG GGTGCATCCAGCAGGGTCACT
CAGCAATATAGTAACTCGTG TTGGCAGCAGCTACTT GACG AGCC SEQ ID NO: 241 SEQ
ID NO: 242 SEQ ID NO: 243 AA RASQSVGSSYLA GASSRVT QQYSNSWT SEQ ID
NO: 244 SEQ ID NO: 245 SEQ ID NO: 246 4F7 NA ACTGGGAGCAGCTCCA
GGTAACAGCAATCGGCCCTCA CAGTCCTATGACAGCAGTCT ATATCGGGACAGGTTA
GAGTGGTTGGGTG TGATGTACAC SEQ ID NO: 247 SEQ ID NO: 248 SEQ ID NO:
249 AA TGSSSNIGTGYDVH GNSNRPS QSYDSSLSGWV SEQ ID NO: 250 SEQ ID NO:
251 SEQ ID NO: 252 5E3 NA TCTGGAGATAAATTGG CAAGATAGCAAGCGGCCCTCA
CAGGCGTGGGACAGCAGCAC GGGATGAATATGCTTG TGTGGTA C SEQ ID NO: 253 SEQ
ID NO: 254 SEQ ID NO: 255 AA SGDKLGDEYAC QDSKRPS QAWDSSTVV SEQ ID
NO: 256 SEQ ID NO: 257 SEQ ID NO: 258 17H8 NA AGGGCCAGTCAGAGTG
GGTGCATCCAGCAGGGCCACT CAGCAGTATGGTAAATCACC 23B6 TTGCCGGCAGCTACCT
GATCACC 28D10 AGCC SEQ ID NO: 259 SEQ ID NO: 260 SEQ ID NO: 261 AA
RASQSVAGSYLA GASSRAT QQYGKSPIT SEQ ID NO: 262 SEQ ID NO: 263 SEQ ID
NO: 264 16C1 NA AGGGCCAGCCAGAGTG GGTGCATCCAGCAGGGCCACT
CAGCAGTATGGTAACTCACC TTAGCAGCAGCTACTT GCTCACT AGCC SEQ ID NO: 265
SEQ ID NO: 266 SEQ ID NO: 267 AA RASQSVSSSYLA GASSRAT QQYGNSPLT SEQ
ID NO: 268 SEQ ID NO: 269 SEQ ID NO: 270 16A4 NA AGGGCCAGTCAGAGTG
GGTACATCCAGCAGGGCCACT CAGCAGTACGGTAGCTCACC TTAGCAGCAGTTATTT TTTCACT
AGCC SEQ ID NO: 271 SEQ ID NO: 272 SEQ ID NO: 273 AA RASQSVSSSYLA
GTSSRAT QQYGSSPFT SEQ ID NO: 274 SEQ ID NO: 275 SEQ ID NO: ***276
16E2 NA CGGGCGAGTCAGGGCA GCTGCATCCAGTTTGCAAAGT CAACACTATTTTACTTACCC
17E10 TTAGCAATTATTTAGC TCGGACG 20B12 C SEQ ID NO: 277 SEQ ID NO:
278 SEQ ID NO: 279 AA RASQGISNYLA AASSLQS QHYFTYPRT SEQ ID NO: 280
SEQ ID NO: 281 SEQ ID NO: 282 22G10 NA AGGGCCAGTCAGAGTA
GGTGCATTTACCAGGGCCACT CAGCAGTATAATTACTGGCC TTAGCAGCAACTTAGC GCTCACT
C SEQ ID NO: 283 SEQ ID NO: 284 SEQ ID NO: 285 AA RASQSISSNLA
GAFTRAT QQYNYWPLT SEQ ID NO: 286 SEQ ID NO: 287 SEQ ID NO: 288 16H2
NA TCTGGAAGCAGCTCCA ACTAATAATCAGCGGCCCTCA GCAACATGGGATGACAGCCT 20D3
ACATCGGAAGTAATTT GAATGGTTGGGTG 23E7 TGTAAAC SEQ ID NO: 289 SEQ ID
NO: 290 SEQ ID NO: 291 AA SGSSSNIGSNFVN TNNQRPS ATWDDSLNGWV SEQ ID
NO: 292 SEQ ID NO: 293 SEQ ID NO: 294 22D1 NA TCTGGAAGCAGCTCCA
ACTAATAATCAGCGGCCCTCA GCAACATGGGATGACAGTAT ACATCGGAAGCAATTT
GAATGGTTGGGTG TGTAAAC SEQ ID NO: 295 SEQ ID NO: 296 SEQ ID NO: 297
AA SGSSSNIGSNFVN TNNQRPS ATWDDSMNGWV SEQ ID NO: 298 SEQ ID NO: 299
SEQ ID NO: 300 25F8 NA TCTGGAAGCAGCTCCA ACTAATAATCAGCGGCCCTCA
GCAGCATGGGATGACAGCCT ACATCGGAAGGAATTT GAATGGTTGGGTG TGTAAAC SEQ ID
NO: 301 SEQ ID NO: 302 SEQ ID NO: 303 AA SGSSSNIGRNFVN TNNQRPS
AAWDDSLNGWV SEQ ID NO: 304 SEQ ID NO: 305 SEQ ID NO: 306 26F12 NA
TCTGGAAGCCGCTCCA ACTAATTATCAGCGGCCCTCA GCAGTATGGGATGACAGCCT 27B3
ACATCGGAAGTAATTT GAATGGTTGGGTG TGTAAAC SEQ ID NO: 307 SEQ ID NO:
308 SEQ ID NO: 309 AA SGSRSNIGSNFVN TNYQRPS AVWDDSLNGWV SEQ ID NO:
310 SEQ ID NO: 311 SEQ ID NO: 312 26D1 NA TCTGGAAGCCGCTCCA
ACTAATAATCAGCGGCCCTCA GCAGTATGGGATGACAGCCT ACATCGGAAGTAATTT
GAATGGTTGGGTG TGTAAAC SEQ ID NO: 313 SEQ ID NO: 314 SEQ ID NO: 315
AA SGSRSNIGSNFVN TNNQRPS AVWDDSLNGWV SEQ ID NO: 316 SEQ ID NO: 317
SEQ ID NO: 318 25G10 NA AGGGCCAGTCAGAGTG GGTGCATCCAGCAGGGCCACT
CAGCAGTATGGTAACTCACC TTAGCAGCAGCTACTT GCTCACT AGCC SEQ ID NO: 319
SEQ ID NO: 320 SEQ ID NO: 321 AA RASQSVSSSYLA GASSRAT QQYGNSPLT SEQ
ID NO: 322 SEQ ID NO: 323 SEQ ID NO: 324 23A10 NA TCTGGAGATAGATTGG
CAAGATAATAAGTGGCCCTCA CAGGCGTGGGACAGCAGcac GGGAGAAATATGTTTG TGTGGTA
C SEQ ID NO: 325 SEQ ID NO: 326 SEQ ID NO: 327 AA SGDRLGEKYVC
QDNKWPS QAWDSSTVV SEQ ID NO: 328 SEQ ID NO: 329 SEQ ID NO: 330 19B5
NA TCTGGAAGCAGGTCCA ACTAATAATCAGCGGCCCTCA GCAACATGGGATGACAGTAT
ACATCGGAAGCAATTT GAATGGTTGGGTG TGTAAAC SEQ ID NO: 331 SEQ ID NO:
332 SEQ ID NO: 333 AA SGSRSNIGSNFVN TNNQRPS ATWDDSMNGWV SEQ ID NO:
334 SEQ ID NO: 335 SEQ ID NO: 336
[0429] Anti-CDH19 Variable Region Amino Acid Sequences and
Polynucleotide Sequences
TABLE-US-00010 TABLE IIa Heavy Chain Variable Region Polynucleotide
and Amino acid Sequences SEQ ID NO. DESIGNATION SOURCE TYPE
SEQUENCE 337 17H8 artificial nt
CAGGTGCAGCTGCAGGAGTCGGGCCCAGGACTGGTGAAGCCTT 23B6
CGGAGACCCTGTCCCTCACGTGCACTGTCTCTGGTGGCTCCAT 28D10
CAATAGTTACTACTGGAGCTGGATCCGGCAGCCCCCAGGGAAG
GGACTGGAGTGGATTGGGTATATCTATTACATTGGGAGCACCA
ACTACAACCCCTCCCTCAAGAGTCGCGTCACCATATCAGTAGA
CACGTCCAAGAACCAGTTCTCCCTGAAGCTGAGCTCTGTGACC
GCTGCGGACACGGCCCTGTATTACTGTGCGAGAGATTCCCGGT
ATAGAAGTGGCTGGTACGATGCTTTTGATATCTGGGGCCAAGG GACAATGGTCACCGTCTCTTCA
338 17H8 artificial aa QVQLQESGPGLVKPSETLSLTCTVSGGSINSYYWSWIRQPPGK
23B6 GLEWIGYIYYIGSTNYNPSLKSRVTISVDTSKNQFSLKLSSVT 28D10
AADTALYYCARDSRYRSGWYDAFDIWGQGTMVTVSS 339 4A2 artificial nt
CAGGTGCAGCTGCAGGAGTCGGGCCCAGGACTGGTGAAGCCTT 5B4
CACAGACCCTGTCCCTCACCTGCACTGTCTCTGGTGGCTCCAT 5C5
CAGCAGTAGTGGTTACTACTGGAGCTGGATCCGCCAGCACCCA
GGGAAGGGCCTGGAGTGGATTGGGTACATCTATTACACTGGGA
GCGCCTACTACAACCCGTCCCTCAAGAGTCGAGTTACCATATC
AGTAGACACGTCTAAGAACCAGTTCTCCCTGAAGCTGAGCTCT
GTGACTGCCGCGGACACGGCCGTGTATTACTGTGCGAGAGATG
GAAGCAGTGGCTGGTACTTCCAGTATTGGGGCCAGGGCACCCT GGTCACCGTCTCCTCA 340
4A2 artificial aa QVQLQESGPGLVKPSQTLSLTCTVSGGSISSSGYYWSWIRQHP 5B4
GKGLEWIGYIYYTGSAYYNPSLKSRVTISVDTSKNQFSLKLSS 5C5
VTAADTAVYYCARDGSSGWYFQYWGQGTLVTVSS 341 16H2 artificial nt
CAGGTGCAGCTGGTGCAGTCTGGGGCTGAGGTGAAGAAGCCTG 20D3
GGGCCTCAGTGAAGGTTTCCTGCAAGGTTTCTGGATACACCTT 23E7
CACCAGCTACTTTATTCACTGGGTGCGCCAGGCCCCTGGACAA
GGGCTTGAGTGGATGGGAATAATCAACCCTATTAGTGTTAGCA
CAAGCTACGCACAGAAGTTCCAGGGCAGAGTCACCATGACCAG
GGACACGTCCACGAGCACAGTCTTCATGGAGCTGAGCAGCCTG
AGATCTGAGGACACGGCCGTGTATTACTGTGCGCGAGGGGGGA
TACAGCTATGGTTACATTTTGACTACTGGGGCCAGGGAACCCT GGTCACCGTCTCCTCA 342
16H2 artificial aa QVQLVQSGAEVKKPGASVKVSCKVSGYTFTSYFIHWVRQAPGQ 20D3
GLEWMGIINPISVSTSYAQKFQGRVTMTRDTSTSTVFMELSSL 23E7
RSEDTAVYYCARGGIQLWLHFDYWGQGTLVTVSS 343 26F12 artificial nt
CAGGTGCAGTTGGTGCAGTCTGGGGCTGAGGTGAAGAAGCCTG 27B3
GGGCCTCAGTGAAGGTTTCCTGCAAGGCATCTAGATACACCTT
CACCAACTACTATATGTCCTGGGTGCGACAGGCCCCTGGACAA
GGGCTTGAGTGGATGGGAATAATCAACCCTAGTGGTGGTGACT
CAACCTACGCACAGAAGTTCCAGGGCAGACTCACCATGACCGG
GGACACGTCCACGAGCACAGTCTACATGGAGCTGAGCAGCCTG
AGATCTGAGGACACGGCCGTGTATTACTGTGCGAGAGGGGGGA
TACAACTATGGTTACATTTTGACTACTGGGGCCAGGGAACCCT GGTCACCGTCTCCTCA 344
26F12 artificial aa QVQLVQSGAEVKKPGASVKVSCKASRYTFTNYYMSWVRQAPGQ
27B3 GLEWMGIINPSGGDSTYAQKFQGRLTMTGDTSTSTVYMELSSL
RSEDTAVYYCARGGIQLWLHFDYWGQGTLVTVSS 345 4B10 artificial nt
CAGGTGCAGTTGGTGGAGTCTGGGGGAGGCGTGGTCCAGCCTG 4C2
GGAGGTCCCTGAGACTCTCCTGTGCAGCCTCTGGATTCACCTT
CAGTAGCTATGACATGCACTGGGTCCGCCAGGCTCCAGGCAAG
GGGCTGGAGTGGGTGGCAGTTATATCATATGATGGAACTAATG
AATACTATGCAGACTCCGTGAAGGGCCGATTCACCATCTCCAG
AGACACTTCCAAGAACACGCTGTATTTGCAAATGAACAGCCTG
AGAGCTGAGGACACGGCTGTATATTACTGTGCGAGAGAACGAT
ATTTTGACTGGTCTTTTGACTACTGGGGCCAGGGAACCCTGGT CAGTGTCTCCTCA 346 4B10
artificial aa QVQLVESGGGVVQPGRSLRLSCAASGFTFSSYDMHWVRQAPGK 4C2
GLEWVAVISYDGTNEYYADSVKGRFTISRDTSKNTLYLQMNSL
RAEDTAVYYCARERYFDWSFDYWGQGTLVSVSS 347 4D3 artificial nt
CAGGTGCAGCTGGTGGAGTCTGGGGGAGGCGTGGTCCAGCCTG 4F3
GGAGGTCCCTGAGACTCTCCTGTGCAGCGTCTGGATTCTCCTT
CAGTAGCTATGACATGGACTGGGTCCGCCAGACTCCAGGCAAG
GGGCTGGAGTGGGTGGCAGTTATATGGTATGATGGAAGTAATA
AATACTATGCAGACTCCGTGAGGGGCCGATTCACCATCTCCAG
AGACAATTCCAAGAACACGCTGTTTCTGCAAATGAACAGCCTG
AGAGTCGAGGACACGGCTGTGTATTACTGTGCGAGAGAAACTG
GGGAGGGCTGGTACTTCGATCTCTGGGGCCGTGGCACCCTGGT CACTGTCTCCTCA 348 4D3
artificial aa QVQLVESGGGVVQPGRSLRLSCAASGFSFSSYDMDWVRQTPGK 4F3
GLEWVAVIWYDGSNKYYADSVRGRFTISRDNSKNTLFLQMNSL
RVEDTAVYYCARETGEGWYFDLWGRGTLVTVSS 349 16E2 artificial nt
CAGGTGCAGCTGGTGGAGTCTGGGGGAGGCGTGGTCCAGCCTG 17E10
GGAGGTCCCTGAGACTCTCCTGTGCAGCGTCTGGATTCATCTT 20B12
CAGTAGCTATGGCATGCACTGGGTCCGCCAGACTCCAGGCAAG
GGGCTGGAGTGGGTGGCAGTGATATGGTATGATGGAAGTAATA
AATACTATGCAGACTCCGTGAAGGGCCGATTCACCATCTCCAG
AGACATTTCCAAGAACACGCTGTATCTGCAAATGAACAGCCTG
AGAGTCGAGGACACGGCTGTGTATTACTGTGCGAGAGACGGGT
GGGAGCTGTCCTTTGACTACTGGGGCCAGGGAACCCTGGTCAC CGTCTCCTCA 350 16E2
artificial aa QVQLVESGGGVVQPGRSLRLSCAASGFIFSSYGMHWVRQTPGK 17E10
GLEWVAVIWYDGSNKYYADSVKGRFTISRDISKNTLYLQMNSL 20B12
RVEDTAVYYCARDGWELSFDYWGQGTLVTVSS 351 1D10 artificial nt
CAGGTGCAGCTGGTGGAGTCTGGGGGAGGCGTGGTCCAGCCTG 2C12
GGAGGTCCCTGAGACTCTCCTGTGCAGCGTCTGGATTCACCTT
CAGTAGCTATGGCATGCACTGGGTCCGCCAGGCTCCAGGCAAG
GGGCTGGAGTGGGTGTCAGTTATATGGTATGATGGAAGTAATA
AATACTATGCAGACTCCGTGAAGGGCCGATTCACCATCTCCAG
AGACAATTCCAAGAACACGCTGTATCTGCAAATGAATAGCCTG
AGAGCTGAGGACACGGCTGTGTATTACTGCGCGAGAAGGGCCG
GTATAATAGGAACTACAGGCTACTACTACGGTATGGACGTCTG
GGGCCAAGGGACCACGGTCACCGTCTCCTCA 352 1D10 artificial aa
QVQLVESGGGVVQPGRSLRLSCAASGFTFSSYGMHWVRQAPGK 2C12
GLEWVSVIWYDGSNKYYADSVKGRFTISRDNSKNTLYLQMNSL
RAEDTAVYYCARRAGIIGTTGYYYGMDVWGQGTTVTVSS 353 16C1 artificial nt
CAGGTGCAGCTGCAGGAGTCGGGCCCAGGACTGGTGAAGCCTT
CGGAGACCCTGTCCCTCACTTGTACTGTCTCTGGTGGCTCCAT
CAGTGGTTACTACTGGAGCTGGATCCGGCAGCCCCCAGGGAAG
GGACTGGAGTGGATTGGGTATATCTATTACATTGGGAGCACCA
ACTACAACCCCTCCCTCAAGAGTCGAGTCACCATGTCAATAGA
CACGTCCAAGAACCAGTTCTCCCTGACGCTGAGCTCTTTGACC
GCTGCGGACACGGCCGTGTATTTCTGTGCGAGAGATGGGAGCA
GTGGCTGGTACCGGTGGTTCGACCCCTGGGGCCAGGGAACCCT GGTCACCGTCTCCTCA 354
16C1 artificial aa QVQLQESGPGLVKPSETLSLTCTVSGGSISGYYWSWIRQPPGK
GLEWIGYIYYIGSTNYNPSLKSRVTMSIDTSKNQFSLTLSSLT
AADTAVYFCARDGSSGWYRWFDPWGQGTLVTVSS 355 25G10 artificial nt
CAGGTGCAGCTGCAGGAGTCGGGCCCAGGACTGGTGAAGCCTT
CGGAGACCCTGTCCCTCACCTGCACTGTCTCTGGTGGCTCCAT
CAGTGGTTACTACTGGAGCTGGATCCGGCAGCCCCCAGGGAAG
GGACTGGAGTGGATTGGGTATATCTATTACATTGGGAGCACCA
ACTACAACCCCTCCCTCAAGAGTCGAGTCACCATGTCAGTAGA
CACGTCCAAGAACCAGTTCTCCCTGAAGCTGAGCTCTGTGACC
GCTGCGGACACGGCCGTGTATTACTGTGCGAGAGATGGGAGCA
GTGGCTGGTACCGGTGGTTCGACCCCTGGGGCCAGGGAACCCT GGTCACCGTCTCCTCA 356
25G10 artificial aa QVQLQESGPGLVKPSETLSLTCTVSGGSISGYYWSWIRQPPGK
GLEWIGYIYYIGSTNYNPSLKSRVTMSVDTSKNQFSLKLSSVT
AADTAVYYCARDGSSGWYRWFDPWGQGTLVTVSS 357 16A4 artificial nt
CAGGTGCAGCTGCAGGAGTCgGGCCCAGGACTGGCGAAgcctt
cGGAGACcctgtccctcacctgCACTGTCTCTGGTGACTCCAT
CACTAGTTACTACTGGAGCTGGATCCGGCAGCCCCCAGGGAAG
GGACTGGAGTGGATTGGGTATATCTATTACAGTGGGAGCACCA
ATTACAACCCCTCCCTCAAGAGTCGAGTCACCATATCAGTAGA
CACGTCCAAGAACCAGTTCTCCCTGAAGCTGAGTTCTGTGACC
GCTGCGGACACGGCCGTGTATTACTGTGCGAGAGATCAAAGGC
GGATAGCAGCAGCTGGTACCCACTTCTACGGTATGGACGTCTG
GGGCCAAGGGACCACGGTCACCGTCTCCTCA 358 16A4 artificial aa
QVQLQESGPGLAKPSETLSLTCTVSGDSITSYYWSWIRQPPGK
GLEWIGYIYYSGSTNYNPSLKSRVTISVDTSKNQFSLKLSSVT
AADTAVYYCARDQRRIAAAGTHFYGMDVWGQGTTVTVSS 359 1F10 artificial nt
CAGGTGCAGCTGCAGGAGTCGGGCCCAGGACTGGTGAAGCCTT
CACAGACCCTGTCCCTCACCTGCACTGTCTCTGGTGGCTCCAT
CAGCAGTGGTGGTTACTACTGGAGCTGGATCCGCCAGCACCCA
GGGAAGGGCCTGGAGTGGATTGGGTACATCTATTACAGTGGGA
GCACCTACTACAACCCGTCCCTCACGAGTCGAGTTACCATATC
AGTAGACACGTCTAAGAACCAGTTCTCCCTGAAGCTGAGCTCT
GTGACTGCCGCGGACACGGCCGTGTATTACTGTGCGAGAGATG
GAAGCAGTGGCTGGTACTTCCAGCACTGGGGCCAGGGCACCCT GGTCACCGTCTCCTCA 360
1F10 artificial aa QVQLQESGPGLVKPSQTLSLTCTVSGGSISSGGYYWSWIRQHP
GKGLEWIGYIYYSGSTYYNPSLTSRVTISVDTSKNQFSLKLSS
VTAADTAVYYCARDGSSGWYFQHWGQGTLVTVSS 361 4A9 artificial nt
CAGGTGCAGCTGCAGGAGTCGGGCCCAGGACTGGTGAAGCCTT
CGGAGACCCTGTCCCTCACCTGCACTGTCTCTGGTGGCTCCAT
CAGTGGTTACTACTGGAGCTGGATCCGGCAGCCCCCAGGAAAG
GGACTGGAGTGGTTTGCATATTTCTCTTACAGTGGGAGCACCA
ACTACAACCCCTCCCTCAAGAGTCGAGTCACCTTATCAGTAGA
CACGTCCAAGAACCAGTTCTCCCTGAAGCTGAGCTCTGTGACC
GCTGCGGACACGGCCGTGTATTACTGTGCGAGGAACTGGGCCT
TCCACTTTGACTTCTGGGGCCAGGGAACCCTGGTCACCGTCTC CCA 362 4A9 artificial
aa QVQLQESGPGLVKPSETLSLTCTVSGGSISGYYWSWIRQPPGK
GLEWFAYFSYSGSTNYNPSLKSRVTLSVDTSKNQFSLKLSSVT
AADTAVYYCARNWAFHFDFWGQGTLVTVSS 363 4F7 artificial nt
CAGGTGCAGCTGCAGGAGTCGGGCCCAGGACTGGTGAAGCCTT
CGGAGACCCTGTCCCTCACCTGCACTGTCTCTGGTGGCTCCAT
CAGTAGTTACTCCTGGAGCTGGATCCGGCAGCCCCCAGGGAAG
GGACTGGAGTGGATTGGGTATATCTATTACAGTGGGAGCACCA
ACTACAACCCCTCCCTCAAGAGTCGAGTCACCATATCATTAGA
CACGTCCAAGAACCAGTTCTCCCTGAAGCTGAGCTCTGTGACC
GCTGCGGACACGGCCGTGTATTACTGTGCGAGGAACTGGGCCT
TCCACTTTGACTACTGGGGCCAGGGAACCCTGGTCACCGTCTC CTCA 364 4F7 artificial
aa QVQLQESGPGLVKPSETLSLTCTVSGGSISSYSWSWIRQPPGK
GLEWIGYIYYSGSTNYNPSLKSRVTISLDTSKNQFSLKLSSVT
AADTAVYYCARNWAFHFDYWGQGTLVTVSS 365 22D1 artificial nt
CAGGTGCAGCTGGTGCAGTCTGGGGCTGAGGTGAAGAAGCCTG
GGGCCTCAGTGAGGGTTTCCTGCAAGGTTTCTGGATACACCTT
CACCAGCTACTTTATTCACTGGGTACGCCAGGCCCCTGGACAA
GGGCTTGAGTGGATGGGAATAATCAACCCTATTAGTGTTAGCA
CAAGCTACGCACAGAAGTTCCAGGGCAGAGTCACCATGACCAG
GGACACGTCCACGAGCACAGTCTTCATGGAGCTGAGCAGCCTG
AGATCTGAGGACACGGCCGTGTATTACTGTGCGCGAGGGGGGA
TACAGCTATGGTTACATTTGGACTACTGGGGCCAGGGAACCCT GGTCACCGTCTCCTCA 366
22D1 artificial aa QVQLVQSGAEVKKPGASVRVSCKVSGYTFTSYFIHWVRQAPGQ
GLEWMGIINPISVSTSYAQKFQGRVTMTRDTSTSTVFMELSSL
RSEDTAVYYCARGGIQLWLHLDYWGQGTLVTVSS 367 19B5 artificial nt
CAGGTGCAGTTGGTGCAGTCTGGGGCTGAGGTGAAGAAGCCTG
GGGCCTCAGTGAAGGTTTCCTGCAAGGTTTCTGGATACACCTT
CACCAGCTACTTTATTCACTGGGTGCGCCAGGCCCCTGGACAA
GGGCTTGAATGGATGGGAATTATCAACCCTATTAGTGTTAGCA
CAAGCTACGCACAGAAGTTCCAGGGCAGAGTCACCATGACCAG
GGACACGTCCACGAGCACAGTCTTCATGGAGCTGAGCAGcCTG
AGATCTGAGGACACGGCCGTGTATTACTGTGCGCGAGGGGGGA
TACAGCTATGGTTACATTTGGACTACTGGGGCCAGGGAACCCT GGTCACCGTCTCCTCA 368
19B5 artificial aa QVQLVQSGAEVKKPGASVKVSCKVSGYTFTSYFIHWVRQAPGQ
GLEWMGIINPISVSTSYAQKFQGRVTMTRDTSTSTVFMELSSL
RSEDTAVYYCARGGIQLWLHLDYWGQGTLVTVSS 369 25F8 artificial nt
CAGGTGCAGCTGGTGCAGTCTGGGGCTGAGGTGAAGAAGCCTG
GGGCCTCAGTGAAGGTTTCCTGCAAGGCATCTGGATACACCTT
CACCAGCTACTATATTCACTGGGTGCGCCAGGCCCCTGGACAA
GGACTTGAGTGGATGGGAATAATCAACCCCAGTGGTGGTAGCA
CAAGGTACGCACAGAAGTTCCAGGGCAGAGTCACCATGACCAG
GGACACGTCCACGAGCACAGTCTTCATGGAGCTGAGCagcctG
AGATCTGAGGACACGGCCGTGTATTACTGTGCGCGAGGGGGAA
TACAGCTATGGTTACATTttGACTACTGGGGCCAGGGAACCCT GGTCACCGTCTCCTCA 370
25F8 artificial aa QVQLVQSGAEVKKPGASVKVSCKASGYTFTSYYIHWVRQAPGQ
GLEWMGIINPSGGSTRYAQKFQGRVTMTRDTSTSTVFMELSSL
RSEDTAVYYCARGGIQLWLHFDYWGQGTLVTVSS 371 26D1 artificial nt
CAGGTGCAGTTGGTGCAGTCTGGGGCTGAGGTGAAGAAGCCTG
GGGCCTCAGTGAAGGTTTCCTGTAAGGCATCTAGATACACCTT
CACCAGCTACTATATGTCCTGGGTGCGACAGGCCCCTGGACAA
GGGCTTGAGTGGATGGGAATAATCCACCCTAGTGGTGGTGACA
CAACCTACGCACAGAAGTTCCAGGGCAGAGTCACCATGACCGG
GGACACGTCCACGAGCACAGTCTACATGGAGCTGAGCAGCCTG
AGATCTGAGGACACGGCCGTGTATTACTGTGCGAGAGGGGGGA
TAAAACTATGGTTACATTTTGACTATTGGGGCCAGGGAACCCT GGTCACCGTCTCCTCA 372
26D1 artificial aa QVQLVQSGAEVKKPGASVKVSCKASRYTFTSYYMSWVRQAPGQ
GLEWMGIIHPSGGDTTYAQKFQGRVTMTGDTSTSTVYMELSSL
RSEDTAVYYCARGGIKLWLHFDYWGQGTLVTVSS 373 4D2 artificial nt
CAGGTGCAGCTGGTGGAGTCTGGGGGAGGCGTGGTCCAGCCTG
GGAGGTCCCTGAGACTCTCCTGTGCAGCCTCTGGATTCACCTT
CAGTAGTTATGACATGCACTGGGTCCGCCAGGCTCCAGGCAAG
GGGCTGGAGTGGGTGGCAGTTATATCATATGATGGAACTAATG
AATACTATGCAGACTCCGTGAAGGGCCGATTCACCATCTCCAG
AGACACTTCCAAGAACACGCTGTATTTGCAAATGAACAGCCTG
AGAGCTGAGGACACGGCTGTATATTACTGTGCGAGAGAACGAT
ATTTTGACTGGTCTTTTGACTACTGGGGCCAGGGAACCCTGGT CAGTGTCTCCTCA 374 4D2
artificial aa QVQLVESGGGVVQPGRSLRLSCAASGFTFSSYDMHWVRQAPGK
GLEWVAVISYDGTNEYYADSVKGRFTISRDTSKNTLYLQMNSL
RAEDTAVYYCARERYFDWSFDYWGQGTLVSVSS 375 4E10 artificial nt
CAGGTGCAGCTGGTGGAGTCTGGGGGAGGCGTGGTCCAGCCTG
GGAGGTCCCTGAGACTCTCCTGTGCAGCGTCTGGATTCACCTT
CAGTAGCTATGACATGCACTGGGTCCGCCAGGCTCCAGGCAAG
GGGCTGGAGTGGGTGGCAGTTATATGGTATGATGGAAGTAATA
AATACTATGCAGACTCCGTGAAGGGCCGATTCACCATCTCCAG
AGACAATTCCACGAACACGCTGCATCTGCAAATGAACAGCCCG
AGAGCCGAGGACACGGCTGTGTACTACTGTGCGAGAGAGTATA
GGTACAGCTGGTACTTTGACTACTGGGGCCAGGGAACCCTGGT CACCGTCTCCTCA 376 4E10
artificial aa QVQLVESGGGVVQPGRSLRLSCAASGFTFSSYDMHWVRQAPGK
GLEWVAVIWYDGSNKYYADSVKGRFTISRDNSTNTLHLQMNSP
RAEDTAVYYCAREYRYSWYFDYWGQGTLVTVSS 377 22G10 artificial nt
GAGGTGCAACTGTTGGAGTCTGGGGGAGGCTTGGTACAGCCTG
GGGGGTCCCTGAGACTCTCCTGTGCAGCCTCTGGATTCACCTT
TAGCAGTTATGCCATGAACTGGGTCCGCCAGGCTCCAGGGAAG
GGGCTGGAGTGGGTCTCAACTATTAGTGGTGGTGGTGCTAACA
CATACTACGCAGACTCCGTGAAGGGCCGGTTCACCATCTCCAG
TGACAATTCCAAGAGCACGCTGTATCTGCAAATGAACAGCCTG
AGAGCCGCGGACACGGCCGTATATCACTGTGCGAAAGGGGGAA
TGGGGGGATACTACTACGGTATGGACGTCTGGGGCCAAGGGAC CACGGTCACCGTCTCCTCA 378
22G10 artificial aa EVQLLESGGGLVQPGGSLRLSCAASGFTFSSYAMNWVRQAPGK
GLEWVSTISGGGANTYYADSVKGRFTISSDNSKSTLYLQMNSL
RAADTAVYHCAKGGMGGYYYGMDVWGQGTTVTVSS 379 2C12_LC#1 artificial nt
CAGGTGCAGCTGGTGGAGTCTGGGGGAGGCGTGGTCCAGCCTG
GGAGGTCCCTGAGACTCTCCTGTGCAGCGTCTGGATTCACCTT
CAGTAGCTATGGCATGCACTGGGTCCGCCAGGCTCCAGGCAAG
GGGCTGGAGTGGGTGTCAGTTATATGGTATGATGGAAGTAATA
AATACTATGCAGACTCCGTGAAGGGCCGATTCACCATCTCCAG
AGACAATTCCAAGAACACGCTGTATCTGCAAATGAATAGCCTG
AGAGCTGAGGACACGGCTGTGTATTACTGCGCGAGAAGGGCCG
GTATAATAGGAACTACAGGCTACTACTACGGTATGGACGTCTG
GGGCCAAGGGACCACGGTCACCGTCTCCTCA 380 2C12_LC#1 artificial aa
QVQLVESGGGVVQPGRSLRLSCAASGFTFSSYGMHWVRQAPGK
GLEWVSVIWYDGSNKYYADSVKGRFTISRDNSKNTLYLQMNSL
RAEDTAVYYCARRAGIIGTTGYYYGMDVWGQGTTVTVSS 381 2H12_LC#2 artificial nt
CAGGTGCAGCTGGTGGAGTCTGGGGGAGGCGTGGTCCAGCCTG
GGAGGTCCCTGAGACTCTCCTGTGCAGCGTCTGGATTCACCTT
CAGTAGCTATGGCATGCACTGGGTCCGCCAGGCTCCAGGCAAG
GGGCTGGAGTGGGTGGCAGTTATATGGTATGATGGAAGTAATA
AATACTATACAGACTCCGTGAAGGGCCGATTCACCATCTCCAG
AGACAATTCCAAGAACACGCTGTATCTGCAAATGAATAGCCTG
AGAGCTGAGGACACGGCTGTGTATTACTGTGCGAGAAGGGCCG
GTATAATAGGAACTACAGGCTACTACTACGGTATGGACGTCTG
GGGCCAAGGGACCACGGTCACCGTCTCCTCA 382 2H12_LC#2 artificial aa
QVQLVESGGGVVQPGRSLRLSCAASGFTFSSYGMHWVRQAPGK
GLEWVAVIWYDGSNKYYTDSVKGRFTISRDNSKNTLYLQMNSL
RAEDTAVYYCARRAGIIGTTGYYYGMDVWGQGTTVTVSS 383 2G6_LC#1 artificial nt
CAGGTGCAGTTGGTGGAGTCTGGGGGAGGCGTGGTCCAGCCTG
GGAGGTCCCTGAGACTCTCCTGTGCAGCGTCTGGATTCACCTT
CAGTAGCTATGGCATGCACTGGGTCCGCCAGGCTCCAGGCAAG
GGGCTGGAGTGGGTGGCATTTATATGGTATGATGGAAGTAATA
AATACTATGCAGACTCCGTGAAGGACCGATTCACCATCTCCAG
AGACAATTCCAAGAACACGCTGTATCTGCAAATGAAAAGCCTG
AGAGCTGAGGACACGGCTGTGTATTACTGTGCGAGAAGGGCCG
GTATAATAGGAACTATAGGCTACTACTACGGTATGGACGTCTG
GGGCCAAGGGACCACGGTCACCGTCTCCTCA 384 2G6_LC#1 artificial aa
QVQLVESGGGVVQPGRSLRLSCAASGFTFSSYGMHWVRQAPGK
GLEWVAFIWYDGSNKYYADSVKDRFTISRDNSKNTLYLQMKSL
RAEDTAVYYCARRAGIIGTIGYYYGMDVWGQGTTVTVSS 385 2H12 artificial nt
CAGGTGCAGCTGGTGGAGTCTGGGGGAGGCGTGGTCCAGCCTG
GGAGGTCCCTGAGACTCTCCTGTGCAGCGTCTGGATTCACCTT
CAGTAGCTATGGCATGCACTGGGTCCGCCAGGCTCCAGGCAAG
GGGCTGGAGTGGGTGGCAGTTATATGGTATGATGGAAGTAATA
AATACTATACAGACTCCGTGAAGGGCCGATTCACCATCTCCAG
AGACAATTCCAAGAACACGCTGTATCTGCAAATGAATAGCCTG
AGAGCTGAGGACACGGCTGTGTATTACTGTGCGAGAAGGGCCG
GTATAATAGGAACTACAGGCTACTACTACGGTATGGACGTCTG
GGGCCAAGGGACCACGGTCACCGTCTCCTCA 386 2H12 artificial aa
QVQLVESGGGVVQPGRSLRLSCAASGFTFSSYGMHWVRQAPGK
GLEWVAVIWYDGSNKYYTDSVKGRFTISRDNSKNTLYLQMNSL
RAEDTAVYYCARRAGIIGTTGYYYGMDVWGQGTTVTVSS 387 2G6 artificial nt
CAGGTGCAGTTGGTGGAGTCTGGGGGAGGCGTGGTCCAGCCTG
GGAGGTCCCTGAGACTCTCCTGTGCAGCGTCTGGATTCACCTT
CAGTAGCTATGGCATGCACTGGGTCCGCCAGGCTCCAGGCAAG
GGGCTGGAGTGGGTGGCATTTATATGGTATGATGGAAGTAATA
AATACTATGCAGACTCCGTGAAGGACCGATTCACCATCTCCAG
AGACAATTCCAAGAACACGCTGTATCTGCAAATGAAAAGCCTG
AGAGCTGAGGACACGGCTGTGTATTACTGTGCGAGAAGGGCCG
GTATAATAGGAACTATAGGCTACTACTACGGTATGGACGTCTG
GGGCCAAGGGACCACGGTCACCGTCTCCTCA 388 2G6 artificial aa
QVQLVESGGGVVQPGRSLRLSCAASGFTFSSYGMHWVRQAPGK
GLEWVAFIWYDGSNKYYADSVKDRFTISRDNSKNTLYLQMKSL
RAEDTAVYYCARRAGIIGTIGYYYGMDVWGQGTTVTVSS 389 23A10 artificial nt
CAGGTGCAGCTGGTGGAGTCTGGGGGAGGCGTGGTCCAGCCTG
GGAGGTCCCTGAGACTCTCCTGTGCAGCGTCTGGATTCACCTT
CAGTCGCTATGGCATACACTGGGTCCGCCAGGCTCCAGGCAAG
GGGCTGGAGTGGGTGGCAGTTATATGGTATGATGGAAGTAATA
AATACTATGCAGACTCCGTGAAGGGCCGATTCACCATCTCCAG
AGACAATTCCAAGAACACGCTGTATCTGCTAATGAACAGCCTG
AGAGCCGAGGACTCGGCTGTGTATTACTGTGCGAGAAGGGCCG
GTATACCTGGAACTACGGGCTACTACTATGGTATGGACGTCTG
GGGCCAAGGGACCACGGTCACCGTCTCCTCA 390 23A10 artificial aa
QVQLVESGGGVVQPGRSLRLSCAASGFTFSRYGIHWVRQAPGK
GLEWVAVIWYDGSNKYYADSVKGRFTISRDNSKNTLYLLMNSL
RAEDSAVYYCARRAGIPGTTGYYYGMDVWGQGTTVTVSS 391 5E3 artificial nt
GAGGTGCAGTTGGTGGAGTCTGGGGGAGGCCTGGTCAAGCCTG
GGGGGTCCCTGAGACTCTCCTGTGCAGCCTCTGGATTCACCTT
CAGTAGCTATAGCATGCACTGGGTCCGCCAGGCTCCAGGGAAG
GGGCTGGAGTGGGTCTCATCCATTAGTAGTAGTAGTAGTTACA
TATACTACGCAGACTCAGTGAAGGGCCGATTCACCATCTCCAG
AGACAACGCCAAGAACTCACTGTATCTGCAAATGAACAGCCTG
AGAGCCGAGGACACGGCTGTGTATTACTGTGCGAGAGGGGAAA
CTGGAACTAACTACTACTACTACGGTATGGACGTCTGGGGCCA
AGGGACCACGGTCACCGTCTCCTCA 392 5E3 artificial aa
EVQLVESGGGLVKPGGSLRLSCAASGFTFSSYSMHWVRQAPGK
GLEWVSSISSSSSYIYYADSVKGRFTISRDNAKNSLYLQMNSL
RAEDTAVYYCARGETGTNYYYYGMDVWGQGTTVTVSS
TABLE-US-00011 TABLE IIB Light Chain Variable Region Polynucleotide
and Amino acid Sequences SEQ ID NO. DESIGNATION SOURCE TYPE
SEQUENCE 393 17H8 artificial nt
GACATTGTATTGACGCAGtctCCAGGCACCCTGTCTTTGTCTC 23B6
CAGGGGAAAGAGCCACCCTCTCCTGCAGGGCCAGTCAGAGTGT 28D10
TGCCGGCAGCTACCTAGCCTGGTACCAGCAGAAACCTGGCCAG
GCTCCCAGGCTCCTCATCTCTGGTGCATCCAGCAGGGCCACTG
GCATCCCAGACAGGTTCAGTGGCAGTGGGTCTGGGACAGACTT
CACTCTCACCATCAGCAGACTGGAGCCTGAAGATTTTGCAGTG
TATTACTGTCAGCAGTATGGTAAATCACCGATCACCTTCGGCC
AAGGGACACGACTGGAGATGAAAGGA 394 17H8 artificial aa
DIVLTQSPGTLSLSPGERATLSCRASQSVAGSYLAWYQQKPGQ 23B6
APRLLISGASSRATGIPDRFSGSGSGTDFTLTISRLEPEDFAV 28D10
YYCQQYGKSPITFGQGTRLEMKG 395 4A2 artificial nt
GAAATTGTGTTGACGCAGTCTCCAGGCACCCTGTCTTTGTCTC 5B4
CAGGGGAAAGAGCCACCCTCTCTTGCAGGGCCAGTCGGAATAT 5C5
TAGCAGCAGCTACTTAGCCTGGTACCAGCAGAAACCTGGCCAG
GCTCCCAGGCTCCTCATCTATGGTCCATCCAGCAGGGCCACTG
GCATCCCAGACAGGTTCAGTGGCAGTGGGTCTGGGACAGACTT
CACTCTCACCATCAGCAGACTGGAGCCTGAAGATTTTACAGTG
TATTACTGTCAGCAGTATGGTAGCTCATTCACTTTCGGCCCTG GGACCAAAGTGGATATCAAACGA
396 4A2 artificial aa EIVLTQSPGTLSLSPGERATLSCRASRNISSSYLAWYQQKPGQ
5B4 APRLLIYGPSSRATGIPDRFSGSGSGTDFTLTISRLEPEDFTV 5C5
YYCQQYGSSFTFGPGTKVDIKR 397 16H2 artificial nt
CAGTCTGCGCTGACTCAGCCACCCTCAGCGACTGGGACCCCCG 20D3
GGCAGAGGGTCACCATCTCTTGTTCTGGAAGCAGCTCCAACAT 23E7
CGGAAGTAATTTTGTAAACTGGTACAAACAACTCCCAGGAACG
GCCCCCAAAGTCCTCATCTATACTAATAATCAGCGGCCCTCAG
GGGTCCCTGACCGATTCTCTGGCTCCAAGTCTGGCACCTCAGC
CTCCCTGGCCATCAGTGGGCTCCAGTCTGAGGATGAGTCTGAT
TATTACTGTGCAACATGGGATGACAGCCTGAATGGTTGGGTGT
TCGGCGGAGGGACCAAGCTGACCGTCCTAGGT 398 16H2 artificial aa
QSALTQPPSATGTPGQRVTISCSGSSSNIGSNFVNWYKQLPGT 20D3
APKVLIYTNNQRPSGVPDRFSGSKSGTSASLAISGLQSEDESD 23E7
YYCATWDDSLNGWVFGGGTKLTVLG 399 26F12 artificial nt
CAGTCTGTGCTGACTCAGTCACCCTCAGCGTCTGGGACCCCCG 27B3
GGCAGAAGGTCACCATCTCTTGTTCTGGAAGCCGCTCCAACAT
CGGAAGTAATTTTGTAAACTGGTACCAGCAGCTCCCAGGAACG
GCCCCCAAACTCCTCATCTATACTAATTATCAGCGGCCCTCAG
GGGTCCCTGACCGATTCTCTGGCTCCAAGTCTGGCACCTCAGC
CTCCCTGGCCATCAGTGGGCTCCAGTCTGAGGATGAGGCTGAT
TATTACTGTGCAGTATGGGATGACAGCCTGAATGGTTGGGTGT
TCGGCGGAGGGACCAAGCTGACCGTCCTAGGT 400 26F12 artificial aa
QSVLTQSPSASGTPGQKVTISCSGSRSNIGSNFVNWYQQLPGT 27B3
APKLLIYTNYQRPSGVPDRFSGSKSGTSASLAISGLQSEDEAD
YYCAVWDDSLNGWVFGGGTKLTVLG 401 4B10 artificial nt
GAAATTGTATTGACGCAGTCTCCAGGCACCCTGTCTTTGTCTC 4C2
CAGGGGAAAGAGCCACCCTCTCCTGCAGGGCCAGTCAGAGTGT
TAGCAACACCTACTTAGCCTGGTACCATCAGAGACCTGGCCAG
GCTCCCAGGCTCCTCATCTATGGTGCATCCAGCAGGGCCACTG
GCATCCCAGACAGATTCAGTGGCAGTGGGTCTGGGACAGACTT
CGCTCTCACCATCAGCAGTCTGGAGCCTGAAGATTTTGCAGTG
TATTACTGTCAGCAGTACAGTAACTCgtgGACGTTCGGCCAAG GGACCAAGGTGGAAATCAaacGA
402 4B10 artificial aa EIVLTQSPGTLSLSPGERATLSCRASQSVSNTYLAWYHQRPGQ
4C2 APRLLIYGASSRATGIPDRFSGSGSGTDFALTISSLEPEDFAV
YYCQQYSNSWTFGQGTKVEIKR 403 4D3 artificial nt
GAAATTGTGTTGACGCAGTCTCCAGGCACCCTGTCTTTGTCTC 4F3
CAGGGGAAAGAGCCACCCTCTCCTGCAGGGCCAGTCAGAGTGT
TAGCAGCAGCTACTTAGCCTGGTACCAGCAGAAACCTGGCCAG
GCTCCCAGGCTCCTCATCTATGGTGCATCCAGCAGGGCCACTG
GCATCCCAGACAGGTTCAGTGGCAGTGGGTCTGGGACAGACTT
CACTCTCACCATCAGCAGACTGGAACCTGAGGATTTTGCAGTG
TATTACTGTCAGCAGTATGGTAGCTCGTGGACGTTCGGCCAAG GGACCAAGGTGGAAATCAAACGA
404 4D3 artificial aa EIVLTQSPGTLSLSPGERATLSCRASQSVSSSYLAWYQQKPGQ
4F3 APRLLIYGASSRATGIPDRFSGSGSGTDFTLTISRLEPEDFAV
YYCQQYGSSWTFGQGTKVEIKR 405 16E2 artificial nt
GACATCCAGATGACCCAGTCTCCATCCTCACTGTCTGCATCTG 17E10
TAGGAGACAGAGTCACCATCACTTGTCGGGCGAGTCAGGGCAT 20B12
TAGCAATTATTTAGCCTGGTTACAGCAGAAACCAGGGAAAGCC
CCTAAGTCCCTGATCTATGCTGCATCCAGTTTGCAAAGTGGGG
TCCCATCAAAGTTCAGCGGCAGTGGATCTGGGACAGATTTCAC
TCTCACCATCAGCAGCCTGCAGCCTGAAGATTTTGCAACTTAT
TACTGCCAACACTATTTTACTTACCCTCGGACGTTCGGCCAAG GGACCAAGGTGGAAATCAAACGA
406 16E2 artificial aa DIQMTQSPSSLSASVGDRVTITCRASQGISNYLAWLQQKPGKA
17E10 PKSLIYAASSLQSGVPSKFSGSGSGTDFTLTISSLQPEDFATY 20B12
YCQHYFTYPRTFGQGTKVEIKR 407 1D10 artificial nt
TCCTATGCGCTGACTCAGCCACCCTCAGTGTCCGTGTCCCCAG 2C12
GACAGACAGCCAGCCTCACCTGCTCTGGAGATAGATTGGGGGA
AAAATATACTTGCTGGTATCAGCAGAGGCCAGGCCAGTCCCCT
TTGCTGGTCATCTATCAAGATACCAAGCGGCCCTCAGGGATCC
CTGAGCGATTCTCTGGCTCCACCTCTGGTAACACAGCCACTCT
GACCATCAGCGGGACCCAGGCTATGGATGAGGCTGACTATTAC
TGTCAGGCGTGGGACAGCAGCACTGTGGTATTCGGCGGAGGGA CCAAGCTGACCGTCCTAGGT
408 1D10 artificial aa SYALTQPPSVSVSPGQTASLTCSGDRLGEKYTCWYQQRPGQSP
2C12 LLVIYQDTKRPSGIPERESGSTSGNTATLTISGTQAMDEADYY
CQAWDSSTVVFGGGTKLTVLG 409 16C1 artificial nt
GAAATTGTGTTGACGCAGTCTCCAGGCACCCTGTCTTTGTCTC
CAGGGGAAAGAGCCACCCTCTCCTGCAGGGCCAGCCAGAGTGT
TAGCAGCAGCTACTTAGCCTGGTACCAGCAGAAACCTGGCCAG
GCTCCCAGGCTCCTCATCTTTGGTGCATCCAGCAGGGCCACTG
GCATCCCAGACAGGTTCAGTGGCAGTGGGTCTGGGACAGACTT
CACTCTCACCATCAGCGGACTGGAGCCTGAAGATTTTGCAGTG
TATCACTGTCAGCAGTATGGTAACTCACCGCTCACTTTCGGCG
GAGGGACCAAGGTGGAGATCAAACGA 410 16C1 artificial aa
EIVLTQSPGTLSLSPGERATLSCRASQSVSSSYLAWYQQKPGQ
APRLLIFGASSRATGIPDRFSGSGSGTDFTLTISGLEPEDFAV YHCQQYGNSPLTFGGGTKVEIKR
411 25G10 artificial nt GAAATTGTGTTGACGCAGTCTCCAGGCACCCTGTCTTTGTCTC
CAGGGGAAAGAGCCACCCTCTCCTGCAGGGCCAGTCAGAGTGT
TAGCAGCAGCTACTTAGCCTGGTACCAGCAGAAACCTGGCCAG
GCTCCCAGGCTCCTCATCTTTGGTGCATCCAGCAGGGCCACTG
GCATCCCAGACAGGTTCAGTGGCAGTGGGTCTGGGACAGactT
CACTCTCACCATCAGCAGACTGGAGCCTGAAGATTTTGCAGTG
TATCACTGTCAGCAGTATGGTAACTCACCGCTCACTTTCGGCG
GAGGGACCAAGGTGGAGATCAAACGA 412 25G10 artificial aa
EIVLTQSPGTLSLSPGERATLSCRASQSVSSSYLAWYQQKPGQ
APRLLIFGASSRATGIPDRFSGSGSGTDFTLTISRLEPEDFAV YHCQQYGNSPLTFGGGTKVEIKR
413 16A4 artificial nt GAAATTGTGTTGACGCAGTCTCCAGGCACCCTGTCTTTGTCTC
CAGGGGAAAGAGCCACCCtCTCCTGCAGGGCCAGTCAGAGTGT
TAGCAGCAGTTATTTAGCCTGGTACCAGCAGAAACCTGGCCAG
GCTCCCAGGCTCCTCATCTATGGTACATCCAGCAGGGCCACTG
GCATCCCAGACAGGTTCAGTGGCAGTGGGTCTGGGACAGACTT
CACTCTCACCATCAGCAGACTGGAGCCTGAAGATTTTGCAGTG
TATTATTGTCAGCAGTACGGTAGCTCACCTTTCACTTTCGGCG
GAGGGACCAAGGTGGAGATCAAACGA 414 16A4 artificial aa
EIVLTQSPGTLSLSPGERATLSCRASQSVSSSYLAWYQQKPGQ
APRLLIYGTSSRATGIPDRFSGSGSGTDFTLTISRLEPEDFAV YYCQQYGSSPFTFGGGTKVEIKR
415 1F10 artificial nt GAAATTGTGTTGACGCAGTCTCCAGGCACCCTGTCTTTGTCTC
CAGGGGAAAGAGCCACCCTCTCCTGCAGGGCCAGTCGGAGTAT
TAGCAGCAGCTACTTAGCCTGGTACCAGCAGAAACCTGGCCAG
GCTCCCAGGCTCCTCATCTATGGTCCATCCAGCAGGGCCACTG
GCATCCCAGACAGGTTCAGTGGCAGTGGGTCTGGGACAGACTT
CACTCTCACCATCAGCAGACTGGAGCCTGAAGATTTTGCAGTG
TATTACTGTCAGCAGTATGGTAGCTCATTCACTTTCGGCCCTG GGACCAAAGTGGATATCAAACGA
416 1F10 artificial aa EIVLTQSPGTLSLSPGERATLSCRASRSISSSYLAWYQQKPGQ
APRLLIYGPSSRATGIPDRFSGSGSGTDFTLTISRLEPEDFAV YYCQQYGSSETFGPGTKVDIKR
417 4A9 artificial nt CAGTCTGTGCTGACGCAGCCGCCCTCAGTGTCTGGGGCCCCAG
GACAGAGGGTCACCATCTCCTGCACTGGGAGCAGCTCCAACAT
CGGGACAGGTTATGCTGTACACTGGTACCAGCAGTTTCCAGGA
ACAGCCCCCAAACTCCTCATCTATGGTAACAACAATCGGCCCT
CAGGGGTTCCTGACCGATTCTCTGGCTCCAAGTCTGGCACCTC
AGCCTCCCTGGCCATCACTGGGCTCCAGGCTGAGGATGAGGCT
GATTATTACTGCCAGTCCTATGACAGCAGACTGAGTGGTTGGG
TGTTCGGCGGAGGGACCAAGCTGACCGTCCTAGGT 418 4A9 artificial aa
QSVLTQPPSVSGAPGQRVTISCTGSSSNIGTGYAVHWYQQFPG
TAPKLLIYGNNNRPSGVPDRFSGSKSGTSASLAITGLQAEDEA
DYYCQSYDSRLSGWVFGGGTKLTVLG 419 4F7 artificial nt
CAGTCTGTgcTGACGCAGCCGCCCTCAGTGTCTGGGGCCCCAG
GGCAGAGGGTCACCATCTCCTGCACTGGGAGCAGCTCCAATAT
CGGGACAGGTTATGATGTACACTGGTATCAGCAGcttcCAGGA
ACAGCCCCCAAACTCCTCATCCATGGTAACAGCAATCGGCCCT
CAGGGGTCCCTGACCGATTCTCTGGCTCCAAGTCTGGCACCTC
AGCCTCCCTGGCCATCACTGGGCTCCAGGCTGAGGATGAGGCT
GATTATTACTGCCAGTCCTATGACAGCAGTCTGAGTGGTTGGG
TGTTCGGCGGAGGGACCAGGTTGACCGTCCTAGGT 420 4F7 artificial aa
QSVLTQPPSVSGAPGQRVTISCTGSSSNIGTGYDVHWYQQLPG
TAPKLLIHGNSNRPSGVPDRFSGSKSGTSASLAITGLQAEDEA
DYYCQSYDSSLSGWVFGGGTRLTVLG 421 22D1 artificial nt
CAGTCTGCGCTGACTCAGCCACCCTCAGCGACTGGGACCCCCG
GGCAGAGGGTCACCATCTCTTGTTCTGGAAGCAGCTCCAACAT
CGGAAGCAATTTTGTAAACTGGTACAAGCAGCTCCCAGGAACG
GCCCCCAAAGTCCTCATCTATACTAATAATCAGCGGCCCTCAG
GGGTCCCTGACCGATTCTCTGGCTCCAAGTCTGGCACCTCAGC
CTCCCTGGCCATCAGTGGGCTCCAGTCTGAGGATGAGTCTGAT
TATTACTGTGCAACATGGGATGACAGTATGAATGGTTGGGTGT
TCGGCGGAGGGACCAAGCTGACCGTCCTAGGT 422 22D1 artificial aa
QSALTQPPSATGTPGQRVTISCSGSSSNIGSNFVNWYKQLPGT
APKVLIYTNNQRPSGVPDRFSGSKSGTSASLAISGLQSEDESD
YYCATWDDSMNGWVFGGGTKLTVLG 423 19B5 artificial nt
CAGTCTGCGCTGACTCAGCCACCCTCAACGACTGGGACCCCCG
GGCAGAGGGTCACCATCTCTTGTTCTGGAAGCAGGTCCAACAT
CGGAAGCAATTTTGTAAACTGGTACAAGCAGCTCCCAGGAACG
GCCCCCAAAGTCCTCATCTATACTAATAATCAGCGGCCCTCAG
GGGTCCCTGACCGATTCTCTGGCTCCAAGTCTGGCACCTCAGC
CTCCCTGGCCATCAGTGGGCTCCAGTCTGAGGATGAGTCTGAT
TATTACTGCGCAACATGGGATGACAGTATGAATGGTTGGGTGT
TCGGCGGAGGGACCAAACTGACCGTCCTAGGT 424 19B5 artificial aa
QSALTQPPSTTGTPGQRVTISCSGSRSNIGSNFVNWYKQLPGT
APKVLIYTNNQRPSGVPDRFSGSKSGTSASLAISGLQSEDESD
YYCATWDDSMNGWVFGGGTKLTVLG 425 25F8 artificial nt
CAGTCTGCGCTGactCAGCCACCCTCAGCGACTGGGACCCCCG
GGCAGAGGGTCACCATCTCTTGTTCTGGAAGCAGCTCCAACAT
CGGAAGGAATTTTGTAAACTGGTATAAGCAGCTCCCAGGAACG
GCCCCCAAAGTCCTCATTTATACTAATAATCAGCGGCCCTCAG
GGGTCCCTGACCGATTCTCTGGCTCCAAGTCTGGCACCTCAGC
CTCCCTGGCCATCAGTGGGCTCCAGTCTGAGGATGAGTCTGAT
TATTACTGTGCAGCATGGGATGACAGCCTGAATGGTTGGGTGT
TCGGCGGAGGGACCAAGCTGACCGTCCTAGGT 426 25F8 artificial aa
QSALTQPPSATGTPGQRVTISCSGSSSNIGRNFVNWYKQLPGT
APKVLIYTNNQRPSGVPDRFSGSKSGTSASLAISGLQSEDESD
YYCAAWDDSLNGWVFGGGTKLTVLG 427 26D1 artificial nt
CACTCTGTGCTGACTCAGTCACCCTCAGCGTCTGGGACCCCCG
GACAGAGGGTCACCATCTCTTGTTCTGGAAGCCGCTCCAACAT
CGGAAGTAATTTTGTAAACTGGTACCAGCAGCTCCCAGGAACG
GCCCCCAAACTCCTCATCTATACTAATAATCAGCGGCCCTCAG
GGGTCCCTGACCGATTCTCTGGCTCCAAGTCTGGCACCTCAGC
CTCCCTGGCCATCAGTGGGCTCCAGTCTGAGGATGAGGCTGAT
TATTACTGTGCAGTATGGGATGACAGCCTGAATGGTTGGGTGT
TCGGCGGAGGGACCAAGCTGACCGTCCTAGGT 428 26D1 artificial aa
HSVLTQSPSASGTPGQRVTISCSGSRSNIGSNFVNWYQQLPGT
APKLLIYTNNQRPSGVPDRFSGSKSGTSASLAISGLQSEDEAD
YYCAVWDDSLNGWVFGGGTKLTVLG 429 4D2 artificial nt
GAAATTGTATTGACGCAGTCTCCAGGCACCCTGTCTTTGTCTC
CAGGGGAAAGAGCCACCCTCTCCTGCAGGGCCAGTCAGAGTGT
TAGCAACACCTACTTAGCCTGGTACCATCAGAGACCTGGCCAG
GCTCCCAGGCTCCTCATCTATGGTGCATCCAGCAGGGCCGCTG
GCATCCCAGACAGGTTCAGTGGCAGTGGGTCTGGGACAGACTT
CACTCTCACCATCAGCAGACTGGAGCCTGAAGATTTTGCAGTG
TATTACTGTCAGCAGTATAGTAACTCGTGGACGTTCGGCCAAG
GGACCAAGGTGGAAATCAAACGA
430 4D2 artificial aa EIVLTQSPGTLSLSPGERATLSCRASQSVSNTYLAWYHQRPGQ
APRLLIYGASSRAAGIPDRFSGSGSGTDFTLTISRLEPEDFAV YYCQQYSNSWTFGQGTKVEIKR
431 4E10 artificial nt GAAATTGTGTTGACGCAGTCTCCAGGCACCCTGTCTTTGTCTC
CAGGGGAAAGAGCCACCCTCTCCTGCAGGGCCAGTCAGAGTGT
TGGCAGCAGCTACTTAGCCTGGTACCAGCAGAAACCTGGCCAG
GCTCCCAGGCTCCTCATCTATGGTGCATCCAGCAGGGTCACTG
GCATCCCAGACAGGTTCAGTGGCAGTGGGTCTGGGACAGATTT
CACTCTCACCATCAGCAGACTGGAGCCTGAAGATTTTGCAGTG
TATTACTGTCAGCAATATAGTAACTCGTGGACGTTCGGCCAAG GGACCAAGGGGAAATCAAACGA
432 4E10 artificial aa EIVLTQSPGTLSLSPGERATLSCRASQSVGSSYLAWYQQKPGQ
APRLLIYGASSRVTGIPDRFSGSGSGTDFTLTISRLEPEDFAV YYCQQYSNSWTFGQGTKVEIKR
433 22G10 artificial nt GAAATAGTGATGACGCAGTCTCCAGTCACCCTGTCTCTGTCTC
TAGGGGAAAGAGCCACCCTCTCCTGCAGGGCCAGTCAGAGTAT
TAGCAGCAACTTAGCCTGGTTCCAGCAGAAACCTGGCCAGGCT
CCCAGACTCCTCATCTATGGTGCATTTACCAGGGCCACTGGTA
TCCCAGCCAGGGTCAGTGGCAGTGGGTCTGGGACAGAGTTCAC
TCTCACCATCAGCAGCCTGCAGTCTGAAGATTTTGCAGTTTAT
TACTGTCAGCAGTATAATTACTGGCCGCTCACTTTCGGCGGAG GGACCAAGGTGGAGATCAAGCGA
434 22G10 artificial aa EIVMTQSPVTLSLSLGERATLSCRASQSISSNLAWFQQKPGQA
PRLLIYGAFTRATGIPARVSGSGSGTEFTLTISSLQSEDFAVY YCQQYNYWPLTFGGGTKVEIKR
435 2C12_LC#1 artificial nt
GATGTTGTGATGactCAGtCTccActctccctgcCCGTCACCC
TTGGACAGCCGGcctCCAtctcctgCAGGtCTAGTCAAAGcct
cgtaTACAGTGATGGAAACAcctACTTGAATTGGTTTCAGCAG
AGGCCAGGCCAATCTCCAAGGcgcctaATTTATAAGGTTTCTA
ACTGGGactctGGGGtCCCAGACAGATTCAGCgGCAGTGGGTC
AGGCActGATTTCACactGAAAAtCAGCAGGGTGGaggctgaG
GATGTTGGGGTTTATTactgCATGCAAGGTATAGTGTGGCCGT
GCAGTTTTGGCCAGGGGACCAAGCTGGAGATCAAaCgA 436 2C12_LC#1 artificial aa
DVVMTQSPLSLPVTLGQPASISCRSSQSLVYSDGNTYLNWFQQ
RPGQSPRRLIYKVSNWDSGVPDRFSGSGSGTDFTLKISRVEAE
DVGVYYCMQGIVWPCSFGQGTKLEIKR 437 2H12_LC#2 artificial nt
GATGTTGTGATGACTCAGTCTCCACTCTCCCTGCCCGTCACCC
TTGGACAGCCGGCCTCCATCTCCTGCAGGTCTAGTCAAAGCCT
CGTATACAGTGATGGAAACACCTACTTGAATTGGTTTCAGCAG
AGGCCAGGCCAATCTCCAAGGCGCCTAATTTATAAGGTTTCTA
ACTGGGACTCTGGGGTCCCAGACAGAATCAGCGGCAGTGGGTC
AGGCACCGATTTCACACTGAAAATCAGCAGGGTGGAGGCTGAG
GATGTTGGGGTTTATTACTGCATGCAAGATACACTGTGGCCGT
GCAGTTTTGGCCAGGGGACCAAGCTGGAGATCAAACGA 438 2H12_LC#2 artificial aa
DVVMTQSPLSLPVTLGQPASISCRSSQSLVYSDGNTYLNWFQQ
RPGQSPRRLIYKVSNWDSGVPDRISGSGSGTDFTLKISRVEAE
DVGVYYCMQDTLWPCSFGQGTKLEIKR 439 2G6_LC#1 artificial nt
GaTGTTGTGATGACTCagtctccACTCTCCCTGCCCGTCACCC
ttggacaGCCGGCCTccaTCTCCTGCAGGTCTAGTCAAAGCCT
CGTATACAGTGATGGAAACACCTACTTGAATTGGTTTCAGCAG
AGGCCAGGCCAATCTCCACGGCGCCTAATTTATCAGGTTTCTA
ACTGGGACTCTGGGGTCCCAGACAGATTCAGCGGCAGTGGGTC
AGGCACTGATTTCACACTGAAAATCAGCAGGGTGGAGGCTGAG
GATGTTGGGATTTATTACTGCATGCAAGATACACTGTGGCCGT
GCAGTTTTGGCCAGGGGACCAAGCTGGAGATCAAACGA 440 2G6_LC#1 artificial aa
DVVMTQSPLSLPVTLGQPASISCRSSQSLVYSDGNTYLNWFQQ
RPGQSPRRLIYQVSNWDSGVPDRFSGSGSGTDFTLKISRVEAE
DVGIYYCMQDTLWPCSFGQGTKLEIKR 441 2H12 artificial nt
TCCTATGAGCTGACTCAGCCACCCTCAGTGTCCGTGTCCCCAG
GACAGACAGCCAGCATCACCTGCTCTGGAGATAGATTGGGGGA
AAAATATACTTGCTGGTATCAGCAGAGGCCAGGCCAGTCCCCT
TTGCTGGTCATCTATCAAGATACCAAGCGGCCCTCAGGGATCC
CTGAGCGATTCTCTGGCTCCAACTCTGGTAACACAGCCACTCT
GACCATCAGCGGGACCCAGCCTATGGATGAGGCTGACTATTAC
TGTCAGGCGTGGGACAGCAGCACTGTGGTATTCGGCGGAGGGA CCAAGCTGACCGTCCtAGGT
442 2H12 artificial aa SYELTQPPSVSVSPGQTASITCSGDRLGEKYTCWYQQRPGQSP
LLVIYQDTKRPSGIPERFSGSNSGNTATLTISGTQPMDEADYY CQAWDSSTVVFGGGTKLTVLG
443 2G6 artificial nt TCCTATGAACTGACTCAGCCACCCTCAGTGTCCGTGTCCCCAG
GACAGACAGCCAGCATCACCTGCTCTGGAGATAGGTTGGGGGA
AAAATATACTTGCTGGTATCAGCAGAGGCCAGGCCAGTCCCCT
TTGCTGGTCATCTATCAAGATACCAAGCGGCCCTCAGGGATCC
CTGAGCGATTCTCTGGCTCCAACTCTGGTAACACAGCCACTCT
GACCATCAGCGGGACCCAGGCTATGGATGAGGCTGACTATTAC
TGTCAGGCGTGGGACAGCAGCACTGTGGTATTCGGCGGAGGGA CCAAGCTGACCGTCCTAGGT
444 2G6 artificial aa SYELTQPPSVSVSPGQTASITCSGDRLGEKYTCWYQQRPGQSP
LLVIYQDTKRPSGIPERFSGSNSGNTATLTISGTQAMDEADYY CQAWDSSTVVFGGGTKLTVLG
445 23A10 artificial nt TCCTATGAGCTGACTCAGCCACCCTCAGTGTCCGTGTCCCCAG
GACAGACAGCCAGCATCACCTGCTCTGGAGATAGATTGGGGGA
GAAATATGTTTGCTGGTATCAGCAGAAGCCAGGCCAGTCCCCT
ATACTGGTCATCTATCAAGATAATAAGTGGCCCTCAGGGATCC
CTGAGCGATTCTCTGGCTCCAACTCTGGGAACACAGCCACTCT
GACCATCAGCGGGACCCAGGCTATGGATGAGGCTGACTATTAC
TGTCAGGCGTGGGACAGCAGCACTGTGGTATTCGGCGGGGGGA CCAAGCTGACCGTCCTAGGT
446 23A10 artificial aa SYELTQPPSVSVSPGQTASITCSGDRLGEKYVCWYQQKPGQSP
ILVIYQDNKWPSGIPERFSGSNSGNTATLTISGTQAMDEADYY CQAWDSSTVVFGGGTKLTVLG
447 5E3 artificial nt TCCTATGAGCTGACTCAGCCACCCTCAGTGTCCGTGTCCCCAG
GACAGACAGCCAGCATCACCTGCTCTGGAGATAAATTGGGGGA
TGAATATGCTTGCTGGTATCAGCAGAAGCCAGGCCAGTCCCCT
GTGCTGGTCATCTATCAAGATAGCAAGCGGCCCTCAGGGATCC
CTGAGCGATTCTCTGGCTCCAACTCTGGGAACACAGCCACTCT
GACCATCAGCGGGACCCAGGCTATGGATGAGGCTGACTATTAC
TGTCAGGCGTGGGACAGCAGCACTGTGGTATTCGGCGGAGGGA CCAAGCTGACCGTCCTAGGT
448 5E3 artificial aa SYELTQPPSVSVSPGQTASITCSGDKLGDEYACWYQQKPGQSP
VIVIYQDSKRPSGIPERFSGSNSGNTATLTISGTQAMDEADYY
CQAWDSSTVVFGGGTKLTVLG
TABLE-US-00012 TABLE IIc Heavy Chain Variable Region Polynucleotide
and Amino acid Sequences 13586 HC [hu anti-<huCDH19> 4F3 VH]
QVQLVESGGGVVQPGRSLRLSCAASGFSFSSYDMDWVRQTPGKGLEWVAVIWYDGSNKYYADSVRG
RFTISRDNSICNTLFLQMNSLRVEDTAVYYCARETGEGWYFDLWGRGTLVTVSS SEQ ID NO:
449 13589 HC [hu anti-<huCDH19> 4A9 VH]
QVQLQESGPGLVKPSETLSLTCTVSGGSISGYYWSWIRQPPGKGLEWFAYFSYSGSTNYNPSLKSRVTLS
VDTSKNQFSLKLSSVTAADTAVYYCARNWAFHFDFWGQGTLVTVSS SEQ ID NO: 450 13590
HC [hu anti-<huCDH19> 4B10 VH]
QVQLVESGGGVVQPGRSLRLSCAASGFTFSSYDMHWVRQAPGKGLEWVAVISYDGTNEYYADSVKGR
FTISRDTSKNTLYLQMNSLRAEDTAVYYCARERYFDWSFDYWGQGTLVSVSS SEQ ID NO: 451
13874 HC [hu anti-<huCDH19> 17118.2 VH]
QVQLQESGPGLVKPSETLSLTCTVSGGSINSYYWSWIRQPPGKGLEWIGYIYYIGSTNYNPSLKSRVTISV
DTSKNQFSLKLSSVTAADTALYYCARDSRYRSGWYDAFDIWGQGTMVTVSS SEQ ID NO: 452
13875 HC [hu anti-<huCDH19> 16C1.1 VH]
QVQLQESGPGLVKPSETLSLTCTVSGGSISGYYWSWIRQPPGKGLEWIGYIYYIGSTNYNPSLKSRVTMS
IDTSKNQFSLTLSSLTAADTAVYFCARDGSSGWYRWFDPWGQGTLVTVSS SEQ ID NO: 453
13876 HC [hu anti-<huCDH19> 16A4.1 VH]
QVQLQESGPGLAKPSETLSLTCTVSGDSITSYYWSWIRQPPGKGLEWIGYIYYSGSTNYNPSLKSRVTISV
DTSKNQFSLKLSSVTAADTAVYYCARDQRRIAAAGTHFYGMDVWGQGTTVTVSS SEQ ID NO:
454 13877 HC [hu anti-<huCDH19> 22G10.1 VH]
EVQLLESGGGLVQPGGSLRLSCAASGFTFSSYAMNWVRQAPGKGLEWVSTISGGGANTYYADSVKGR
FTISSDNSKSTLYLQMNSLRAADTAVYHCAKGGMGGYYYGMDVWGQGTTVTVSS SEQ ID NO:
455 13878 HC [hu anti-<huCDH19> 20D3.1 VH]
QVQLVQSGAEVKKPGASVKVSCKVSGYTFTSYFIHWVRQAPGQGLEWMGIINPISVSTSYAQKFQGRV
TMTRDTSTSTVFMELSSLRSEDTAVYYCARGGIQLWLHFDYWGQGTLVTVSS SEQ ID NO: 456
13879 HC [hu anti-<huCDH19> 22D1.1 VH]
QVQLVQSGAEVKKPGASVRVSCKVSGYTFTSYFIHWVRQAPGQGLEWMGIINPISVSTSYAQKFQGRV
TMTRDTSTSTVFMELSSLRSEDTAVYYCARGGIQLWLHLDYWGQGTLVTVSS SEQ ID NO: 457
13880 HC [hu anti-<huCDH19> 25F8.1 VH]
QVQLVQSGAEVKKPGASVKVSCKASGYTFTSYYIHWVRQAPGQGLEWMGIINPSGGSTRYAQKFQGR
VTMTRDTSTSTVFMELSSLRSEDTAVYYCARGGIQLWLHFDYWGQGTLVTVSS SEQ ID NO:
458 13881 HC [hu anti-<huCDH19> 26F12.1 VH]
QVQLVQSGAEVKKPGASVKVSCKASRYTFTNYYMSWVRQAPGQGLEWMGIINPSGGDSTYAQKFQG
RLTMTGDTSTSTVYMELSSLRSEDTAVYYCARGGIQLWLHFDYWGQGTLVTVSS SEQ ID NO:
459 13882 HC [hu anti-<huCDH19> 26D1.1 VH]
QVQLVQSGAEVKKPGASVKVSCKASRYTFTSYYMSWVRQAPGQGLEWMGIIHPSGGDTTYAQKFQGR
VTMTGDTSTSTVYMELSSLRSEDTAVYYCARGGIKLWLHFDYWGQGTLVTVSS SEQ ID NO:
460 13883 HC [hu anti-<huCDH19> 25G10.1 VH]
QVQLQESGPGLVKPSETLSLTCTVSGGSISGYYWSWIRQPPGKGLEWIGYIYYIGSTNYNPSLKSRVTMS
VDTSKNQFSLKLSSVTAADTAVYYCARDGSSGWYRWFDPWGQGTLVTVSS SEQ ID NO: 461
13885 HC [hu anti-<huCDH19> 19B5.1 VH]
QVQLVQSGAEVKKPGASVKVSCKVSGYTFTSYFIHWVRQAPGQGLEWMGIINPISVSTSYAQKFQGRV
TMTRDTSTSTVFMELSSLRSEDTAVYYCARGGIQLWLHLDYWGQGTLVTVSS SEQ ID NO: 462
14022 HC [hu anti-<huCDH19> 4A2 VH]
QVQLQESGPGLVKPSQTLSLTCTVSGGSISSSGYYWSWIRQHPGKGLEWICIYIYYTGSAYYNPSLKSRV
TISVDTSKNQFSLKLSSVTAADTAVYYCARDGSSGWYFQYWGQGTLVTVSS SEQ ID NO: 463
14024 HC [hu anti-<huCDH19> 4A2 (1-472)(Q7E, H47P) VH]
QVQLQESGPGLVKPSETLSLTCTVSGGSISSSGYYWSWIRQPPGKGLEWIGYIYYTGSAYYNPSLKSRVT
ISVDTSKNQFSLKLSSVTAADTAVYYCARDGSSGWYFQYWGQGTLVTVSS SEQ ID NO: 464
14025 HC [hu anti-<huCDH19> 4A2 VH]
QVQLQESGPGLVKPSQTLSLTCTVSGGSISSSGYYWSWIRQHPGKGLEWIGYIYYTGSAYYNPSLKSRV
TISVDTSKNQFSLKLSSVTAADTAVYYCARDGSSGWYFQYWGQGTLVTVSS SEQ ID NO: 465
14026 HC [hu anti-<huCDH19> 4A2 (1-472)(Q17E, H47P) VH]
QVQLQESGPGLVKPSETLSLTCTVSGGSISSSGYYWSWIRQPPGKGLEWIGYIYYTGSAYYNPSLKSRVT
ISVDTSKNQFSLKLSSVTAADTAVYYCARDGSSGWYFQYWGQGTLVTVSS SEQ ID NO: 466
14027 HC [hu anti-<huCDH19> 4A2 (1-472)(Q17E, H47P, D111E)
VH]
QVQLQESGPGLVKPSETLSLTCTVSGGSISSSGYYWSWIRQPPGKGLEWIGYIYYTGSAYYNPSLKSRVT
ISVDTSKNQFSLKLSSVTAADTAVYYCAREGSSGWYFQYWGQGTLVTVSS SEQ ID NO: 467
14028 HC [hu anti-<huCDH19> 4A2 (1-472)(Q17E, H47P, D111E,
W134Y) VH]
QVQLQESGPGLVKPSETLSLTCTVSGGSISSSGYYWSWIRQPPGKGLEWIGYIYYTGSAYYNPSLKSRVT
ISVDTSKNQFSLKLSSVTAADTAVYYCAREGSSGYYFQYWGQGTLVTVSS SEQ ID NO: 468
14029 HC [hu anti-<huCDH19> 4A2 VH]
QVQLQESGPGLVKPSQTLSLTCTVSGGSISSSGYYWSWIRQHPGKGLEWIGYIYYTGSAYYNPSLKSRV
TISVDTSKNQFSLKLSSVTAADTAVYYCARDGSSGWYFQYWGQGTLVTVSS SEQ ID NO: 469
14030 HC [hu anti-<huCDH19> 4F3 (1-471)(R17G) VH]
QVQLVESGGGVVQPGGSLRLSCAASGFSFSSYDMDWVRQTPGKGLEWVAVIWYDGSNKYYADSVRG
RFTISRDNSKNTLFLQMNSLRVEDTAVYYCARETGEGWYFDLWGRGTLVTVSS SEQ ID NO:
470 14031 HC [hu anti-<huCDH19> 4F3 (1-471)(R17G, T47A) VH]
QVQLVESGGGVVQPGGSLRLSCAASGFSFSSYDMDWVRQAPGKGLEWVAVIWYDGSNKYYADSVRG
RFTISRDNSICNTLFLQMNSLRVEDTAVYYCARETGEGWYFDLWGRGTLVTVSS SEQ ID NO:
471 14032 HC [hu anti-<huCDH19> 4F3 (1-471)(R17G, T47A,
R141Q) VH]
QVQLVESGGGVVQPGGSLRLSCAASGFSFSSYDMDWVRQAPGKGLEWVAVIWYDGSNKYYADSVRG
RFTISRDNSKNTLFLQMNSLRVEDTAVYYCARETGEGWYFDLWGQGTLVTVSS SEQ ID NO:
472 14033 HC [hu Anti-<huCDH19> 4F3 (1-471)(R17G, T47A, D61E,
D72E, R141Q) VH]
QVQLVESGGGVVQPGGSLRLSCAASGFSFSSYDMDWVRQAPGKGLEWVAVIWYEGSNKYYAESVRG
RFTISRDNSICNTLFLQMNSLRVEDTAVYYCARETGEGWYFDLWGQGTLVTVSS SEQ ID NO:
473 14034 HC [hu anti-<huCDH19> 4F3 (1-471)(R17G, T47A, D61E,
D72E, W134Y, R141Q) VH]
QVQLVESGGGVVQPGGSLRLSCAASGFSFSSYDMDWVRQAPGKGLEWVAVIWYEGSNKYYAESVRG
RFTISRDNSKNTLFLQMNSLRVEDTAVYYCARETGEGYYFDLWGQGTLVTVSS SEQ ID NO:
474 14039 HC [hu anti-<huCDH19> 2G6 (1-477)(R17G, D61E, D72E,
K94N) VH]
QVQLVESGGGVVQPGGSLRLSCAASGFTFSSYGMHWVRQAPGKGLEWVAFIWYEGSNKYYAESVKD
RFTISRDNSKNTLYLQMNSLRAEDTAVYYCARRAGIIGTIGYYYGMDVWGQGTTVTVSS SEQ ID
NO: 475 14040 HC [hu anti-<huCDH19> 16C1.1 VH]
QVQLQESGPGLVKPSETLSLTCTVSGGSISGYYWSWIRQPPGKGLEWIGYIYYIGSTNYNPSLKSRVTMS
IDTSKNQFSLTLSSLTAADTAVYFCARDGSSGWYRWFDPWGQGTLVTVSS SEQ ID NO: 476
14041 HC [hu anti-<huCDH19> 16C1.1 (1-469)(T92K) VH]
QVQLQESGPGLVKPSETLSLTCTVSGGSISCiYYWSWIRQPPGKGLEWIGYIYYIGSTNYNPSLKSRVTMS
IDTSKNQFSLKLSSLTAADTAVYFCARDGSSGWYRWFDPWGQGTLVTVSS SEQ ID NO: 477
14042 HC [hu anti-<huCDH19> 16C1.1 (1-469)(T92K, D109E) VH]
QVQLQESGPGLVKPSETLSLTCTVSGGSISCiYYWSWIRQPPGKGLEWIGYIYYIGSTNYNPSLKSRVTMS
IDTSKNQFSLKLSSLTAADTAVYFCAREGSSGWYRWFDPWGQGTLVTVSS SEQ ID NO: 478
14043 HC [hu anti-<huCDH19> 16C1.1 (1-469)(T92K, W132Y,
W135Y) VH]
QVQLQESGPGLVKPSETLSLTCTVSGGSISCiYYWSWIRQPPGKGLEWIGYIYYIGSTNYNPSLKSRVTMS
IDTSKNQFSLKLSSLTAADTAVYFCARDGSSGYYRYFDPWGQGTLVTVSS SEQ ID NO: 479
14044 HC [hu anti-<huCDH19> 16C1.1 (1-469)(T92K) VH]
QVQLQESGPGLVKPSETLSLTCTVSGGSISCiYYWSWIRQPPGKGLEWIGYIYYIGSTNYNPSLKSRVTMS
IDTSKNQFSLKLSSLTAADTAVYFCARDGSSGWYRWFDPWGQGTLVTVSS SEQ ID NO: 480
14045 HC [hu anti-<huCDH19> 17118.2 VH]
QVQLQESGPGLVKPSETLSLTCTVSGGSINSYYWSWIRQPPGKGLEWIGYIYYIGSTNYNPSLKSRVTISV
DTSKNQFSLKLSSVTAADTALYYCARDSRYRSGWYDAFDIWGQGTMVTVSS SEQ ID NO: 481
14046 HC [hu anti-<huCDH19> 17118.2 (1-471)(D109E) VH]
QVQLQESGPGLVKPSETLSLTCTVSGGSINSYYWSWIRQPPGKGLEWIGYIYYIGSTNYNPSLKSRVTISV
DTSKNQFSLKLSSVTAADTALYYCARESRYRSGWYDAFDIWGQGTMVTVSS SEQ ID NO: 482
14047 HC [hu anti-<huCDH19> 17118.2 (1-471)(D109E, W132Y) VH]
QVQLQESGPGLVKPSETLSLTCTVSGGSINSYYWSWIRQPPGKGLEWIGYIYYIGSTNYNPSLKSRVTISV
DTSKNQFSLKLSSVTAADTALYYCARESRYRSGYYDAFDIWGQGTMVTVSS SEQ ID NO: 483
14048 HC [hu anti-<huCDH19> 17118.2 (1-471)(D109E) VH]
QVQLQESGPGLVKPSETLSLTCTVSGGSINSYYWSWIRQPPGKGLEWIGYIYYIGSTNYNPSLKSRVTISV
DTSKNQFSLKLSSVTAADTALYYCARESRYRSGWYDAFDIWGQGTMVTVSS SEQ ID NO: 484
14049 HC [hu anti-<huCDH19> 4F7 VH]
QVQLQESGPGLVKPSETLSLTCTVSGGSISSYSWSWIRQPPGKGLEWIGYIYYSGSTNYNPSLKSRVTISL
DTSKNQFSLKLSSVTAADTAVYYCARNWAFHFDYWGQGTLVTVSS SEQ ID NO: 485 14050
HC [hu anti-<huCDH19> 4F7 VVH]
QVQLQESGPGLVKPSETLSLTCTVSGGSISSYSWSWIRQPPGKGLEWIGYIYYSGSTNYNPSLKSRVTISL
DTSKNQFSLKLSSVTAADTAVYYCARNWAFHFDYWGQGTLVTVSS SEQ ID NO: 486 14051
HC [hu anti-<huCDH19> 4F7 (1-468)(W113Y) VH]
QVQLQESGPGLVKPSETLSLTCTVSGGSISSYSWSWIRQPPGKGLEWIGYIYYSGSTNYNPSLKSRVTISL
DTSKNQFSLKLSSVTAADTAVYYCARNYAFHFDYWGQGTLVTVSS SEQ ID NO: 487 14052
HC [hu anti-<huCDH19> 4B10 (1-471)(R17G, D61E, D72E, W134Y)
VH]
QVQLVESGGGVVQPGGSLRLSCAASGFTFSSYDMHWVRQAPGKGLEWVAVISYEGTNEYYAESVKGR
FTISRDTSKNTLYLQMNSLRAEDTAVYYCARERYFDYSFDYWCiQGTLVSVSS SEQ ID NO:
488 14053 HC [hu anti-<huCDH19> 4B10 VH]
QVQLVESGGGVVQPGRSLRLSCAASGFTFSSYDMHWVRQAPGKGLEWVAVISYDGTNEYYADSVKGR
FTISRDTSKNTLYLQMNSLRAEDTAVYYCARERYFDWSFDYWGQGTLVSVSS SEQ ID NO: 489
14054 HC [hu anti-<huCDH19> 4B10 (1-471)(R17G) VH]
QVQLVESGGGVVQPGGSLRLSCAASGFTFSSYDMHWVRQAPGKGLEWVAVISYDGTNEYYADSVKG
RFTISRDTSKNTLYLQMNSLRAEDTAVYYCARERYFDWSFDYWGQGTLVSVSS SEQ ID NO:
490 14055 HC [hu anti-<huCDH19> 4B10 (1-471)(R17G, D61E,
D72E) VH]
QVQLVESGGGVVQPGGSLRLSCAASGFTFSSYDMHWVRQAPGKGLEWVAVISYEGTNEYYAESVKGR
FTISRDTSKNTLYLQMNSLRAEDTAVYYCARERYFDWSFDYWGQGTLVSVSS SEQ ID NO: 491
14056 HC [hu anti-<huCDH19> 4A9 VH]
QVQLQESGPGLVKPSETLSLTCTVSGGSISGYYWSWIRQPPGKGLEWFAYFSYSGSTNYNPSLKSRVTLS
VDTSKNQFSLKLSSVTAADTAVYYCARNWAFHFDFWGQGTLVTVSS SEQ ID NO: 492 14057
HC [hu anti-<huCDH19> 4A9 (1-468)(F55I, A56G) VH]
QVQLQESGPGLVKPSETLSLTCTVSGGSISGYYWSWIRQPPGKGLEWIGYFSYSGSTNYNPSLKSRVTLS
VDTSKNQFSLKLSSVTAADTAVYYCARNWAFHFDFWGQGTLVTVSS SEQ ID NO: 493 14058
HC [hu anti-<huCDH19> 4A9 (1-468)(F55I, A56G) VH]
QVQLQESGPGLVKPSETLSLTCTVSGGSISGYYWSWIRQPPGKGLEWIGYFSYSGSTNYNPSLKSRVTLS
VDTSKNQFSLKLSSVTAADTAVYYCARNWAFHFDFWGQGTLVTVSS SEQ ID NO: 494 14059
HC [hu anti-<huCDH19> 4A9 (1-468)(F55I, A56G, W113Y) VH]
QVQLQESGPGLVKPSETLSLTCTVSGGSISGYYWSWIRQPPGKGLEWIGYFSYSGSTNYNPSLKSRVTLS
VDTSKNQFSLKLSSVTAADTAVYYCARNYAFHFDFWGQGTLVTVSS SEQ ID NO: 495 14060
HC [hu anti-<huCDH19> 20D3.1 VH]
QVQLVQSGAEVKKPGASVKVSCKVSGYTFTSYFIHWVRQAPGQGLEWMGIINPISVSTSYAQKFQGRV
TMTRDTSTSTVFMELSSLRSEDTAVYYCARGGIQLWLHFDYWGQGTLVTVSS SEQ ID NO:
496
14061 HC [hu anti-<huCDH19> 20D3.1 VH]
QVQLVQSGAEVKKPGASVKVSCKVSGYTFTSYFIHWVRQAPGQGLEWMGIINPISVSTSYAQKFQGRV
TMTRDTSTSTVFMELSSLRSEDTAVYYCARGGIQLWLHFDYWGQGTLVTVSS SEQ ID NO: 497
14062 HC [hu anti-<huCDH19> 20D3.1 (1-469)(W133Y) VH]
QVQLVQSGAEVKKPGASVKVSCKVSGYTFTSYFIHWVRQAPGQGLEWMGIINPISVSTSYAQKFQGRV
TMTRDTSTSTVFMELSSLRSEDTAVYYCARGGIQLYLHFDYWGQGTLVTVSS SEQ ID NO: 498
14063 HC [hu anti-<huCDH19> 20D3.1 (1-469)(W133Y) VH]
QVQLVQSGAEVKKPGASVKVSCKVSGYTFTSYFIHWVRQAPGQGLEWMGIINPISVSTSYAQKFQGRV
TMTRDTSTSTVFMELSSLRSEDTAVYYCARGGIQLYLHFDYWGQGTLVTVSS SEQ ID NO: 499
14064 HC [hu anti-<huCDH19> 20D3.1 (1-469)(W133Y) VH]
QVQLVQSGAEVKKPGASVKVSCKVSGYTFTSYFIHWVRQAPGQGLEWMGIINPISVSTSYAQKFQGRV
TMTRDTSTSTVFMELSSLRSEDTAVYYCARGGIQLYLHFDYWGQGTLVTVSS SEQ ID NO: 500
14065 HC [hu anti-<huCDH19> 22G10.1 (1-470)(S82R, A99E) VH]
EVQLLESGGGLVQPGGSLRLSCAASGFTFSSYAMNWVRQAPGKGLEWVSTISGGGANTYYADSVKGR
FTISRDNSKSTLYLQMNSLRAEDTAVYHCAKGGMGGYYYGMDVWGQGTTVTVSS SEQ ID NO:
501 14066 HC [hu anti-<huCDH19> 22G10.1 (1-470)(A99E, H105Y)
VH]
EVQLLESGGGLVQPGGSLRLSCAASGFTFSSYAMNWVRQAPGKGLEWVSTISGGGANTYYADSVKGR
FTISSDNSKSTLYLQMNSLRAEDTAVYYCAKGGMGGYYYCiMDVWGQGTTVTVSS SEQ ID NO:
502 14067 HC [hu anti-<huCDH19> 22G10.1 (1-470)(A99E) VH]
EVQLLESGGGLVQPGGSLRLSCAASGFTFSSYAMNWVRQAPGKGLEWVSTISGGGANTYYADSVKGR
FTISSDNSKSTLYLQMNSLRAEDTAVYHCAKGGMGGYYYGMDVWGQGTTVTVSS SEQ ID NO:
503 14068 HC [hu anti-<huCDH19> 22G10.1 (1-470)(A99E) VH]
EVQLLESGGGLVQPGGSLRLSCAASGFTFSSYAMNWVRQAPGKGLEWVSTISGGGANTYYADSVKGR
FTISSDNSKSTLYLQMNSLRAEDTAVYHCAKGGMGGYYYGMDVWGQGTTVTVSS SEQ ID NO:
504 14069 HC [hu anti-<huCDH19> 22G10.1 (1-470)(D72E, A99E)
VH]
EVQLLESGGGLVQPGGSLRLSCAASGFTFSYAMNWVRQAPGKGLEWVSTISGGGANTYYAESVKGRF
TISSDNSKSTLYLQMNSLRAEDTAVYHCAKGGMGGYYYGMDVWGQGTTVTVSS SEQ ID NO:
505 14070 HC [hu anti-<huCDH19> 22G10.1 (1-470)(H105Y) VH]
EVQLLESGGGLVQPGGSLRLSCAASGFTFSSYAMNWVRQAPGKGLEWVSTISGGGANTYYADSVKGR
FTISSDNSKSTLYLQMNSLRAADTAVYYCAKGGMGGYYYGMDVWGQGTTVTVSS SEQ ID NO:
506 14071 HC [hu anti-<huCDH19> 16A4.1 (1-474)(T144L) VH]
QVQLQESGPGLAKPSETLSLTCTVSGDSITSYYWSWIRQPPGKGLEWIGYIYYSGSTNYNPSLKSRVTISV
DTSKNQFSLKLSSVTAADTAVYYCARDQRRIAAAGTHFYGMDVWGQGTLVTVSS SEQ ID NO:
507 14072 HC [hu anti-<huCDH19> 19B5.1 VH]
QVQLVQSGAEVKKPGASVKVSCKVSGYTFTSYFIHWVRQAPGQGLEWMGIINPISVSTSYAQKFQGRV
TMTRDTSTSTVFMELSSLRSEDTAVYYCARGGIQLWLHLDYWGQGTLVTVSS SEQ ID NO: 508
14073 HC [hu anti-<huCDH19> 19B5.1 (1-469)(W133Y) VH]
QVQLVQSGAEVKKPGASVKVSCKVSGYTFTSYFIHWVRQAPGQGLEWMGIINPISVSTSYAQKFQGRV
TMTRDTSTSTVFMELSSLRSEDTAVYYCARGGIQLYLHLDYWGQGTLVTVSS SEQ ID NO: 509
14074 HC [hu anti-<huCDH19> 19B5.1 VH]
QVQLVQSGAEVKKPGASVKVSCKVSGYTFTSYFIHWVRQAPGQGLEWMGIINPISVSTSYAQKFQGRV
TMTRDTSTSTVFMELSSLRSEDTAVYYCARGGIQLWLHLDYWGQGTLVTVSS SEQ ID NO: 510
14075 HC [hu anti-<huCDH19> 19B5.1 VH]
QVQLVQSGAEVKKPGASVKVSCKVSGYTFTSYFIHWVRQAPGQGLEWMGIINPISVSTSYAQKFQGRV
TMTRDTSTSTVFMELS SLRSEDTAVYYCARGGIQLWLHLDYWGQGTLVTVSS SEQ ID NO:
511 14076 HC [hu anti-<huCDH19> 19B5.1 (1-469)(W133Y) VH]
QVQLVQSGAEVKKPGASVKVSCKVSGYTFTSYFIHWVRQAPGQGLEWMGIINPISVSTSYAQKFQGRV
TMTRDTSTSTVFMELS SLRSEDTAVYYCARGGIQLYLHLDYWGQGTLVTVSS SEQ ID NO:
512 14077 HC [hu anti-<huCDH19> 23A10.3 (1-474)(L92Q) VH]
QVQLVESGGGVVQPGRSLRLSCAASGFTFSRYGIHWVRQAPGKGLEWVAVIWYDGSNKYYADSVKGR
FTISRDNSKNTLYLQMNSLRAEDSAVYYCARRAGIPGTTGYYYGMDVWGQGTTVTVSS SEQ ID
NO: 513 14078 HC [hu anti-<huCDH19> 23A10.3 (1-474)(R17G,
L92Q) VH]
QVQLVESGGGVVQPGGSLRLSCAASGFTFSRYGIHWVRQAPGKGLEWVAVIWYDGSNKYYADSVKG
RFTISRDNSKNTLYLQMNSLRAEDSAVYYCARRAGIPGTTGYYYGMDVWGQGTTVTVSS SEQ ID
NO: 514 14079 HC [hu anti-<huCDH19> 23A10.3 (1-474)(R17G,
D61E, D72E, L92Q) VH]
QVQLVESGGGVVQPGGSLRLSCAASGFTFSRYGIHWVRQAPGKGLEWVAVIWYEGSNKYYAESVKGR
FTISRDNSKNTLYLQMNSLRAEDSAVYYCARRAGIPGTTGYYYGMDVWGQGTTVTVSS SEQ ID
NO: 515 14080 HC [hu anti-<huCDH19> 23A10.3 VH]
QVQLVESGGGVVQPGRSLRLSCAASGFTFSRYGIHWVRQAPGKGLEWVAVIWYDGSNKYYADSVKGR
FTISRDNSKNTLYLLMNSLRAEDSAVYYCARRAGIPGTTGYYYGMDVWGQGTTVTVSS SEQ ID
NO: 516 14081 HC [hu anti-<huCDH19> 25G10.1 VH]
QVQLQESGPGLVKPSETLSLTCTVSGGSISGYYWSWIRQPPGKGLEWIGYIYYIGSTNYNPSLKSRVTMS
VDTSKNQFSLKLSSVTAADTAVYYCARDGSSGWYRWFDPWGQGTLVTVSS SEQ ID NO: 517
14082 HC [hu anti-<huCDH19> 25G10.1 (1-469)(D109E, W132Y,
W135Y) VH]
QVQLQESGPGLVKPSETLSLTCTVSGGSISGYYWSWIRQPPGKGLEWIGYIYYIGSTNYNPSLKSRVTMS
VDTSKNQFSLKLSSVTAADTAVYYCAREGSSGYYRYFDPWGQGTLVTVSS SEQ ID NO: 518
14083 HC [hu anti-<huCDH19> 26D1.1 VH]
QVQLVQSGAEVKKPGASVKVSCKASRYTFTSYYMSWVRQAPGQGLEWMGIIHPSGGDTTYAQKFQGR
VTMTGDTSTSTVYMELSSLRSEDTAVYYCARGGIKLWLHFDYWGQGTLVTVSS SEQ ID NO:
519 14084 HC [hu anti-<huCDH19> 26D1.1 VH]
QVQLVQSGAEVKKPGASVKVSCKASRYTFTSYYMSWVRQAPGQGLEWMGIIHPSGGDTTYAQKFQGR
VTMTGDTSTSTVYMELSSLRSEDTAVYYCARGGIKLWLHFDYWGQGTLVTVSS SEQ ID NO:
520 14085 HC [hu anti-<huCDH19> 26D1.1 VH]
QVQLVQSGAEVKKPGASVKVSCKASRYTFTSYYMSWVRQAPGQGLEWMGIIHPSGGDTTYAQKFQGR
VTMTGDTSTSTVYMELSSLRSEDTAVYYCARGGIKLWLHFDYWGQGTLVTVSS SEQ ID NO:
521 14086 HC [hu anti-<huCDH19> 26D1.1 VH]
QVQLVQSGAEVKKPGASVKVSCKASRYTFTSYYMSWVRQAPGQGLEWMGIIHPSGGDTTYAQKFQGR
VTMTGDTSTSTVYMELSSLRSEDTAVYYCARGGIKLWLHFDYWGQGTLVTVSS SEQ ID NO:
522 14087 HC [hu anti-<huCDH19> 26D1.1 (1-469)(W133Y) VH]
QVQLVQSGAEVKKPGASVKVSCKASRYTFTSYYMSWVRQAPGQGLEWMGIIHPSGGDTTYAQKFQGR
VTMTGDTSTSTVYMELSSLRSEDTAVYYCARGGIKLYLHFDYWGQGTLVTVSS SEQ ID NO:
523 14088 HC [hu anti-<huCDH19> 26D1.1 (1-469)(R27G, G82R)
VH]
QVQLVQSGAEVKKPGASVKVSCKASGYTFTSYYMSWVRQAPGQGLEWMGIIHPSGGDTTYAQKFQGR
VTMTRDTSTSTVYMELSSLRSEDTAVYYCARGGIKLWLHFDYWGQGTLVTVSS SEQ ID NO:
524 14089 HC [hu anti-<huCDH19> 26F12.1 VH]
QVQLVQSGAEVKKPGASVKVSCKASRYTFTNYYMSWVRQAPGQGLEWMGIINPSGGDSTYAQKFQG
RLTMTGDTSTSTVYMELSSLRSEDTAVYYCARGGIQLWLHFDYWGQGTLVTVSS SEQ ID NO:
525 14090 HC [hu anti-<huCDH19> 26F12.1 VH]
QVQLVQSGAEVKKPGASVKVSCKASRYTFTNYYMSWVRQAPGQGLEWMGIINPSGGDSTYAQKFQG
RLTMTGDTSTSTVYMELSSLRSEDTAVYYCARGGIQLWLHFDYWGQGTLVTVSS SEQ ID NO:
526 14091 HC [hu anti-<huCDH19> 26F12.1 (1-469)(W133Y) VH]
QVQLVQSGAEVKKPGASVKVSCKASRYTFTNYYMSWVRQAPGQGLEWMGIINPSGGDSTYAQKFQG
RLTMTGDTSTSTVYMELSSLRSEDTAVYYCARGGIQLYLHFDYWGQGTLVTVSS SEQ ID NO:
527 14092 HC [hu anti-<huCDH19> 26F12.1 (1-469)(W133Y) VH]
QVQLVQSGAEVKKPGASVKVSCKASRYTFTNYYMSWVRQAPGQGLEWMGIINPSGGDSTYAQKFQG
RLTMTGDTSTSTVYMELSSLRSEDTAVYYCARGGIQLYLHFDYWGQGTLVTVSS SEQ ID NO:
528 14093 HC [hu anti-<huCDH19> 25F8.1 VH]
QVQLVQSGAEVKKPGASVKVSCKASGYTFTSYYIHWVRQAPGQGLEWMGIINPSGGSTRYAQKFQGR
VTMTRDTSTSTVFMELSSLRSEDTAVYYCARGGIQLWLHFDYWGQGTLVTVSS SEQ ID NO:
529 14094 HC [hu anti-<huCDH19> 25F8.1 VH]
QVQLVQSGAEVKKPGASVKVSCKASGYTFTSYYIHWVRQAPGQGLEWMGIINPSGGSTRYAQKFQGR
VTMTRDTSTSTVFMELSSLRSEDTAVYYCARGGIQLWLHFDYWGQGTLVTVSS SEQ ID NO:
530 14095 HC [hu anti-<huCDH19> 25F8.1 (1-469)(F90Y) VH]
QVQLVQSGAEVKKPGASVKVSCKASGYTFTSYYIHWVRQAPGQGLEWMGIINPSGGSTRYAQKFQGR
VTMTRDTSTSTVYMELSSLRSEDTAVYYCARGGIQLWLHFDYWGQGTLVTVSS SEQ ID NO:
531 14096 HC [hu anti-<huCDH19> 25F8.1 (1-469)(F90Y) VH]
QVQLVQSGAEVKKPGASVKVSCKASGYTFTSYYIHWVRQAPGQGLEWMGIINPSGGSTRYAQKFQGR
VTMTRDTSTSTVYMELSSLRSEDTAVYYCARGGIQLWLHFDYWGQGTLVTVSS SEQ ID NO:
532 14097 HC [hu anti-<huCDH19> 25F8.1 (1-469)(F90Y, W133Y)
VH]
QVQLVQSGAEVKKPGASVKVSCKASGYTFTSYYIHWVRQAPGQGLEWMGIINPSGGSTRYAQKFQGR
VTMTRDTSTSTVYMELSSLRSEDTAVYYCARGGIQLYLHFDYWGQGTLVTVSS SEQ ID NO:
533 14098 HC [hu anti-<huCDH19> 22D1.1 VH]
QVQLVQSGAEVKKPGASVRVSCKVSGYTFTSYFIHWVRQAPGQGLEWMGIINPISVSTSYAQKFQGRV
TMTRDTSTSTVFMELSSLRSEDTAVYYCARGGIQLWLHLDYWGQGTLVTVSS SEQ ID NO: 534
14099 HC [hu anti-<huCDH19> 22D1.1 VH]
QVQLVQSGAEVKKPGASVRVSCKVSGYTFTSYFIHWVRQAPGQGLEWMGIINPISVSTSYAQKFQGRV
TMTRDTSTSTVFMELSSLRSEDTAVYYCARGGIQLWLHLDYWGQGTLVTVSS SEQ ID NO: 535
14100 HC [hu anti-<huCDH19> 22D1.1 (1-469)(W133Y) VH]
QVQLVQSGAEVKKPGASVRVSCKVSGYTFTSYFIHWVRQAPGQGLEWMGIINPISVSTSYAQKFQGRV
TMTRDTSTSTVFMELSSLRSEDTAVYYCARGGIQLYLHLDYWGQGTLVTVSS SEQ ID NO: 536
14101 HC [hu anti-<huCDH19> 22D1.1 (1-469)(W133Y) VH]
QVQLVQSGAEVKKPGASVRVSCKVSGYTFTSYFIHWVRQAPGQGLEWMGIINPISVSTSYAQKFQGRV
TMTRDTSTSTVFMELSSLRSEDTAVYYCARGGIQLYLHLDYWGQGTLVTVSS SEQ ID NO: 537
14102 HC [hu anti-<huCDH19> 22D1.1 (1-469)(F90Y) VH]
QVQLVQSGAEVKKPGASVRVSCKVSGYTFTSYFIHWVRQAPGQGLEWMGIINPISVSTSYAQKFQGRV
TMTRDTSTSTVYMELSSLRSEDTAVYYCARGGIQLWLHLDYWGQGTLVTVSS SEQ ID NO: 538
13591 HC [hu anti-<huCDH19> 4F7 VH]
QVQLQESGPGLVKPSETLSLTCTVSGGSISSYSWSWIRQPPGKOLEWIGYIYYSGSTNYNPSLKSRVTISL
DTSKNQFSLKLSSVTAADTAVYYCARNWAFHFDYWGQGTLVTVSS SEQ ID NO: 539 14301
HC [hu anti-<huCDH19> 2G6 VH]
QVQLVESGGGVVQPGRSLRLSCAASGFTFSSYGMHWVRQAPGKGLEWVAFIWYDGSNKYYADSVKD
RFTISRDNSKNTLYLQMKSLRAEDTAVYYCARRAGIIGTIGYYYGMDVWGQGTTVTVSS SEQ ID
NO: 540 14302 HC [hu anti-<huCDH19> 2G6 (1-477)(R17G, K94N)
VH]
QVQLVESGGGVVQPGGSLRLSCAASGFTFSSYGMHWVRQAPGKGLEWVAFIWYDGSNKYYADSVKD
RFTISRDNSKNTLYLQMNSLRAEDTAVYYCARRAGIIGTIGYYYGMDVWGQGTTVTVSS SEQ ID
NO: 541 14303 HC [hu anti-<huCDH19> 2G6 (1-477)(D61E, D72E)
VH]
QVQLVESGGGVVQPGRSLRLSCAASGFTFSSYGMHWVRQAPGKGLEWVAFIWYEGSNKYYAESVKD
RFTISRDNSKNTLYLQMKSLRAEDTAVYYCARRAGIIGTIGYYYGMDVWGQGTTVTVSS SEQ ID
NO: 542 14304 HC [hu anti-<huCDH19> 2G6 (1-477)(R17G) VH]
QVQLVESGGGVVQPGGSLRLSCAASGFTFSSYGMHWVRQAPGKGLEWVAFIWYDGSNKYYADSVKD
RFTISRDNSKNTLYLQMKSLRAEDTAVYYCARRAGIIGTIGYYYGMDVWGQGTTVTVSS SEQ ID
NO: 543
TABLE-US-00013 TABLE IId Light Chain Variable Region Amino acid
Sequences 13586 LC [hu anti-<huCDH19> 4F3 VL]
EIVLTQSPGTLSLSPGERATLSCRASQSVSSSYLAWYQQKPGQAPRLLIYGASSRATGIPDRFSGSGSGTD
FTLTISRLEPEDFAVYYCQQYGSSWTFGQGTKVEIKR SEQ ID NO: 544 13589 LC [hu
anti-<huCDH19> 4A9 VL]
QSVLTQPPSVSGAPGQRVTISCTGSSSNIGTGYAVHWYQQFPGTAPKLLIYGNNNRPSGVPDRFSGSKSG
TSASLAITGLQAEDEADYYCQSYDSRLSGWVFGGGTKLTVLG SEQ ID NO: 545 13590 LC
[hu anti-<huCDH19> 4B10 VL]
EIVLTQSPGTLSLSPGERATLSCRASQSVSNTYLAWYHQRPGQAPRLLIYGASSRATGIPDRFSGSGSGTD
FALTISSLEPEDFAVYYCQQYSNSWTFGQGTKVEIKR SEQ ID NO: 546 13874 LC [hu
anti-<huCDH19> 17H8.2 VL]
DIVLTQSPGTLSLSPGERATLSCRASQSVAGSYLAWYQQKPGQAPRLLISGASSRATGIPDRFSGSGSGT
DFTLTISRLEPEDFAVYYCQQYGKSPITFGQGTRLEMKG SEQ ID NO: 547 13875 LC [hu
anti-<huCDH19> 16C1.1 VL]
EIVLTQSPGTLSLSPGERATLSCRASQSVSSSYLAWYQQKPGQAPRLLIFGASSRATGIPDRFSGSGSGTD
FTLTISGLEPEDFAVYHCQQYGNSPLTFGGGTKVEIKR SEQ ID NO: 548 13876 LC [hu
anti-<huCDH19> 16A4.1 VL]
EIVLTQSPGTLSLSPGERATLSCRASQSVSSSYLAWYQQKPGQAPRLLIYGTSSRATGIPDRFSGSGSGTD
FTLTISRLEPEDFAVYYCQQYGSSPFTFGGGTKVEIKR SEQ ID NO: 549 13877 LC [hu
anti-<huCDH19> 22G10.1 VL]
EIVMTQSPVTLSLSLGERATLSCRASQSISSNLAWFQQKPGQAPRLLIYGAFTRATGIPARVSGSGSGTEF
TLTISSLQSEDFAVYYCQQYNYWPLTFGGGTKVEIKR SEQ ID NO: 552 13878 LC [hu
anti-<huCDH19> 20D3.1 VL]
QSALTQPPSATGTPGQRVTISCSGSSSNIGSNFVNWYKQLPGTAPKVLIYTNNQRPSGVPDRFSGSKSGTS
ASLAISGLQSEDESDYYCATWDDSLNGWVFGGGTKLTVLG SEQ ID NO: 554 13879 LC
[hu anti-<huCDH19> 22D1.1 VL]
QSALTQPPSATGTPGQRVTISCSGSSSNIGSNFVNWYKQLPGTAPKVLIYTNNQRPSGVPDRFSGSKSGTS
ASLAISGLQSEDESDYYCATWDDSMNGWVFGGGTKLTVLG SEQ ID NO: 555 13880 LC
[hu anti-<huCDH19> 25F8.1 VL]
QSALTQPPSATGTPGQRVTISCSGSSSNIGRNFVNWYKQLPGTAPKVLIYTNNQRPSGVPDRFSGSKSGT
SASLAISGLQSEDESDYYCAAWDDSLNGWVFGGGTKLTVLG SEQ ID NO: 556 13881 LC
[hu anti-<huCDH19> 26F12.1 VL]
QSVLTQSPSASGTPGQKVTISCSGSRSNIGSNFVNWYQQLPGTAPKLLIYTNYQRPSGVPDRFSGSKSGTS
ASLAISGLQSEDEADYYCAVWDDSLNGWVFGGGTKLTVLG SEQ ID NO: 557 13882 LC
[hu anti-<huCDH19> 26D1.1 VL]
HSVLTQSPSASGTPGQRVTISCSGSRSNIGSNFVNWYQQLPGTAPKLLIYTNNQRPSGVPDRFSGSKSGTS
ASLAISGLQSEDEADYYCAVWDDSLNGWVFGGGTKLTVLG SEQ ID NO: 555 13883 LC
[hu anti-<huCDH19> 25G10.1 VL]
EIVLTQSPGTLSLSPGERATLSCRASQSVSSSYLAWYQQKPGQAPRLLIFGASSRATGIPDRFSGSGSGTD
FTLTISRLEPEDFAVYHCQQYGNSPLTFGGGTKVEIKR SEQ ID NO: 556 13885 LC [hu
anti-<huCDH19> 19B5.1 VL]
QSALTQPPSTTGTPGQRVTISCSGSRSNIGSNFVNWYKQLPGTAPKVLIYTNNQRPSGVPDRFSGSKSGTS
ASLAISGLQSEDESDYYCATWDDSMNGWVFGGGTKLTVLG SEQ ID NO: 557 14022 LC
[hu anti-<huCDH19> 4A2 (1-236)(N30Q) VL]
EIVLTQSPGTLSLSPGERATLSCRASRQISSSYLAWYQQKPGQAPRLLIYGPSSRATGIPDRFSGSGSGTDF
TLTISRLEPEDFTVYYCQQYGSSFTFGPGTKVDIKR SEQ ID NO: 558 14024 LC [hu
anti-<huCDH19> 4A2 (1-236)(N30Q,T102A,P141Q) VL]
EIVLTQSPGTLSLSPGERATLSCRASRQISSSYLAWYQQKPGQAPRLLIYGPSSRATGIPDRFSGSGSGTDF
TLTISRLEPEDFAVYYCQQYGSSFTFGQGTKVDIKR SEQ ID NO: 559 14025 LC [hu
anti-<huCDH19> 4A2 (1-236)(N30Q, T102A) VL]
EIVLTQSPGTLSLSPGERATLSCRASRQISSSYLAWYQQKPGQAPRLLIYGPSSRATGIPDRFSGSGSGTDF
TLTISRLEPEDFAVYYCQQYGSSFTFGPGTKVDIKR SEQ ID NO: 560 14026 LC [hu
anti-<huCDH19> 4A2 (1-236)(N30Q, T102A) VL]
EIVLTQSPGTLSLSPGERATLSCRASRQISSSYLAWYQQKPGQAPRLLIYGPSSRATGIPDRFSGSGSGTDF
TLTISRLEPEDFAVYYCQQYGSSFTFGPGTKVDIKR SEQ ID NO: 561 14027 LC [hu
anti-<huCDH19> 4A2 (1-236)(N30Q, T102A, P141Q) VL]
EIVLTQSPGTLSLSPGERATLSCRASRQISSSYLAWYQQKPGQAPRLLIYGPSSRATGIPDRFSGSGSGTDF
TLTISRLEPEDFAVYYCQQYGSSFTFGQGTKVDIKR SEQ ID NO: 562 14028 LC [hu
anti-<huCDH19> 4A2 (1-236)(N30Q, T102A, P141Q) VL]
EIVLTQSPGTLSLSPGERATLSCRASRQISSSYLAWYQQKPGQAPRLLIYGPSSRATGIPDRFSGSGSGTDF
TLTISRLEPEDFAVYYCQQYGSSFTFGQGTKVDIKR SEQ ID NO: 563 14029 LC [hu
anti-<huCDH19> 4A2 (1-236)(R29Q, N30S) VL]
EIVLTQSPGTLSLSPGERATLSCRASQSISSSYLAWYQQKPGQAPRLLIYGPSSRATGIPDRFSGSGSGTDF
TLTISRLEPEDFTVYYCQQYGSSFTFGPGTKVDIKR SEQ ID NO: 564 14030 LC [hu
anti-<huCDH19> 4F3 VL]
EIVLTQSPGTLSLSPGERATLSCRASQSVSSSYLAWYQQKPGQAPRLLIYGASSRATGIPDRFSGSGSGTD
FTLTISRLEPEDFAVYYCQQYGSSWTFGQGTKVEIKR SEQ ID NO: 565 14031 LC [hu
anti-<huCDH19> 4F3 VL]
EIVLTQSPGTLSLSPGERATLSCRASQSVSSSYLAWYQQKPGQAPRLLIYGASSRATGIPDRFSGSGSGTD
FTLTISRLEPEDFAVYYCQQYGSSWTFGQGTKVEIKR SEQ ID NO: 566 14032 LC [hu
anti-<huCDH19> 4F3 VL]
EIVLTQSPGTLSLSPGERATLSCRASQSVSSSYLAWYQQKPGQAPRLLIYGASSRATGIPDRFSGSGSGTD
FTLTISRLEPEDFAVYYCQQYGSSWTFGQGTKVEIKR SEQ ID NO: 567 14033 LC [hu
anti-<huCDH19> 4F3 VL]
EIVLTQSPGTLSLSPGERATLSCRASQSVSSSYLAWYQQKPGQAPRLLIYGASSRATGIPDRFSGSGSGTD
FTLTISRLEPEDFAVYYCQQYGSSWTFGQGTKVEIKR SEQ ID NO: 568 14034 LC [hu
anti-<huCDH19> 4F3 VL]
EIVLTQSPGTLSLSPGERATLSCRASQSVSSSYLAWYQQKPGQAPRLLIYGASSRATGIPDRFSGSGSGTD
FTLTISRLEPEDFAVYYCQQYGSSWTFGQGTKVEIKR SEQ ID NO: 569 14039 LC [hu
anti-<huCDH19> 2G6 (1-234)(C42S, D110E) VL]
SYELTQPPSVSVSPGQTASITCSGDRLGEKYTSWYQQRPGQSPLLVIYQDTKRPSGIPERFSGSNSGNTAT
LTISGTQAMDEADYYCQAWESSTVVFGGGTKLTVLG SEQ ID NO: 570 14040 LC [hu
anti-<huCDH19> 16C1.1 (1-235)(H105Y) VL]
EIVLTQSPGTLSLSPGERATLSCRASQSVSSSYLAWYQQKPGQAPRLLIFGASSRATGIPDRFSGSGSGTD
FTLTISGLEPEDFAVYYCQQYGNSPLTFGGGTKVEIKR SEQ ID NO: 571 14041 LC [hu
anti-<huCDH19> 16C1.1 (1-235)(H105Y) VL]
EIVLTQSPGTLSLSPGERATLSCRASQSVSSSYLAWYQQKPGQAPRLLIFGASSRATGIPDRFSGSGSGTD
FTLTISGLEPEDFAVYYCQQYGNSPLTFGGGTKVEIKR SEQ ID NO: 572 14042 LC [hu
anti-<huCDH19> 16C1.1 (1-235)(H105Y) VL]
EIVLTQSPGTLSLSPGERATLSCRASQSVSSSYLAWYQQKPGQAPRLLIFGASSRATGIPDRFSGSGSGTD
FTLTISGLEPEDFAVYYCQQYGNSPLTFGGGTKVEIKR SEQ ID NO: 573 14043 LC [hu
anti-<huCDH19> 16C1.1 (1-235)(H105Y) VL]
EIVLTQSPGTLSLSPGERATLSCRASQSVSSSYLAWYQQKPGQAPRLLIFGASSRATGIPDRFSGSGSGTD
FTLTISGLEPEDFAVYYCQQYGNSPLTFGGGTKVEIKR SEQ ID NO: 574 14044 LC [hu
anti-<huCDH19> 16C1.1 (1-235)(G95R, H105Y, G141Q) VL]
EIVLTQSPGTLSLSPGERATLSCRASQSVSSSYLAWYQQKPGQAPRLLIFGASSRATGIPDRFSGSGSGTD
FTLTISRLEPEDFAVYYCQQYGNSPLTFGQGTKVEIKR SEQ ID NO: 575 14045 LC [hu
anti-<huCDH19> 17H8.2 (1-235)(G149R) VL]
DIVLTQSPGTLSLSPGERATLSCRASQSVAGSYLAWYQQKPGQAPRLLISGASSRATGIPDRFSGSGSGT
DFTLTISRLEPEDFAVYYCQQYGKSPITFGQGTRLEMKR SEQ ID NO: 576 14046 LC [hu
anti-<huCDH19> 17H8.2 (1-235)(G149R) VL]
DIVLTQSPGTLSLSPGERATLSCRASQSVAGSYLAWYQQKPGQAPRLLISGASSRATGIPDRFSGSGSGT
DFTLTISRLEPEDFAVYYCQQYGKSPITFGQGTRLEMKR SEQ ID NO: 577 14047 LC [hu
anti-<huCDH19> 17H8.2 (1-235)(G149R) VL]
DIVLTQSPGTLSLSPGERATLSCRASQSVAGSYLAWYQQKPGQAPRLLISGASSRATGIPDRFSGSGSGT
DFTLTISRLEPEDFAVYYCQQYGKSPITFGQGTRLEMKR SEQ ID NO: 578 14048 LC [hu
anti-<huCDH19> 17H8.2 (1-235)(S57Y, G149R) VL]
DIVLTQSPOTLSLSPGERATLSCRASQSVAGSYLAWYQQKPGQAPRLLIYGASSRATGIPDRFSGSGSGT
DFTLTISRLEPEDFAVYYCQQYGKSPITFGQGTRLEMKR SEQ ID NO: 579 14049 LC [hu
anti-<huCDH19> 4F7 (1-239)(H57Y) VL]
QSVLTQPPSVSGAPGQRVTISCTGSSSNIGTGYDVHWYQQLPGTAPKLLIYGNSNRPSGVPDRFSGSKSG
TSASLAITGLQAEDEADYYCQSYDSSLSGWVFGGGTRLTVLG SEQ ID NO: 580 14050 LC
[hu anti-<huCDH19> 4F7 (1-239)(H57Y, D110E) VL]
QSVLTQPPSVSGAPGQRVTISCTGSSSNIGTGYDVHWYQQLPGTAPKLLIYGNSNRPSGVPDRFSGSKSG
TSASLAITGLQAEDEADYYCQSYESSLSGWVFGGGTRLTVLG SEQ ID NO: 581 14051 LC
[hu anti-<huCDH19> 4F7 (1-239)(D110E) VL]
QSVLTQPPSVSGAPGQRVTISCTGSSSNIGTGYDVHWYQQLPGTAPKLLIHGNSNRPSGVPDRFSGSKSG
TSASLAITGLQAEDEADYYCQSYESSLSGWVFGGGTRLTVLG SEQ ID NO: 582 14052 LC
[hu anti-<huCDH19> 4B10 (1-236)(H45Q, A90T) VL]
EIVLTQSPOTLSLSPGERATLSCRASQSVSNTYLAWYQQRPGQAPRLLIYGASSRATGIPDRFSGSGSGTD
FTLTISSLEPEDFAVYYCQQYSNSWTFGQGTKVEIKR SEQ ID NO: 583 14053 LC [hu
anti-<huCDH19> 4B10 (1-236)(H45Q, A90T) VL]
EIVLTQSPOTLSLSPGERATLSCRASQSVSNTYLAWYQQRPGQAPRLLIYGASSRATGIPDRFSGSGSGTD
FTLTISSLEPEDFAVYYCQQYSNSWTFGQGTKVEIKR SEQ ID NO: 584 14054 LC [hu
anti-<huCDH19> 4B10 (1-236)(H45Q, A90T) VL]
EIVLTQSPOTLSLSPGERATLSCRASQSVSNTYLAWYQQRPGQAPRLLIYGASSRATGIPDRFSGSGSGTD
FTLTISSLEPEDFAVYYCQQYSNSWTFGQGTKVEIKR SEQ ID NO: 585 14055 LC [hu
anti-<huCDH19> 4B10 (1-236)(H45Q, A90T) VL]
EIVLTQSPOTLSLSPGERATLSCRASQSVSNTYLAWYQQRPGQAPRLLIYGASSRATGIPDRFSGSGSGTD
FTLTISSLEPEDFAVYYCQQYSNSWTFGQGTKVEIKR SEQ ID NO: 586 14056 LC [hu
anti-<huCDH19> 4A9 (1-239)(F47L) VL]
QSVLTQPPSVSGAPGQRVTISCTGSSSNIGTGYAVHWYQQLPGTAPKLLIYGNNNRPSGVPDRFSGSKSG
TSASLAITGLQAEDEADYYCQSYDSRLSGWVFGGGTKLTVLG SEQ ID NO: 587 14057 LC
[hu anti-<huCDH19> 4A9 (1-239)(F47L) VL]
QSVLTQPPSVSGAPGQRVTISCTGSSSNIGTGYAVHWYQQLPGTAPKLLIYGNNNRPSGVPDRFSGSKSG
TSASLAITGLQAEDEADYYCQSYDSRLSGWVFGGGTKLTVLG SEQ ID NO: 588 14058 LC
[hu anti-<huCDH19> 4A9 (1-239)(F47L, D110E) VL]
QSVLTQPPSVSGAPGQRVTISCTGSSSNIGTGYAVHWYQQLPGTAPKLLIYGNNNRPSGVPDRFSGSKSG
TSASLAITGLQAEDEADYYCQSYESRLSGWVFGGGTKLTVLG SEQ ID NO: 589 14059 LC
[hu anti-<huCDH19> 4A9 (1-239)(F47L, D110E) VL]
QSVLTQPPSVSGAPGQRVTISCTGSSSNIGTGYAVHWYQQLPGTAPKLLIYGNNNRPSGVPDRFSGSKSG
TSASLAITGLQAEDEADYYCQSYESRLSGWVFGGGTKLTVLG SEQ ID NO: 590 14060 LC
[hu anti-<huCDH19> 20D3.1 (1-235)(S102A) VL]
QSALTQPPSATGTPGQRVTISCSGSSSNIGSNFVNWYKQLPGTAPKVLIYTNNQRPSGVPDRFSGSKSGTS
ASLAISGLQSEDEADYYCATWDDSLNGWVFGGGTKLTVLG SEQ ID NO: 591 14061 LC
[hu anti-<huCDH19> 20D3.1 (1-235)(K45Q, S102A) VL]
QSALTQPPSATGTPGQRVTISCSGSSSNIGSNFVNWYQQLPGTAPKVLIYTNNQRPSGVPDRFSGSKSGTS
ASLAISGLQSEDEADYYCATWDDSLNGWVFGGGTKLTVLG SEQ ID NO: 592
14062 LC [hu anti-<huCDH19> 20D3.1 (1-235)(K45Q, S102A) VL]
QSALTQPPSATGTPGQRVTISCSGSSSNIGSNFVNWYQQLPGTAPKVLIYTNNQRPSGVPDRFSGSKSGTS
ASLAISGLQSEDEADYYCATWDDSLNGWVFGGGTKLTVLG SEQ ID NO: 593 14063 LC
[hu anti-<huCDH19> 20D3.1 (1-235)(K45Q, S102A, D111E, N135Q)
VL]
QSALTQPPSATGTPGQRVTISCSGSSSNIGSNFVNWYQQLPGTAPKVLIYTNNQRPSGVPDRFSGSKSGTS
ASLAISGLQSEDEADYYCATWDESLQGWVFGGGTKLTVLG SEQ ID NO: 594 14064 LC
[hu anti-<huCDH19> 20D3.1 (1-235)(W109Y) VL]
QSALTQPPSATGTPGQRVTISCSGSSSNIGSNFVNWYKQLPGTAPKVLIYTNNQRPSGVPDRFSGSKSGTS
ASLAISGLQSEDESDYYCATYDDSLNGWVFGGGTKLTVLG SEQ ID NO: 595 14065 LC
[hu anti-<huCDH19> 22G10.1 VL]
EIVMTQSPVTLSLSLGERATLSCRASQSISSNLAWFQQKPGQAPRLLIYGAFTRATGIPARVSGSGSGTEF
TLTISSLQSEDFAVYYCQQYNYWPLTFGGGTKVEIKR SEQ ID NO: 596 14066 LC [hu
anti-<huCDH19> 22G10.1 VL]
EIVMTQSPVTLSLSLGERATLSCRASQSISSNLAWFQQKPGQAPRLLIYGAFTRATGIPARVSGSGSGTEF
TLTISSLQSEDFAVYYCQQYNYWPLTFGGGTKVEIKR SEQ ID NO: 597 14067 LC [hu
anti-<huCDH19> 22G10.1 (1-234)(Q97E, S98P) VL]
EIVMTQSPVTLSLSLGERATLSCRASQSISSNLAWFQQKPGQAPRLLIYGAFTRATGIPARVSGSGSGTEF
TLTISSLEPEDFAVYYCQQYNYWPLTFGGGTKVEIKR SEQ ID NO: 598 14068 LC [hu
anti-<huCDH19> 22G10.1 (1-234)(V78F, Q97E, S98P) VL]
EIVMTQSPVTLSLSLGERATLSCRASQSISSNLAWFQQKPGQAPRLLIYGAFTRATGIPARFSOSGSGTEF
TLTISSLEPEDFAVYYCQQYNYWPLTFGGGTKVEIKR SEQ ID NO: 599 14069 LC [hu
anti-<huCDH19> 22G10.1 (1-234)(V78F, Q97E, S98P) VL]
EIVMTQSPVTLSLSLGERATLSCRASQSISSNLAWFQQKPGQAPRLLIYGAFTRATGIPARFSGSGSGTEF
TLTISSLEPEDFAVYYCQQYNYWPLTFGGGTKVEIKR SEQ ID NO: 600 14070 LC [hu
anti-<huCDH19> 22G10.1 VL]
EIVMTQSPVTLSLSLGERATLSCRASQSISSNLAWFQQKPGQAPRLLIYGAFTRATGIPARVSGSGSGTEF
TLTISSLQSEDFAVYYCQQYNYWPLTFGGGTKVEIKR SEQ ID NO: 601 14071 LC [hu
anti-<huCDH19> 16A4.1 (1-235)(G141Q) VL]
EIVLTQSPGTLSLSPGERATLSCRASQSVSSSYLAWYQQKPGQAPRLLIYGTSSRATGIPDRFSGSGSGTD
FTLTISRLEPEDFAVYYCQQYGSSPFTFGQGTKVEIKR SEQ ID NO: 602 14072 LC [hu
anti-<huCDH19> 19B5.1 (1-235)(K45Q, S102A) VL]
QSALTQPPSTTGTPGQRVTISCSGSRSNIGSNFVNWYQQLPGTAPKVLIYTNNQRPSGVPDRFSGSKSGTS
ASLAISGLQSEDEADYYCATWDDSMNGWVFGGGTKLTVLG SEQ ID NO: 603 14073 LC
[hu anti-<huCDH19> 19B5.1 (1-235)(K45Q, S102A) VL]
QSALTQPPSTTGTPGQRVTISCSGSRSNIGSNFVNWYQQLPGTAPKVLIYTNNQRPSGVPDRFSGSKSGTS
ASLAISGLQSEDEADYYCATWDDSMNGWVFGGGTKLTVLG SEQ ID NO: 604 14074 LC
[hu anti-<huCDH19> 19B5.1 (1-235)(T11V, K45Q, S102A) VL]
QSALTQPPSVTGTPGQRVTISCSGSRSNIGSNFVNWYQQLPGTAPKVLIYTNNQRPSGVPDRFSGSKSGT
SASLAISGLQSEDEADYYCATWDDSMNGWVFGGGTKLTVLG SEQ ID NO: 605 14075 LC
[hu anti-<huCDH19> 19B5.1 (1-235)(T11V, K45Q, S102A, D111E,
N135Q) VL]
QSALTQPPSVTGTPGQRVTISCSGSRSNIGSNFVNWYQQLPGTAPKVLIYTNNQRPSGVPDRFSGSKSGT
SASLAISGLQSEDEADYYCATWDESMQGWVFGGGTKLTVLG SEQ ID NO: 606 14076 LC
[hu anti-<huCDH19> 19B5.1 (1-235)(T11V, K45Q, S102A, W109Y,
D111E, N135Q) VL]
QSALTQPPSVTGTPGQRVTISCSGSRSNIGSNFVNWYQQLPGTAPKVLIYTNNQRPSGVPDRFSGSKSGT
SASLAISGLQSEDEADYYCATYDESMQGWVFGGGTKLTVLG SEQ ID NO: 607 14077 LC
[hu anti-<huCDH19> 23A10.3 (1-231)(C42S) VL]
SYELTQPPSVSVSPGQTASITCSGDRLGEKYVSWYQQKPGQSPILVIYQDNKWPSGIPERFSGSNSGNTA
TLTISGTQAMDEADYYCQAWDSSTVVFGGGTKLTVLG SEQ ID NO: 608 14078 LC [hu
anti-<huCDH19> 23A10.3 (1-231)(C42S) VL]
SYELTQPPSVSVSPGQTASITCSGDRLGEKYVSWYQQKPGQSPILVIYQDNKWPSGIPERFSGSNSGNTA
TLTISGTQAMDEADYYCQAWDSSTVVFGGGTKLTVLG SEQ ID NO: 609 14079 LC [hu
anti-<huCDH19> 23A10.3 (1-231)(C42S, D110E) VL]
SYELTQPPSVSVSPGQTASITCSGDRLGEKYVSWYQQKPGQSPILVIYQDNKWPSGIPERFSGSNSGNTA
TLTISGTQAMDEADYYCQAWESSTVVFGGGTKLTVLG SEQ ID NO: 610 14080 LC [hu
anti-<huCDH19> 23A10.3 (1-231)(C42Y) VL]
SYELTQPPSVSVSPGQTASITCSGDRLGEKYVYWYQQKPGQSPILVIYQDNKWPSGIPERFSGSNSGNTA
TLTISGTQAMDEADYYCQAWDSSTVVFGGGTKLTVLG SEQ ID NO: 611 14081 LC [hu
anti-<huCDH19> 25G10.1 (1-235)(H105Y) VL]
EIVLTQSPGTLSLSPGERATLSCRASQSVSSSYLAWYQQKPGQAPRLLIFGASSRATGIPDRFSGSGSGTD
FTLTISRLEPEDFAVYYCQQYGNSPLTFGGGTKVEIKR SEQ ID NO: 612 14082 LC [hu
anti-<huCDH19> 25G10.1 (1-235)(H105Y) VL]
EIVLTQSPGTLSLSPGERATLSCRASQSVSSSYLAWYQQKPGQAPRLLIFGASSRATGIPDRFSGSGSGTD
FTLTISRLEPEDFAVYYCQQYGNSPLTFGGGTKVEIKR SEQ ID NO: 613 14083 LC [hu
anti-<huCDH19> 26D1.1 (1-235)(S7P) VL]
HSVLTQPPSASGTPGQRVTISCSGSRSNIGSNFVNWYQQLPGTAPKLLIYTNNQRPSGVPDRFSGSKSGTS
ASLAISGLQSEDEADYYCAVWDDSLNGWVFGGGTKLTVLG SEQ ID NO: 614 14084 LC
[hu anti-<huCDH19> 26D1.1 (1-235)(H1Q, S7P) VL]
QSVLTQPPSASGTPGQRVTISCSGSRSNIGSNFVNWYQQLPGTAPKLLIYTNNQRPSGVPDRFSGSKSGTS
ASLAISGLQSEDEADYYCAVWDDSLNGWVFGGGTKLTVLG SEQ ID NO: 615 14085 LC
[hu anti-<huCDH19> 26D1.1 (1-235)(H1Q, S7P, W109Y) VL]
QSVLTQPPSASGTPGQRVTISCSGSRSNIGSNFVNWYQQLPGTAPKLLIYTNNQRPSGVPDRFSGSKSGTS
ASLAISGLQSEDEADYYCAVYDDSLNGWVFGGGTKLTVLG SEQ ID NO: 616 14086 LC
[hu anti-<huCDH19> 26D1.1 (1-235)(H1Q, S7P, W109Y, D111E,
N135Q) VL]
QSVLTQPPSASGTPGQRVTISCSGSRSNIGSNFVNWYQQLPGTAPKLLIYTNNQRPSGVPDRFSGSKSGTS
ASLAISGLQSEDEADYYCAVYDESLQGWVFGGGTKLTVLG SEQ ID NO: 617 14087 LC
[hu anti-<huCDH19> 26D1.1 (1-235)(H1Q, S7P, W109Y, D111E,
N135Q) VL]
QSVLTQPPSASGTPGQRVTISCSGSRSNIGSNFVNWYQQLPGTAPKLLIYTNNQRPSGVPDRFSGSKSGTS
ASLAISGLQSEDEADYYCAVYDESLQGWVFGGGTKLTVLG SEQ ID NO: 618 14088 LC
[hu anti-<huCDH19> 26D1.1 (1-235)(H1Q, S7P) VL]
QSVLTQPPSASGTPGQRVTISCSGSRSNIGSNFVNWYQQLPGTAPKLLIYTNNQRPSGVPDRFSGSKSGTS
ASLAISGLQSEDEADYYCAVWDDSLNGWVFGGGTKLTVLG SEQ ID NO: 619 14089 LC
[hu anti-<huCDH19> 26F12.1 (1-235)(S7P) VL]
QSVLTQPPSASGTPGQKVTISCSGSRSNIGSNFVNWYQQLPGTAPKLLIYTNYQRPSGVPDRFSGSKSGTS
ASLAISGLQSEDEADYYCAVWDDSLNGWVFGGGTKLTVLG SEQ ID NO: 620 14090 LC
[hu anti-<huCDH19> 26F12.1 (1-235)(S7P, D111E) VL]
QSVLTQPPSASGTPGQKVTISCSGSRSNIGSNFVNWYQQLPGTAPKLLIYTNYQRPSGVPDRFSGSKSGTS
ASLAISGLQSEDEADYYCAVWDESLNGWVFGGGTKLTVLG SEQ ID NO: 621 14091 LC
[hu anti-<huCDH19> 26F12.1 (1-235)(S7P, D111E) VL]
QSVLTQPPSASGTPGQKVTISCSGSRSNIGSNFVNWYQQLPGTAPKLLIYTNYQRPSGVPDRFSGSKSGTS
ASLAISGLQSEDEADYYCAVWDESLNGWVFGGGTKLTVLG SEQ ID NO: 622 14092 LC
[hu anti-<huCDH19> 26F12.1 (1-235)(S7P, W109Y, D111E, N135Q)
VL]
QSVLTQPPSASGTPGQKVTISCSGSRSNIGSNFVNWYQQLPGTAPKLLIYTNYQRPSGVPDRFSGSKSGTS
ASLAISGLQSEDEADYYCAVYDESLQGWVFGGGTKLTVLG SEQ ID NO: 623 14093 LC
[hu anti-<huCDH19> 25F8.1 (1-235)(K45Q) VL]
QSALTQPPSATGTPGQRVTISCSGSSSNIGRNFVNWYQQLPGTAPKVLIYTNNQRPSGVPDRFSGSKSGT
SASLAISGLQSEDESDYYCAAWDDSLNGWVFGGGTKLTVLG SEQ ID NO: 624 14094 LC
[hu anti-<huCDH19> 25F8.1 (1-235)(K45Q, S102A) VL]
QSALTQPPSATGTPGQRVTISCSGSSSNIGRNFVNWYQQLPGTAPKVLIYTNNQRPSGVPDRFSGSKSGT
SASLAISGLQSEDEADYYCAAWDDSLNGWVFGGGTKLTVLG SEQ ID NO: 625 14095 LC
[hu anti-<huCDH19> 25F8.1 (1-235)(K45Q, S102A) VL]
QSALTQPPSATGTPGQRVTISCSGSSSNIGRNFVNWYQQLPGTAPKVLIYTNNQRPSGVPDRFSGSKSGT
SASLAISGLQSEDEADYYCAAWDDSLNGWVFGGGTKLTVLG SEQ ID NO: 626 14096 LC
[hu anti-<huCDH19> 25F8.1 (1-235)(K45Q, S102A, D111E) VL]
QSALTQPPSATGTPGQRVTISCSGSSSNIGRNFVNWYQQLPGTAPKVLIYTNNQRPSGVPDRFSGSKSGT
SASLAISGLQSEDEADYYCAAWDESLNGWVFGGGTKLTVLG SEQ ID NO: 627 14097 LC
[hu anti-<huCDH19> 25F8.1 (1-235)(K45Q, S102A, D111E, N135Q)
VL]
QSALTQPPSATGTPGQRVTISCSGSSSNIGRNFVNWYQQLPGTAPKVLIYTNNQRPSGVPDRFSGSKSGT
SASLAISGLQSEDEADYYCAAWDESLQGWVFGGGTKLTVLG SEQ ID NO: 628 14098 LC
[hu anti-<huCDH19> 22D1.1 (1-235)(K45Q, S102A) VL]
QSALTQPPSATGTPGQRVTISCSGSSSNIGSNFVNWYQQLPGTAPKVLIYTNNQRPSGVPDRFSGSKSGTS
ASLAISGLQSEDEADYYCATWDDSMNGWVFGGGTKLTVLG SEQ ID NO: 629 14099 LC
[hu anti-<huCDH19> 22D1.1 (1-235)(K45Q, S102A, D111E, N135Q)
VL]
QSALTQPPSATGTPGQRVTISCSGSSSNIGSNFVNWYQQLPGTAPKVLIYTNNQRPSGVPDRFSGSKSGTS
ASLAISGLQSEDEADYYCATWDESMQGWVFGGGTKLTVLG SEQ ID NO: 630 14100 LC
[hu anti-<huCDH19> 22D1.1 (1-235)(K45Q, S102A, W109Y, D111E,
N135Q) VL]
QSALTQPPSATGTPGQRVTISCSGSSSNIGSNFVNWYQQLPGTAPKVLIYTNNQRPSGVPDRFSGSKSGTS
ASLAISGLQSEDEADYYCATYDESMQGWVFGGGTKLTVLG SEQ ID NO: 631 14101 LC
[hu anti-<huCDH19> 22D1.1 (1-235)(K45Q, S102A, W109Y) VL]
QSALTQPPSATGTPGQRVTISCSGSSSNIGSNFVNWYQQLPGTAPKVLIYTNNQRPSGVPDRFSGSKSGTS
ASLAISGLQSEDEADYYCATYDDSMNGWVFGGGTKLTVLG SEQ ID NO: 632 14102 LC
[hu anti-<huCDH19> 22D1.1 (1-235)(K45Q, S102A) VL]
QSALTQPPSATGTPGQRVTISCSGSSSNIGSNFVNWYQQLPGTAPKVLIYTNNQRPSGVPDRFSGSKSGTS
ASLAISGLQSEDEADYYCATWDDSMNGWVFGGGTKLTVLG SEQ ID NO: 633 13591 LC
[hu anti-<huCDH19> 4F7 VL]
QSVLTQPPSVSGAPGQRVTISCTGSSSNIGTGYDVHWYQQLPGTAPKLLIHGNSNRPSGVPDRFSGSKSG
TSASLAITGLQAEDEADYYCQSYDSSLSGWVFGGGTRLTVLG SEQ ID NO: 634 14301 LC
[hu anti-<huCDH19> 2G6 (1-234)(D110E) VL]
SYELTQPPSVSVSPGQTASITCSGDRLGEKYTCWYQQRPGQSPLLVIYQDTKRPSGIPERFSGSNSGNTAT
LTISGTQAMDEADYYCQAWESSTVVFGGGTKLTVLG SEQ ID NO: 635 14302 LC [hu
anti-<huCDH19> 2G6 (1-234)(C42S, D110E) VL]
SYELTQPPSVSVSPGQTASITCSGDRLGEKYTSWYQQRPGQSPLLVIYQDTKRPSGIPERFSGSNSGNTAT
LTISGTQAMDEADYYCQAWESSTVVFGGGTKLTVLG SEQ ID NO: 636 14303 LC [hu
anti-<huCDH19> 2G6 (1-234)(C42S, D110E) VL]
SYELTQPPSVSVSPGQTASITCSGDRLGEKYTSWYQQRPGQSPLLVIYQDTKRPSGIPERFSGSNSGNTAT
LTISGTQAMDEADYYCQAWESSTVVFGGGTKLTVLG SEQ ID NO: 637 14304 LC [hu
anti-<huCDH19> 23A10.3 (1-231)(C42S) VL]
SYELTQPPSVSVSPGQTASITCSGDRLGEKYVSWYQQKPGQSPILVIYQDNKWPSGIPERFSGSNSGNTA
TLTISGTQAMDEADYYCQAWDSSTVVFGGGTKLTVLG SEQ ID NO: 638
[0430] Anti-CDH19 Variable and Constant Region Polynucleotide and
Amino Acid Sequences
TABLE-US-00014 TABLE IIIa Heavy Chain Variable and Contant Region
Polynucleotide and Amino acid Sequences 2G6 SEQ ID NO: 639
CAGGTGCAGTTGGTGGAGTCTGGGGGAGGCGTGGTCCAGCCTGGGAGGTCCCTGAGACTCTCCTGT
GCAGCGTCTGGATTCACCTTCAGTAGCTATGGCATGCACTGGGTCCGCCAGGCTCCAGGCAAGGGG
CTGGAGTGGGTGGCATTTATATGGTATGATGGAAGTAATAAATACTATGCAGACTCCGTGAAGGAC
CGATTCACCATCTCCAGAGACAATTCCAAGAACACGCTGTATCTGCAAATGAAAAGCCTGAGAGCT
GAGGACACGGCTGTGTATTACTGTGCGAGAAGGGCCGGTATAATAGGAACTATAGGCTACTACTAC
GGTATGGACGTCTGGGGCCAAGGGACCACGGTCACCGTCTCTAGTGCCTCCACCAAGGGCCCATCG
GTCTTCCCCCTGGCACCCTCCTCCAAGAGCACCTCTGGGGGCACAGCGGCCCTGGGCTGCCTGGTC
AAGGACTACTTCCCCGAACCGGTGACGGTGTCGTGGAACTCAGGCGCCCTGACCAGCGGCGTGCAC
ACCTTCCCGGCTGTCCTACAGTCCTCAGGACTCTACTCCCTCAGCAGCGTGGTGACCGTGCCCTCC
AGCAGCTTGGGCACCCAGACCTACATCTGCAACGTGAATCACAAGCCCAGCAACACCAAGGTGGAC
AAGAAAGTTGAGCCCAAATCTTGTGACAAAACTCACACATGCCCACCGTGCCCAGCACCTGAACTC
CTGGGGGGACCGTCAGTCTTCCTCTTCCCCCCAAAACCCAAGGACACCCTCATGATCTCCCGGACC
CCTGAGGTCACATGCGTGGTGGTGGACGTGAGCCACGAAGACCCTGAGGTCAAGTTCAACTGGTAC
GTGGACGGCGTGGAGGTGCATAATGCCAAGACAAAGCCGCGGGAGGAGCAGTACAACAGCACGTAC
CGTGTGGTCAGCGTCCTCACCGTCCTGCACCAGGACTGGCTGAATGGCAAGGAGTACAAGTGCAAG
GTCTCCAACAAAGCCCTCCCAGCCCCCATCGAGAAAACCATCTCCAAAGCCAAAGGGCAGCCCCGA
GAACCACAGGTGTACACCCTGCCCCCATCCCGGGAGGAGATGACCAAGAACCAGGTCAGCCTGACC
TGCCTGGTCAAAGGCTTCTATCCCAGCGACATCGCCGTGGAGTGGGAGAGCAATGGGCAGCCGGAG
AACAACTACAAGACCACGCCTCCCGTGCTGGACTCCGACGGCTCCTTCTTCCTCTATAGCAAGCTC
ACCGTGGACAAGAGCAGGTGGCAGCAGGGGAACGTCTTCTCATGCTCCGTGATGCATGAGGCTCTG
CACAACCACTACACGCAGAAGAGCCTCTCCCTGTCTCCGGGTAAATGA SEQ ID NO: 640
QVQLVESGGGVVQPGRSLRLSCAASGFTFSSYGMHWVRQAPGKGLEWVAFIWYDGSNKYYADSVKD
RFTISRDNSKNTLYLQMKSLRAEDTAVYYCARRAGIIGTIGYYYGMDVWGQGTTVTVSSASTKGPS
VFPLAPSSKSTSGGTAALGCLVKDYFPEPVTVSWNSGALTSGVHTFPAVLQSSGLYSLSSVVTVPS
SSLGTQTYICNVNHKPSNTKVDKKVEPKSCDKTHTCPPCPAPELLGGPSVFLFPPKPKDTLMISRT
PEVTCVVVDVSHEDPEVKFNWYVDGVEVHNAKTKPREEQYNSTYRVVSVLTVLHQDWLNGKEYKCK
VSNKALPAPIEKTISKAKGQPREPQVYTLPPSREEMTKNQVSLTCLVKGFYPSDIAVEWESNGQPE
NNYKTTPPVLDSDGSFFLYSKLTVDKSRWQQGNVFSCSVMHEALHNHYTQKSLSLSPGK 4A2 SEQ
ID NO: 641
CAGGTGCAGCTGCAGGAGTCGGGCCCAGGACTGGTGAAGCCTTCACAGACCCTGTCCCTCACCTGC
ACTGTCTCTGGTGGCTCCATCAGCAGTAGTGGTTACTACTGGAGCTGGATCCGCCAGCACCCAGGG
AAGGGCCTGGAGTGGATTGGGTACATCTATTACACTGGGAGCGCCTACTACAACCCGTCCCTCAAG
AGTCGAGTTACCATATCAGTAGACACGTCTAAGAACCAGTTCTCCCTGAAGCTGAGCTCTGTGACT
CCCGCGGACACGGCCGTGTATTACTCTGCGAGAGATGGAAGCAGTGGCTGGTACTTCCAGTATTGG
GGCCAGGGCACCCTGGTCACCGTCTCTAGTGCCTCCACCAAGGGCCCATCGGTCTTCCCCCTGGCA
CCCTCCTCCAAGAGCACCTCTGGGGGCACAGCGGCCCTGGGCTGCCTGGTCAAGGACTACTTCCCC
GAACCGGTGACGGTGTCGTGGAACTCAGGCGCCCTGACCAGCGGCGTGCACACCTTCCCGGCTGTC
CTACAGTCCTCAGGACTCTACTCCCTCAGCAGCGTGGTGACCGTGCCCTCCAGCAGCTTGGGCACC
CAGACCTACATCTGCAACGTGAATCACAAGCCCAGCAACACCAAGGTGGACAAGAAAGTTGAGCCC
AAATCTTGTGACAAAACTCACACATGCCCACCGTGCCCAGCACCTGAACTCCTGGGGGGACCGTCA
GTCTTCCTCTTCCCCCCAAAACCCAAGGACACCCTCATGATCTCCCGGACCCCTGAGGTCACATGC
GTGGTGGTGGACGTGAGCCACGAAGACCCTGAGGTCAAGTTCAACTGGTACGTGGACGGCGTGGAG
GTGCATAATGCCAAGACAAAGCCGCGGGAGGAGCAGTACAACAGCACGTACCGTGTGGTCAGCGTC
CTCACCGTCCTGCACCAGGACTGGCTGAATGGCAAGGAGTACAAGTGCAAGGTCTCCAACAAAGCC
CTCCCAGCCCCCATCGAGAAAACCATCTCCAAAGCCAAAGGGCAGCCCCGAGAACCACAGGTGTAC
ACCCTGCCCCCATCCCGGGAGGAGATGACCAAGAACCAGGTCAGCCTGACCTGCCTGGTCAAAGGC
TTCTATCCCAGCGACATCGCCGTGGAGTGGGAGAGCAATGGGCAGCCGGAGAACAACTACAAGACC
ACGCCTCCCGTGCTGGACTCCGACGGCTCCTTCTTCCTCTATAGCAAGCTCACCGTGGACAAGAGC
AGGTGGCAGCAGGGGAACGTCTTCTCATCCTCCGTGATCCATGAGGCTCTCCACAACCACTACACG
CAGAAGAGCCTCTCCCTGTCTCCGGGTAAATGA SEQ ID NO: 642
QVQLQESGPGLVKPSQTLSLTCTVSGGSISSSGYYWSWIRQHPGKGLEWIGYIYYTGSAYYNPSLK
SRVTISVDTSKNQFSLKLSSVTAADTAVYYCARDGSSGWYFQYWGQGTLVTVSSASTKGPSVFPLA
PSSKSTSGGTAALGCLVKDYFPEPVTVSWNSGALTSGVHTFPAVLQSSGLYSLSSVVTVPSSSLGT
QTYICNVNHKPSNTKVDKKVEPKSCDKTHTCPPCPAPELLGGPSVFLFPPKPKDTLMISRTPEVTC
VVVDVSHEDPEVKFNWYVDGVEVHNAKTKPREEQYNSTYRVVSVLTVLHQDWLNGKEYKCKVSNKA
LPAPIEKTISKAKGQPREPQVYTLPPSREEMTKNQVSLTCLVKGFYPSDIAVEWESNGQPENNYKT
TPPVLDSDGSFFLYSKLTVDKSRWQQGNVFSCSVMHEALHNHYTQKSLSLSPGK 4A9 SEQ ID
NO: 643
CAGGTGCAGCTGCAGGAGTCGGGCCCAGGACTGGTGAAGCCTTCGGAGACCCTGTCCCTCACCTGC
ACTGTCTCTGGTGGCTCCATCAGTGGTTACTACTGGAGCTGGATCCGGCAGCCCCCAGGAAAGGGA
CTGGAGTGGTTTGCATATTTCTCTTACAGTGGGAGCACCAACTACAACCCCTCCCTCAAGAGTCGA
GTCACCTTATCAGTAGACACGTCCAAGAACCAGTTCTCCCTGAAGCTGAGCTCTGTGACCGCTGCG
GACACGGCCGTGTATTACTGTGCGAGGAACTGGGCCTTCCACTTTGACTTCTGGGGCCAGGGAACC
CTGGTCACCGTCTCTAGTGCCTCCACCAAGGGCCCATCGGTCTTCCCCCTGGCACCCTCCTCCAAG
AGCACCTCTGGGGGCACAGCGGCCCTGGGCTGCCTGGTCAAGGACTACTTCCCCGAACCGGTGACG
GTGTCGTGGAACTCAGGCGCCCTGACCAGCGGCGTGCACACCTTCCCGGCTGTCCTACAGTCCTCA
GGACTCTACTCCCTCAGCAGCGTGGTGACCGTGCCCTCCAGCAGCTTGGGCACCCAGACCTACATC
TGCAACGTGAATCACAAGCCCAGCAACACCAAGGTGGACAAGAAAGTTGAGCCCAAATCTTGTGAC
AAAACTCACACATGCCCACCGTGCCCAGCACCTGAACTCCTGGGGGGACCGTCAGTCTTCCTCTTC
CCCCCAAAACCCAAGGACACCCTCATTATCTCCCGGACCCCTGAGGTCACATGCGTGGTGGTCGAC
GTGAGCCACGAAGACCCTGAGGTCAAGTTCAACTGGTACGTGGACGGCGTGGAGGTGCATAATGCC
AAGACAAAGCCGCGGGAGGAGCAGTACAACAGCACGTACCGTGTGGTCAGCGTCCTCACCGTCCTG
CACCAGGACTGGCTGAATGGCAAGGAGTACAAGTGCAAGGTCTCCAACAAAGCCCTCCCAGCCCCC
ATCGAGAAAACCATCTCCAAAGCCAAAGGGCAGCCCCGAGAACCACAGGTGTACACCCTGCCCCCA
TCCCGGGAGGAGATGACCAAGAACCAGGTCAGCCTGACCTGCCTGGTCAAAGGCTTCTATCCCAGC
GACATCGCCGTGGAGTGGGAGAGCAATGGGCAGCCGGAGAACAACTACAAGACCACGCCTCCCGTG
CTGGACTCCGACGGCTCCTTCTTCCTCTATAGCAAGCTCACCGTGGACAAGAGCAGGTGGCAGCAG
GGGAACGTCTTCTCATGCTCCGTGATGCATGAGGCTCTGCACAACCACTACACGCAGAAGAGCCTC
TCCCTGTCTCCGGGTAAATGA SEQ ID NO: 644
QVQLQESGPGLVKPSETLSLTCTVSGGSISGYYWSWIRQPPGKGLEWFAYFSYSGSTNYNPSLKSR
VTLSVDTSKNQFSLKLSSVTAADTAVYYCARNWAFHFDFWGQGTLVTVSSASTKGPSVFPLAPSSK
STSGGTAALGCLVKDYFPEPVTVSWNSGALTSGVHTFPAVLQSSGLYSLSSVVTVPSSSLGTQTYI
CNVNHKPSNTKVDKKVEPKSCDKTHTCPPCPAPELLGGPSVFLFPPKPKDTLMISRTPEVTCVVVD
VSHEDPEVKFNWYVDGVEVHNAKTKPREEQYNSTYRVVSVLTVLHQDWLNGKEYKCKVSNKALPAP
IEKTISKAKGQPREPQVYTLPPSREEMTKNQVSLTCLVKGFYPSDIAVEWESNGQPENNYKTTPPV
LDSDGSFFLYSKLTVDKSRWQQGNVFSCSVMHEALHNHYTQKSLSLSPGK 4B10 SEQ ID NO:
645
CAGGTGCAGCTGGTGGAGTCTGGGGGAGGCGTGGTCCAGCCTGGGAGGTCCCTGAGACTCTCCTGT
GCAGCCTCTGGATTCACCTTCAGTAGCTATGACATGCACTGGGTCCGCCAGGCTCCAGGCAAGGGG
CTGGAGTGGGTGGCAGTTATATCATATGATGGAACTAATGAATACTATGCAGACTCCGTGAAGGGC
CGATTCACCATCTCCAGAGACACTTCCAAGAACACGCTGTATTTGCAAATGAACAGCCTGAGAGCT
GAGGACACGGCTGTATATTACTGTGCGAGAGAACGATATTTTGACTGGTCTTTTGACTACTGGGGC
CAGGGAACCCTGGTCAGCGTCTCTAGTGCCTCCACCAAGGGCCCATCGGTCTTCCCCCTGGCACCC
TCCTCCAAGAGCACCTCTGGGGGCACAGCGGCCCTGGGCTGCCTGGTCAAGGACTACTTCCCCGAA
CCGGTGACGGTGTCGTGGAACTCAGGCGCCCTGACCAGCGGCGTGCACACCTTCCCGGCTGTCCTA
CAGTCCTCAGGACTCTACTCCCTCAGCAGCGTGGTGACCGTGCCCTCCAGCAGCTTGGGCACCCAG
ACCTACATCTGCAACGTGAATCACAAGCCCAGCAACACCAAGGTGGACAAGAAAGTTGAGCCCAAA
TCTTGTGACAAAACTCACACATGCCCACCGTGCCCAGCACCTGAACTCCTGGGGGGACCGTCAGTC
TTCCTCTTCCCCCCAAAACCCAAGGACACCCTCATGATCTCCCGGACCCCTGAGGTCACATGCGTG
GTGGTGGACGTGAGCCACGAAGACCCTGAGGTCAAGTTCAACTGGTACGTGGACGGCGTGGAGGTG
CATAATGCCAAGACAAAGCCGCGGGAGGAGCAGTACAACAGCACGTACCGTGTGGTCAGCGTCCTC
ACCGTCCTGCACCAGGACTGGCTGAATGGCAAGGAGTACAAGTGCAAGGTCTCCAACAAAGCCCTC
CCAGCCCCCATCGAGAAAACCATCTCCAAAGCCAAAGGGCAGCCCCGAGAACCACAGGTGTACACC
CTGCCCCCATCCCGGGAGGAGATGACCAAGAACCAGGTCAGCCTGACCTGCCTGGTCAAAGGCTTC
TATCCCAGCGACATCGCCGTGGAGTGGGAGAGCAATGGGCAGCCGGAGAACAACTACAAGACCACG
CCTCCCGTGCTGGACTCCGACGGCTCCTTCTTCCTCTATAGCAAGCTCACCGTGGACAAGAGCAGG
TGGCAGCAGGGGAACGTCTTCTCATGCTCCGTGATGCATGAGGCTCTGCACAACCACTACACGCAG
AAGAGCCTCTCCCTGTCTCCGGGTAAATGA SEQ ID NO: 646
QVQLVESGGGVVQPGRSLRLSCAASGFTFSSYDMHWVRQAPGKGLEWVAVISYDGTNEYYADSVKG
RFTISRDTSKNTLYLQMNSLRAEDTAVYYCARERYFDWSFDYWGQGTLVSVSSASTKGPSVFPLAP
SSKSTSGGTAALGCLVKDYFPEPVTVSWNSGALTSGVHTFPAVLQSSGLYSLSSVVTVPSSSLGTQ
TYICNVNHKPSNTKVDKKVEPKSCDKTHTCPPCPAPELLGGPSVFLFPPKPKDTLMISRTPEVTCV
VVDVSHEDPEVKFNWYVDGVEVHNAKTKPREEQYNSTYRVVSVLTVLHQDWLNGKEYKCKVSNKAL
PAPIEKTISKAKGQPREPQVYTLPPSREEMTKNQVSLTCLVKGFYPSDIAVEWESNGQPENNYKTT
PPVLDSDGSFFLYSKLTVDKSRWQQGNVFSCSVMHEALHNHYTQKSLSLSPGK 4F3 SEQ ID
NO: 647
CAGGTGCAGCTGGTGGAGTCTGGGGGAGGCGTGGTCCAGCCTGGGAGGTCCCTGAGACTCTCCTGT
GCAGCGTCTGGATTCTCCTTCAGTAGCTATGACATGTACTCGGTCCGCCAGACTCCAGGCAAGGGG
CTGGAGTGGGTGGCAGTTATATGGTATGATGGAAGTAATAAATACTATGCAGACTCCGTGAGGGGC
CGATTCACCATCTCCAGAGACAATTCCAAGAACACGCTGTTTCTGCAAATGAACAGCCTGAGAGTC
GAGGACACGGCTGTGTATTACTGTGCGAGAGAAACTGGGGAGGGCTGGTACTTCGATCTCTGGGGC
CGTGGCACCCTGGTCACCGTCTCTAGTGCCTCCACCAAGGGCCCATCGGTCTTCCCCCTGGCACCC
TCCTCCAAGAGCACCTCTGCGGGCACAGCGGCCCTGGGCTCCCTGCTCAAGGACTACTTCCCCGAA
CCGGTGACGGTGTCGTGGAACTCAGGCGCCCTGACCAGCGGCGTGCACACCTTCCCGGCTGTCCTA
CAGTCCTCAGGACTCTACTCCCTCAGCAGCGTGGTGACCGTGCCCTCCAGCAGCTTGGGCACCCAG
ACCTACATCTGCAACGTGAATCACAAGCCCAGCAACACCAAGGTGGACAAGAAAGTTGAGCCCAAA
TCTTGTGACAAAACTCACACATGCCCACCGTGCCCAGCACCTGAACTCCTGGGGGGACCGTCAGTC
TTCCTCTTCCCCCCAAAACCCAAGTACACCCTCATGATCTCCCGGACCCCTGAGGTCACATGCGTG
GTGGTGGACGTGAGCCACGAAGACCCTGAGGTCAAGTTCAACTGGTACGTGGACGGCGTGGAGGTG
CATAATGCCAAGACAAAGCCGCGGGAGGAGCAGTACAACAGCACGTACCGTGTGGTCAGCGTCCTC
ACCGTCCTGCACCAGGACTGGCTGAATGGCAAGGAGTACAAGTGCAAGGTCTCCAACAAAGCCCTC
CCAGCCCCCATCGAGAAAACCATCTCCAAAGCCAAAGGGCAGCCCCGAGAACCACAGGTGTACACC
CTCCCCCCATCCCCGTAGGAGATGACCAAGAACCAGGTCAGCCTGACCTGCCTGGTCAAAGGCTTC
TATCCCAGCGACATCGCCGTGGAGTGGGAGAGCAATGGGCAGCCGGAGAACAACTACAAGACCACG
CCTCCCGTGCTGGACTCCGACGGCTCCTTCTTCCTCTATAGCAAGCTCACCGTGGACAAGAGCAGG
TGGCAGCAGGGGAACGTCTTCTCATGCTCCGTGATGCATGAGGCTCTGCACAACCACTACACGCAG
AAGAGCCTCTCCCTGTCTCCGGGTAAATGA SEQ ID NO: 648
QVQLVESGGGVVQPGRSLRLSCAASGFSFSSYDMDWVRQTPGKGLEWVAVIWYDGSNKYYADSVRG
RFTISRDNSKNTLFLQMNSLRVEDTAVYYCARETGEGWYFDLWGRGTLVTVSSASTKGPSVFPLAP
SSKSTSGGTAALGCLVKDYFPEPVTVSWNSGALTSGVHTFPAVLQSSGLYSLSSVVTVPSSSLGTQ
TYICNVNHKPSNTKVDKKVEPKSCDKTHTCPPCPAPELLGGPSVFLFPPKPKDTLMISRTPEVTCV
VVDVSHEDPEVKFNWYVDGVEVHNAKTKPREEQYNSTYRVVSVLTVLHQDWLNGKEYKCKVSNKAL
PAPIEKTISKAKGQPREPQVYTLPPSREEMTKNQVSLTCLVKGFYPSDIAVEWESNGQPENNYKTT
PPVLDSDGSFFLYSKLTVDKSRWQQGNVFSCSVMHEALHNHYTQKSLSLSPGK 4F7 SEQ ID
NO: 649
CAGGTGCAGCTGCAGGAGTCGGGCCCAGGACTGGTGAAGCCTTCGGAGACCCTGTCCCTCACCTGC
ACTGTCTCTGGTGGCTCCATCAGTAGTTACTCCTGGAGCTGGATCCGGCAGCCCCCAGGGAAGGGA
CTGGAGTGGATTGGGTATATCTATTACAGTGGGAGCACCAACTACAACCCCTCCCTCAAGAGTCGA
GTCACCATATCATTAGACACGTCCAAGAACCAGTTCTCCCTGAAGCTGAGCTCTGTGACCGCTGCG
GACACGGCCGTGTATTACTGTGCGAGGAACTGGGCCTTCCACTTTGACTACTGGGGCCAGGGAACC
CTGGTCACCGTCTCTAGTGCCTCCACCAAGGGCCCATCGGTCTTCCCCCTGGCACCCTCCTCCAAG
AGCACCTCTGGGGGCACAGCGGCCCTGGGCTGCCTGGTCAAGGACTACTTCCCCGAACCGGTGACG
GTGTCGTGGAACTCAGGCGCCCTGACCAGCGGCGTGCACACCTTCCCGGCTGTCCTACAGTCCTCA
GGACTCTACTCCCTCAGCAGCGTGGTGACCGTGCCCTCCAGCAGCTTGGGCACCCAGACCTACATC
TGCAACGTGAATCACAAGCCCAGCAACACCAAGGTGGACAAGAAAGTTGAGCCCAAATCTTGTGAC
AAAACTCACACATGCCCACCGTGCCCAGCACCTGAACTCCTGGGGGGACCGTCAGTCTTCCTCTTC
CCCCCAAAACCCAAGGACACCCTCATGATCTCCCGGACCCCTGAGGTCACATGCGTGGTGGTGGAC
GTGAGCCACGAAGACCCTGAGGTCAAGTTCAACTGGTACGTGGACGGCGTGGAGGTGCATAATGCC
AAGACAAAGCCGCGGGAGGAGCAGTACAACAGCACGTACCGTGTGGTCAGCGTCCTCACCGTCCTG
CACCAGGACTGGCTGAATGGCAAGGAGTACAAGTGCAAGGTCTCCAACAAAGCCCTCCCAGCCCCC
ATCGAGAAAACCATCTCCAAAGCCAAAGGGCAGCCCCGAGAACCACAGGTGTACACCCTGCCCCCA
TCCCGGGAGGAGATGACCAAGAACCAGGTCAGCCTGACCTGCCTGGTCAAAGGCTTCTATCCCAGC
GACATCGCCGTGGAGTGGGAGAGCAATGGGCAGCCGGAGAACAACTACAAGACCACGCCTCCCGTG
CTGGACTCCGACGGCTCCTTCTTCCTCTATAGCAAGCTCACCGTGGACAAGAGCAGGTGGCAGCAG
GGGAACGTCTTCTCATGCTCCGTGATGCATGAGGCTCTGCACAACCACTACACGCAGAAGAGCCTC
TCCCTGTCTCCGGGTAAATGA SEQ ID NO: 650
QVQLQESGPGLVKPSETLSLTCTVSGGSISSYSWSWIRQPPGKGLEWIGYIYYSGSTNYNPSLKSR
VTISLDTSKNQFSLKLSSVTAADTAVYYCARNWAFHFDYWGQGTLVTVSSASTKGPSVFPLAPSSK
STSGGTAALGCLVKDYFPEPVTVSWNSGALTSGVHTFPAVLQSSGLYSLSSVVTVPSSSLGTQTYI
CNVNHKPSNTKVDKKVEPKSCDKTHTCPPCPAPELLGGPSVFLFPPKPKDTLMISRTPEVTCVVVD
VSHEDPEVKFNWYVDGVEVHNAKTKPREEQYNSTYRVVSVLTVLHQDWLNGKEYKCKVSNKALPAP
IEKTISKAKGQPREPQVYTLPPSREEMTKNQVSLTCLVKGFYPSDIAVEWESNGQPENNYKTTPPV
LDSDGSFFLYSKLTVDKSRWQQGNVFSCSVMHEALHNHYTQKSLSLSPGK 16A4 SEQ ID NO:
651
CAGGTGCAGCTGCAGGAGTCGGGCCCAGGACTGGCGAAGCCTTCGGAGACCCTGTCCCTCACCTGC
ACTGTCTCTGGTGACTCCATCACTAGTTACTACTGGAGCTGGATCCGCCAGCCCCCAGGGAAGGGA
CTGGAGTGGATTGGGTATATCTATTACAGCGGGAGCACCAATTACAACCCCTCCCTCAAGAGTCGA
GTCACCATATCAGTAGACACGTCCAAGAACCAGTTCTCCCTGAAGCTGAGTTCTGTGACCGCTGCG
GACACGGCCGTGTATTACTGTGCGAGAGATCAAAGGCGGATAGCAGCAGCTGGTACCCACTTCTAC
GGTATGGACGTCTGGGGCCAAGGGACCACGGTCACTGTCTCCTCAGCTTCCACCAAGGGCCCATCC
GTCTTCCCCCTGGCGCCCTCCTCCAAGAGCACCTCTGGGGGCACAGCGCCCCTGGGCTGCCTGGTC
AAGGACTACTTCCCCGAACCGGTGACGGTGTCGTGGAACTCAGGGGCCCTGACCAGCGGCGTGCAC
ACCTTCCCGGCTGTCCTACAGTCCTCAGGACTCTACTCCCTCAGCAGCGTGGTGACCGTGCCCTCC
AGCAGCTTGGGCACCCAGACCTACATCTGCAACGTGAATCACAAGCCCAGCAACACCAAGGTGGAC
AAGAAAGTTGAGCCCAAATCTTGTGACAAAACTCACACATGCCCACCGTGCCCAGCACCTGAACTC
CTGGGGGGACCGTCAGTCTTCCTCTTCCCCCCAAAACCCAAGGACACCCTCATGATCTCCCGGACC
CCTGAGGTCACATGCGTGGTGGTGGACGTGAGCCACGAAGACCCTGAGGTCAAGTTCAACTGGTAC
GTGGACGGCGTGGAGGTGCATAATGCCAAGACAAAGCCGCGGGAGGAGCAGTACAACAGCACGTAC
CGTGTGGTCAGCGTCCTCACCGTCCTGCACCAGGACTGGCTGAATGGCAAGGAGTACAAGTGCAAG
GTCTCCAACAAAGCCCTCCCAGCCCCCATCGAGAAAACCATCTCCAAAGCCAAAGGGCAGCCCCGA
GAACCACAGGTCTACACCCTGCCCCCATCCCGGGAGGAGATGACCAAGAACCAGGTCAGCCTGACC
TGCCTGGTCAAAGGCTTCTATCCCAGCGACATCGCCGTGGAGTGGGAGAGCAATGGGCAGCCGGAG
AACAACTACAAGACCACGCCTCCCGTGCTGGACTCCGACGGCTCCTTCTTCCTCTATAGCAAGCTC
ACCGTGGACAAGAGCAGGTGGCAGCAGGGGAACGTCTTCTCATGCTCCGTGATGCATGAGGCTCTG
CACAACCACTACACGCAGAAGAGCCTCTCCCTGTCTCCGGGTAAATGA SEQ ID NO: 652
QVQLQESGPGLAKPSETLSLTCTVSGDSITSYYWSWIRQPPGKGLEWIGYIYYSGSTNYNPSLKSR
VTISVDTSKNQFSLKLSSVTAADTAVYYCARDQRRIAAAGTHFYGMDVWGQGTTVTVSSASTKGPS
VFPLAPSSKSTSGGTAALGCLVKDYFPEPVTVSWNSGALTSGVHTFPAVLQSSGLYSLSSVVTVPS
SSLGTQTYICNVNHKPSNTKVDKKVEPKSCDKTHTCPPCPAPELLGGPSVFLFPPKPKDTLMISRT
PEVTCVVVDVSHEDPEVKFNWYVDGVEVHNAKTKPREEQYNSTYRVVSVLTVLHQDWLNGKEYKCK
VSNKALPAPIEKTISKAKGQPREPQVYTLPPSREEMTKNQVSLTCLVKGFYPSDIAVEWESNGQPE
NNYKTTPPVLDSDGSFFLYSKLTVDKSRWQQGNVFSCSVMHEALHNHYTQKSLSLSPGK 16C1
SEQ ID NO: 653
CAGGTGCAGCTGCAGGAGTCGGGCCCAGGACTGGTGAAGCCTTCGGAGACCCTGTCCCTCACTTGT
ACTGTCTCTGGTGGCTCCATCAGTGGTTACTACTGGAGCTGGATCCGGCAGCCCCCAGGGAAGGGA
CTGGAGTGGATTGGGTATATCTATTACATTGGGAGCACCAACTACAACCCCTCCCTCAAGAGTCGA
GTCACCATGTCAATAGACACGTCCAAGAACCAGTTCTCCCTGACGCTGAGCTCTTTGACCGCTGCG
GACACGGCCGTGTATTTCTGTGCGAGAGATGGGAGCAGTGGCTGGTACCGGTGGTTCGACCCCTGG
GGCCAGGGAACCCTGGTCACCGTCTCCTCAGCTTCCACCAAGGGCCCATCCGTCTTCCCCCTGGCG
CCCTCCTCCAAGAGCACCTCTGGGGGCACAGCGGCCCTGGGCTGCCTGGTCAAGGACTACTTCCCC
GAACCGGTGACGGTGTCGTGGAACTCAGGGGCCCTGACCAGCGGCGTGCACACCTTCCCGGCTGTC
CTACAGTCCTCAGGACTCTACTCCCTCAGCAGCGTGGTGACCGTGCCCTCCAGCAGCTTGGGCACC
CAGACCTACATCTGCAACGTGAATCACAAGCCCAGCAACACCAAGGTGGACAAGAAAGTTGAGCCC
AAATCTTGTGACAAAACTCACACATGCCCACCGTGCCCAGCACCTGAACTCCTGGGGGGACCGTCA
GTCTTCCTCTTCCCCCCAAAACCCAAGGACACCCTCATGATCTCCCGGACCCCTGAGGTCACATGC
GTGGTGGTGGACGTGAGCCACGAAGACCCTGAGGTCAAGTTCAACTGGTACGTGGACGGCGTGGAG
GTGCATAATGCCAAGACAAAGCCGCGGGAGGAGCAGTACAACAGCACGTACCGTGTGGTCAGCGTC
CTCACCGTCCTGCACCAGGACTGGCTGAATGGCAAGGAGTACAAGTGCAAGGTCTCCAACAAAGCC
CTCCCAGCCCCCATCGAGAAAACCATCTCCAAAGCCAAAGGGCAGCCCCGAGAACCACAGGTGTAC
ACCCTGCCCCCATCCCGGGAGGAGATGACCAAGAACCAGGTCAGCCTGACCTGCCTGGTCAAAGGC
TTCTATCCCAGCGACATCGCCGTGGAGTGGGAGAGCAATGGGCAGCCGGAGAACAACTACAAGACC
ACGCCTCCCGTGCTGGACTCCGACGGCTCCTTCTTCCTCTATAGCAAGCTCACCGTGGACAAGAGC
AGGTGGCAGCAGGGGAACGTCTTCTCATGCTCCGTGATGCATGAGGCTCTGCACAACCACTACACG
CAGAAGAGCCTCTCCCTGTCTCCGGGTAAATGA SEQ ID NO: 654
QVQLQESGPGLVKPSETLSLTCTVSGGSISGYYWSWIRQPPGKGLEWIGYIYYIGSTNYNPSLKSR
VTMSIDTSKNQFSLTLSSLTAADTAVYFCARDGSSGWYRWFDPWGQGTLVTVSSASTKGPSVFPLA
PSSKSTSGGTAALGCLVKDYFPEPVTVSWNSGALTSGVHTFPAVLQSSGLYSLSSVVTVPSSSLGT
QTYICNVNHKPSNTKVDKKVEPKSCDKTHTCPPCPAPELLGGPSVFLFPPKPKDTLMISRTPEVTC
VVVDVSHEDPEVKFNWYVDGVEVHNAKTKPREEQYNSTYRVVSVLTVLHQDWLNGKEYKCKVSNKA
LPAPIEKTISKAKGQPREPQVYTLPPSREEMTKNQVSLTCLVKGFYPSDIAVEWESNGQPENNYKT
TPPVLDSDGSFFLYSKLTVDKSRWQQGNVFSCSVMHEALHNHYTQKSLSLSPGK 17H8 SEQ ID
NO: 655
CAGGTGCAGCTGCAGGAGTCGGGCCCAGGACTGGTGAAGCCTTCGGAGACCCTGTCCCTCACGTGC
ACTGTCTCTGGTGGCTCCATCAATAGTTACTACTGGAGCTGGATCCGGCAGCCCCCAGGGAAGGGA
CTGGAGTGGATTGGGTATATCTATTACATTGGGAGCACCAACTACAACCCCTCCCTCAAGAGTCGC
GTCACCATATCAGTAGACACGTCCAAGAACCAGTTCTCCCTGAAGCTGAGCTCTGTGACCGCTGCG
GACACGGCCCTGTATTACTGTGCGAGAGATTCCCGGTATAGAAGTGGCTGGTACGATGCTTTTGAT
ATCTGGGGCCAAGGGACAATGGTCACCGTCTCTTCAGCTTCCACCAAGGGCCCATCCGTCTTCCCC
CTGGCGCCCTCCTCCAAGAGCACCTCTGGGGGCACAGCGGCCCTGGGCTGCCTGGTCAAGGACTAC
TTCCCCGAACCGGTGACGGTGTCGTGGAACTCAGGGGCCCTGACCAGCGGCGTGCACACCTTCCCG
GCTGTCCTACAGTCCTCAGGACTCTACTCCCTCAGCAGCGTGGTGACCGTGCCCTCCAGCAGCTTG
GGCACCCAGACCTACATCTGCAACGTGAATCACAAGCCCAGCAACACCAAGGTGGACAAGAAAGTT
GAGCCCAAATCTTGTGACAAAACTCACACATGCCCACCGTGCCCAGCACCTGAACTCCTGGGGGGA
CCGTCAGTCTTCCTCTTCCCCCCAAAACCCAAGGACACCCTCATGATCTCCCGGACCCCTGAGGTC
ACATGCGTGGTGGTGGACGTGAGCCACGAAGACCCTGAGGTCAAGTTCAACTGGTACGTGGACGGC
GTGGAGGTGCATAATGCCAAGACAAAGCCGCGGGAGGAGCAGTACAACAGCACGTACCGTGTGGTC
AGCGTCCTCACCGTCCTGCACCAGGACTGGCTGAATGGCAAGGAGTACAAGTGCAAGGTCTCCAAC
AAAGCCCTCCCAGCCCCCATCGAGAAAACCATCTCCAAAGCCAAAGGGCAGCCCCGAGAACCACAG
GTGTACACCCTGCCCCCATCCCGGGAGGAGATGACCAAGAACCAGGTCAGCCTGACCTGCCTGGTC
AAAGGCTTCTATCCCAGCGACATCGCCGTGGAGTGGGAGAGCAATGGGCAGCCGGAGAACAACTAC
AAGACCACGCCTCCCGTGCTGGACTCCGACGGCTCCTTCTTCCTCTATAGCAAGCTCACCGTGGAC
AAGAGCAGGTGGCAGCAGGGGAACGTCTTCTCATGCTCCGTGATGCATGAGGCTCTGCACAACCAC
TACACGCAGAAGAGCCTCTCCCTGTCTCCGGGTAAATGA SEQ ID NO: 656
QVQLQESGPGLVKPSETLSLTCTVSGGSINSYYWSWIRQPPGKGLEWIGYIYYIGSTNYNPSLKSR
VTISVDTSKNQFSLKLSSVTAADTALYYCARDSRYRSGWYDAFDIWGQGTMVTVSSASTKGPSVFP
LAPSSKSTSGGTAALGCLVKDYFPEPVTVSWNSGALTSGVHTFPAVLQSSGLYSLSSVVTVPSSSL
GTQTYICNVNHKPSNTKVDKKVEPKSCDKTHTCPPCPAPELLGGPSVFLFPPKPKDTLMISRTPEV
TCVVVDVSHEDPEVKFNWYVDGVEVHNAKTKPREEQYNSTYRVVSVLTVLHQDWLNGKEYKCKVSN
KALPAPIEKTISKAKGQPREPQVYTLPPSREEMTKNQVSLTCLVKGFYPSDIAVEWESNGQPENNY
KTTPPVLDSDGSFFLYSKLTVDKSRWQQGNVFSCSVMHEALHNHYTQKSLSLSPGK 19B5 SEQ
ID NO: 657
CAGGTGCAGTTGGTGCAGTCTGGGGCTGAGGTGAAGAAGCCTGGGGCCTCAGTGAAGGTTTCCTGC
AAGGTTTCTGGATACACCTTCACCAGCTACTTTATTCACTGGGTGCGCCAGGCCCCTGGACAAGGG
CTTGAATGGATGGGAATTATCAACCCTATTAGTGTTAGCACAAGCTACGCACAGAAGTTCCAGGGC
AGAGTCACCATGACCAGGGACACGTCCACGAGCACAGTCTTCATGGAGCTGAGCAGCCTGAGATCT
GAGGACACGGCCGTCTATTACTCTGCGCGAGGGGGGATACAGCTATGGTTACATTTGGACTACTGG
GGCCAGGGAACCCTGGTCACCGTCTCCTCAGCTTCCACCAAGGGCCCATCCGTCTTCCCCCTGGCG
CCCTCCTCCAAGAGCACCTCTGGGGGCACAGCGGCCCTGGGCTGCCTGGTCAAGGACTACTTCCCC
GAACCGGTGACGGTGTCGTGGAACTCAGGGGCCCTGACCAGCGGCGTGCACACCTTCCCGGCTGTC
CTACAGTCCTCAGGACTCTACTCCCTCAGCAGCGTGGTGACCGTGCCCTCCAGCAGCTTGGGCACC
CAGACCTACATCTGCAACGTGAATCACAAGCCCAGCAACACCAAGGTGGACAAGAAAGTTGAGCCC
AAATCTTGTGACAAAACTCACACATGCCCACCGTGCCCAGCACCTGAACTCCTGGGGGGACCGTCA
GTCTTCCTCTTCCCCCCAAAACCCAAGGACACCCTCATGATCTCCCGGACCCCTGAGGTCACATGC
GTGGTGGTGGACGTGAGCCACGAAGACCCTGAGGTCAAGTTCAACTGGTACGTGGACGGCGTGGAG
GTGCATAATGCCAAGACAAAGCCGCGGGAGGAGCAGTACAACAGCACGTACCGTGTGGTCAGCGTC
CTCACCGTCCTGCACCAGGACTGGCTGAATGGCAAGGAGTACAAGTGCAAGGTCTCCAACAAAGCC
CTCCCAGCCCCCATCGAGAAAACCATCTCCAAAGCCAAAGGGCAGCCCCGAGAACCACAGGTGTAC
ACCCTGCCCCCATCCCGGGAGGAGATGACCAAGAACCAGGTCAGCCTGACCTGCCTGGTCAAAGGC
TTCTATCCCAGCGACATCGCCGTGGAGTGGGAGAGCAATGGGCAGCCGGAGAACAACTACAAGACC
ACGCCTCCCGTGCTGGACTCCGACGGCTCCTTCTTCCTCTATAGCAAGCTCACCGTGGACAAGAGC
AGGTGGCAGCAGGGGAACGTCTTCTCATGCTCCGTGATGCATGAGGCTCTGCACAACCACTACACG
CAGAAGAGCCTCTCCCTGTCTCCGGGTAAATGA SEQ ID NO: 658
QVQLVQSGAEVKKPGASVKVSCKVSGYTFTSYFIHWVRQAPGQGLEWMGIINPISVSTSYAQKFQG
RVTMTRDTSTSTVFMELSSLRSEDTAVYYCARGGIQLWLHLDYWGQGTLVTVSSASTKGPSVFPLA
PSSKSTSGGTAALGCLVKDYFPEPVTVSWNSGALTSGVHTFPAVLQSSGLYSLSSVVTVPSSSLGT
QTYICNVNHKPSNTKVDKKVEPKSCDKTHTCPPCPAPELLGGPSVFLFPPKPKDTLMISRTPEVTC
VVVDVSHEDPEVKFNWYVDGVEVHNAKTKPREEQYNSTYRVVSVLTVLHQDWLNGKEYKCKVSNKA
LPAPIEKTISKAKGQPREPQVYTLPPSREEMTKNQVSLTCLVKGFYPSDIAVEWESNGQPENNYKT
TPPVLDSDGSFFLYSKLTVDKSRWQQGNVFSCSVMHEALHNHYTQKSLSLSPGK 20D3 SEQ ID
NO: 659
CAGGTGCAGCTGGTGCAGTCTGGGGCTGAGGTGAAGAAGCCTGGGGCCTCAGTGAAGGTTTCCTGC
AAGGTTTCTGGATACACCTTCACCAGCTACTTTATTCACTGGGTGCGCCAGGCCCCTGGACAAGGG
CTTGAGTGGATGGGAATAATCAACCCTATTAGTGTTAGCACAAGCTACGCACAGAAGTTCCAGGGC
AGAGTCACCATGACCAGGGACACGTCCACGAGCACAGTCTTCATGGAGCTGAGCAGCCTGAGATCT
GAGGACACGGCCGTGTATTACTGTGCGCGAGGGGGGATACAGCTATGGTTACATTTTGACTACTGG
GGCCAGGGAACCCTGGTCACCGTCTCCTCAGCTTCCACCAAGGGCCCATCCGTCTTCCCCCTGGCG
CCCTCCTCCAAGAGCACCTCTGGGGGCACAGCGGCCCTGGGCTGCCTGGTCAAGGACTACTTCCCC
GAACCGGTGACGGTGTCGTGGAACTCAGGGGCCCTGACCAGCGGCGTGCACACCTTCCCGGCTGTC
CTACAGTCCTCAGGACTCTACTCCCTCAGCAGCGTGGTGACCGTGCCCTCCAGCAGCTTGGGCACC
CAGACCTACATCTGCAACGTGAATCACAAGCCCAGCAACACCAAGGTGGACAAGAAAGTTGAGCCC
AAATCTTGTGACAAAACTCACACATGCCCACCGTGCCCAGCACCTGAACTCCTGGGGGGACCGTCA
GTCTTCCTCTTCCCCCCAAAACCCAAGGACACCCTCATGATCTCCCGGACCCCTGAGGTCACATGC
GTGGTGGTGGACGTGAGCCACGAAGACCCTGAGGTCAAGTTCAACTGGTACGTGGACGGCGTGGAG
GTGCATAATGCCAAGACAAAGCCGCGGGAGGAGCAGTACAACAGCACGTACCGTGTGGTCAGCGTC
CTCACCGTCCTGCACCAGGACTGGCTGAATGGCAAGGAGTACAAGTGCAAGGTCTCCAACAAAGCC
CTCCCAGCCCCCATCGAGAAAACCATCTCCAAAGCCAAAGGGCAGCCCCGAGAACCACAGGTGTAC
ACCCTGCCCCCATCCCGGGAGGAGATGACCAAGAACCAGGTCAGCCTGACCTGCCTGGTCAAAGGC
TTCTATCCCAGCGACATCGCCGTGGAGTGGGAGAGCAATGGGCAGCCGGAGAACAACTACAAGACC
ACGCCTCCCGTGCTGGACTCCGACGGCTCCTTCTTCCTCTATAGCAAGCTCACCGTGGACAAGAGC
AGGTGGCAGCAGGGGAACGTCTTCTCATGCTCCGTGATGCATGAGGCTCTGCACAACCACTACACG
CAGAAGAGCCTCTCCCTGTCTCCGGGTAAATGA SEQ ID NO: 660
QVQLVQSGAEVKKPGASVKVSCKVSGYTFTSYFIHWVRQAPGQGLEWMGIINPISVSTSYAQKFQG
RVTMTRDTSTSTVFMELSSLRSEDTAVYYCARGGIQLWLHFDYWGQGTLVTVSSASTKGPSVFPLA
PSSKSTSGGTAALGCLVKDYFPEPVTVSWNSGALTSGVHTFPAVLQSSGLYSLSSVVTVPSSSLGT
QTYICNVNHKPSNTKVDKKVEPKSCDKTHTCPPCPAPELLGGPSVFLFPPKPKDTLMISRTPEVTC
VVVDVSHEDPEVKFNWYVDGVEVHNAKTKPREEQYNSTYRVVSVLTVLHQDWLNGKEYKCKVSNKA
LPAPIEKTISKAKGQPREPQVYTLPPSREEMTKNQVSLTCLVKGFYPSDIAVEWESNGQPENNYKT
TPPVLDSDGSFFLYSKLTVDKSRWQQGNVFSCSVMHEALHNHYTQKSLSLSPGK 22D1 SEQ ID
NO: 661
CAGGTGCAGCTGGTGCAGTCTGGGGCTGAGGTGAAGAAGCCTGGGGCCTCAGTGAGGGTTTCCTGC
AAGGTTTCTGGATACACCTTCACCAGCTACTTTATTCACTGGGTACGCCAGGCCCCTGGACAAGGG
CTTGAGTGGATGGGAATAATCAACCCTATTAGTGTTAGCACAAGCTACGCACAGAAGTTCCAGGGC
AGAGTCACCATGACCAGGGACACGTCCACGAGCACAGTCTTCATGGAGCTGAGCAGCCTGAGATCT
GAGGACACGGCCGTCTATTACTCTGCGCGACTGGGGGATACAGCTATGGTTACATTTTGACTACTG
GGGCCAGGGAACCCTGGTCACCGTCTCCTCAGCTTCCACCAAGGGCCCATCCGTCTTCCCCCTGGC
GCCCTCCTCCAAGAGCACCTCTGGGGGCACAGCGGCCCTGGGCTGCCTGGTCAAGGACTACTTCCC
CGAACCGGTGACGGTGTCGTGGAACTCAGGGGCCCTGACCAGCGGCGTGCACACCTTCCCGGCTGT
CCTACAGTCCTCAGGACTCTACTCCCTCAGCAGCGTGGTGACCGTGCCCTCCAGCAGCTTGGGCAC
CCAGACCTACATCTGCAACGTGAATCACAAGCCCAGCAACACCAAGGTGGACAAGAAAGTTGAGCC
CAAATCTTGTGACAAAACTCACACATGCCCACCGTGCCCAGCACCTGAACTCCTGGGGGGACCGTC
AGTCTTCCTCTTCCCCCCAAAACCCAAGGACACCCTCATGATCTCCCGGACCCCTGAGGTCACATG
CGTGGTGGTGGACGTGAGCCACGAAGACCCTGAGGTCAAGTTCAACTGGTACGTGGACGGCGTGGA
GGTGCATAATGCCAAGACAAAGCCGCGGGAGGAGCAGTACAACAGCACGTACCGTGTGGTCAGCGT
CCTCACCGTCCTGCACCAGGACTGGCTGAATGGCAAGGAGTACAAGTGCAAGGTCTCCAACAAAGC
CCTCCCAGCCCCCATCGAGAAAACCATCTCCAAAGCCAAAGGGCAGCCCCGAGAACCACAGGTGTA
CACCCTGCCCCCATCCCGGGAGGAGATGACCAAGAACCAGGTCAGCCTGACCTGCCTGGTCAAAGG
CTTCTATCCCAGCGACATCGCCGTGGAGTGGGAGAGCAATGGGCAGCCGGAGAACAACTACAAGAC
CACGCCTCCCGTGCTGGACTCCGACGGCTCCTTCTTCCTCTATAGCAAGCTCACCGTGGACAAGAG
CAGGTGGCAGCAGGGGAACGTCTTCTCATGCTCCGTGATGCATGAGGCTCTGCACAACCACTACAC
GCAGAAGAGCCTCTCCCTGTCTCCGGGTAAATGA SEQ ID NO: 662
QVQLVQSGAEVKKPGASVRVSCKVSGYTFTSYFIHWVRQAPGQGLEWMGIINPISVSTSYAQKFQG
RVTMTRDTSTSTVFMELSSLRSEDTAVYYCARGGIQLWLHLDYWGQGTLVTVSSASTKGPSVFPLA
PSSKSTSGGTAALGCLVKDYFPEPVTVSWNSGALTSGVHTFPAVLQSSGLYSLSSVVTVPSSSLGT
QTYICNVNHKPSNTKVDKKVEPKSCDKTHTCPPCPAPELLGGPSVFLFPPKPKDTLMISRTPEVTC
VVVDVSHEDPEVKFNWYVDCTVEVHNAKTKPREEQYNSTYRVVSVLTVLHQDWLNGKEYKCKVSNK
ALPAPIEKTISKAKGQPREPQVYTLPPSREEMTKNQVSLTCLVKGFYPSDIAVEWESNGQPENNYK
TTPPVLDSDGSFFLYSKLTVDKSRWQQGNVFSCSVMHEALHNHYTQKSLSLSPGK 22G10 SEQ
ID NO: 663
GAGGTGCAACTGTTGGAGTCTGGGGGAGGCTTGGTACAGCCTGGGGGGTCCCTGAGACTCTCCTGT
GCAGCCTCTGGATTCACCTTTAGCAGTTATGCCATGAACTGGGTCCGCCAGGCTCCAGGGAAGGGG
CTGGAGTGGGTCTCAACTATTAGTGGTGGTGGTGCTAACACATACTACGCAGACTCCGTGAAGGGC
CGGTTCACCATCTCCAGTGACAATTCCAAGAGCACGCTGTATCTGCAAATGAACAGCCTGAGAGCC
GCGGACACGGCCGTATATCACTGTGCGAAAGGGGGAATGGGGGGATACTACTACGGTATGGACGTC
TGGGGCCAAGGGACCACGGTCACCGTCTCCTCAGCTTCCACCAAGGGCCCATCCGTCTTCCCCCTG
GCGCCCTCCTCCAAGAGCACCTCTGGGGGCACAGCGGCCCTGGGCTGCCTGGTCAAGGACTACTTC
CCCGAACCGGTGACGGTGTCGTGGAACTCAGGGGCCCTGACCAGCGGCGTGCACACCTTCCCGGCT
GTCCTACAGTCCTCAGGACTCTACTCCCTCAGCAGCGTGGTGACCGTGCCCTCCAGCAGCTTGGGC
ACCCAGACCTACATCTGCAACGTGAATCACAAGCCCAGCAACACCAAGGTGGACAAGAAAGTTGAG
CCCAAATCTTGTGACAAAACTCACACATGCCCACCGTGCCCAGCACCTGAACTCCTGGGGGGACCG
TCAGTCTTCCTCTTCCCCCCAAAACCCAAGGACACCCTCATGATCTCCCGGACCCCTGAGGTCACA
TGCGTGGTGGTGGACGTGAGCCACGAAGACCCTGAGGTCAAGTTCAACTGGTACGTGGACGGCGTG
GAGGTGCATAATGCCAAGACAAAGCCGCGGGAGGAGCAGTACAACAGCACGTACCGTGTGGTCAGC
GTCCTCACCGTCCTGCACCAGGACTGGCTGAATGGCAAGGAGTACAAGTGCAAGGTCTCCAACAAA
GCCCTCCCAGCCCCCATCGAGAAAACCATCTCCAAAGCCAAAGGGCAGCCCCGAGAACCACAGGTG
TACACCCTGCCCCCATCCCGGGAGGAGATGACCAAGAACCAGGTCAGCCTGACCTGCCTGGTCAAA
GGCTTCTATCCCAGCGACATCGCCGTGGAGTGGGAGAGCAATGGGCAGCCGGAGAACAACTACAAG
ACCACGCCTCCCGTGCTGGACTCCGACGGCTCCTTCTTCCTCTATAGCAAGCTCACCGTGGACAAG
AGCAGGTGGCAGCAGGGGAACGTCTTCTCATGCTCCGTGATGCATGAGGCTCTGCACAACCACTAC
ACGCAGAAGAGCCTCTCCCTGTCTCCGGGTAAATGA SEQ ID NO: 664
EVQLLESGGGLVQPGGSLRLSCAASGFTFSSYAMNWVRQAPGKGLEWVSTISGGGANTYYADSVKG
RFTISSDNSKSTLYLQMNSLRAADTAVYHCAKGGMGGYYYGMDVWGQGTTVTVSSASTKGPSVFPL
APSSKSTSGGTAALGCLVKDYFPEPVTVSWNSGALTSGVHTFPAVLQSSGLYSLSSVVTVPSSSLG
TQTYICNVNHKPSNTKVDKKVEPKSCDKTHTCPPCPAPELLGGPSVFLFPPKPKDTLMISRTPEVT
CVVVDVSHEDPEVKFNWYVDGVEVHNAKTKPREEQYNSTYRVVSVLTVLHQDWLNGKEYKCKVSNK
ALPAPIEKTISKAKGQPREPQVYTLPPSREEMTKNQVSLTCLVKGFYPSDIAVEWESNGQPENNYK
TTPPVLDSDGSFFLYSKLTVDKSRWQQGNVFSCSVMHEALHNHYTQKSLSLSPGK 23A10 SEQ
ID NO: 665
CAGGTGCAGCTGGTGGAGTCTGGGGGAGGCGTGGTCCAGCCTGGGAGGTCCCTGAGACTCTCCTGT
GCAGCGTCTGGATTCACCTTCAGTCGCTATGGCATACACTGGGTCCGCCAGGCTCCAGGCAAGGGG
CTGGAGTGGGTGGCAGTTATATGGTATGATGGAAGTAATAAATACTATGCAGACTCCGTGAAGGGC
CGATTCACCATCTCCAGAGACAATTCCAAGAACACGCTGTATCTGCTAATGAACAGCCTGAGAGCC
GAGGACTCGGCTGTGTATTACTGTCCGAGAAGGGCCGCTATACCTCGAACTACGGGCTACTACTAT
GGTATGGACGTCTGGGGCCAAGGGACCACGGTCACCGTCTCCTCAGCTTCCACCAAGGGCCCATCC
GTCTTCCCCCTGGCGCCCTCCTCCAAGAGCACCTCTGGGGGCACAGCGGCCCTGGGCTGCCTGGTC
AAGGACTACTTCCCCGAACCGGTGACGGTGTCGTGGAACTCAGGGGCCCTGACCAGCGGCGTGCAC
ACCTTCCCGGCTGTCCTACAGTCCTCAGGACTCTACTCCCTCAGCAGCGTGGTGACCGTGCCCTCC
AGCAGCTTGGGCACCCAGACCTACATCTGCAACGTGAATCACAAGCCCAGCAACACCAAGGTGGAC
AAGAAAGTTGAGCCCAAATCTTGTGACAAAACTCACACATGCCCACCGTGCCCAGCACCTGAACTC
CTGGGGGGACCGTCAGTCTTCCTCTTCCCCCCAAAACCCAAGGACACCCTCATGATCTCCCGGACC
CCTGAGGTCACATGCGTGGTGGTGGACGTGAGCCACGAAGACCCTGAGGTCAAGTTCAACTGGTAC
GTGGACGGCGTGGAGGTGCATAATGCCAAGACAAAGCCGCGGGAGGAGCAGTACAACAGCACGTAC
CGTGTGGTCAGCGTCCTCACCGTCCTGCACCAGGACTGGCTGAATGGCAAGGAGTACAAGTGCAAG
GTCTCCAACAAAGCCCTCCCAGCCCCCATCGAGAAAACCATCTCCAAAGCCAAAGGGCAGCCCCGA
GAACCACAGGTGTACACCCTGCCCCCATCCCGGGAGGAGATGACCAAGAACCAGGTCAGCCTGACC
TGCCTGGTCAAAGGCTTCTATCCCAGCGACATCGCCGTGGAGTGGGAGAGCAATGGGCAGCCGGAG
AACAACTACAAGACCACGCCTCCCGTGCTGGACTCCGACGGCTCCTTCTTCCTCTATAGCAAGCTC
ACCGTGGACAAGAGCAGGTGGCAGCAGGGGAACGTCTTCTCATGCTCCGTGATGCATGAGGCTCTG
CACAACCACTACACGCAGAAGAGCCTCTCCCTGTCTCCGGGTAAATGA SEQ ID NO: 666
QVQLVESGGGVVQPGRSLRLSCAASGFTFSRYGIHWVRQAPGKGLEWVAVIWYDGSNKYYADSVKG
RFTISRDNSKNTLYLLMNSLRAEDSAVYYCARRAGIPGTTGYYYGMDVWGQGTTVTVSSASTKGPS
VFPLAPSSKSTSGGTAALGCLVKDYFPEPVTVSWNSGALTSGVHTFPAVLQSSGLYSLSSVVTVPS
SSLGTQTYICNVNHKPSNTKVDKKVEPKSCDKTHTCPPCPAPELLGGPSVFLFPPKPKDTLMISRT
PEVTCVVVDVSHEDPEVKFNWYVDGVEVHNAKTKPREEQYNSTYRVVSVLTVLHQDWLNGKEYKCK
VSNKALPAPIEKTISKAKGQPREPQVYTLPPSREEMTKNQVSLTCLVKGFYPSDIAVEWESNGQPE
NNYKTTPPVLDSDGSFFLYSKLTVDKSRWQQGNVFSCSVMHEALHNHYTQKSLSLSPGK 25F8
SEQ ID NO: 667
CAGGTGCAGCTGGTGCAGTCTGGGGCTGAGGTGAAGAAGCCTGGGGCCTCAGTGAAGGTTTCCTGC
AAGGCATCTGGATACACCTTCACCAGCTACTATATTCACTGGGTGCGCCAGGCCCCTGGACAAGGA
CTTGAGTGGATGGGAATAATCAACCCCAGTGGTGGTAGCACAAGGTACGCACAGAAGTTCCAGGGC
AGAGTCACCATGACCAGGGACACGTCCACGAGCACAGTCTTCATGGAGCTGAGCAGCCTGAGATCT
GAGGACACGGCCGTGTATTACTGTGCGCGAGGGGGAATACAGCTATGGTTACATTTTGACTACTGG
GGCCAGGGAACCCTGGTCACCGTCTCCTCAGCTTCCACCAAGGGCCCATCCGTCTTCCCCCTGGCG
CCCTCCTCCAAGAGCACCTCTGGGGGCACAGCGGCCCTGGGCTGCCTGGTCAAGGACTACTTCCCC
GAACCGGTGACGGTGTCGTGGAACTCAGGGGCCCTGACCAGCGGCGTGCACACCTTCCCGGCTGTC
CTACAGTCCTCAGGACTCTACTCCCTCAGCAGCGTGGTGACCGTGCCCTCCAGCAGCTTGGGCACC
CAGACCTACATCTGCAACGTGAATCACAAGCCCAGCAACACCAAGGTGGACAAGAAAGTTGAGCCC
AAATCTTGTGACAAAACTCACACATGCCCACCGTGCCCAGCACCTGAACTCCTGGGGGGACCGTCA
GTCTTCCTCTTCCCCCCAAAACCCAAGGACACCCTCATGATCTCCCGGACCCCTGAGGTCACATGC
GTGGTGGTGGACGTGAGCCACGAAGACCCTGAGGTCAAGTTCAACTGGTACGTGGACGGCGTGGAG
GTGCATAATGCCAAGACAAAGCCGCGGGAGGAGCAGTACAACAGCACGTACCGTGTGGTCAGCGTC
CTCACCGTCCTGCACCAGGACTGGCTGAATGGCAAGGAGTACAAGTGCAAGGTCTCCAACAAAGCC
CTCCCAGCCCCCATCGAGAAAACCATCTCCAAAGCCAAAGGGCAGCCCCGAGAACCACAGGTGTAC
ACCCTGCCCCCATCCCGGGAGGAGATGACCAAGAACCAGGTCAGCCTGACCTGCCTGGTCAAAGGC
TTCTATCCCAGCGACATCGCCGTGGAGTGGGAGAGCAATCGGCAGCCCGAGAACAACTACAAGACC
ACGCCTCCCGTGCTGGACTCCGACGGCTCCTTCTTCCTCTATAGCAAGCTCACCGTGGACAAGAGC
AGGTGGCAGCAGGGGAACGTCTTCTCATGCTCCGTGATGCATGAGGCTCTGCACAACCACTACACG
CAGAAGAGCCTCTCCCTGTCTCCGGGTAAATGA SEQ ID NO: 668
QVQLVQSGAEVKKPGASVKVSCKASGYTFTSYYIHWVRQAPGQGLEWMGIINPSGGSTRYAQKFQG
RVTMTRDTSTSTVFMELSSLRSEDTAVYYCARGGIQLWLHFDYWGQGTLVTVSSASTKGPSVFPLA
PSSKSTSGGTAALGCLVKDYFPEPVTVSWNSGALTSGVHTFPAVLQSSGLYSLSSVVTVPSSSLGT
QTYICNVNHKPSNTKVDKKVEPKSCDKTHTCPPCPAPELLGGPSVFLFPPKPKDTLMISRTPEVTC
VVVDVSHEDPEVKFNWYVDGVEVHNAKTKPREEQYNSTYRVVSVLTVLHQDWLNGKEYKCKVSNKA
LPAPIEKTISKAKGQPREPQVYTLPPSREEMTKNQVSLTCLVKGFYPSDIAVEWESNGQPENNYKT
TPPVLDSDGSFFLYSKLTVDKSRWQQGNVFSCSVMHEALHNHYTQKSLSLSPGK 25G10 SEQ ID
NO: 669
CAGGTGCAGCTGCAGGAGTCGGGCCCAGGACTGGTGAAGCCTTCGGAGACCCTGTCCCTCACCTGC
ACTGTCTCTGGTGGCTCCATCAGTGGTTACTACTGGAGCTGGATCCGGCAGCCCCCAGGGAAGGGA
CTGGAGTGGATTGGGTATATCTATTACATTGGGAGCACCAACTACAACCCCTCCCTCAAGAGTCGA
GTCACCATGTCAGTAGACACGTCCAAGAACCAGTTCTCCCTGAAGCTGAGCTCTGTGACCGCTGCG
GACACGCCCGTGTATTACTGTGCGAGAGATGGGAGCAGTGGCTGGTACCGGTGGTTCGACCCCTGG
GGCCAGGGAACCCTGGTCACCGTCTCCTCAGCTTCCACCAAGGGCCCATCCGTCTTCCCCCTGGCG
CCCTCCTCCAAGAGCACCTCTGGGGGCACAGCGGCCCTGGGCTGCCTGGTCAAGGACTACTTCCCC
GAACCGGTGACGGTGTCGTGGAACTCAGGGGCCCTGACCAGCGGCGTGCACACCTTCCCGGCTGTC
CTACAGTCCTCAGGACTCTACTCCCTCAGCAGCGTGGTGACCGTGCCCTCCAGCAGCTTGGGCACC
CAGACCTACATCTGCAACGTGAATCACAAGCCCAGCAACACCAAGGTGGACAAGAAAGTTGAGCCC
AAATCTTGTGACAAAACTCACACATGCCCACCGTGCCCAGCACCTGAACTCCTGGGGGGACCGTCA
GTCTTCCTCTTCCCCCCAAAACCCAAGGACACCCTCATGATCTCCCGGACCCCTGAGGTCACATGC
GTGGTGGTGGACGTGAGCCACGAAGACCCTGAGGTCAAGTTCAACTGGTACGTGGACGGCGTGGAG
GTGCATAATGCCAAGACAAAGCCGCGGGAGGAGCAGTACAACAGCACGTACCGTGTGGTCAGCGTC
CTCACCGTCCTGCACCAGGACTGGCTGAATGGCAAGGAGTACAAGTGCAAGGTCTCCAACAAAGCC
CTCCCAGCCCCCATCGAGAAAACCATCTCCAAAGCCAAAGGGCAGCCCCGAGAACCACAGGTGTAC
ACCCTGCCCCCATCCCGGGAGGAGATGACCAAGAACCAGGTCAGCCTGACCTGCCTGGTCAAAGGC
TTCTATCCCAGCGACATCGCCGTGGAGTGGGAGAGCAATGGGCAGCCGGAGAACAACTACAAGACC
ACGCCTCCCGTGCTGGACTCCGACGGCTCCTTCTTCCTCTATAGCAAGCTCACCGTGGACAAGAGC
AGGTGGCAGCAGGGGAACGTCTTCTCATGCTCCGTGATGCATGAGGCTCTGCACAACCACTACACG
CAGAAGAGCCTCTCCCTGTCTCCGGGTAAATGA SEQ ID NO: 670
QVQLQESGPGLVKPSETLSLTCTVSGGSISGYYWSWIRQPPGKGLEWIGYIYYIGSTNYNPSLKSR
VTMSVDTSKNQFSLKLSSVTAADTAVYYCARDGSSGWYRWFDPWGQGTLVTVSSASTKGPSVFPLA
PSSKSTSGGTAALGCLVKDYFPEPVTVSWNSGALTSGVHTFPAVLQSSGLYSLSSVVTVPSSSLGT
QTYICNVNHKPSNTKVDKKVEPKSCDKTHTCPPCPAPELLGGPSVFLFPPKPKDTLMISRTPEVTC
VVVDVSHEDPEVKFNWYVDGVEVHNAKTKPREEQYNSTYRVVSVLTVLHQDWLNGKEYKCKVSNKA
LPAPIEKTISKAKGQPREPQVYTLPPSREEMTKNQVSLTCLVKGFYPSDIAVEWESNGQPENNYKT
TPPVLDSDGSFFLYSKLTVDKSRWQQGNVFSCSVMHEALHNHYTQKSLSLSPG 26D1 SEQ ID
NO: 671
CAGGTGCAGTTGGTGCAGTCTGGGGCTGAGGTGAAGAAGCCTGGGGCCTCAGTGAAGGTTTCCTGT
AAGGCATCTAGATACACCTTCACCAGCTACTATATGTCCTGGGTGCGACAGGCCCCTGGACAAGGG
CTTGAGTGGATGGGAATAATCCACCCTAGTGGTGGTGACACAACCTACGCACAGAAGTTCCAGGGC
AGAGTCACCATGACCGGGGACACGTCCACGAGCACAGTCTACATGGAGCTGAGCAGCCTGAGATCT
GAGGACACGGCCGTGTATTACTGTGCGAGAGGGGGGATAAAACTATGGTTACATTTTGACTATTGG
GGCCAGGGAACCCTGGTCACCGTCTCCTCAGCTTCCACCAAGGGCCCATCCGTCTTCCCCCTGGCG
CCCTCCTCCAAGAGCACCTCTGGGGGCACAGCGGCCCTGGGCTGCCTGGTCAAGGACTACTTCCCC
GAACCGGTGACGGTGTCGTGGAACTCAGGGGCCCTGACCAGCGGCGTGCACACCTTCCCGGCTGTC
CTACAGTCCTCAGGACTCTACTCCCTCAGCAGCGTGGTGACCGTGCCCTCCAGCAGCTTGGGCACC
CAGACCTACATCTGCAACGTGAATCACAAGCCCAGCAACACCAAGGTGGACAAGAAAGTTGAGCCC
AAATCTTGTGACAAAACTCACACATGCCCACCGTGCCCAGCACCTGAACTCCTGGGGGGACCGTCA
GTCTTCCTCTTCCCCCCAAAACCCAAGGACACCCTCATGATCTCCCGGACCCCTGAGGTCACATGC
GTGGTGGTGGACGTGAGCCACGAAGACCCTGAGGTCAAGTTCAACTGGTACGTGGACGGCGTGGAG
GTGCATAATGCCAAGACAAAGCCGCGGGAGGAGCAGTACAACAGCACGTACCGTGTGGTCAGCGTC
CTCACCGTCCTGCACCAGGACTGGCTGAATGGCAAGGAGTACAAGTGCAAGGTCTCCAACAAAGCC
CTCCCAGCCCCCATCGAGAAAACCATCTCCAAAGCCAAAGGGCAGCCCCGAGAACCACAGGTGTAC
ACCCTGCCCCCATCCCGGGAGGAGATGACCAAGAACCAGGTCAGCCTGACCTGCCTGGTCAAAGGC
TTCTATCCCAGCGACATCGCCGTGGAGTGGGAGAGCAATGGGCAGCCGGAGAACAACTACAAGACC
ACGCCTCCCGTGCTGGACTCCGACGGCTCCTTCTTCCTCTATAGCAAGCTCACCGTGGACAAGAGC
AGGTGGCAGCAGGGGAACGTCTTCTCATGCTCCGTGATGCATGAGGCTCTGCACAACCACTACACG
CAGAAGAGCCTCTCCCTGTCTCCGGGTAAATGA SEQ ID NO: 672
QVQLVQSGAEVKKPGASVKVSCKASRYTFTSYYMSWVRQAPGQGLEWMGIIHPSGGDTTYAQKFQG
RVTMTGDTSTSTVYMELSSLRSEDTAVYYCARGGIKLWLHFDYWGQGTLVTVSSASTKGPSVFPLA
PSSKSTSGGTAALGCLVKDYFPEPVTVSWNSGALTSGVHTFPAVLQSSGLYSLSSVVTVPSSSLGT
QTYICNVNHKPSNTKVDKKVEPKSCDKTHTCPPCPAPELLGGPSVFLFPPKPKDTLMISRTPEVTC
VVVDVSHEDPEVKFNWYVDGVEVHNAKTKPREEQYNSTYRVVSVLTVLHQDWLNGKEYKCKVSNKA
LPAPIEKTISKAKGQPREPQVYTLPPSREEMTKNQVSLTCLVKGFYPSDIAVEWESNGQPENNYKT
TPPVLDSDGSFFLYSKLTVDKSRWQQGNVFSCSVMHEALHNHYTQKSLSLSPGK 26F12 SEQ ID
NO: 673
CAGGTGCAGTTGGTGCAGTCTGGGGCTGAGGTGAAGAAGCCTGGGGCCTCAGTGAAGGTTTCCTGC
AAGGCATCTAGATACACCTTCACCAACTACTATATGTCCTGGGTGCGACAGGCCCCTGGACAAGGG
CTTGAGTGGATGGGAATAATCAACCCTAGTGGTGGTGACTCAACCTACGCACAGAAGTTCCAGGGC
AGACTCACCATGACCGGGGACACGTCCACGAGCACAGTCTACATGGAGCTGAGCAGCCTGAGATCT
GAGGACACCTGCCGTCTATTACTCTGCGAGAGGTTGGATACAACTATGGTTACATTTTGACTACTG
GGGCCAGGGAACCCTGGTCACCGTCTCCTCAGCTTCCACCAAGGGCCCATCCGTCTTCCCCCTGGC
GCCCTCCTCCAAGAGCACCTCTGGGGGCACAGCGGCCCTGGGCTGCCTGGTCAAGGACTACTTCCC
CGAACCGGTGACGGTGTCGTGGAACTCAGGGGCCCTGACCAGCGGCGTGCACACCTTCCCGGCTGT
CCTACAGTCCTCAGGACTCTACTCCCTCAGCAGCGTGGTGACCGTGCCCTCCAGCAGCTTGGGCAC
CCAGACCTACATCTGCAACGTGAATCACAAGCCCAGCAACACCAAGGTGGACAAGAAAGTTGAGCC
CAAATCTTGTGACAAAACTCACACATGCCCACCGTGCCCAGCACCTGAACTCCTGGGGGGACCGTC
AGTCTTCCTCTTCCCCCCAAAACCCAAGGACACCCTCATGATCTCCCGGACCCCTGAGGTCACATG
CGTGGTGGTGGACGTGAGCCACGAAGACCCTGAGGTCAAGTTCAACTGGTACGTGGACGGCGTGGA
GGTGCATAATGCCAAGACAAAGCCGCGGGAGGAGCAGTACAACAGCACGTACCGTGTGGTCAGCGT
CCTCACCGTCCTGCACCAGGACTGGCTGAATGGCAAGGAGTACAAGTGCAAGGTCTCCAACAAAGC
CCTCCCAGCCCCCATCGAGAAAACCATCTCCAAAGCCAAAGGGCAGCCCCGAGAACCACAGGTGTA
CACCCTGCCCCCATCCCGGGAGGAGATGACCAAGAACCAGGTCAGCCTGACCTGCCTGGTCAAAGG
CTTCTATCCCAGCGACATCGCCGTGGAGTGGGAGAGCAATGGGCAGCCGGAGAACAACTACAAGAC
CACGCCTCCCGTGCTGGACTCCGACGGCTCCTTCTTCCTCTATAGCAAGCTCACCGTGGACAAGAG
CAGGTGGCAGCAGGGGAACGTCTTCTCATGCTCCGTGATGCATGAGGCTCTGCACAACCACTACAC
GCAGAAGAGCCTCTCCCTGTCTCCGGGTAAATGA SEQ ID NO: 674
QVQLVQSGAEVKKPGASVKVSCKASRYTFTNYYMSWVRQAPGQGLEWMGIINPSGGDSTYAQKFQG
RLTMTGDTSTSTVYMELSSLRSEDTAVYYCARGGIQLWLHFDYWGQGTLVTVSSASTKGPSVFPLA
PSSKSTSGGTAALGCLVKDYFPEPVTVSWNSGALTSGVHTFPAVLQSSGLYSLSSVVTVPSSSLGT
QTYICNVNHKPSNTKVDKKVEPKSCDKTHTCPPCPAPELLGGPSVFLFPPKPKDTLMISRTPEVTC
VVVDVSHEDPEVKFNWYVDGVEVHNAKTKPREEQYNSTYRVVSVLTVLHQDWLNGKEYKCKVSNKA
LPAPIEKTISKAKGQPREPQVYTLPPSREEMTKNQVSLTCLVKGFYPSDIAVEWESNGQPENNYKT
TPPVLDSDGSFFLYSKLTVDKSRWQQGNVFSCSVMHEALHNHYTQKSLSLSPGK
TABLE-US-00015 TABLE IIIb Light Chain Variable and Contant Region
Polynucleotide and Amino acid Sequences 2G6 SEQ ID NO: 675
TCCTATGAACTGACTCAGCCACCCTCAGTGTCCGTGTCCCCAGGACAGACAGCCAGCATCACCTGC
TCTGGAGATAGGTTGGGGGAAAAATATACTTGCTGGTATCAGCAGAGGCCAGGCCAGTCCCCTTTG
CTGGTCATCTATCAAGATACCAAGCGGCCCTCAGGGATCCCTGAGCGATTCTCTGGCTCCAACTCT
GGTAACACAGCCACTCTGACCATCAGCGGGACCCAGGCTATGGATGAGGCTGACTATTACTGTCAG
GCGTGGGACAGCAGCACTGTGGTATTCGGCGGAGGGACCAAGCTGACCGTCCTAGGTCAGCCCAAG
GCCAACCCCACTGTCACTCTGTTCCCGCCCTCCTCTGAGGAGCTCCAAGCCAACAAGGCCACACTA
GTGTGTCTGATCAGTGACTTCTACCCGGGAGCTGTGACAGTGGCCTGGAAGGCAGATGGCAGCCCC
GTCAAGGCGGGAGTGGAGACCACCAAACCCTCCAAACAGAGCAACAACAAGTACGCGGCCAGCAGC
TACCTGAGCCTGACGCCCGAGCAGTGGAAGTCCCACAGAAGCTACAGCTGCCAGGTCACGCATGAA
GGGAGCACCGTGGAGAAGACAGTGGCCCCTACAGAATGTTCATGA SEQ ID NO: 676
SYELTQPPSVSVSPGQTASITCSGDRLGEKYTCWYQQRPGQSPLLVIYQDTKRPSGIPERFSGSNS
GNTATLTISGTQAMDEADYYCQAWDSSTVVFGGGTKLTVLGQPKANPTVTLFPPSSEELQANKATL
VCLISDFYPGAVTVAWKADGSPVKAGVETTKPSKQSNNKYAASSYLSLTPEQWKSHRSYSCQVTHE
GSTVEKTVAPTECS 4A2 SEQ ID NO: 677
GAAATTGTGTTGACGCAGTCTCCAGGCACCCTGTCTTTGTCTCCAGGGGAAAGAGCCACCCTCTCC
TGCAGGGCCAGTCGGAATATTAGCAGCAGCTACTTAGCCTGGTACCAGCAGAAACCTGGCCAGGCT
CCCAGGCTCCTCATCTATGGTCCATCCAGCAGGGCCACTGGCATCCCAGACAGGTTCAGTGGCAGT
GGGTCTGGGACAGACTTCACTCTCACCATCAGCAGACTGGAGCCTGAAGATTTTACAGTGTATTAC
TGTCAGCAGTATGGTAGCTCATTCACTTTCGGCCCTGGGACCAAAGTGGATATCAAACGTACGGTG
GCTGCACCATCTGTCTTCATCTTCCCGCCATCTGATGAGCAGTTGAAATCTGGAACTGCCTCTGTT
GTGTGCCTGCTGAATAACTTCTATCCCAGAGAGGCCAAAGTACAGTGGAAGGTGGATAACGCCCTC
CAATCGGGTAACTCCCAGGAGAGTGTCACAGAGCAGGACAGCAAGGACAGCACCTACAGCCTCAGC
AGCACCCTGACGCTGAGCAAAGCAGACTACGAGAAACACAAAGTCTACGCCTGCGAAGTCACCCAT
CAGGGCCTGAGCTCGCCCGTCACAAAGAGCTTCAACAGGGGAGAGTGTTGA SEQ ID NO: 678
EIVLTQSPGTLSLSPGERATLSCRASRNISSSYLAWYQQKPGQAPRLLIYGPSSRATGIPDRFSGS
GSGTDFTLTISRLEPEDFTVYYCQQYGSSFTFGPGTKVDIKRTVAAPSVFIFPPSDEQLKSGTASV
VCLLNNFYPREAKVQWKVDNALQSGNSQESVTEQDSKDSTYSLSSTLTLSKADYEKHKVYACEVTH
QGLSSPVTKSFNRGEC 4A9 SEQ ID NO: 679
CAGTCTGTGCTGACGCAGCCGCCCTCAGTGTCTGGGGCCCCAGGACAGAGGGTCACCATCTCCTGC
ACTGGGAGCAGCTCCAACATCGGGACAGGTTATGCTGTACACTGGTACCAGCAGTTTCCAGGAACA
GCCCCCAAACTCCTCATCTATGGTAACAACAATCGGCCCTCAGGGGTTCCTGACCGATTCTCTGGC
TCCAAGTCTGGCACCTCAGCCTCCCTGGCCATCACTGGGCTCCAGGCTGAGGATGAGGCTGATTAT
TACTGCCAGTCCTATGACAGCAGACTGAGTGGTTGGGTGTTCGGCGGAGGGACCAAGCTGACCGTC
CTAGGTCAGCCCAAGGCCAACCCCACTGTCACTCTGTTCCCGCCCTCCTCTGAGGAGCTCCAAGCC
AACAAGGCCACACTAGTGTGTCTGATCAGTGACTTCTACCCGGGAGCTGTGACAGTGGCCTGGAAG
GCAGATGGCAGCCCCGTCAAGGCGGGAGTGGAGACCACCAAACCCTCCAAACAGAGCAACAACAAG
TACGCGGCCAGCAGCTACCTGAGCCTGACGCCCGAGCAGTGGAAGTCCCACAGAAGCTACAGCTGC
CAGGTCACGCATGAAGGGAGCACCGTGGAGAAGACAGTGGCCCCTACAGAATGTTCATGA SEQ ID
NO: 680
QSVLTQPPSVSGAPGQRVTISCTGSSSNIGTGYAVHWYQQFPGTAPKLLIYGNNNRPSGVPDRFSG
SKSGTSASLAITGLQAEDEADYYCQSYDSRLSGWVFGGGTKLTVLGQPKANPTVTLFPPSSEELQA
NKATLVCLISDFYPGAVTVAWKADGSPVKAGVETTKPSKQSNNKYAASSYLSLTPEQWKSHRSYSC
QVTHEGSTVEKTVAPTECS 4B10 SEQ ID NO: 681
GAAATTGTATTGACGCAGTCTCCAGGCACCCTGTCTTTGTCTCCAGGGGAAAGAGCCACCCTCTCC
TGCAGGGCCAGTCAGAGTGTTAGCAACACCTACTTAGCCTGGTACCATCAGAGACCTGGCCAGGCT
CCCAGGCTCCTCATCTATGGTGCATCCAGCAGGGCCACTGGCATCCCAGACAGATTCAGTGGCAGT
GGGTCTGGGACAGACTTCGCTCTCACCATCAGCAGTCTGGAGCCTGAAGATTTTGCAGTGTATTAC
TGTCAGCAGTACAGTAACTCGTGGACGTTCGGCCAAGGGACCAAGGTGGAAATCAAACGAACTGTG
GCTGCACCATCTGTCTTCATCTTCCCGCCATCTGATGAGCAGTTGAAATCTGGAACTGCCTCTGTT
GTGTGCCTGCTGAATAACTTCTATCCCAGAGAGGCCAAAGTACAGTGGAAGGTGGATAACGCCCTC
CAATCGGGTAACTCCCAGGAGAGTGTCACAGAGCAGGACAGCAAGGACAGCACCTACAGCCTCAGC
AGCACCCTGACGCTGAGCAAAGCAGACTACGAGAAACACAAAGTCTACGCCTGCGAAGTCACCCAT
CAGGGCCTGAGCTCGCCCGTCACAAAGAGCTTCAACAGGGGAGAGTGTTGA SEQ ID NO: 682
EIVLTQSPGTLSLSPGERATLSCRASQSVSNTYLAWYHQRPGQAPRLLIYGASSRATGIPDRFSGS
GSGTDFALTISSLEPEDFAVYYCQQYSNSWTFGQGTKVEIKRTVAAPSVFIFPPSDEQLKSGTASV
VCLLNNFYPREAKVQWKVDNALQSGNSQESVTEQDSKDSTYSLSSTLTLSKADYEKHKVYACEVTH
QGLSSPVTKSFNRGEC 4F3 SEQ ID NO: 683
GAAATTGTGTTGACGCAGTCTCCAGGCACCCTGTCTTTGTCTCCAGGGGAAAGAGCCACCCTCTCC
TGCAGGGCCAGTCAGAGTGTTAGCAGCAGCTACTTAGCCTGGTACCAGCAGAAACCTGGCCAGGCT
CCCAGGCTCCTCATCTATGGTGCATCCAGCAGGGCCACTGGCATCCCAGACAGGTTCAGTGGCAGT
GGGTCTGGGACAGACTTCACTCTCACCATCAGCAGACTGGAACCTGAGGATTTTGCAGTGTATTAC
TGTCAGCAGTATGGTAGCTCGTGGACGTTCGGCCAAGGGACCAAGGTGGAAATCAAACGTACGGTG
GCTGCACCATCTGTCTTCATCTTCCCGCCATCTGATGAGCAGTTGAAATCTGGAACTGCCTCTGTT
GTGTGCCTCCTGAATAACTTCTATCCCAGAGAGGCCAAAGTACAGTCGAAGGTGGATAACGCCCTC
CAATCGGGTAACTCCCAGGAGAGTGTCACAGAGCAGGACAGCAAGGACAGCACCTACAGCCTCAGC
AGCACCCTGACGCTGAGCAAAGCAGACTACGAGAAACACAAAGTCTACGCCTGCGAAGTCACCCAT
CAGGGCCTGAGCTCGCCCGTCACAAAGAGCTTCAACAGGGGAGAGTGTTGA SEQ ID NO: 684
EIVLTQSPGTLSLSPGERATLSCRASQSVSSSYLAWYQQKPGQAPRLLIYGASSRATGIPDRFSGS
GSGTDFTLTISRLEPEDFAVYYCQQYGSSWTFGQGTKVEIKRTVAAPSVFIFPPSDEQLKSGTASV
VCLLNNFYPREAKVQWKVDNALQSGNSQESVTEQDSKDSTYSLSSTLTLSKADYEKHKVYACEVTH
QGLSSPVTKSFNRGEC 4F7 SEQ ID NO: 685
CAGTCTGTGCTGACGCAGCCGCCCTCAGTGTCTGGGGCCCCAGGGCAGAGGGTCACCATCTCCTGC
ACTGGGAGCAGCTCCAATATCGGGACAGGTTATGATGTACACTGGTATCAGCAGCTTCCAGGAACA
GCCCCCAAACTCCTCATCCATGGTAACAGCAATCGGCCCTCAGGGGTCCCTGACCGATTCTCTGGC
TCCAAGTCTGGCACCTCAGCCTCCCTGGCCATCACTGGGCTCCAGGCTGAGGATGAGGCTGATTAT
TACTGCCAGTCCTATGACAGCAGTCTGAGTGGTTGGGTGTTCGGCGGAGGGACCAGGTTGACCGTC
CTAGGTCAGCCCAAGGCCAACCCCACTGTCACTCTGTTCCCGCCCTCCTCTGAGGAGCTCCAAGCC
AACAAGGCCACACTAGTGTGTCTGATCAGTGACTTCTACCCGGGAGCTGTGACAGTGGCCTGGAAG
GCAGATGGCAGCCCCGTCAAGGCGGGAGTGGAGACCACCAAACCCTCCAAACAGAGCAACAACAAG
TACGCGGCCAGCAGCTACCTGAGCCTGACGCCCGAGCAGTGGAAGTCCCACAGAAGCTACAGCTGC
CAGGTCACGCATGAAGGGAGCACCGTGGAGAAGACAGTGGCCCCTACAGAATGTTCATGA SEQ ID
NO: 686
QSVLTQPPSVSGAPGQRVTISCTGSSSNIGTGYDVHWYQQLPGTAPKLLIHGNSNRPSGVPDRFSG
SKSGTSASLAITGLQAEDEADYYCQSYDSSLSGWVFGGGTRLTVLGQPKANPTVTLFPPSSEELQA
NKATLVCLISDFYPGAVTVAWKADGSPVKAGVETTKPSKQSNNKYAASSYLSLTPEQWKSHRSYSC
QVTHEGSTVEKTVAPTECS 16A4 SEQ ID NO: 687
GAAATTGTGTTGACGCAGTCTCCAGGCACCCTGTCTTTGTCTCCAGGGGAAAGAGCCACCCTCTCC
TGCAGGGCCAGTCAGAGTGTTAGCAGCAGTTATTTAGCCTGGTACCAGCAGAAACCTGGCCAGGCT
CCCAGGCTCCTCATCTATGGTACATCCAGCAGGGCCACTGGCATCCCAGACAGGTTCAGTGGCAGT
GGGTCTGGGACAGACTTCACTCTCACCATCAGCAGACTGGAGCCTGAAGATTTTGCAGTGTATTAT
TGTCAGCAGTACGGTAGCTCACCTTTCACTTTCGGCGGAGGGACCAAGGTGGAGATCAAACGAACT
GTGGCTGCACCATCTGTCTTCATCTTCCCGCCATCTGATGAGCAGTTGAAATCTGGTACCGCCTCT
GTTGTGTGCCTGCTGAATAACTTCTATCCCAGAGAGGCCAAAGTACAGTGGAAGGTGGATAACGCC
CTCCAATCGGGTAACTCCCAGGAGAGTGTCACAGAGCAGGACAGCAAGGACAGCACCTACAGCCTC
AGCAGCACCCTGACGCTGAGCAAAGCAGACTACGAGAAACACAAAGTCTACGCCTGCGAAGTCACC
CATCAGGGCCTGAGCTCGCCCGTCACAAAGAGCTTCAACAGGGGAGAGTGTTGA SEQ ID NO:
688
EIVLTQSPGTLSLSPGERATLSCRASQSVSSSYLAWYQQKPGQAPRLLIYGTSSRATGIPDRFSGS
GSGTDFTLTISRLEPEDFAVYYCQQYGSSPFTFGGGTKVEIKRTVAAPSVFIFPPSDEQLKSGTAS
VVCLLNNFYPREAKVQWKVDNALQSGNSQESVTEQDSKDSTYSLSSTLTLSKADYEKHKVYACEVT
HQGLSSPVTKSFNRGEC 16C1 SEQ ID NO: 689
GAAATTGTGTTGACGCAGTCTCCAGGCACCCTGTCTTTGTCTCCAGGGGAAAGAGCCACCCTCTCC
TGCAGGGCCATCCAGAGTGTTAGCAGCAGCTACTTAGCCTGGTACCAGCAGAAACCTGGCCAGGCT
CCCAGGCTCCTCATCTTTGGTGCATCCAGCAGGGCCACTGGCATCCCAGACAGGTTCAGTGGCAGT
GGGTCTGGGACAGACTTCACTCTCACCATCAGCGGACTGGAGCCTGAAGATTTTGCAGTGTATCAC
TGTCAGCAGTATGGTAACTCACCGCTCACTTTCGGCGGAGGGACCAAGGTGGAGATCAAACGAACT
GTGGCTGCACCATCTGTCTTCATCTTCCCGCCATCTGATGAGCAGTTGAAATCTGGTACCGCCTCT
GTTGTGTGCCTCCTGAATAACTTCTATCCCAGAGAGGCCAAAGTACAGTCGAAGGTGGATAACGCC
CTCCAATCGGGTAACTCCCAGGAGAGTGTCACAGAGCAGGACAGCAAGGACAGCACCTACAGCCTC
AGCAGCACCCTGACGCTGAGCAAAGCAGACTACGAGAAACACAAAGTCTACGCCTGCGAAGTCACC
CATCAGGGCCTGAGCTCGCCCGTCACAAAGAGCTTCAACAGGGGAGAGTCTTGA SEQ ID NO:
690
EIVLTQSPGTLSLSPGERATLSCRASQSVSSSYLAWYQQKPGQAPRLLIFGASSRATGIPDRFSGS
GSGTDFTLTISGLEPEDFAVYHCQQYGNSPLTFGGGTKVEIKRTVAAPSVFIFPPSDEQLKSGTAS
VVCLLNNFYPREAKVQWKVDNALQSGNSQESVTEQDSKDSTYSLSSTLTLSKADYEKHKVYACEVT
HQGLSSPVTKSFNRGEC 17H8 SEQ ID NO: 691
GACATTGTATTGACGCAGTCTCCAGGCACCCTGTCTTTGTCTCCAGGGGAAAGAGCCACCCTCTCC
TGCAGGGCCAGTCAGAGTGTTGCCGGCAGCTACCTAGCCTGGTACCAGCAGAAACCTGGCCAGGCT
CCCAGGCTCCTCATCTCTCGTCCATCCAGCAGGGCCACTGGCATCCCAGACAGGTTCAGTGGCAGT
GGGTCTGGGACAGACTTCACTCTCACCATCAGCAGACTGGAGCCTGAAGATTTTGCAGTGTATTAC
TGTCAGCAGTATGGTAAATCACCGATCACCTTCGGCCAAGGGACACGACTGGAGATGAAAGGAACT
GTGGCTGCACCATCTGTCTTCATCTTCCCGCCATCTGATGAGCAGTTGAAATCTGGTACCGCCTCT
GTTGTGTGCCTGCTGAATAACTTCTATCCCAGAGAGGCCAAAGTACAGTGGAAGGTGGATAACGCC
CTCCAATCGGGTAACTCCCAGGAGAGTCTCACAGAGCAGGACAGCAAGGACAGCACCTACAGCCTC
AGCAGCACCCTGACGCTGAGCAAAGCAGACTACGAGAAACACAAAGTCTACGCCTGCGAAGTCACC
CATCAGGGCCTGAGCTCGCCCGTCACAAAGAGCTTCAACAGGGGAGAGTGTTGA SEQ ID NO:
692
DIVLTQSPGTLSLSPGERATLSCRASQSVAGSYLAWYQQKPGQAPRLLISGASSRATGIPDRFSGS
GSGTDFTLTISRLEPEDFAVYYCQQYGKSPITFGQGTRLEMKGTVAAPSVFIFPPSDEQLKSGTAS
VVCLLNNFYPREAKVQWKVDNALQSGNSQESVTEQDSKDSTYSLSSTLTLSKADYEKHKVYACEVT
HQGLSSPVTKSFNRGEC 19B5 SEQ ID NO: 693
CAGTCTGCGCTGACTCAGCCACCCTCAACGACTGGGACCCCCGGGCAGAGGGTCACCATCTCTTGT
TCTGGAAGCAGGTCCAACATCGGAAGCAATTTTGTAAACTGGTACAAGCAGCTCCCAGGAACGGCC
CCCAAAGTCCTCATCTATACTAATAATCAGCGGCCCTCAGGGGTCCCTGACCGATTCTCTGGCTCC
AAGTCTGGCACCTCAGCCTCCCTGGCCATCAGTGGGCTCCAGTCTGAGGATGAGTCTGATTATTAC
TGCGCAACATGGGATGACAGTATGAATGGTTGGGTGTTCGGCGGAGGGACCAAACTGACCGTCCTA
GGTCAGCCCAAGGCTGCCCCCTCGGTCACTCTGTTCCCACCCTCCTCTGAGGAGCTTCAAGCCAAC
AAGGCCACACTGGTGTGTCTCATAAGTGACTTCTACCCGGGAGCCGTGACAGTGGCCTGGAAGGCA
GATAGCAGCCCCGTCAAGGCGGGAGTGGAGACCACCACACCCTCCAAACAAAGCAACAACAAGTAC
GCGGCCAGCAGCTATCTGAGCCTGACGCCTGAGCAGTGGAAGTCCCACAGAAGCTACAGCTGCCAG
GTCACGCATGAAGGGAGCACCGTGGAGAAGACAGTGGCCCCTACAGAATGTTCATGA SEQ ID
NO: 694
QSALTQPPSTTGTPGQRVTISCSGSRSNIGSNFVNWYKQLPGTAPKVLIYTNNQRPSGVPDRFSGS
KSGTSASLAISGLQSEDESDYYCATWDDSMNGWVFGGGTKLTVLGQPKAAPSVTLFPPSSEELQAN
KATLVCLISDFYPGAVTVAWKADSSPVKAGVETTTPSKQSNNKYAASSYLSLTPEQWKSHRSYSCQ
VTHEGSTVEKTVAPTECS 20D3 SEQ ID NO: 695
CAGTCTCCGCTGACTCAGCCACCCTCAGCGACTGGGACCCCCGGGCAGAGGGTCACCATCTCTTGT
TCTGGAAGCAGCTCCAACATCGGAAGCAATTTTGTAAACTGGTACAAGCAGCTCCCAGGAACGGCC
CCCAAAGTCCTCATCTATACTAATAATCAGCGGCCCTCAGGGGTCCCTGACCGATTCTCTGGCTCC
AAGTCTGGCACCTCAGCCTCCCTGGCCATCAGTGGGCTCCAGTCTGAGGATGAGTCTGATTATTAC
TGTGCAACATGGGATGACAGCCTGAATGGTTGGGTGTTCGGCGGAGGGACCAAGCTGACCGTCCTA
GGTCAGCCCAAGGCTTCCCCCTCGCTCACTCTCTTCCCACCCTCCTCTGAGGAGCTTCAATCCAAC
AAGGCCACACTGGTGTGTCTCATAAGTGACTTCTACCCGGGAGCCGTGACAGTGGCCTGGAAGGCA
GATAGCAGCCCCGTCAAGGCGGGAGTGGAGACCACCACACCCTCCAAACAAAGCAACAACAAGTAC
GCGGCCAGCAGCTATCTGAGCCTGACGCCTGAGCAGTGGAAGTCCCACAGAAGCTACAGCTGCCAG
GTCACGCATGAAGGGAGCACCGTGGAGAAGACAGTGGCCCCTACAGAATGTTCATGA SEQ ID
NO: 696
QSALTQPPSATGTPGQRVTISCSGSSSNIGSNFVNWYKQLPGTAPKVLIYTNNQRPSGVPDRFSGS
KSGTSASLAISGLQSEDESDYYCATWDDSLNGWVFGGGTKLTVLGQPKAAPSVTLFPPSSEELQAN
KATLVCLISDFYPGAVTVAWKADSSPVKAGVETTTPSKQSNNKYAASSYLSLTPEQWKSHRSYSCQ
VTHEGSTVEKTVAPTECS 22D1 SEQ ID NO: 697
CAGTCTGCGCTGACTCAGCCACCCTCAGCGACTGGGACCCCCGGGCAGAGGGTCACCATCTCTTGT
TCTGGAAGCAGCTCCAACATCGGAAGCAATTTTGTAAACTGGTACAAGCAGCTCCCAGGAACCGCC
CCCAAAGTCCTCATCTATACTAATAATCAGCGGCCCTCAGGGGTCCCTGACCGATTCTCTGGCTCC
AAGTCTGGCACCTCAGCCTCCCTGGCCATCAGTGGGCTCCAGTCTGAGGATGAGTCTGATTATTAC
TGTGCAACATGGGATGACAGTATGAATGGTTGGGTGTTCGGCGGAGGGACCAAGCTGACCGTCCTA
GGTCAGCCCAAGGCTGCCCCCTCGGTCACTCTGTTCCCACCCTCCTCTGAGGAGCTTCAAGCCAAC
AAGGCCACACTGGTGTGTCTCATAAGTGACTTCTACCCGGGAGCCGTGACAGTGGCCTGGAAGGCA
GATAGCAGCCCCGTCAAGGCGGGAGTGGAGACCACCACACCCTCCAAACAAAGCAACAACAAGTAC
GCGGCCAGCAGCTATCTGAGCCTGACGCCTGAGCAGTGGAAGTCCCACAGAAGCTACAGCTGCCAG
GTCACGCATGAAGGGAGCACCGTGGAGAAGACAGTGGCCCCTACAGAATGTTCATGA SEQ ID
NO: 698
QSALTQPPSATGTPGQRVTISCSGSSSNIGSNFVNWYKQLPGTAPKVLIYTNNQRPSGVPDRFSGS
KSGTSASLAISGLQSEDESDYYCATWDDSMNGWVFGGGTKLTVLGQPKAAPSVTLFPPSSEELQAN
KATLVCLISDFYPGAVTVAWKADSSPVKAGVETTTPSKQSNNKYAASSYLSLTPEQWKSHRSYSCQ
VTHEGSTVEKTVAPTECS 22G10 SEQ ID NO: 699
GAAATAGTGATGACGCAGTCTCCAGTCACCCTGTCTCTGTCTCTAGGGGAAAGAGCCACCCTCTCC
TGCAGGGCCAGTCAGAGTATTAGCAGCAACTTAGCCTGGTTCCAGCAGAAACCTGGCCAGGCTCCC
AGACTCCTCATCTATGGTGCATTTACCAGGGCCACTGGTATCCCAGCCAGGGTCAGTGGCAGTGGG
TCTGGGACAGAGTTCACTCTCACCATCAGCAGCCTGCAGTCTGAAGATTTTGCAGTTTATTACTGT
CAGCAGTATAATTACTGGCCGCTCACTTTCGGCGGAGGGACCAAGGTGGAGATCAAGCGAACTGTG
GCTGCACCATCTGTCTTCATCTTCCCGCCATCTGATGAGCAGTTGAAATCTGGTACCGCCTCTGTT
GTGTGCCTGCTGAATAACTTCTATCCCAGAGAGGCCAAAGTACAGTGGAAGGTGGATAACGCCCTC
CAATCGGGTAACTCCCAGGAGAGTGTCACAGAGCAGGACAGCAAGGACAGCACCTACAGCCTCAGC
AGCACCCTGACGCTGAGCAAAGCAGACTACGAGAAACACAAAGTCTACGCCTGCGAAGTCACCCAT
CAGGGCCTGAGCTCGCCCGTCACAAAGAGCTTCAACAGGGGAGAGTGTTGA SEQ ID NO: 700
EIVMTQSPVTLSLSLGERATLSCRASQSISSNLAWFQQKPGQAPRLLIYGAFTRATGIPARVSGSG
SGTEFTLTISSLQSEDFAVYYCQQYNYWPLTFGGGTKVEIKRTVAAPSVFIFPPSDEQLKSGTASV
VCLLNNFYPREAKVQWKVDNALQSGNSQESVTEQDSKDSTYSLSSTLTLSKADYEKHKVYACEVTH
QGLSSPVTKSFNRGEC 23A10 SEQ ID NO: 701
TCCTATGAGCTGACTCAGCCACCCTCAGTGTCCGTGTCCCCAGGACAGACAGCCAGCATCACCTGC
TCTGGAGATAGATTGGGGGAGAAATATGTTTGCTGGTATCAGCAGAAGCCAGGCCAGTCCCCTATA
CTGGTCATCTATCAAGATAATAAGTGGCCCTCAGGGATCCCTGAGCGATTCTCTGGCTCCAACTCT
GGGAACACAGCCACTCTGACCATCAGCGGGACCCAGGCTATGGATGAGGCTGACTATTACTGTCAG
GCGTGGGACAGCAGCACTGTGGTATTCGGCGGGGGGACCAAGCTGACCGTCCTAGGTCAGCCCAAG
GCTGCCCCCTCGGTCACTCTGTTCCCACCCTCCTCTGAGGAGCTTCAAGCCAACAAGGCCACACTG
GTGTGTCTCATAAGTGACTTCTACCCGGGAGCCGTGACAGTGGCCTGGAAGGCAGATAGCAGCCCC
GTCAAGGCGGGAGTGGAGACCACCACACCCTCCAAACAAAGCAACAACAAGTACGCGGCCAGCAGC
TATCTGAGCCTGACGCCTGAGCAGTGGAAGTCCCACAGAAGCTACAGCTGCCAGGTCACGCATGAA
GGGAGCACCGTGGAGAAGACAGTGGCCCCTACAGAATGTTCATGA SEQ ID NO: 702
SYELTQPPSVSVSPGQTASITCSGDRLGEKYVCWYQQKPGQSPILVIYQDNKWPSGIPERFSGSNS
GNTATLTISGTQAMDEADYYCQAWDSSTVVFGGGTKLTVLGQPKAAPSVTLFPPSSEELQANKATL
VCLISDFYPGAVTVAWKADSSPVKAGVETTTPSKQSNNKYAASSYLSLTPEQWKSHRSYSCQVTHE
GSTVEKTVAPTECS 25F8 SEQ ID NO: 703
CAGTCTGCGCTGACTCAGCCACCCTCAGCGACTGGGACCCCCGGGCAGAGGGTCACCATCTCTTGT
TCTGGAAGCAGCTCCAACATCGGAAGGAATTTTGTAAACTGGTATAAGCAGCTCCCAGGAACGGCC
CCCAAAGTCCTCATTTATACTAATAATCAGCGGCCCTCAGGGGTCCCTGACCGATTCTCTGGCTCC
AAGTCTGGCACCTCAGCCTCCCTGGCCATCAGTGGGCTCCAGTCTGAGGATGAGTCTGATTATTAC
TGTGCAGCATGGGATGACAGCCTGAATGGTTGGGTGTTCGGCGGAGGGACCAAGCTGACCGTCCTA
GGTCAGCCCAAGGCTGCCCCCTCGGTCACTCTGTTCCCACCCTCCTCTGAGGAGCTTCAAGCCAAC
AAGGCCACACTGGTGTGTCTCATAAGTGACTTCTACCCGGGAGCCGTGACAGTGGCCTGGAAGGCA
GATAGCAGCCCCGTCAAGGCGGGAGTGGAGACCACCACACCCTCCAAACAAAGCAACAACAAGTAC
GCGGCCAGCAGCTATCTGAGCCTGACGCCTGAGCAGTGGAAGTCCCACAGAAGCTACAGCTGCCAG
GTCACGCATGAAGGGAGCACCGTGGAGAAGACAGTGGCCCCTACAGAATGTTCATGA SEQ ID
NO: 704
QSALTQPPSATGTPGQRVTISCSGSSSNIGRNFVNWYKQLPGTAPKVLIYTNNQRPSGVPDRFSGS
KSGTSASLAISGLQSEDESDYYCAAWDDSLNGWVFGGGTKLTVLGQPKAAPSVTLFPPSSEELQAN
KATLVCLISDFYPGAVTVAWKADSSPVKAGVETTTPSKQSNNKYAASSYLSLTPEQWKSHRSYSCQ
VTHEGSTVEKTVAPTECS 25G10 SEQ ID NO: 705
GAAATTGTGTTGACGCAGTCTCCAGGCACCCTGTCTTTGTCTCCAGGGGAAAGAGCCACCCTCTCC
TGCAGGGCCAGTCAGAGTGTTAGCAGCAGCTACTTAGCCTGGTACCAGCAGAAACCTGGCCAGGCT
CCCAGGCTCCTCATCTTTGGTGCATCCAGCAGGGCCACTGGCATCCCAGACAGGTTCAGTGGCAGT
GGGTCTGGGACAGACTTCACTCTCACCATCAGCAGACTGGAGCCTGAAGATTTTGCAGTGTATCAC
TGTCAGCAGTATGGTAACTCACCGCTCACTTTCGGCGGAGGGACCAAGGTGGAGATCAAACGAACT
GTGGCTGCACCATCTGTCTTCATCTTCCCGCCATCTGATGAGCAGTTGAAATCTGGTACCGCCTCT
GTTGTGTGCCTGCTGAATAACTTCTATCCCAGAGAGGCCAAAGTACAGTGGAAGGTGGATAACGCC
CTCCAATCGGGTAACTCCCAGGAGAGTGTCACAGAGCAGGACAGCAAGGACAGCACCTACAGCCTC
AGCAGCACCCTGACGCTGAGCAAAGCAGACTACGAGAAACACAAAGTCTACGCCTGCGAAGTCACC
CATCAGGCTCCTGAGCTCGCCCGTCACAAACTAGCTTCAACAGGGCTAGAGTCTTCTA SEQ ID
NO: 706
EIVLTQSPGTLSLSPGERATLSCRASQSVSSSYLAWYQQKPGQAPRLLIFGASSRATGIPDRFSGS
GSGTDFTLTISRLEPEDFAVYHCQQYGNSPLTFGGGTKVEIKRTVAAPSVFIFPPSDEQLKSGTAS
VVCLLNNFYPREAKVQWKVDNALQSGNSQESVTEQDSKDSTYSLSSTLTLSKADYEKHKVYACEVT
HQGLSSPVTKSFNRGEC 26D1 SEQ ID NO: 707
CACTCTGTGCTGACTCAGTCACCCTCAGCGTCTGGGACCCCCGGACAGAGGGTCACCATCTCTTGT
TCTGGAAGCCGCTCCAACATCGGAAGTAATTTTGTAAACTGGTACCAGCAGCTCCCAGGAACGGCC
CCCAAACTCCTCATCTATACTAATAATCAGCGGCCCTCAGGGGTCCCTGACCGATTCTCTGGCTCC
AAGTCTGGCACCTCAGCCTCCCTGGCCATCAGTGGGCTCCAGTCTGAGGATGAGGCTGATTATTAC
TGTGCAGTATGGGATGACAGCCTGAATGGTTGGGTGTTCGGCGGAGGGACCAAGCTGACCGTCCTA
GGTCAGCCCAAGGCTGCCCCCTCGGTCACTCTGTTCCCACCCTCCTCTGAGGAGCTTCAAGCCAAC
AAGGCCACACTGGTGTGTCTCATAAGTGACTTCTACCCGGGAGCCGTGACAGTGGCCTGGAAGGCA
GATAGCAGCCCCGTCAAGGCGGGAGTGGAGACCACCACACCCTCCAAACAAAGCAACAACAAGTAC
GCGCCCAGCAGCTATCTGAGCCTGACGCCTGAGCAGTGGAAGTCCCACAGAAGCTACAGCTGCCAG
GTCACGCATGAAGGGAGCACCGTGGAGAAGACAGTGGCCCCTACAGAATGTTCATGA SEQ ID
NO: 708
HSVLTQSPSASGTPGQRVTISCSGSRSNIGSNFVNWYQQLPGTAPKLLIYTNNQRPSGVPDRFSGS
KSGTSASLAISGLQSEDEADYYCAVWDDSLNGWVFGGGTKLTVLGQPKAAPSVTLFPPSSEELQAN
KATLVCLISDFYPGAVTVAWKADSSPVKAGVETTTPSKQSNNKYAASSYLSLTPEQWKSHRSYSCQ
VTHEGSTVEKTVAPTECS 26F12 SEQ ID NO: 709
CAGTCTGTGCTGACTCAGTCACCCTCAGCGTCTGGGACCCCCGGGCAGAAGGTCACCATCTCTTGT
TCTGGAAGCCGCTCCAACATCGGAAGTAATTTTGTAAACTGGTACCAGCAGCTCCCAGGAACGGCC
CCCAAACTCCTCATCTATACTAATTATCAGCGGCCCTCAGGGGTCCCTGACCGATTCTCTGGCTCC
AAGTCTGGCACCTCAGCCTCCCTGGCCATCAGTGGGCTCCAGTCTGAGGATGAGGCTGATTATTAC
TGTGCAGTATGGGATGACAGCCTGAATGGTTGGGTGTTCGGCGGAGGGACCAAGCTGACCGTCCTA
GGTCAGCCCAAGGCTGCCCCCTCGGTCACTCTGTTCCCACCCTCCTCTGAGGAGCTTCAAGCCAAC
AAGGCCACACTGGTGTGTCTCATAAGTGACTTCTACCCGGGAGCCGTGACAGTGGCCTGGAAGGCA
GATAGCAGCCCCGTCAAGGCGGGAGTGGAGACCACCACACCCTCCAAACAAAGCAACAACAAGTAC
GCGGCCAGCAGCTATCTGAGCCTGACGCCTGAGCAGTGGAAGTCCCACAGAAGCTACAGCTGCCAG
GTCACGCATGAAGGGAGCACCGTGGAGAAGACAGTGGCCCCTACAGAATGTTCATGA SEQ ID
NO: 710
QSVLTQSPSASGTPGQKVTISCSGSRSNIGSNFVNWYQQLPGTAPKLLIYTNYQRPSGVPDRFSGS
KSGTSASLAISGLQSEDEADYYCAVWDDSLNGWVFGGGTKLTVLGQPKAAPSVTLFPPSSEELQAN
KATLVCLISDFYPGAVTVAWKADSSPVKAGVETTTPSKQSNNKYAASSYLSLTPEQWKSHRSYSCQ
VTHEGSTVEKTVAPTECS
TABLE-US-00016 TABLE 111c Heavy Chain Variable and Contant Region
Polynucleotide and Amino acid Sequences 13586_HC [hu
anti-<huCDH19> 4F3 VH]::huIgG1z SEQ ID NO: 711
QVQLVESGGGVVQPGRSLRLSCAASGFSFSSYDMDWVRQTPGKGLEWVAVIWYDGSNKYYADSVRG
RFTISRDNSKNTLFLQMNSLRVEDTAVYYCARETGEGWYFDLWGRGTLVTVSSASTKGPSVFPLAP
SSKSTSGGTAALGCLVKDYFPEPVTVSWNSGALTSGVHTFPAVLQSSGLYSLSSVVTVPSSSLGTQ
TYICNVNHKPSNTKVDKKVEPKSCDKTHTCPPCPAPELLGGPSVFLFPPKPKDTLMISRTPEVTCV
VVDVSHEDPEVKFNWYVDGVEVHNAKTKPREEQYNSTYRVVSVLTVLHQDWLNGKEYKCKVSNKAL
PAPIEKTISKAKGQPREPQVYTLPPSREEMTKNQVSLTCLVKGFYPSDIAVEWESNGQPENNYKTT
PPVLDSDGSFFLYSKLTVDKSRWQQGNVFSCSVMHEALHNHYTQKSLSLSPGK 13589_HC [hu
anti-<huCDH19> 4A9 VH]::huIgG1z SEQ ID NO: 712
QVQLQESGPGLVKPSETLSLTCTVSGGSISGYYWSWIRQPPGKGLEWFAYFSYSGSTNYNPSLKSR
VTLSVDTSKNQFSLKLSSVTAADTAVYYCARNWAFHFDFWGQGTLVTVSSASTKGPSVFPLAPSSK
STSGGTAALGCLVKDYFPEPVTVSWNSGALTSGVHTFPAVLQSSGLYSLSSVVTVPSSSLGTQTYI
CNVNHKPSNTKVDKKVEPKSCDKTHTCPPCPAPELLGGPSVFLFPPKPKDTLMISRTPEVTCVVVD
VSHEDPEVKFNWYVDGVEVHNAKTKPREEQYNSTYRVVSVLTVLHQDWLNGKEYKCKVSNKALPAP
IEKTISKAKGQPREPQVYTLPPSREEMTKNQVSLTCLVKGFYPSDIAVEWESNGQPENNYKTTPPV
LDSDGSFFLYSKLTVDKSRWQQGNVFSCSVMHEALHNHYTQKSLSLSPGK 13590_HC [hu
anti-<huCDH19> 4B10 VH]::huIgG1z SEQ ID NO: 713
QVQLVESGGGVVQPGRSLRLSCAASGFTFSSYDMHWVRQAPGKGLEWVAVISYDGTNEYYADSVKG
RFTISRDTSKNTLYLQMNSLRAEDTAVYYCARERYFDWSFDYWGQGTLVSVSSASTKGPSVFPLAP
SSKSTSGGTAALGCLVKDYFPEPVTVSWNSGALTSGVHTFPAVLQSSGLYSLSSVVTVPSSSLGTQ
TYICNVNHKPSNTKVDKKVEPKSCDKTHTCPPCPAPELLGGPSVFLFPPKPKDTLMISRTPEVTCV
VVDVSHEDPEVKFNWYVDGVEVHNAKTKPREEQYNSTYRVVSVLTVLHQDWLNGKEYKCKVSNKAL
PAPIEKTISKAKGQPREPQVYTLPPSREEMTKNQVSLTCLVKGFYPSDIAVEWESNGQPENNYKTT
PPVLDSDGSFFLYSKLTVDKSRWQQGNVFSCSVMHEALHNHYTQKSLSLSPGK 13874_HC [hu
anti-<huCDH19> 17H8.2 VH]::huIgG1z SEQ ID NO: 714
QVQLQESGPGLVKPSETLSLTCTVSGGSINSYYWSWIRQPPGKGLEWIGYIYYIGSTNYNPSLKSR
VTISVDTSKNQFSLKLSSVTAADTALYYCARDSRYRSGWYDAFDIWGQGTMVTVSSASTKGPSVFP
LAPSSKSTSGGTAALGCLVKDYFPEPVTVSWNSGALTSGVHTFPAVLQSSGLYSLSSVVTVPSSSL
GTQTYICNVNHKPSNTKVDKKVEPKSCDKTHTCPPCPAPELLGGPSVFLFPPKPKDTLMISRTPEV
TCVVVDVSHEDPEVKFNWYVDGVEVHNAKTKPREEQYNSTYRVVSVLTVLHQDWLNGKEYKCKVSN
KALPAPIEKTISKAKGQPREPQVYTLPPSREEMTKNQVSLTCLVKGFYPSDIAVEWESNGQPENNY
KTTPPVLDSDGSFFLYSKLTVDKSRWQQGNVFSCSVMHEALHNHYTQKSLSLSPGK 13875_HC
[hu anti-<huCDH19> 16C1.1 VH]::huIgG1z SEQ ID NO: 715
QVQLQESGPGLVKPSETLSLTCTVSGGSISGYYWSWIRQPPGKGLEWIGYIYYIGSTNYNPSLKSR
VTMSIDTSKNQFSLTLSSLTAADTAVYFCARDGSSGWYRWFDPWGQGTLVTVSSASTKGPSVFPLA
PSSKSTSGGTAALGCLVKDYFPEPVTVSWNSGALTSGVHTFPAVLQSSGLYSLSSVVTVPSSSLGT
QTYICNVNHKPSNTKVDKKVEPKSCDKTHTCPPCPAPELLGGPSVFLFPPKPKDTLMISRTPEVTC
VVVDVSHEDPEVKFNWYVDGVEVHNAKTKPREEQYNSTYRVVSVLTVLHQDWLNGKEYKCKVSNKA
LPAPIEKTISKAKGQPREPQVYTLPPSREEMTKNQVSLTCLVKGFYPSDIAVEWESNGQPENNYKT
TPPVLDSDGSFFLYSKLTVDKSRWQQGNVFSCSVMHEALHNHYTQKSLSLSPGK 13876_HC [hu
anti-<huCDH19> 16A4.1 VH]::huIgG1z SEQ ID NO: 716
QVQLQESGPGLAKPSETLSLTCTVSGDSITSYYWSWIRQPPGKGLEWIGYIYYSGSTNYNPSLKSR
VTISVDTSKNQFSLKLSSVTAADTAVYYCARDQRRIAAAGTHFYGMDVWGQGTTVTVSSASTKGPS
VFPLAPSSKSTSGGTAALGCLVKDYFPEPVTVSWNSGALTSGVHTFPAVLQSSGLYSLSSVVTVPS
SSLGTQTYICNVNHKPSNTKVDKKVEPKSCDKTHTCPPCPAPELLGGPSVFLFPPKPKDTLMISRT
PEVTCVVVDVSHEDPEVKFNWYVDGVEVHNAKTKPREEQYNSTYRVVSVLTVLHQDWLNGKEYKCK
VSNKALPAPIEKTISKAKGQPREPQVYTLPPSREEMTKNQVSLTCLVKGFYPSDIAVEWESNGQPE
NNYKTTPPVLDSDGSFFLYSKLTVDKSRWQQCINVFSCSVMHEALHNHYTQKSLSLSPGK
13877_HC [hu anti-<huCDH19> 22G10.1 VH]::huIgG1z SEQ ID NO:
717
EVQLLESGGGLVQPGGSLRLSCAASGFTFSSYAMNWVRQAPGKGLEWVSTISGGGANTYYADSVKG
RFTISSDNSKSTLYLQMNSLRAADTAVYHCAKGGMGGYYYGMDVWGQGTTVTVSSASTKGPSVFPL
APSSKSTSGGTAALGCLVKDYFPEPVTVSWNSGALTSGVHTFPAVLQSSGLYSLSSVVTVPSSSLG
TQTYICNVNHKPSNTKVDKKVEPKSCDKTHTCPPCPAPELLGGPSVFLFPPKPKDTLMISRTPEVT
CVVVDVSHEDPEVKFNWYVDGVEVHNAKTKPREEQYNSTYRVVSVLTVLHQDWLNGKEYKCKVSNK
ALPAPIEKTISKAKGQPREPQVYTLPPSREEMTKNQVSLTCLVKGFYPSDIAVEWESNGQPENNYK
TTPPVLDSDGSFFLYSKLTVDKSRWQQGNVFSCSVMHEALHNHYTQKSLSLSPGK 13878_HC
[hu anti-<huCDH19> 20D3.1 VH]::huIgG1z SEQ ID NO: 718
QVQLVQSGAEVKKPGASVKVSCKVSGYTFTSYFIHWVRQAPGQGLEWMGIINPISVSTSYAQKFQG
RVTMTRDTSTSTVFMELSSLRSEDTAVYYCARGGIQLWLHFDYWGQGTLVTVSSASTKGPSVFPLA
PSSKSTSGGTAALGCLVKDYFPEPVTVSWNSGALTSGVHTFPAVLQSSGLYSLSSVVTVPSSSLGT
QTYICNVNHKPSNTKVDKKVEPKSCDKTHTCPPCPAPELLGGPSVFLFPPKPKDTLMISRTPEVTC
VVVDVSHEDPEVKFNWYVDGVEVHNAKTKPREEQYNSTYRVVSVLTVLHQDWLNGKEYKCKVSNKA
LPAPIEKTISKAKGQPREPQVYTLPPSREEMTKNQVSLTCLVKGFYPSDIAVEWESNGQPENNYKT
TPPVLDSDGSFFLYSKLTVDKSRWQQGNVFSCSVMHEALHNHYTQKSLSLSPGK 13879_HC [hu
anti-<huCDH19> 22D1.1 VH]::huIgG1z SEQ ID NO: 719
QVQLVQSGAEVKKPGASVRVSCKVSGYTFTSYFIHWVRQAPGQGLEWMGIINPISVSTSYAQKFQG
RVTMTRDTSTSTVFMELSSLRSEDTAVYYCARGGIQLWLHLDYWGQGTLVTVSSASTKGPSVFPLA
PSSKSTSGGTAALGCLVKDYFPEPVTVSWNSGALTSGVHTFPAVLQSSGLYSLSSVVTVPSSSLGT
QTYICNVNHKPSNTKVDKKVEPKSCDKTHTCPPCPAPELLGGPSVFLFPPKPKDTLMISRTPEVTC
VVVDVSHEDPEVKFNWYVDGVEVHNAKTKPREEQYNSTYRVVSVLTVLHQDWLNGKEYKCKVSNKA
LPAPIEKTISKAKGQPREPQVYTLPPSREEMTKNQVSLTCLVKGFYPSDIAVEWESNGQPENNYKT
TPPVLDSDGSFFLYSKLTVDKSRWQQGNVFSCSVMHEALHNHYTQKSLSLSPGK 13880_HC [hu
anti-huCDH19> 25F8.1 VH]::huIgG1z SEQ ID NO: 720
QVQLVQSGAEVKKPGASVKVSCKASGYTFTSYYIHWVRQAPGQGLEWMGIINPSGGSTRYAQKFQG
RVTMTRDTSTSTVFMELSSLRSEDTAVYYCARGGIQLWLHFDYWGQGTLVTVSSASTKGPSVFPLA
PSSKSTSGGTAALGCLVKDYFPEPVTVSWNSGALTSGVHTFPAVLQSSGLYSLSSVVTVPSSSLGT
QTYICNVNHKPSNTKVDKKVEPKSCDKTHTCPPCPAPELLGGPSVFLFPPKPKDTLMISRTPEVTC
VVVDVSHEDPEVKFNWYVDGVEVHNAKTKPREEQYNSTYRVVSVLTVLHQDWLNGKEYKCKVSNKA
LPAPIEKTISKAKGQPREPQVYTLPPSREEMTKNQVSLTCLVKGFYPSDIAVEWESNGQPENNYKT
TPPVLDSDGSFFLYSKLTVDKSRWQQGNVFSCSVMHEALHNHYTQKSLSLSPGK 13881_HC [hu
anti-<huCDH19> 26F12.1 VH]::huIgG1z SEQ ID NO: 721
QVQLVQSGAEVKKPGASVKVSCKASRYTFTNYYMSWVRQAPGQGLEWMGIINPSGGDSTYAQKFQG
RLTMTGDTSTSTVYMELSSLRSEDTAVYYCARGGIQLWLHFDYWGQGTLVTVSSASTKGPSVFPLA
PSSKSTSGGTAALGCLVKDYFPEPVTVSWNSGALTSGVHTFPAVLQSSGLYSLSSVVTVPSSSLGT
QTYICNVNHKPSNTKVDKKVEPKSCDKTHTCPPCPAPELLGGPSVFLFPPKPKDTLMISRTPEVTC
VVVDVSHEDPEVKFNWYVDGVEVHNAKTKPREEQYNSTYRVVSVLTVLHQDWLNGKEYKCKVSNKA
LPAPIEKTISKAKGQPREPQVYTLPPSREEMTKNQVSLTCLVKGFYPSDIAVEWESNGQPENNYKT
TPPVLDSDGSFFLYSKLTVDKSRWQQGNVFSCSVMHEALHNHYTQKSLSLSPGK 13882_HC [hu
anti-<huCDH19> 26D1.1 VH]::huIgG1z SEQ ID NO: 722
QVQLVQSGAEVKKPGASVKVSCKASRYTFTSYYMSWVRQAPGQGLEWMGIIHPSGGDTTYAQKFQG
RVTMTGDTSTSTVYMELSSLRSEDTAVYYCARGGIKLWLHFDYWGQGTLVTVSSASTKGPSVFPLA
PSSKSTSGGTAALGCLVKDYFPEPVTVSWNSGALTSGVHTFPAVLQSSGLYSLSSVVTVPSSSLGT
QTYICNVNHKPSNTKVDKKVEPKSCDKTHTCPPCPAPELLGGPSVFLFPPKPKDTLMISRTPEVTC
VVVDVSHEDPEVKFNWYVDGVEVHNAKTKPREEQYNSTYRVVSVLTVLHQDWLNGKEYKCKVSNKA
LPAPIEKTISKAKGQPREPQVYTLPPSREEMTKNQVSLTCLVKGFYPSDIAVEWESNGQPENNYKT
TPPVLDSDGSFFLYSKLTVDKSRWQQGNVFSCSVMHEALHNHYTQKSLSLSPGK 13883_HC [hu
anti-<huCDH19> 25G10.1 VH]::huIgG1z SEQ ID NO: 723
QVQLQESGPGLVKPSETLSLTCTVSGGSISGYYWSWIRQPPGKGLEWIGYIYYIGSTNYNPSLKSR
VTMSVDTSKNQFSLKLSSVTAADTAVYYCARDGSSGWYRWFDPWGQGTLVTVSSASTKGPSVFPLA
PSSKSTSGGTAALGCLVKDYFPEPVTVSWNSGALTSGVHTFPAVLQSSGLYSLSSVVTVPSSSLGT
QTYICNVNHKPSNTKVDKKVEPKSCDKTHTCPPCPAPELLGGPSVFLFPPKPKDTLMISRTPEVTC
VVVDVSHEDPEVKFNWYVDGVEVHNAKTKPREEQYNSTYRVVSVLTVLHQDWLNGKEYKCKVSNKA
LPAPIEKTISKAKGQPREPQVYTLPPSREEMTKNQVSLTCLVKGFYPSDIAVEWESNGQPENNYKT
TPPVLDSDGSFFLYSKLTVDKSRWQQGNVFSCSVMHEALHNHYTQKSLSLSPGK 13885_HC [hu
anti-<huCDH19> 19B5.1 VH]::huIgG1z SEQ ID NO: 724
QVQLVQSGAEVKKPGASVKVSCKVSGYTFTSYFIHWVRQAPGQGLEWMGIINPISVSTSYAQKFQG
RVTMTRDTSTSTVFMELSSLRSEDTAVYYCARCiGIQLWLHLDYWGQGTLVTVSSASTKGPSVFPL
APSSKSTSGGTAALGCLVKDYFPEPVTVSWNSGALTSGVHTFPAVLQSSGLYSLSSVVTVPSSSLG
TQTYICNVNHKPSNTKVDKKVEPKSCDKTHTCPPCPAPELLGGPSVFLFPPKPKDTLMISRTPEVT
CVVVDVSHEDPEVKENWYVDGVEVHNAKTKPREEQYNSTYRVVSVLTVLHQDWLNGKEYKCKVSNK
ALPAPIEKTISKAKGQPREPQVYTLPPSREEMTKNQVSLTCLVKGFYPSDIAVEWESNGQPENNYK
TTPPVLDSDGSFFLYSKLTVDKSRWQQGNVFSCSVMHEALHNHYTQKSLSLSPGK 14022_HC
[hu anti-<huCDH19> 4A2 VH]::huIgG1z SEQ ID NO: 725
QVQLQESGPGLVKPSQTLSLTCTVSGGSISSSGYYWSWIRQHPGKGLEWIGYIYYTGSAYYNPSLK
SRVTISVDTSKNQFSLKLSSVTAADTAVYYCARDGSSGWYFQYWGQGTLVTVSSASTKGPSVFPLA
PSSKSTSGGTAALGCLVKDYFPEPVTVSWNSGALTSGVHTFPAVLQSSGLYSLSSVVTVPSSSLGT
QTYICNVNHKPSNTKVDKKVEPKSCDKTHTCPPCPAPELLGGPSVFLFPPKPKDTLMISRTPEVTC
VVVDVSHEDPEVKFNWYVDGVEVHNAKTKPREEQYNSTYRVVSVLTVLHQDWLNGKEYKCKVSNKA
LPAPIEKTISKAKGQPREPQVYTLPPSREEMTKNQVSLTCLVKGFYPSDIAVEWESNGQPENNYKT
TPPVLDSDGSFFLYSKLTVDKSRWQQGNVFSCSVMHEALHNHYTQKSLSLSPGK 14024_HC [hu
anti-<huCDH19> 4A2 (1-472)(Q17E,H47P) VH]::huIgG1z SEQ ID NO:
726
QVQLQESGPGLVKPSETLSLTCTVSGGSISSSGYYWSWIRQPPGKGLEWIGYIYYTGSAYYNPSLK
SRVTISVDTSKNQFSLKLSSVTAADTAVYYCARDGSSGWYFQYWGQGTLVTVSSASTKGPSVFPLA
PSSKSTSGGTAALGCLVKDYFPEPVTVSWNSGALTSGVHTFPAVLQSSGLYSLSSVVTVPSSSLGT
QTYICNVNHKPSNTKVDKKVEPKSCDKTHTCPPCPAPELLGGPSVFLFPPKPKDTLMISRTPEVTC
VVVDVSHEDPEVKFNWYVDGVEVHNAKTKPREEQYNSTYRVVSVLTVLHQDWLNGKEYKCKVSNKA
LPAPIEKTISKAKGQPREPQVYTLPPSREEMTKNQVSLTCLVKGFYPSDIAVEWESNGQPENNYKT
TPPVLDSDGSFFLYSKLTVDKSRWQQGNVFSCSVMHEALHNHYTQKSLSLSPGK 14025_HC [hu
anti-<huCDH19> 4A2 VH]::huIgG1z SEQ ID NO: 727
QVQLQESGPGLVKPSQTLSLTCTVSGGSISSSGYYWSWIRQHPGKGLEWIGYIYYTGSAYYNPSLK
SRVTISVDTSKNQFSLKLSSVTAADTAVYYCARDGSSGWYFQYWGQGTLVTVSSASTKGPSVFPLA
PSSKSTSGGTAALGCLVKDYFPEPVTVSWNSGALTSGVHTFPAVLQSSGLYSLSSVVTVPSSSLGT
QTYICNVNHKPSNTKVDKKVEPKSCDKTHTCPPCPAPELLGGPSVFLFPPKPKDTLMISRTPEVTC
VVVDVSHEDPEVKFNWYVDGVEVHNAKTKPREEQYNSTYRVVSVLTVLHQDWLNGKEYKCKVSNKA
LPAPIEKTISKAKGQPREPQVYTLPPSREEMTKNQVSLTCLVKGFYPSDIAVEWESNGQPENNYKT
TPPVLDSDGSFFLYSKLTVDKSRWQQGNVFSCSVMHEALHNHYTQKSLSLSPGK 14026_HC [hu
anti-<huCDH19> 4A2 (1-472)(Q17E,H47P) VH]::huIgG1z SEQ ID NO:
728
QVQLQESGPGLVKPSETLSLTCTVSGGSISSSGYYWSWIRQPPGKGLEWIGYIYYTGSAYYNPSLK
SRVTISVDTSKNQFSLKLSSVTAADTAVYYCARDGSSGWYFQYWGQGTLVTVSSASTKGPSVFPLA
PSSKSTSGGTAALGCLVKDYFPEPVTVSWNSGALTSGVHTFPAVLQSSGLYSLSSVVTVPSSSLGT
QTYICNVNHKPSNTKVDKKVEPKSCDKTHTCPPCPAPELLGGPSVFLFPPKPKDTLMISRTPEVTC
VVVDVSHEDPEVKFNWYVDGVEVHNAKTKPREEQYNSTYRVVSVLTVLHQDWLNGKEYKCKVSNKA
LPAPIEKTISKAKGQPREPQVYTLPPSREEMTKNQVSLTCLVKGFYPSDIAVEWESNGQPENNYKT
TPPVLDSDGSFFLYSKLTVDKSRWQQGNVFSCSVMHEALHNHYTQKSLSLSPGK 14027_HC [hu
anti-<huCDH19> 4A2 (1-472) (Q17E,H47P,D111E) VH]::huIgG1z SEQ
ID NO: 729
QVQLQESGPGLVKPSETLSLTCTVSGGSISSSGYYWSWIRQPPGKGLEWIGYIYYTGSAYYNPSLK
SRVTISVDTSKNQFSLKLSSVTAADTAVYYCAREGSSGWYFQYWGQGTLVTVSSASTKGPSVFPLA
PSSKSTSGGTAALGCLVKDYFPEPVTVSWNSGALTSGVHTFPAVLQSSGLYSLSSVVTVPSSSLGT
QTYICNVNHKPSNTKVDKKVEPKSCDKTHTCPPCPAPELLGGPSVFLFPPKPKDTLMISRTPEVTC
VVVDVSHEDPEVKFNWYVDGVEVHNAKTKPREEQYNSTYRVVSVLTVLHQDWLNGKEYKCKVSNKA
LPAPIEKTISKAKGQPREPQVYTLPPSREEMTKNQVSLTCLVKGFYPSDIAVEWESNGQPENNYKT
TPPVLDSDGSFFLYSKLTVDKSRWQQGNVFSCSVMHEALHNHYTQKSLSLSPGK 14028_HC [hu
anti-<huCDH19> 4A2 (1-472) (Q17E,H47P,D111E,W134Y)
VH]::huIgG1z SEQ ID NO: 730
QVQLQESGPGLVKPSETLSLTCTVSGGSISSSGYYWSWIRQPPGKGLEWIGYIYYTGSAYYNPSLK
SRVTISVDTSKNQFSLKLSSVTAADTAVYYCAREGSSGYYFQYWGQGTLVTVSSASTKGPSVFPLA
PSSKSTSGGTAALGCLVKDYFPEPVTVSWNSGALTSGVHTFPAVLQSSGLYSLSSVVTVPSSSLGT
QTYICNVNHKPSNTKVDKKVEPKSCDKTHTCPPCPAPELLGGPSVFLFPPKPKDTLMISRTPEVTC
VVVDVSHEDPEVKFNWYVDGVEVHNAKTKPREEQYNSTYRVVSVLTVLHQDWLNGKEYKCKVSNKA
LPAPIEKTISKAKGQPREPQVYTLPPSREEMTKNQVSLTCLVKGFYPSDIAVEWESNGQPENNYKT
TPPVLDSDGSFFLYSKLTVDKSRWQQGNVFSCSVMHEALHNHYTQKSLSLSPGK 14029_HC [hu
anti-<huCDH19> 4A2 VH]::huIgG1z SEQ ID NO: 731
QVQLQESGPGLVKPSQTLSLTCTVSGGSISSSGYYWSWIRQHPGKGLEWIGYIYYTGSAYYNPSLK
SRVTISVDTSKNQFSLKLSSVTAADTAVYYCARDGSSGWYFQYWGQGTLVTVSSASTKGPSVFPLA
PSSKSTSGGTAALGCLVKDYFPEPVTVSWNSGALTSGVHTFPAVLQSSGLYSLSSVVTVPSSSLGT
QTYICNVNHKPSNTKVDKKVEPKSCDKTHTCPPCPAPELLGGPSVFLFPPKPKDTLMISRTPEVTC
VVVDVSHEDPEVKFNWYVDGVEVHNAKTKPREEQYNSTYRVVSVLTVLHQDWLNGKEYKCKVSNKA
LPAPIEKTISKAKGQPREPQVYTLPPSREEMTKNQVSLTCLVKGFYPSDIAVEWESNGQPENNYKT
TPPVLDSDGSFFLYSKLTVDKSRWQQGNVFSCSVMHEALHNHYTQKSLSLSPGK 14030_HC [hu
anti-<huCDH19> 4F3 (1-471)(R17G) VH]::huIgG1z SEQ ID NO: 732
QVQLVESGGGVVQPGGSLRLSCAASGFSFSSYDMDWVRQTPGKGLEWVAVIWYDGSNKYYADSVRG
RFTISRDNSKNTLFLQMNSLRVEDTAVYYCARETGEGWYFDLWGRGTLVTVSSASTKGPSVFPLAP
SSKSTSGGTAALGCLVKDYFPEPVTVSWNSGALTSGVHTFPAVLQSSGLYSLSSVVTVPSSSLGTQ
TYICNVNHKPSNTKVDKKVEPKSCDKTHTCPPCPAPELLGGPSVFLFPPKPKDTLMISRTPEVTCV
VVDVSHEDPEVKFNWYVDGVEVHNAKTKPREEQYNSTYRVVSVLTVLHQDWLNGKEYKCKVSNKAL
PAPIEKTISKAKGQPREPQVYTLPPSREEMTKNQVSLTCLVKGFYPSDIAVEWESNGQPENNYKTT
PPVLDSDGSFFLYSKLTVDKSRWQQGNVFSCSVMHEALHNHYTQKSLSLSPGK 14031_HC [hu
anti-<huCDH19> 4F3 (1-471)(R17G,T47A) VH]::huIgG1z SEQ ID NO:
733
QVQLVESGGGVVQPGGSLRLSCAASGFSFSSYDMDWVRQAPGKGLEWVAVIWYDGSNKYYADSVRG
RFTISRDNSKNTLFLQMNSLRVEDTAVYYCARETGEGWYFDLWGRGTLVTVSSASTKGPSVFPLAP
SSKSTSGGTAALGCLVKDYFPEPVTVSWNSGALTSGVHTFPAVLQSSGLYSLSSVVTVPSSSLGTQ
TYICNVNHKPSNTKVDKKVEPKSCDKTHTCPPCPAPELLGGPSVFLFPPKPKDTLMISRTPEVTCV
VVDVSHEDPEVKFNWYVDGVEVHNAKTKPREEQYNSTYRVVSVLTVLHQDWLNGKEYKCKVSNKAL
PAPIEKTISKAKGQPREPQVYTLPPSREEMTKNQVSLTCLVKGFYPSDIAVEWESNGQPENNYKTT
PPVLDSDGSFFLYSKLTVDKSRWQQGNVFSCSVMHEALHNHYTQKSLSLSPGK 14032_HC [hu
anti-<huCDH19> 4F3 (1-471) (R17G,T47A,R141Q) VH]::huIgG1z SEQ
ID NO: 734
QVQLVESGGGVVQPGGSLRLSCAASGFSFSSYDMDWVRQAPGKGLEWVAVIWYDGSNKYYADSVRG
RFTISRDNSKNTLFLQMNSLRVEDTAVYYCARETGEGWYFDLWGQGTLVTVSSASTKGPSVFPLAP
SSKSTSGGTAALGCLVKDYFPEPVTVSWNSGALTSGVHTFPAVLQSSGLYSLSSVVTVPSSSLGTQ
TYICNVNHKPSNTKVDKKVEPKSCDKTHTCPPCPAPELLGGPSVFLFPPKPKDTLMISRTPEVTCV
VVDVSHEDPEVKFNWYVDGVEVHNAKTKPREEQYNSTYRVVSVLTVLHQDWLNGKEYKCKVSNKAL
PAPIEKTISKAKGQPREPQVYTLPPSREEMTKNQVSLTCLVKGFYPSDIAVEWESNGQPENNYKTT
PPVLDSDGSFFLYSKLTVDKSRWQQGNVFSCSVMHEALHNHYTQKSLSLSPGK 14033_HC [hu
anti-<huCDH19> 4F3 (1-471)
(R17G,T47A,D61E,D72E,R141Q) VH]::huIgG1z SEQ ID NO: 735
QVQLVESGGGVVQPGGSLRLSCAASGFSFSSYDMDWVRQAPGKGLEWVAVIWYEGSNKYYAESVRG
RFTISRDNSKNTLFLQMNSLRVEDTAVYYCARETGEGWYFDLWGQGTLVTVSSASTKGPSVFPLAP
SSKSTSGGTAALGCLVKDYFPEPVTVSWNSGALTSGVHTFPAVLQSSGLYSLSSVVTVPSSSLGTQ
TYICNVNHKPSNTKVDKKVEPKSCDKTHTCPPCPAPELLGGPSVFLFPPKPKDTLMISRTPEVTCV
VVDVSHEDPEVKFNWYVDGVEVHNAKTKPREEQYNSTYRVVSVLTVLHQDWLNGKEYKCKVSNKAL
PAPIEKTISKAKGQPREPQVYTLPPSREEMTKNQVSLTCLVKGFYPSDIAVEWESNGQPENNYKTT
PPVLDSDGSFFLYSKLTVDKSRWQQGNVFSCSVMHEALHNHYTQKSLSLSPGK 14034_HC [hu
anti-<huCDH19> 4F3 (1-471) (R17G,T47A,D61E,D72E,W134Y,R141Q)
VH]::huIgG1z SEQ ID NO: 736
QVQLVESGGGVVQPGGSLRLSCAASGFSFSSYDMDWVRQAPGKGLEWVAVIWYEGSNKYYAESVRG
RFTISRDNSKNTLFLQMNSLRVEDTAVYYCARETGEGYYFDLWGQGTLVTVSSASTKGPSVFPLAP
SSKSTSGGTAALGCLVKDYFPEPVTVSWNSGALTSGVHTFPAVLQSSGLYSLSSVVTVPSSSLGTQ
TYICNVNHKPSNTKVDKKVEPKSCDKTHTCPPCPAPELLGGPSVFLFPPKPKDTLMISRTPEVTCV
VVDVSHEDPEVKFNWYVDGVEVHNAKTKPREEQYNSTYRVVSVLTVLHQDWLNGKEYKCKVSNKAL
PAPIEKTISKAKGQPREPQVYTLPPSREEMTKNQVSLTCLVKGFYPSDIAVEWESNGQPENNYKTT
PPVLDSDGSFFLYSKLTVDKSRWQQGNVFSCSVMHEALHNHYTQKSLSLSPGK 14039_HC [hu
anti-<huCDH19> 2G6 (1-477) (R17G,D61E,D72E,K94N) VH]::huIgG1z
SEQ ID NO: 737
QVQLVESGGGVVQPGGSLRLSCAASGFTFSSYGMHWVRQAPGKGLEWVAFIWYEGSNKYYAESVKD
RFTISRDNSKNTLYLQMNSLRAEDTAVYYCARRAGIIGTIGYYYGMDVWGQGTTVTVSSASTKGPS
VFPLAPSSKSTSGGTAALGCLVKDYFPEPVTVSWNSGALTSGVHTFPAVLQSSGLYSLSSVVTVPS
SSLGTQTYICNVNHKPSNTKVDKKVEPKSCDKTHTCPPCPAPELLGGPSVFLFPPKPKDTLMISRT
PEVTCVVVDVSHEDPEVKFNWYVDGVEVHNAKTKPREEQYNSTYRVVSVLTVLHQDWLNGKEYKCK
VSNKALPAPIEKTISKAKGQPREPQVYTLPPSREEMTKNQVSLTCLVKGFYPSDIAVEWESNGQPE
NNYKTTPPVLDSDGSFFLYSKLTVDKSRWQQGNVFSCSVMHEALHNHYTQKSLSLSPGK
14040_HC [hu anti-<huCDH19> 16C1.1 VH]::huIgG1z SEQ ID NO:
738
QVQLQESGPGLVKPSETLSLTCTVSGGSISGYYWSWIRQPPGKGLEWIGYIYYIGSTNYNPSLKSR
VTMSIDTSKNQFSLTLSSLTAADTAVYFCARDGSSGWYRWFDPWGQGTLVTVSSASTKGPSVFPLA
PSSKSTSGGTAALGCLVKDYFPEPVTVSWNSGALTSGVHTFPAVLQSSGLYSLSSVVTVPSSSLGT
QTYICNVNHKPSNTKVDKKVEPKSCDKTHTCPPCPAPELLGGPSVFLFPPKPKDTLMISRTPEVTC
VVVDVSHEDPEVKFNWYVDGVEVHNAKTKPREEQYNSTYRVVSVLTVLHQDWLNGKEYKCKVSNKA
LPAPIEKTISKAKGQPREPQVYTLPPSREEMTKNQVSLTCLVKGFYPSDIAVEWESNGQPENNYKT
TPPVLDSDGSFFLYSKLTVDKSRWQQGNVFSCSVMHEALHNHYTQKSLSLSPGK 14041_HC [hu
anti-<huCDH19> 16C1.1 (1-469)(T92K) VH]::huIgG1z SEQ ID NO:
739
QVQLQESGPGLVKPSETLSLTCTVSGGSISGYYWSWIRQPPGKGLEWIGYIYYIGSTNYNPSLKSR
VTMSIDTSKNQFSLKLSSLTAADTAVYFCARDGSSGWYRWFDPWGQGTLVTVSSASTKGPSVFPLA
PSSKSTSGGTAALGCLVKDYFPEPVTVSWNSGALTSGVHTFPAVLQSSGLYSLSSVVTVPSSSLGT
QTYICNVNHKPSNTKVDKKVEPKSCDKTHTCPPCPAPELLGGPSVFLFPPKPKDTLMISRTPEVTC
VVVDVSHEDPEVKFNWYVDGVEVHNAKTKPREEQYNSTYRVVSVLTVLHQDWLNGKEYKCKVSNKA
LPAPIEKTISKAKGQPREPQVYTLPPSREEMTKNQVSLTCLVKGFYPSDIAVEWESNGQPENNYKT
TPPVLDSDGSFFLYSKLTVDKSRWQQGNVFSCSVMHEALHNHYTQKSLSLSPGK 14042_HC [hu
anti-<huCDH19> 16C1.1 (1-469) (T92K,D109E) VH]::huIgG1z SEQ
ID NO: 740
QVQLQESGPGLVKPSETLSLTCTVSGGSISGYYWSWIRQPPGKGLEWIGYIYYIGSTNYNPSLKSR
VTMSIDTSKNQFSLKLSSLTAADTAVYFCAREGSSGWYRWFDPWGQGTLVTVSSASTKGPSVFPLA
PSSKSTSGGTAALGCLVKDYFPEPVTVSWNSGALTSGVHTFPAVLQSSGLYSLSSVVTVPSSSLGT
QTYICNVNHKPSNTKVDKKVEPKSCDKTHTCPPCPAPELLGGPSVFLFPPKPKDTLMISRTPEVTC
VVVDVSHEDPEVKFNWYVDGVEVHNAKTKPREEQYNSTYRVVSVLTVLHQDWLNGKEYKCKVSNKA
LPAPIEKTISKAKGQPREPQVYTLPPSREEMTKNQVSLTCLVKGFYPSDIAVEWESNGQPENNYKT
TPPVLDSDGSFFLYSKLTVDKSRWQQGNVFSCSVMHEALHNHYTQKSLSLSPGK 14043_HC [hu
anti-<huCDH19> 16C1.1 (1-469) (T92K,W132Y,W135Y) VH]::huIgG1z
SEQ ID NO: 741
QVQLQESGPGLVKPSETLSLTCTVSGGSISGYYWSWIRQPPGKGLEWIGYIYYIGSTNYNPSLKSR
VTMSIDTSKNQFSLKLSSLTAADTAVYFCARDGSSGYYRYFDPWGQGTLVTVSSASTKGPSVFPLA
PSSKSTSGGTAALGCLVKDYFPEPVTVSWNSGALTSGVHTFPAVLQSSGLYSLSSVVTVPSSSLGT
QTYICNVNHKPSNTKVDKKVEPKSCDKTHTCPPCPAPELLGGPSVFLFPPKPKDTLMISRTPEVTC
VVVDVSHEDPEVKFNWYVDGVEVHNAKTKPREEQYNSTYRVVSVLTVLHQDWLNGKEYKCKVSNKA
LPAPIEKTISKAKGQPREPQVYTLPPSREEMTKNQVSLTCLVKGFYPSDIAVEWESNGQPENNYKT
TPPVLDSDGSFFLYSKLTVDKSRWQQGNVFSCSVMHEALHNHYTQKSLSLSPGK 14044_HC [hu
anti-<huCDH19> 16C1.1 (1-469)(T92K) VH]::huIgG1z SEQ ID NO:
742
QVQLQESGPGLVKPSETLSLTCTVSGGSISGYYWSWIRQPPGKGLEWIGYIYYIGSTNYNPSLKSR
VTMSIDTSKNQFSLKLSSLTAADTAVYFCARDGSSGWYRWFDPWGQGTLVTVSSASTKGPSVFPLA
PSSKSTSGGTAALGCLVKDYFPEPVTVSWNSGALTSGVHTFPAVLQSSGLYSLSSVVTVPSSSLGT
QTYICNVNHKPSNTKVDKKVEPKSCDKTHTCPPCPAPELLGGPSVFLFPPKPKDTLMISRTPEVTC
VVVDVSHEDPEVKFNWYVDGVEVHNAKTKPREEQYNSTYRVVSVLTVLHQDWLNGKEYKCKVSNKA
LPAPIEKTISKAKGQPREPQVYTLPPSREEMTKNQVSLTCLVKGFYPSDIAVEWESNGQPENNYKT
TPPVLDSDGSFFLYSKLTVDKSRWQQGNVFSCSVMHEALHNHYTQKSLSLSPGK 14045_HC [hu
anti-<huCDH19> 17H8.2 VH]::huIgG1z SEQ ID NO: 743
QVQLQESGPGLVKPSETLSLTCTVSGGSINSYYWSWIRQPPGKGLEWIGYIYYIGSTNYNPSLKSR
VTISVDTSKNQFSLKLSSVTAADTALYYCARDSRYRSGWYDAFDIWGQGTMVTVSSASTKGPSVFP
LAPSSKSTSGGTAALGCLVKDYFPEPVTVSWNSGALTSGVHTFPAVLQSSGLYSLSSVVTVPSSSL
GTQTYICNVNHKPSNTKVDKKVEPKSCDKTHTCPPCPAPELLGGPSVFLFPPKPKDTLMISRTPEV
TCVVVDVSHEDPEVKFNWYVDGVEVHNAKTKPREEQYNSTYRVVSVLTVLHQDWLNGKEYKCKVSN
KALPAPIEKTISKAKGQPREPQVYTLPPSREEMTKNQVSLTCLVKGFYPSDIAVEWESNGQPENNY
KTTPPVLDSDGSFFLYSKLTVDKSRWQQGNVFSCSVMHEALHNHYTQKSLSLSPGK 14046_HC
[hu anti-<huCDH19> 17H8.2 (1-471)(D109E) VH]::huIgG1z SEQ ID
NO: 744
QVQLQESGPGLVKPSETLSLTCTVSGGSINSYYWSWIRQPPGKGLEWIGYIYYIGSTNYNPSLKSR
VTISVDTSKNQFSLKLSSVTAADTALYYCARESRYRSGWYDAFDIWGQGTMVTVSSASTKGPSVFP
LAPSSKSTSGGTAALGCLVKDYFPEPVTVSWNSGALTSGVHTFPAVLQSSGLYSLSSVVTVPSSSL
GTQTYICNVNHKPSNTKVDKKVEPKSCDKTHTCPPCPAPELLGGPSVFLFPPKPKDTLMISRTPEV
TCVVVDVSHEDPEVKFNWYVDGVEVHNAKTKPREEQYNSTYRVVSVLTVLHQDWLNGKEYKCKVSN
KALPAPIEKTISKAKGQPREPQVYTLPPSREEMTKNQVSLTCLVKGFYPSDIAVEWESNGQPENNY
KTTPPVLDSDGSFFLYSKLTVDKSRWQQGNVFSCSVMHEALHNHYTQKSLSLSPGK 14047_HC
[hu anti-<huCDH19> 17H8.2 (1-471) (D109E,W132Y) VH]::huIgG1z
SEQ ID NO: 745
QVQLQESGPGLVKPSETLSLTCTVSGGSINSYYWSWIRQPPGKGLEWIGYIYYIGSTNYNPSLKSR
VTISVDTSKNQFSLKLSSVTAADTALYYCARESRYRSGYYDAFDIWGQGTMVTVSSASTKGPSVFP
LAPSSKSTSGGTAALGCLVKDYFPEPVTVSWNSGALTSGVHTFPAVLQSSGLYSLSSVVTVPSSSL
GTQTYICNVNHKPSNTKVDKKVEPKSCDKTHTCPPCPAPELLGGPSVFLFPPKPKDTLMISRTPEV
TCVVVDVSHEDPEVKFNWYVDGVEVHNAKTKPREEQYNSTYRVVSVLTVLHQDWLNGKEYKCKVSN
KALPAPIEKTISKAKGQPREPQVYTLPPSREEMTKNQVSLTCLVKGFYPSDIAVEWESNGQPENNY
KTTPPVLDSDGSFFLYSKLTVDKSRWQQGNVFSCSVMHEALHNHYTQKSLSLSPGK 14048_HC
[hu anti-<huCDH19> 17H8.2 (1-471)(D109E) VH]::huIgG1z SEQ ID
NO: 746
QVQLQESGPGLVKPSETLSLTCTVSGGSINSYYWSWIRQPPGKGLEWIGYIYYIGSTNYNPSLKSR
VTISVDTSKNQFSLKLSSVTAADTALYYCARESRYRSGWYDAFDIWGQGTMVTVSSASTKGPSVFP
LAPSSKSTSGGTAALGCLVKDYFPEPVTVSWNSGALTSGVHTFPAVLQSSGLYSLSSVVTVPSSSL
GTQTYICNVNHKPSNTKVDKKVEPKSCDKTHTCPPCPAPELLGGPSVFLFPPKPKDTLMISRTPEV
TCVVVDVSHEDPEVKFNWYVDGVEVHNAKTKPREEQYNSTYRVVSVLTVLHQDWLNGKEYKCKVSN
KALPAPIEKTISKAKGQPREPQVYTLPPSREEMTKNQVSLTCLVKGFYPSDIAVEWESNGQPENNY
KTTPPVLDSDGSFFLYSKLTVDKSRWQQGNVFSCSVMHEALHNHYTQKSLSLSPGK 14049_HC
[hu anti-<huCDH19> 4F7 VH]::huIgG1z SEQ ID NO: 747
QVQLQESGPGLVKPSETLSLTCTVSGGSISSYSWSWIRQPPGKGLEWIGYIYYSGSTNYNPSLKSR
VTISLDTSKNQFSLKLSSVTAADTAVYYCARNWAFHFDYWGQGTLVTVSSASTKGPSVFPLAPSSK
STSGGTAALGCLVKDYFPEPVTVSWNSGALTSGVHTFPAVLQSSGLYSLSSVVTVPSSSLGTQTYI
CNVNHKPSNTKVDKKVEPKSCDKTHTCPPCPAPELLGGPSVFLFPPKPKDTLMISRTPEVTCVVVD
VSHEDPEVKFNWYVDGVEVHNAKTKPREEQYNSTYRVVSVLTVLHQDWLNGKEYKCKVSNKALPAP
IEKTISKAKGQPREPQVYTLPPSREEMTKNQVSLTCLVKGFYPSDIAVEWESNGQPENNYKTTPPV
LDSDGSFFLYSKLTVDKSRWQQGNVFSCSVMHEALHNHYTQKSLSLSPGK 14050_HC [hu
anti-<huCDH19> 4F7 VH]::huIgG1z SEQ ID NO: 748
QVQLQESGPGLVKPSETESLTCTVSGGSISSYSWSWIRQPPGKGLEWIGYIYYSGSTNYNPSLKSR
VTISLDTSKNQFSLKLSSVTAADTAVYYCARNWAFHFDYWGQGTLVTVSSASTKGPSVFPLAPSSK
STSGGTAALGCLVKDYFPEPVTVSWNSGALTSGVHTFPAVLQSSGLYSLSSVVTVPSSSLGTQTYI
CNVNHKPSNTKVDKKVEPKSCDKTHTCPPCPAPELLGGPSVFLFPPKPKDTLMISRTPEVTCVVVD
VSHEDPEVKFNWYVDGVEVHNAKTKPREEQYNSTYRVVSVLTVLHQDWLNGKEYKCKVSNKALPAP
IEKTISKAKGQPREPQVYTLPPSREEMTKNQVSLTCLVKGFYPSDIAVEWESNGQPENNYKTTPPV
LDSDGSFFLYSKLTVDKSRWQQGNVFSCSVMHEALHNHYTQKSLSLSPGK 14051_HC [hu
anti-<huCDH19> 4F7 (1-468)(W113Y) VH]::huIgG1z SEQ ID NO: 749
QVQLQESGPGLVKPSETLSLTCTVSGGSISSYSWSWIRQPPGKGLEWIGYIYYSGSTNYNPSLKSR
VTISLDTSKNQFSLKLSSVTAADTAVYYCARNYAFHFDYWGQGTLVTVSSASTKGPSVFPLAPSSK
STSGGTAALGCLVKDYFPEPVTVSWNSGALTSGVHTFPAVLQSSGLYSLSSVVTVPSSSLGTQTYI
CNVNHKPSNTKVDKKVEPKSCDKTHTCPPCPAPELLGGPSVFLFPPKPKDTLMISRTPEVTCVVVD
VSHEDPEVKFNWYVDGVEVHNAKTKPREEQYNSTYRVVSVLTVLHQDWLNGKEYKCKVSNKALPAP
IEKTISKAKGQPREPQVYTLPPSREEMTKNQVSLTCLVKGFYPSDIAVEWESNGQPENNYKTTPPV
LDSDGSFFLYSKLTVDKSRWQQGNVFSCSVMHEALHNHYTQKSLSLSPGK 14052_HC [hu
anti-<huCDH19> 4B10 (1-471) (R17G,D61E,D72E,W134Y)
VH]::huIgG1z SEQ ID NO: 750
QVQLVESGGGVVQPGGSLRLSCAASGFTFSSYDMHWVRQAPGKGLEWVAVISYEGTNEYYAESVKG
RFTISRDTSKNTLYLQMNSLRAEDTAVYYCARERYFDYSFDYWGQGTLVSVSSASTKGPSVFPLAP
SSKSTSGGTAALGCLVKDYFPEPVTVSWNSGALTSGVHTFPAVLQSSGLYSLSSVVTVPSSSLGTQ
TYICNVNHKPSNTKVDKKVEPKSCDKTHTCPPCPAPELLGGPSVFLFPPKPKDTLMISRTPEVTCV
VVDVSHEDPEVKFNWYVDGVEVHNAKTKPREEQYNSTYRVVSVLTVLHQDWLNGKEYKCKVSNKAL
PAPIEKTISKAKGQPREPQVYTLPPSREEMTKNQVSLTCLVKGFYPSDIAVEWESNGQPENNYKTT
PPVLDSDGSFFLYSKLTVDKSRWQQGNVFSCSVMHEALHNHYTQKSLSLSPGK 14053_HC [hu
anti-<huCDH19> 4B10 VH]::huIgG1z SEQ ID NO: 751
QVQLVESGGGVVQPGRSLRLSCAASGFTFSSYDMHWVRQAPGKGLEWVAVISYDGTNEYYADSVKG
RFTISRDTSKNTLYLQMNSLRAEDTAVYYCARERYFDWSFDYWGQGTLVSVSSASTKGPSVFPLAP
SSKSTSGGTAALGCLVKDYFPEPVTVSWNSGALTSGVHTFPAVLQSSGLYSLSSVVTVPSSSLGTQ
TYICNVNHKPSNTKVDKKVEPKSCDKTHTCPPCPAPELLGGPSVFLFPPKPKDTLMISRTPEVTCV
VVDVSHEDPEVKFNWYVDGVEVHNAKTKPREEQYNSTYRVVSVLTVLHQDWLNGKEYKCKVSNKAL
PAPIEKTISKAKGQPREPQVYTLPPSREEMTKNQVSLTCLVKGFYPSDIAVEWESNGQPENNYKTT
PPVLDSDGSFFLYSKLTVDKSRWQQGNVFSCSVMHEALHNHYTQKSLSLSPGK 14054_HC [hu
anti-<huCDH19> 4B10 (1-471)(R17G) VH]::huIgG1z SEQ ID NO: 752
QVQLVESGGGVVQPGGSLRLSCAASGFTFSSYDMHWVRQAPGKGLEWVAVISYDGTNEYYADSVKG
RFTISRDTSKNTLYLQMNSLRAEDTAVYYCARERYFDWSFDYWGQGTLVSVSSASTKGPSVFPLAP
SSKSTSGGTAALGCLVKDYFPEPVTVSWNSGALTSGVHTFPAVLQSSGLYSLSSVVTVPSSSLGTQ
TYICNVNHKPSNTKVDKKVEPKSCDKTHTCPPCPAPELLGGPSVFLFPPKPKDTLMISRTPEVTCV
VVDVSHEDPEVKFNWYVDGVEVHNAKTKPREEQYNSTYRVVSVLTVLHQDWLNGKEYKCKVSNKAL
PAPIEKTISKAKGQPREPQVYTLPPSREEMTKNQVSLTCLVKGFYPSDIAVEWESNGQPENNYKTT
PPVLDSDGSFFLYSKLTVDKSRWQQGNVFSCSVMHEALHNHYTQKSLSLSPGK 14055_HC [hu
anti-<huCDH19> 4B10 (1-471) (R17G,D61E,D72E) VH]::huIgG1z SEQ
ID NO: 753
QVQLVESGGGVVQPGGSLRLSCAASGFTFSSYDMHWVRQAPGKGLEWVAVISYEGTNEYYAESVKG
RFTISRDTSKNTLYLQMNSLRAEDTAVYYCARERYFDWSFDYWGQGTLVSVSSASTKGPSVFPLAP
SSKSTSGGTAALGCLVKDYFPEPVTVSWNSGALTSGVHTFPAVLQSSGLYSLSSVVTVPSSSLGTQ
TYICNVNHKPSNTKVDKKVEPKSCDKTHTCPPCPAPELLGGPSVFLFPPKPKDTLMISRTPEVTCV
VVDVSHEDPEVKFNWYVDGVEVHNAKTKPREEQYNSTYRVVSVLTVLHQDWLNGKEYKCKVSNKAL
PAPIEKTISKAKGQPREPQVYTLPPSREEMTKNQVSLTCLVKGFYPSDIAVEWESNGQPENNYKTT
PPVLDSDGSFFLYSKLTVDKSRWQQGNVFSCSVMHEALHNHYTQKSLSLSPGK 14056_HC [hu
anti-<huCDH19> 4A9 VH]::huIgG1z SEQ ID NO: 754
QVQLQESGPGLVKPSETLSLTCTVSGGSISGYYWSWIRQPPGKGLEWFAYFSYSGSTNYNPSLKSR
VTLSVDTSKNQFSLKLSSVTAADTAVYYCARNWAFHFDFWGQGTLVTVSSASTKGPSVFPLAPSSK
STSGGTAALGCLVKDYFPEPVTVSWNSGALTSGVHTFPAVLQSSGLYSLSSVVTVPSSSLGTQTYI
CNVNHKPSNTKVDKKVEPKSCDKTHTCPPCPAPELLGGPSVFLFPPKPKDTLMISRTPEVTCVVVD
VSHEDPEVKFNWYVDGVEVHNAKTKPREEQYNSTYRVVSVLTVLHQDWLNGKEYKCKVSNKALPAP
IEKTISKAKGQPREPQVYTLPPSREEMTKNQVSLTCLVKGFYPSDIAVEWESNGQPENNYKTTPPV
LDSDGSFFLYSKLTVDKSRWQQGNVFSCSVMHEALHNHYTQKSLSLSPGK 14057_HC [hu
anti-<huCDH19> 4A9 (1-468)(F55I,A56G) VH]::huIgG1z SEQ ID NO:
755
QVQLQESGPGLVKPSETLSLTCTVSGGSISGYYWSWIRQPPGKGLEWIGYFSYSGSTNYNPSLKSR
VTLSVDTSKNQFSLKLSSVTAADTAVYYCARNWAFHFDFWGQGTLVTVSSASTKGPSVFPLAPSSK
STSGGTAALGCLVKDYFPEPVTVSWNSGALTSGVHTFPAVLQSSGLYSLSSVVTVPSSSLGTQTYI
CNVNHKPSNTKVDKKVEPKSCDKTHTCPPCPAPELLGGPSVFLFPPKPKDTLMISRTPEVTCVVVD
VSHEDPEVKFNWYVDGVEVHNAKTKPREEQYNSTYRVVSVLTVLHQDWLNGKEYKCKVSNKALPAP
IEKTISKAKGQPREPQVYTLPPSREEMTKNQVSLTCLVKGFYPSDIAVEWESNGQPENNYKTTPPV
LDSDGSFFLYSKLTVDKSRWQQGNVFSCSVMHEALHNHYTQKSLSLSPGK 14058_HC [hu
anti-<huCDH19> 4A9 (1-468)(F55I,A56G) VH]::huIgG1z SEQ ID NO:
756
QVQLQESGPGLVKPSETLSLTCTVSGGSISGYYWSWIRQPPGKGLEWIGYFSYSGSTNYNPSLKSR
VTLSVDTSKNQFSLKLSSVTAADTAVYYCARNWAFHFDFWGQGTLVTVSSASTKGPSVFPLAPSSK
STSGGTAALGCLVKDYFPEPVTVSWNSGALTSGVHTFPAVLQSSGLYSLSSVVTVPSSSLGTQTYI
CNVNHKPSNTKVDKKVEPKSCDKTHTCPPCPAPELLGGPSVFLFPPKPKDTLMISRTPEVTCVVVD
VSHEDPEVKFNWYVDGVEVHNAKTKPREEQYNSTYRVVSVLTVLHQDWLNGKEYKCKVSNKALPAP
IEKTISKAKGQPREPQVYTLPPSREEMTKNQVSLTCLVKGFYPSDIAVEWESNGQPENNYKTTPPV
LDSDGSFFLYSKLTVDKSRWQQGNVFSCSVMHEALHNHYTQKSLSLSPGK 14059_HC [hu
anti-<huCDH19> 4A9 (1-468) (F55I,A56G,W113Y) VH]::huIgG1z SEQ
ID NO: 757
QVQLQESGPGLVKPSETLSLTCTVSGGSISGYYWSWIRQPPGKGLEWIGYFSYSGSTNYNPSLKSR
VTLSVDTSKNQFSLKLSSVTAADTAVYYCARNYAFHFDFWGQGTLVTVSSASTKGPSVFPLAPSSK
STSGGTAALGCLVKDYFPEPVTVSWNSGALTSGVHTFPAVLQSSGLYSLSSVVTVPSSSLGTQTYI
CNVNHKPSNTKVDKKVEPKSCDKTHTCPPCPAPELLGGPSVFLFPPKPKDTLMISRTPEVTCVVVD
VSHEDPEVKFNWYVDGVEVHNAKTKPREEQYNSTYRVVSVLTVLHQDWLNGKEYKCKVSNKALPAP
IEKTISKAKGQPREPQVYTLPPSREEMTKNQVSLTCLVKGFYPSDIAVEWESNGQPENNYKTTPPV
LDSDGSFFLYSKLTVDKSRWQQGNVFSCSVMHEALHNHYTQKSLSLSPGK 14060_HC [hu
anti-<huCDH19> 20D3.1 VH]::huIgG1z SEQ ID NO: 758
QVQLVQSGAEVKKPGASVKVSCKVSGYTFTSYFIHWVRQAPGQGLEWMGIINPISVSTSYAQKFQG
RVTMTRDTSTSTVFMELSSLRSEDTAVYYCARGGIQLWLHFDYWGQGTLVTVSSASTKGPSVFPLA
PSSKSTSGGTAALGCLVKDYFPEPVTVSWNSGALTSGVHTFPAVLQSSGLYSLSSVVTVPSSSLGT
QTYICNVNHKPSNTKVDKKVEPKSCDKTHTCPPCPAPELLGGPSVFLFPPKPKDTLMISRTPEVTC
VVVDVSHEDPEVKFNWYVDGVEVHNAKTKPREEQYNSTYRVVSVLTVLHQDWLNGKEYKCKVSNKA
LPAPIEKTISKAKGQPREPQVYTLPPSREEMTKNQVSLTCLVKGFYPSDIAVEWESNGQPENNYKT
TPPVLDSDGSFFLYSKLTVDKSRWQQGNVFSCSVMHEALHNHYTQKSLSLSPGK 14061_HC [hu
anti-<huCDH19> 20D3.1 VH]::huIgG1z SEQ ID NO: 759
QVQLVQSGAEVKKPGASVKVSCKVSGYTFTSYFIHWVRQAPGQGLEWMGIINPISVSTSYAQKFQG
RVTMTRDTSTSTVFMELSSLRSEDTAVYYCARGGIQLWLHFDYWGQGTLVTVSSASTKGPSVFPLA
PSSKSTSGGTAALGCLVKDYFPEPVTVSWNSGALTSGVHTFPAVLQSSGLYSLSSVVTVPSSSLGT
QTYICNVNHKPSNTKVDKKVEPKSCDKTHTCPPCPAPELLGGPSVFLFPPKPKDTLMISRTPEVTC
VVVDVSHEDPEVKFNWYVDGVEVHNAKTKPREEQYNSTYRVVSVLTVLHQDWLNGKEYKCKVSNKA
LPAPIEKTISKAKGQPREPQVYTLPPSREEMTKNQVSLTCLVKGFYPSDIAVEWESNGQPENNYKT
TPPVLDSDGSFFLYSKLTVDKSRWQQGNVFSCSVMHEALHNHYTQKSLSLSPGK 14062_HC [hu
anti-<huCDH19> 20D3.1 (1-469)(W133Y) VH]::huIgG1z SEQ ID NO:
760
QVQLVQSGAEVKKPGASVKVSCKVSGYTFTSYFIHWVRQAPGQGLEWMGIINPISVSTSYAQKFQG
RVTMTRDTSTSTVFMELSSERSEDTAVYYCARGGIQLYLHFDYWGQGTLVTVSSASTKGPSVFPLA
PSSKSTSGGTAALGCLVKDYFPEPVTVSWNSGALTSGVHTFPAVLQSSGLYSLSSVVTVPSSSLGT
QTYICNVNHKPSNTKVDKKVEPKSCDKTHTCPPCPAPELLGGPSVFLFPPKPKDTLMISRTPEVTC
VVVDVSHEDPEVKFNWYVDGVEVHNAKTKPREEQYNSTYRVVSVLTVLHQDWLNGKEYKCKVSNKA
LPAPIEKTISKAKGQPREPQVYTLPPSREEMTKNQVSLTCLVKGFYPSDIAVEWESNGQPENNYKT
TPPVLDSDGSFFLYSKLTVDKSRWQQGNVFSCSVMHEALHNHYTQKSLSLSPGK 14063_HC [hu
anti-<huCDH19> 20D3.1 (1-469)(W133Y) VH]::huIgG1z SEQ ID NO:
761
QVQLVQSGAEVKKPGASVKVSCKVSGYTFTSYFIHWVRQAPGQGLEWMGIINPISVSTSYAQKFQG
RVTMTRDTSTSTVFMELSSLRSEDTAVYYCARGGIQLYLHFDYWGQGTLVTVSSASTKGPSVFPLA
PSSKSTSGGTAALGCLVKDYFPEPVTVSWNSGALTSGVHTFPAVLQSSGLYSLSSVVTVPSSSLGT
QTYICNVNHKPSNTKVDKKVEPKSCDKTHTCPPCPAPELLGGPSVFLFPPKPKDTLMISRTPEVTC
VVVDVSHEDPEVKFNWYVDGVEVHNAKTKPREEQYNSTYRVVSVLTVLHQDWLNGKEYKCKVSNKA
LPAPIEKTISKAKGQPREPQVYTLPPSREEMTKNQVSLTCLVKGFYPSDIAVEWESNGQPENNYKT
TPPVLDSDGSFFLYSKLTVDKSRWQQGNVFSCSVMHEALHNHYTQKSLSLSPGK 14064_HC [hu
anti-<huCDH19> 20D3.1 (1-469)(W133Y) VH]::huIgG1z SEQ ID NO:
762
QVQLVQSGAEVKKPGASVKVSCKVSGYTFTSYFIHWVRQAPGQGLEWMGIINPISVSTSYAQKFQG
RVTMTRDTSTSTVFMELSSLRSEDTAVYYCARGGIQLYLHFDYWGQGTLVTVSSASTKGPSVFPLA
PSSKSTSGGTAALGCLVKDYFPEPVTVSWNSGALTSGVHTFPAVLQSSGLYSLSSVVTVPSSSLGT
QTYICNVNHKPSNTKVDKKVEPKSCDKTHTCPPCPAPELLGGPSVFLFPPKPKDTLMISRTPEVTC
VVVDVSHEDPEVKFNWYVDGVEVHNAKTKPREEQYNSTYRVVSVLTVLHQDWLNGKEYKCKVSNKA
LPAPIEKTISKAKGQPREPQVYTLPPSREEMTKNQVSLTCLVKGFYPSDIAVEWESNGQPENNYKT
TPPVLDSDGSFFLYSKLTVDKSRWQQGNVFSCSVMHEALHNHYTQKSLSLSPGK 14065_HC [hu
anti-<huCDH19> 22G10.1 (1-470) (S82R,A99E) VH]::huIgG1z SEQ
ID NO: 763
EVQLLESGGGLVQPGGSLRLSCAASGFTFSSYAMNWVRQAPGKGLEWVSTISGGGANTYYADSVKG
RFTISRDNSKSTLYLQMNSLRAEDTAVYHCAKGGMGGYYYGMDVWGQGTTVTVSSASTKGPSVFPL
APSSKSTSGGTAALGCLVKDYFPEPVTVSWNSGALTSGVHTFPAVLQSSGLYSLSSVVTVPSSSLG
TQTYICNVNHKPSNTKVDKKVEPKSCDKTHTCPPCPAPELLGGPSVFLFPPKPKDTLMISRTPEVT
CVVVDVSHEDPEVKFNWYVDGVEVHNAKTKPREEQYNSTYRVVSVLTVLHQDWLNGKEYKCKVSNK
ALPAPIEKTISKAKGQPREPQVYTLPPSREEMTKNQVSLTCLVKGFYPSDIAVEWESNGQPENNYK
TTPPVLDSDGSFFLYSKLTVDKSRWQQGNVFSCSVMHEALHNHYTQKSLSLSPGK 14066_HC
[hu anti-<huCDH19> 22G10.1 (1-470) (A99E,H105Y) VH]::huIgG1z
SEQ ID NO: 764
EVQLLESGGGLVQPGGSLRLSCAASGFTFSSYAMNWVRQAPGKGLEWVSTISGGGANTYYADSVKG
RFTISSDNSKSTLYLQMNSLRAEDTAVYYCAKGGMGGYYYGMDVWGQGTTVTVSSASTKGPSVFPL
APSSKSTSGGTAALGCLVKDYFPEPVTVSWNSGALTSGVHTFPAVLQSSGLYSLSSVVTVPSSSLG
TQTYICNVNHKPSNTKVDKKVEPKSCDKTHTCPPCPAPELLGGPSVFLFPPKPKDTLMISRTPEVT
CVVVDVSHEDPEVKFNWYVDGVEVHNAKTKPREEQYNSTYRVVSVLTVLHQDWLNGKEYKCKVSNK
ALPAPIEKTISKAKGQPREPQVYTLPPSREEMTKNQVSLTCLVKGFYPSDIAVEWESNGQPENNYK
TTPPVLDSDGSFFLYSKLTVDKSRWQQGNVFSCSVMHEALHNHYTQKSLSLSPGK 14067_HC
[hu anti-<huCDH19> 22G10.1 (1-470)(A99E) VH]::huIgG1z SEQ ID
NO: 765
EVQLLESGGGLVQPGGSLRLSCAASGFTFSSYAMNWVRQAPGKGLEWVSTISGGGANTYYADSVKG
RFTISSDNSKSTLYLQMNSLRAEDTAVYHCAKGGMGGYYYGMDVWGQGTTVTVSSASTKGPSVFPL
APSSKSTSGGTAALGCLVKDYFPEPVTVSWNSGALTSGVHTFPAVLQSSGLYSLSSVVTVPSSSLG
TQTYICNVNHKPSNTKVDKKVEPKSCDKTHTCPPCPAPELLGGPSVFLFPPKPKDTLMISRTPEVT
CVVVDVSHEDPEVKFNWYVDGVEVHNAKTKPREEQYNSTYRVVSVLTVLHQDWLNGKEYKCKVSNK
ALPAPIEKTISKAKGQPREPQVYTLPPSREEMTKNQVSLTCLVKGFYPSDIAVEWESNGQPENNYK
TTPPVLDSDGSFFLYSKLTVDKSRWQQGNVFSCSVMHEALHNHYTQKSLSLSPGK 14068_HC
[hu anti-<huCDH19> 22G10.1 (1-470)(A99E) VH]::huIgG1z SEQ ID
NO: 766
EVQLLESGGGLVQPGGSLRLSCAASGFTFSSYAMNWVRQAPGKGLEWVSTISGGGANTYYADSVKG
RFTISSDNSKSTLYLQMNSLRAEDTAVYHCAKGGMGGYYYGMDVWGQGTTVTVSSASTKGPSVFPL
APSSKSTSGGTAALGCLVKDYFPEPVTVSWNSGALTSGVHTFPAVLQSSGLYSLSSVVTVPSSSLG
TQTYICNVNHKPSNTKVDKKVEPKSCDKTHTCPPCPAPELLGGPSVFLFPPKPKDTLMISRTPEVT
CVVVDVSHEDPEVKFNWYVDGVEVHNAKTKPREEQYNSTYRVVSVLTVLHQDWLNGKEYKCKVSNK
ALPAPIEKTISKAKGQPREPQVYTLPPSREEMTKNQVSLTCLVKGFYPSDIAVEWESNGQPENNYK
TTPPVLDSDGSFFLYSKLTVDKSRWQQGNVFSCSVMHEALHNHYTQKSLSLSPGK 14069_HC
[hu anti-<huCDH19> 22G10.1 (1-470) (D72E,A99E) VH]::huIgG1z
SEQ ID NO: 767
EVQLLESGGGLVQPGGSLRLSCAASGFTFSSYAMNWVRQAPGKGLEWVSTISGGGANTYYAESVKG
RFTISSDNSKSTLYLQMNSLRAEDTAVYHCAKGGMGGYYYGMDVWGQGTTVTVSSASTKGPSVFPL
APSSKSTSGGTAALGCLVKDYFPEPVTVSWNSGALTSGVHTFPAVLQSSGLYSLSSVVTVPSSSLG
TQTYICNVNHKPSNTKVDKKVEPKSCDKTHTCPPCPAPELLGGPSVFLFPPKPKDTLMISRTPEVT
CVVVDVSHEDPEVKFNWYVDGVEVHNAKTKPREEQYNSTYRVVSVLTVLHQDWLNGKEYKCKVSNK
ALPAPIEKTISKAKGQPREPQVYTLPPSREEMTKNQVSLTCLVKGFYPSDIAVEWESNGQPENNYK
TTPPVLDSDGSFFLYSKLTVDKSRWQQGNVFSCSVMHEALHNHYTQKSLSLSPGK 14070_HC
[hu anti-<huCDH19> 22G10.1 (1-470)(H105Y) VH]::huIgG1z SEQ ID
NO: 768
EVQLLESGGGLVQPGGSLRLSCAASGFTFSSYAMNWVRQAPGKGLEWVSTISGGGANTYYADSVKG
RFTISSDNSKSTLYLQMNSLRAADTAVYYCAKGGMGGYYYGMDVWGQGTTVTVSSASTKGPSVFPL
APSSKSTSGGTAALGCLVKDYFPEPVTVSWNSGALTSGVHTFPAVLQSSGLYSLSSVVTVPSSSLG
TQTYICNVNHKPSNTKVDKKVEPKSCDKTHTCPPCPAPELLGGPSVFLFPPKPKDTLMISRTPEVT
CVVVDVSHEDPEVKFNWYVDGVEVHNAKTKPREEQYNSTYRVVSVLTVLHQDWLNGKEYKCKVSNK
ALPAPIEKTISKAKGQPREPQVYTLPPSREEMTKNQVSLTCLVKGFYPSDIAVEWESNGQPENNYK
TTPPVLDSDGSFFLYSKLTVDKSRWQQGNVFSCSVMHEALHNHYTQKSLSLSPGK 14071_HC
[hu anti-<huCDH19> 16A4.1 (1-474)(T144L) VH]::huIgG1z SEQ ID
NO: 769
QVQLQESGPGLAKPSETLSLTCTVSGDSITSYYWSWIRQPPGKGLEWIGYIYYSGSTNYNPSLKSR
VTISVDTSKNQFSLKLSSVTAADTAVYYCARDQRRIAAAGTHFYGMDVWGQGTLVTVSSASTKGPS
VFPLAPSSKSTSGGTAALGCLVKDYFPEPVTVSWNSGALTSGVHTFPAVLQSSGLYSLSSVVTVPS
SSLGTQTYICNVNHKPSNTKVDKKVEPKSCDKTHTCPPCPAPELLGGPSVFLFPPKPKDTLMISRT
PEVTCVVVDVSHEDPEVKFNWYVDGVEVHNAKTKPREEQYNSTYRVVSVLTVLHQDWLNGKEYKCK
VSNKALPAPIEKTISKAKGQPREPQVYTLPPSREEMTKNQVSLTCLVKGFYPSDIAVEWESNGQPE
NNYKTTPPVLDSDGSFFLYSKLTVDKSRWQQGNVFSCSVMHEALHNHYTQKSLSLSPGK
14072_HC [hu anti-<huCDH19> 19B5.1 VH]::huIgG1z SEQ ID NO:
770
QVQLVQSGAEVKKPGASVKVSCKVSGYTFTSYFIHWVRQAPGQGLEWMGIINPISVSTSYAQKFQG
RVTMTRDTSTSTVFMELSSLRSEDTAVYYCARGGIQLWLHLDYWGQGTLVTVSSASTKGPSVFPLA
PSSKSTSGGTAALGCLVKDYFPEPVTVSWNSGALTSGVHTFPAVLQSSGLYSLSSVVTVPSSSLGT
QTYICNVNHKPSNTKVDKKVEPKSCDKTHTCPPCPAPELLGGPSVFLFPPKPKDTLMISRTPEVTC
VVVDVSHEDPEVKFNWYVDGVEVHNAKTKPREEQYNSTYRVVSVLTVLHQDWLNGKEYKCKVSNKA
LPAPIEKTISKAKGQPREPQVYTLPPSREEMTKNQVSLTCLVKGFYPSDIAVEWESNGQPENNYKT
TPPVLDSDGSFFLYSKLTVDKSRWQQGNVFSCSVMHEALHNHYTQKSLSLSPGK 14073_HC [hu
anti-<huCDH19> 19B5.1 (1-469)(W133Y) VH]::huIgG1z SEQ ID NO:
771
QVQLVQSGAEVKKPGASVKVSCKVSGYTFTSYFIHWVRQAPGQGLEWMGIINPISVSTSYAQKFQG
RVTMTRDTSTSTVFMELSSLRSEDTAVYYCARGGIQLYLHLDYWGQGTLVTVSSASTKGPSVFPLA
PSSKSTSGGTAALGCLVKDYFPEPVTVSWNSGALTSGVHTFPAVLQSSGLYSLSSVVTVPSSSLGT
QTYICNVNHKPSNTKVDKKVEPKSCDKTHTCPPCPAPELLGGPSVFLFPPKPKDTLMISRTPEVTC
VVVDVSHEDPEVKFNWYVDGVEVHNAKTKPREEQYNSTYRVVSVLTVLHQDWLNGKEYKCKVSNKA
LPAPIEKTISKAKGQPREPQVYTLPPSREEMTKNQVSLTCLVKGFYPSDIAVEWESNGQPENNYKT
TPPVLDSDGSFFLYSKLTVDKSRWQQGNVFSCSVMHEALHNHYTQKSLSLSPGK 14074_HC [hu
anti-<huCDH19> 19B5.1 VH]::huIgG1z SEQ ID NO: 772
QVQLVQSGAEVKKPGASVKVSCKVSGYTFTSYFIHWVRQAPGQGLEWMGIINPISVSTSYAQKFQG
RVTMTRDTSTSTVFMELSSLRSEDTAVYYCARGGIQLWLHLDYWGQGTLVTVSSASTKGPSVFPLA
PSSKSTSGGTAALGCLVKDYFPEPVTVSWNSGALTSGVHTFPAVLQSSGLYSLSSVVTVPSSSLGT
QTYICNVNHKPSNTKVDKKVEPKSCDKTHTCPPCPAPELLGGPSVFLFPPKPKDTLMISRTPEVTC
VVVDVSHEDPEVKFNWYVDGVEVHNAKTKPREEQYNSTYRVVSVLTVLHQDWLNGKEYKCKVSNKA
LPAPIEKTISKAKGQPREPQVYTLPPSREEMTKNQVSLTCLVKGFYPSDIAVEWESNGQPENNYKT
TPPVLDSDGSFFLYSKLTVDKSRWQQGNVFSCSVMHEALHNHYTQKSLSLSPGK 14075_HC [hu
anti-<huCDH19> 19B5.1 VH]::huIgG1z SEQ ID NO: 773
QVQLVQSGAEVKKPGASVKVSCKVSGYTFTSYFIHWVRQAPGQGLEWMGIMPISVSTSYAQKFQGR
VTMTRDTSTSTVFMELSSLRSEDTAVYYCARGGIQLWLHLDYWGQGTLVTVSSASTKGPSVFPLAP
SSKSTSGGTAALGCLVKDYFPEPVTVSWNSGALTSGVHTFPAVLQSSGLYSLSSVVTVPSSSLGTQ
TYICNVNHKPSNTKVDKKVEPKSCDKTHTCPPCPAPELLGGPSVFLFPPKPKDTLMISRTPEVTCV
VVDVSHEDPEVKFNWYVDGVEVHNAKTKPREEQYNSTYRVVSVLTVLHQDWLNGKEYKCKVSNKAL
PAPIEKTISKAKGQPREPQVYTLPPSREEMTKNQVSLTCLVKGFYPSDIAVEWESNGQPENNYKTT
PPVLDSDGSFFLYSKLTVDKSRWQQGNVFSCSVMHEALHNHYTQKSLSLSPGK 14076_HC [hu
anti-<huCDH19> 19B5.1 (1-469)(W133Y) VH]::huIgG1z SEQ ID NO:
774
QVQLVQSGAEVKKPGASVKVSCKVSGYTFTSYFIHWVRQAPGQGLEWMGIINPISVSTSYAQKFQG
RVTMTRDTSTSTVFMELSSLRSEDTAVYYCARGGIQLYLHLDYWGQGTLVTVSSASTKGPSVFPLA
PSSKSTSGGTAALGCLVKDYFPEPVTVSWNSGALTSGVHTFPAVLQSSGLYSLSSVVTVPSSSLGT
QTYICNVNHKPSNTKVDKKVEPKSCDKTHTCPPCPAPELLGGPSVFLFPPKPKDTLMISRTPEVTC
VVVDVSHEDPEVKFNWYVDGVEVHNAKTKPREEQYNSTYRVVSVLTVLHQDWLNGKEYKCKVSNKA
LPAPIEKTISKAKGQPREPQVYTLPPSREEMTKNQVSLTCLVKGFYPSDIAVEWESNGQPENNYKT
TPPVLDSDGSFFLYSKLTVDKSRWQQGNVFSCSVMHEALHNHYTQKSLSLSPGK 14077_HC [hu
anti-<huCDH19> 23A10.3 (1-474)(L92Q) VH]::huIgG1z SEQ ID NO:
775
QVQLVESGGGVVQPGRSLRLSCAASGFTFSRYGIHWVRQAPGKGLEWVAVIWYDGSNKYYADSVKG
RFTISRDNSKNTLYLQMNSLRAEDSAVYYCARRAGIPGTTGYYYGMDVWGQGTTVTVSSASTKGPS
VFPLAPSSKSTSGGTAALGCLVKDYFPEPVTVSWNSGALTSGVHTFPAVLQSSGLYSLSSVVTVPS
SSLGTQTYICNVNHKPSNTKVDKKVEPKSCDKTHTCPPCPAPELLGGPSVFLFPPKPKDTLMISRT
PEVTCVVVDVSHEDPEVKFNWYVDGVEVHNAKTKPREEQYNSTYRVVSVLTVLHQDWLNGKEYKCK
VSNKALPAPIEKTISKAKGQPREPQVYTLPPSREEMTKNQVSLTCLVKGFYPSDIAVEWESNGQPE
NNYKTTPPVLDSDGSFFLYSKLTVDKSRWQQGNVFSCSVMHEALHNHYTQKSLSLSPGK
14078_HC [hu anti-<huCDH19> 23A10.3 (1-474) (R17G,L92Q)
VH]::huIgG1z SEQ ID NO: 776
QVQLVESGGGVVQPGGSLRLSCAASGFTFSRYGIHWVRQAPGKGLEWVAVIWYDGSNKYYADSVKG
RFTISRDNSKNTLYLQMNSLRAEDSAVYYCARRAGIPGTTGYYYGMDVWGQGTTVTVSSASTKGPS
VFPLAPSSKSTSGGTAALGCLVKDYFPEPVTVSWNSGALTSGVHTFPAVLQSSGLYSLSSVVTVPS
SSLGTQTYICNVNHKPSNTKVDKKVEPKSCDKTHTCPPCPAPELLGGPSVFLFPPKPKDTLMISRT
PEVTCVVVDVSHEDPEVKFNWYVDGVEVHNAKTKPREEQYNSTYRVVSVLTVLHQDWLNGKEYKCK
VSNKALPAPIEKTISKAKGQPREPQVYTLPPSREEMTKNQVSLTCLVKGFYPSDIAVEWESNGQPE
NNYKTTPPVLDSDGSFFLYSKLTVDKSRWQQGNVFSCSVMHEALHNHYTQKSLSLSPGK
14079_HC [hu anti-<huCDH19> 23A10.3 (1-474)
(R17G,D61E,D72E,L92Q) VH]::huIgG1z SEQ ID NO: 777
QVQLVESGGGVVQPGGSLRLSCAASGFTFSRYGIHWVRQAPGKGLEWVAVIWYEGSNKYYAESVKG
RFTISRDNSKNTLYLQMNSLRAEDSAVYYCARRAGIPGTTGYYYGMDVWGQGTTVTVSSASTKGPS
VFPLAPSSKSTSGGTAALGCLVKDYFPEPVTVSWNSGALTSGVHTFPAVLQSSGLYSLSSVVTVPS
SSLGTQTYICNVNHKPSNTKVDKKVEPKSCDKTHTCPPCPAPELLGGPSVFLFPPKPKDTLMISRT
PEVTCVVVDVSHEDPEVKFNWYVDGVEVHNAKTKPREEQYNSTYRVVSVLTVLHQDWLNGKEYKCK
VSNKALPAPIEKTISKAKGQPREPQVYTLPPSREEMTKNQVSLTCLVKGFYPSDIAVEWESNGQPE
NNYKTTPPVLDSDGSFFLYSKLTVDKSRWQQGNVFSCSVMHEALHNHYTQKSLSLSPGK
14080_HC [hu anti-<huCDH19> 23A10.3 VH]::huIgG1z SEQ ID NO:
778
QVQLVESGGGVVQPGRSLRLSCAASGFTFSRYGIHWVRQAPGKGLEWVAVIWYDGSNKYYADSVKG
RFTISRDNSKNTLYLLMNSLRAEDSAVYYCARRAGIPGTTGYYYGMDVWGQGTTVTVSSASTKGPS
VFPLAPSSKSTSGGTAALGCLVKDYFPEPVTVSWNSGALTSGVHTFPAVLQSSGLYSLSSVVTVPS
SSLGTQTYICNVNHKPSNTKVDKKVEPKSCDKTHTCPPCPAPELLGGPSVFLFPPKPKDTLMISRT
PEVTCVVVDVSHEDPEVKFNWYVDGVEVHNAKTKPREEQYNSTYRVVSVLTVLHQDWLNGKEYKCK
VSNKALPAPIEKTISKAKGQPREPQVYTLPPSREEMTKNQVSLTCLVKGFYPSDIAVEWESNGQPE
NNYKTTPPVLDSDGSFFLYSKLTVDKSRWQQGNVFSCSVMHEALHNHYTQKSLSLSPGK
14081_HC [hu anti-<huCDH19> 25G10.1 VH]::huIgG1z SEQ ID NO:
779
QVQLQESGPGLVKPSETLSLTCTVSGGSISGYYWSWIRQPPGKGLEWIGYIYYIGSTNYNPSLKSR
VTMSVDTSKNQFSLKLSSVTAADTAVYYCARDGSSGWYRWFDPWGQGTLVTVSSASTKGPSVFPLA
PSSKSTSGGTAALGCLVKDYFPEPVTVSWNSGALTSGVHTFPAVLQSSGLYSLSSVVTVPSSSLGT
QTYICNVNHKPSNTKVDKKVEPKSCDKTHTCPPCPAPELLGGPSVFLFPPKPKDTLMISRTPEVTC
VVVDVSHEDPEVKFNWYVDGVEVHNAKTKPREEQYNSTYRVVSVLTVLHQDWLNGKEYKCKVSNKA
LPAPIEKTISKAKGQPREPQVYTLPPSREEMTKNQVSLTCLVKGFYPSDIAVEWESNGQPENNYKT
TPPVLDSDGSFFLYSKLTVDKSRWQQGNVFSCSVMHEALHNHYTQKSLSLSPGK 14082_HC [hu
anti-<huCDH19> 25G10.1 (1-469) (D109E,W132Y,W135Y)
VH]::huIgG1z SEQ ID NO: 780
QVQLQESGPGLVKPSETLSLTCTVSGGSISGYYWSWIRQPPGKGLEWIGYIYYIGSTNYNPSLKSR
VTMSVDTSKNQFSLKLSSVTAADTAVYYCAREGSSGYYRYFDPWGQGTLVTVSSASTKGPSVFPLA
PSSKSTSGGTAALGCLVKDYFPEPVTVSWNSGALTSGVHTFPAVLQSSGLYSLSSVVTVPSSSLGT
QTYICNVNHKPSNTKVDKKVEPKSCDKTHTCPPCPAPELLGGPSVFLFPPKPKDTLMISRTPEVTC
VVVDVSHEDPEVKFNWYVDGVEVHNAKTKPREEQYNSTYRVVSVLTVLHQDWLNGKEYKCKVSNKA
LPAPIEKTISKAKGQPREPQVYTLPPSREEMTKNQVSLTCLVKGFYPSDIAVEWESNGQPENNYKT
TPPVLDSDGSFFLYSKLTVDKSRWQQGNVFSCSVMHEALHNHYTQKSLSLSPGK 14083_HC [hu
anti-<huCDH19> 26D1.1 VH]::huIgG1z SEQ ID NO: 781
QVQLVQSGAEVKKPGASVKVSCKASRYTFTSYYMSWVRQAPGQGLEWMGIIHPSGGDTTYAQKFQG
RVTMTGDTSTSTVYMELSSLRSEDTAVYYCARGGIKLWLHFDYWGQGTLVTVSSASTKGPSVFPLA
PSSKSTSGGTAALGCLVKDYFPEPVTVSWNSGALTSGVHTFPAVLQSSGLYSLSSVVTVPSSSLGT
QTYICNVNHKPSNTKVDKKVEPKSCDKTHTCPPCPAPELLGGPSVFLFPPKPKDTLMISRTPEVTC
VVVDVSHEDPEVKFNWYVDGVEVHNAKTKPREEQYNSTYRVVSVLTVLHQDWLNGKEYKCKVSNKA
LPAPIEKTISKAKGQPREPQVYTLPPSREEMTKNQVSLTCLVKGFYPSDIAVEWESNGQPENNYKT
TPPVLDSDGSFFLYSKLTVDKSRWQQGNVFSCSVMHEALHNHYTQKSLSLSPGK 14084_HC [hu
anti-<huCDH19> 26D1.1 VH]::huIgG1z SEQ ID NO: 782
QVQLVQSGAEVKKPGASVKVSCKASRYTFTSYYMSWVRQAPGQGLEWMGIIHPSGGDTTYAQKFQG
RVTMTGDTSTSTVYMELSSLRSEDTAVYYCARGGIKLWLHFDYWGQGTLVTVSSASTKGPSVFPLA
PSSKSTSGGTAALGCLVKDYFPEPVTVSWNSGALTSGVHTFPAVLQSSGLYSLSSVVTVPSSSLGT
QTYICNVNHKPSNTKVDKKVEPKSCDKTHTCPPCPAPELLGGPSVFLFPPKPKDTLMISRTPEVTC
VVVDVSHEDPEVKFNWYVDGVEVHNAKTKPREEQYNSTYRVVSVLTVLHQDWLNGKEYKCKVSNKA
LPAPIEKTISKAKGQPREPQVYTLPPSREEMTKNQVSLTCLVKGFYPSDIAVEWESNGQPENNYKT
TPPVLDSDGSFFLYSKLTVDKSRWQQGNVFSCSVMHEALHNHYTQKSLSLSPGK 14085_HC [hu
anti-<huCDH19> 26D1.1 VH]::huIgG1z SEQ ID NO: 783
QVQLVQSGAEVKKPGASVKVSCKASRYTFTSYYMSWVRQAPGQGLEWMGIIHPSGGDTTYAQKFQG
RVTMTGDTSTSTVYMELSSLRSEDTAVYYCARGGIKLWLHFDYWGQGTLVTVSSASTKGPSVFPLA
PSSKSTSGGTAALGCLVKDYFPEPVTVSWNSGALTSGVHTFPAVLQSSGLYSLSSVVTVPSSSLGT
QTYICNVNHKPSNTKVDKKVEPKSCDKTHTCPPCPAPELLGGPSVFLFPPKPKDTLMISRTPEVTC
VVVDVSHEDPEVKFNWYVDGVEVHNAKTKPREEQYNSTYRVVSVLTVLHQDWLNGKEYKCKVSNKA
LPAPIEKTISKAKGQPREPQVYTLPPSREEMTKNQVSLTCLVKGFYPSDIAVEWESNGQPENNYKT
TPPVLDSDGSFFLYSKLTVDKSRWQQGNVFSCSVMHEALHNHYTQKSLSLSPGK 14086_HC [hu
anti-<huCDH19> 26D1.1 VH]::huIgG1z SEQ ID NO: 784
QVQLVQSGAEVKKPGASVKVSCKASRYTFTSYYMSWVRQAPGQGLEWMGIIHPSGGDTTYAQKFQG
RVTMTGDTSTSTVYMELSSLRSEDTAVYYCARGGIKLWLHFDYWGQGTLVTVSSASTKGPSVFPLA
PSSKSTSGGTAALGCLVKDYFPEPVTVSWNSGALTSGVHTFPAVLQSSGLYSLSSVVTVPSSSLGT
QTYICNVNHKPSNTKVDKKVEPKSCDKTHTCPPCPAPELLGGPSVFLFPPKPKDTLMISRTPEVTC
VVVDVSHEDPEVKFNWYVDGVEVHNAKTKPREEQYNSTYRVVSVLTVLHQDWLNGKEYKCKVSNKA
LPAPIEKTISKAKGQPREPQVYTLPPSREEMTKNQVSLTCLVKGFYPSDIAVEWESNGQPENNYKT
TPPVLDSDGSFFLYSKLTVDKSRWQQGNVFSCSVMHEALHNHYTQKSLSLSPGK 14087_HC [hu
anti-<huCDH19> 26D1.1 (1-469)(W133Y) VH]::huIgG1z SEQ ID NO:
785
QVQLVQSGAEVKKPGASVKVSCKASRYTFTSYYMSWVRQAPGQGLEWMGIIHPSGGDTTYAQKFQG
RVTMTGDTSTSTVYMELSSLRSEDTAVYYCARGGIKLYLHFDYWGQGTLVTVSSASTKGPSVFPLA
PSSKSTSGGTAALGCLVKDYFPEPVTVSWNSGALTSGVHTFPAVLQSSGLYSLSSVVTVPSSSLGT
QTYICNVNHKPSNTKVDKKVEPKSCDKTHTCPPCPAPELLGGPSVFLFPPKPKDTLMISRTPEVTC
VVVDVSHEDPEVKFNWYVDGVEVHNAKTKPREEQYNSTYRVVSVLTVLHQDWLNGKEYKCKVSNKA
LPAPIEKTISKAKGQPREPQVYTLPPSREEMTKNQVSLTCLVKGFYPSDIAVEWESNGQPENNYKT
TPPVLDSDGSFFLYSKLTVDKSRWQQGNVFSCSVMHEALHNHYTQKSLSLSPGK 14088_HC [hu
anti-<huCDH19> 26D1.1 (1-469) (R27G,G82R) VH]::huIgG1z SEQ ID
NO: 786
QVQLVQSGAEVKKPGASVKVSCKASGYTFTSYYMSWVRQAPGQGLEWMGIIHPSGGDTTYAQKFQG
RVTMTRDTSTSTVYMELSSLRSEDTAVYYCARGGIKLWLHFDYWGQGTLVTVSSASTKGPSVFPLA
PSSKSTSGGTAALGCLVKDYFPEPVTVSWNSGALTSGVHTFPAVLQSSGLYSLSSVVTVPSSSLGT
QTYICNVNHKPSNTKVDKKVEPKSCDKTHTCPPCPAPELLGGPSVFLFPPKPKDTLMISRTPEVTC
VVVDVSHEDPEVKFNWYVDGVEVHNAKTKPREEQYNSTYRVVSVLTVLHQDWLNGKEYKCKVSNKA
LPAPIEKTISKAKGQPREPQVYTLPPSREEMTKNQVSLTCLVKGFYPSDIAVEWESNGQPENNYKT
TPPVLDSDGSFFLYSKLTVDKSRWQQGNVFSCSVMHEALHNHYTQKSLSLSPGK 14089_HC [hu
anti-<huCDH19> 26F12.1 VH]::huIgG1z SEQ ID NO: 787
QVQLVQSGAEVKKPGASVKVSCKASRYTFTNYYMSWVRQAPGQGLEWMGIINPSGGDSTYAQKFQG
RLTMTGDTSTSTVYMELSSLRSEDTAVYYCARGGIQLWLHFDYWGQGTLVTVSSASTKGPSVFPLA
PSSKSTSGGTAALGCLVKDYFPEPVTVSWNSGALTSGVHTFPAVLQSSGLYSLSSVVTVPSSSLGT
QTYICNVNHKPSNTKVDKKVEPKSCDKTHTCPPCPAPELLGGPSVFLFPPKPKDTLMISRTPEVTC
VVVDVSHEDPEVKFNWYVDGVEVHNAKTKPREEQYNSTYRVVSVLTVLHQDWLNGKEYKCKVSNKA
LPAPIEKTISKAKGQPREPQVYTLPPSREEMTKNQVSLTCLVKGFYPSDIAVEWESNGQPENNYKT
TPPVLDSDGSFFLYSKLTVDKSRWQQGNVFSCSVMHEALHNHYTQKSLSLSPGK 14090_HC [hu
anti-<huCDH19> 26F12.1 VH]::huIgG1z SEQ ID NO: 788
QVQLVQSGAEVKKPGASVKVSCKASRYTFTNYYMSWVRQAPGQGLEWMGIINPSGGDSTYAQKFQG
RLTMTGDTSTSTVYMELSSLRSEDTAVYYCARGGIQLWLHFDYWGQGTLVTVSSASTKGPSVFPLA
PSSKSTSGGTAALGCLVKDYFPEPVTVSWNSGALTSGVHTFPAVLQSSGLYSLSSVVTVPSSSLGT
QTYICNVNHKPSNTKVDKKVEPKSCDKTHTCPPCPAPELLGGPSVFLFPPKPKDTLMISRTPEVTC
VVVDVSHEDPEVKFNWYVDGVEVHNAKTKPREEQYNSTYRVVSVLTVLHQDWLNGKEYKCKVSNKA
LPAPIEKTISKAKGQPREPQVYTLPPSREEMTKNQVSLTCLVKGFYPSDIAVEWESNGQPENNYKT
TPPVLDSDGSFFLYSKLTVDKSRWQQGNVFSCSVMHEALHNHYTQKSLSLSPGK 14091_HC [hu
anti-<huCDH19> 26F12.1 (1-469)(W133Y) VH]::huIgG1z SEQ ID NO:
789
QVQLVQSGAEVKKPGASVKVSCKASRYTFTNYYMSWVRQAPGQGLEWMGIINPSGGDSTYAQKFQG
RLTMTGDTSTSTVYMELSSLRSEDTAVYYCARGGIQLYLHFDYWGQGTLVTVSSASTKGPSVFPLA
PSSKSTSGGTAALGCLVKDYFPEPVTVSWNSGALTSGVHTFPAVLQSSGLYSLSSVVTVPSSSLGT
QTYICNVNHKPSNTKVDKKVEPKSCDKTHTCPPCPAPELLGGPSVFLFPPKPKDTLMISRTPEVTC
VVVDVSHEDPEVKFNWYVDGVEVHNAKTKPREEQYNSTYRVVSVLTVLHQDWLNGKEYKCKVSNKA
LPAPIEKTISKAKGQPREPQVYTLPPSREEMTKNQVSLTCLVKGFYPSDIAVEWESNGQPENNYKT
TPPVLDSDGSFFLYSKLTVDKSRWQQGNVFSCSVMHEALHNHYTQKSLSLSPGK 14092_HC [hu
anti-<huCDH19> 26F12.1 (1-469)(W133Y) VH]::huIgG1z SEQ ID NO:
790
QVQLVQSGAEVKKPGASVKVSCKASRYTFTNYYMSWVRQAPGQGLEWMGIINPSGGDSTYAQKFQG
RLTMTGDTSTSTVYMELSSLRSEDTAVYYCARGGIQLYLHFDYWGQGTLVTVSSASTKGPSVFPLA
PSSKSTSGGTAALGCLVKDYFPEPVTVSWNSGALTSGVHTFPAVLQSSGLYSLSSVVTVPSSSLGT
QTYICNVNHKPSNTKVDKKVEPKSCDKTHTCPPCPAPELLGGPSVFLFPPKPKDTLMISRTPEVTC
VVVDVSHEDPEVKFNWYVDGVEVHNAKTKPREEQYNSTYRVVSVLTVLHQDWLNGKEYKCKVSNKA
LPAPIEKTISKAKGQPREPQVYTLPPSREEMTKNQVSLTCLVKGFYPSDIAVEWESNGQPENNYKT
TPPVLDSDGSFFLYSKLTVDKSRWQQGNVFSCSVMHEALHNHYTQKSLSLSPGK 14093_HC [hu
anti-<huCDH19> 25F8.1 VH]::huIgG1z SEQ ID NO: 791
QVQLVQSGAEVKKPGASVKVSCKASGYTFTSYYIHWVRQAPGQGLEWMGI1NPSGGSTRYAQKFQG
RVTMTRDTSTSTVFMELSSLRSEDTAVYYCARGGIQLWLHFDYWGQGTLVTVSSASTKGPSVFPLA
PSSKSTSGGTAALGCLVKDYFPEPVTVSWNSGALTSGVHTFPAVLQSSGLYSLSSVVTVPSSSLGT
QTYICNVNHKPSNTKVDKKVEPKSCDKTHTCPPCPAPELLGGPSVFLFPPKPKDTLMISRTPEVTC
VVVDVSHEDPEVKFNWYVDGVEVHNAKTKPREEQYNSTYRVVSVLTVLHQDWLNGKEYKCKVSNKA
LPAPIEKTISKAKGQPREPQVYTLPPSREEMTKNQVSLTCLVKGFYPSDIAVEWESNGQPENNYKT
TPPVLDSDGSFFLYSKLTVDKSRWQQGNVFSCSVMHEALHNHYTQKSLSLSPGK 14094_HC [hu
anti-<huCDH19> 25F8.1 VH]::huIgG1z SEQ ID NO: 792
QVQLVQSGAEVKKPGASVKVSCKASGYTFTSYYIHWVRQAPGQGLEWMGIINPSGGSTRYAQKFQG
RVTMTRDTSTSTVFMELSSLRSEDTAVYYCARGGIQLWLHFDYWGQGTLVTVSSASTKGPSVFPLA
PSSKSTSGGTAALGCLVKDYFPEPVTVSWNSGALTSGVHTFPAVLQSSGLYSLSSVVTVPSSSLGT
QTYICNVNHKPSNTKVDKKVEPKSCDKTHTCPPCPAPELLGGPSVFLFPPKPKDTLMISRTPEVTC
VVVDVSHEDPEVKFNWYVDGVEVHNAKTKPREEQYNSTYRVVSVLTVLHQDWLNGKEYKCKVSNKA
LPAPIEKTISKAKGQPREPQVYTLPPSREEMTKNQVSLTCLVKGFYPSDIAVEWESNGQPENNYKT
TPPVLDSDGSFFLYSKLTVDKSRWQQGNVFSCSVMHEALHNHYTQKSLSLSPGK 14095_HC [hu
anti-<huCDH19> 25F8.1 (1-469)(F90Y) VH]::huIgG1z SEQ ID NO:
793
QVQLVQSGAEVKKPGASVKVSCKASGYTFTSYYIHWVRQAPGQGLEWMGIINPSGGSTRYAQKFQG
RVTMTRDTSTSTVYMELSSLRSEDTAVYYCARGGIQLWLHFDYWGQGTLVTVSSASTKGPSVFPLA
PSSKSTSGGTAALGCLVKDYFPEPVTVSWNSGALTSGVHTFPAVLQSSGLYSLSSVVTVPSSSLGT
QTYICNVNHKPSNTKVDKKVEPKSCDKTHTCPPCPAPELLGGPSVFLFPPKPKDTLMISRTPEVTC
VVVDVSHEDPEVKFNWYVDGVEVHNAKTKPREEQYNSTYRVVSVLTVLHQDWLNGKEYKCKVSNKA
LPAPIEKTISKAKGQPREPQVYTLPPSREEMTKNQVSLTCLVKGFYPSDIAVEWESNGQPENNYKT
TPPVLDSDGSFFLYSKLTVDKSRWQQGNVFSCSVMHEALHNHYTQKSLSLSPGK 14096_HC [hu
anti-<huCDH19> 25F8.1 (1-469)(F90Y) VH]::huIgG1z SEQ ID NO:
794
QVQLVQSGAEVKKPGASVKVSCKASGYTFTSYYIHWVRQAPGQGLEWMGIINPSGGSTRYAQKFQG
RVTMTRDTSTSTVYMELSSLRSEDTAVYYCARGGIQLWLHFDYWGQGTLVTVSSASTKGPSVFPLA
PSSKSTSGGTAALGCLVKDYFPEPVTVSWNSGALTSGVHTFPAVLQSSGLYSLSSVVTVPSSSLGT
QTYICNVNHKPSNTKVDKKVEPKSCDKTHTCPPCPAPELLGGPSVFLFPPKPKDTLMISRTPEVTC
VVVDVSHEDPEVKFNWYVDGVEVHNAKTKPREEQYNSTYRVVSVLTVLHQDWLNGKEYKCKVSNKA
LPAPIEKTISKAKGQPREPQVYTLPPSREEMTKNQVSLTCLVKGFYPSDIAVEWESNGQPENNYKT
TPPVLDSDGSFFLYSKLTVDKSRWQQGNVFSCSVMHEALHNHYTQKSLSLSPGK 14097_HC [hu
anti-<huCDH19> 25F8.1 (1-469) (F90Y,W133Y) VH]::huIgG1z SEQ
ID NO: 795
QVQLVQSGAEVKKPGASVKVSCKASGYTFTSYYIHWVRQAPGQGLEWMGIINPSGGSTRYAQKFQG
RVTMTRDTSTSTVYMELSSLRSEDTAVYYCARGGIQLYLHFDYWGQGTLVTVSSASTKGPSVFPLA
PSSKSTSGGTAALGCLVKDYFPEPVTVSWNSGALTSGVHTFPAVLQSSGLYSLSSVVTVPSSSLGT
QTYICNVNHKPSNTKVDKKVEPKSCDKTHTCPPCPAPELLGGPSVFLFPPKPKDTLMISRTPEVTC
VVVDVSHEDPEVKFNWYVDGVEVHNAKTKPREEQYNSTYRVVSVLTVLHQDWLNGKEYKCKVSNKA
LPAPIEKTISKAKGQPREPQVYTLPPSREEMTKNQVSLTCLVKGFYPSDIAVEWESNGQPENNYKT
TPPVLDSDGSFFLYSKLTVDKSRWQQGNVFSCSVMHEALHNHYTQKSLSLSPGK 14098_HC [hu
anti-<huCDH19> 22D1.1 VH]::huIgG1z SEQ ID NO: 796
QVQLVQSGAEVKKPGASVRVSCKVSGYTFTSYFIHWVRQAPGQGLEWMGIINPISVSTSYAQKFQG
RVTMTRDTSTSTVFMELSSLRSEDTAVYYCARGGIQLWLHLDYWGQGTLVTVSSASTKGPSVFPLA
PSSKSTSGGTAALGCLVKDYFPEPVTVSWNSGALTSGVHTFPAVLQSSGLYSLSSVVTVPSSSLGT
QTYICNVNHKPSNTKVDKKVEPKSCDKTHTCPPCPAPELLGGPSVFLFPPKPKDTLMISRTPEVTC
VVVDVSHEDPEVKFNWYVDGVEVHNAKTKPREEQYNSTYRVVSVLTVLHQDWLNGKEYKCKVSNKA
LPAPIEKTISKAKGQPREPQVYTLPPSREEMTKNQVSLTCLVKGFYPSDIAVEWESNGQPENNYKT
TPPVLDSDGSFFLYSKLTVDKSRWQQGNVFSCSVMHEALHNHYTQKSLSLSPGK 14099_HC [hu
anti-<huCDH19> 22D1.1 VH]::huIgG1z SEQ ID NO: 797
QVQLVQSGAEVKKPGASVRVSCKVSGYTFTSYFIHWVRQAPGQGLEWMGIINPISVSTSYAQKFQG
RVTMTRDTSTSTVFMELSSLRSEDTAVYYCARGGIQLWLHLDYWGQGTLVTVSSASTKGPSVFPLA
PSSKSTSGGTAALGCLVKDYFPEPVTVSWNSGALTSGVHTFPAVLQSSGLYSLSSVVTVPSSSLGT
QTYICNVNHKPSNTKVDKKVEPKSCDKTHTCPPCPAPELLGGPSVFLFPPKPKDTLMISRTPEVTC
VVVDVSHEDPEVKFNWYVDGVEVHNAKTKPREEQYNSTYRVVSVLTVLHQDWLNGKEYKCKVSNKA
LPAPIEKTISKAKGQPREPQVYTLPPSREEMTKNQVSLTCLVKGFYPSDIAVEWESNGQPENNYKT
TPPVLDSDGSFFLYSKLTVDKSRWQQGNVFSCSVMHEALHNHYTQKSLSLSPGK 14100_HC [hu
anti-<huCDH19> 22D1.1 (1-469)(W133Y) VH]::huIgG1z SEQ ID NO:
798
QVQLVQSGAEVKKPGASVRVSCKVSGYTFTSYFIHWVRQAPGQGLEWMGIINPISVSTSYAQKFQG
RVTMTRDTSTSTVFMELSSLRSEDTAVYYCARGGIQLYLHLDYWGQGTLVTVSSASTKGPSVFPLA
PSSKSTSGGTAALGCLVKDYFPEPVTVSWNSGALTSGVHTFPAVLQSSGLYSLSSVVTVPSSSLGT
QTYICNVNHKPSNTKVDKKVEPKSCDKTHTCPPCPAPELLGGPSVFLFPPKPKDTLMISRTPEVTC
VVVDVSHEDPEVKFNWYVDGVEVHNAKTKPREEQYNSTYRVVSVLTVLHQDWLNGKEYKCKVSNKA
LPAPIEKTISKAKGQPREPQVYTLPPSREEMTKNQVSLTCLVKGFYPSDIAVEWESNGQPENNYKT
TPPVLDSDGSFFLYSKLTVDKSRWQQGNVFSCSVMHEALHNHYTQKSLSLSPGK 14101_HC [hu
anti-<huCDH19> 22D1.1 (1-469)(W133Y) VH]::huIgG1z SEQ ID NO:
799
QVQLVQSGAEVKKPGASVRVSCKVSGYTFTSYFIHWVRQAPGQGLEWMGIINPISVSTSYAQKFQG
RVTMTRDTSTSTVFMELSSLRSEDTAVYYCARGGIQLYLHLDYWGQGTLVTVSSASTKGPSVFPLA
PSSKSTSGGTAALGCLVKDYFPEPVTVSWNSGALTSGVHTFPAVLQSSGLYSLSSVVTVPSSSLGT
QTYICNVNHKPSNTKVDKKVEPKSCDKTHTCPPCPAPELLGGPSVFLFPPKPKDTLMISRTPEVTC
VVVDVSHEDPEVKFNWYVDGVEVHNAKTKPREEQYNSTYRVVSVLTVLHQDWLNGKEYKCKVSNKA
LPAPIEKTISKAKGQPREPQVYTLPPSREEMTKNQVSLTCLVKGFYPSDIAVEWESNGQPENNYKT
TPPVLDSDGSFFLYSKLTVDKSRWQQGNVFSCSVMHEALHNHYTQKSLSLSPGK 14102_HC [hu
anti-<huCDH19> 22D1.1 (1-469)(F90Y) VH]::huIgG1z SEQ ID NO:
800
QVQLVQSGAEVKKPGASVRVSCKVSGYTFTSYFIHWVRQAPGQGLEWMGIINPISVSTSYAQKFQG
RVTMTRDTSTSTVYMELSSLRSEDTAVYYCARGGIQLWLHLDYWGQGTLVTVSSASTKGPSVFPLA
PSSKSTSGGTAALGCLVKDYFPEPVTVSWNSGALTSGVHTFPAVLQSSGLYSLSSVVTVPSSSLGT
QTYICNVNHKPSNTKVDKKVEPKSCDKTHTCPPCPAPELLGGPSVFLFPPKPKDTLMISRTPEVTC
VVVDVSHEDPEVKFNWYVDGVEVHNAKTKPREEQYNSTYRVVSVLTVLHQDWLNGKEYKCKVSNKA
LPAPIEKTISKAKGQPREPQVYTLPPSREEMTKNQVSLTCLVKGFYPSDIAVEWESNGQPENNYKT
TPPVLDSDGSFFLYSKLTVDKSRWQQGNVFSCSVMHEALHNHYTQKSLSLSPGK 13591_HC [hu
anti-<huCDH19> 4F7 VH]::huIgG1z SEQ ID NO: 801
QVQLQESGPGLVKPSETLSLTCTVSGGSISSYSWSWIRQPPGKGLEWIGYIYYSGSTNYNPSLKSR
VTISLDTSKNQFSLKLSSVTAADTAVYYCARNWAFHFDYWGQGTLVTVSSASTKGPSVFPLAPSSK
STSGGTAALGCLVKDYFPEPVTVSWNSGALTSGVHTFPAVLQSSGLYSLSSVVTVPSSSLGTQTYI
CNVNHKPSNTKVDKKVEPKSCDKTHTCPPCPAPELLGGPSVFLFPPKPKDTLMISRTPEVTCVVVD
VSHEDPEVKFNWYVDGVEVHNAKTKPREEQYNSTYRVVSVLTVLHQDWLNGKEYKCKVSNKALPAP
IEKTISKAKGQPREPQVYTLPPSREEMTKNQVSLTCLVKGFYPSDIAVEWESNGQPENNYKTTPPV
LDSDGSFFLYSKLTVDKSRWQQGNVFSCSVMHEALHNHYTQKSLSLSPGK 14301_HC [hu
anti-<huCDH19> 2G6 VH]::huIgG1z SEQ ID NO: 802
QVQLVESGGGVVQPGRSLRLSCAASGFTFSSYGMHWVRQAPGKGLEWVAFIWYDGSNKYYADSVKD
RFTISRDNSKNTLYLQMKSLRAEDTAVYYCARRAGIIGTIGYYYGMDVWGQGTTVTVSSASTKGPS
VFPLAPSSKSTSGGTAALGCLVKDYFPEPVTVSWNSGALTSGVHTFPAVLQSSGLYSLSSVVTVPS
SSLGTQTYICNVNHKPSNTKVDKKVEPKSCDKTHTCPPCPAPELLGGPSVFLFPPKPKDTLMISRT
PEVTCVVVDVSHEDPEVKFNWYVDGVEVHNAKTKPREEQYNSTYRVVSVLTVLHQDWLNGKEYKCK
VSNKALPAPIEKTISKAKGQPREPQVYTLPPSREEMTKNQVSLTCLVKGFYPSDIAVEWESNGQPE
NNYKTTPPVLDSDGSFFLYSKLTVDKSRWQQGNVFSCSVMHEALHNHYTQKSLSLSPGK
14302_HC [hu anti-<huCDH19> 2G6 (1-477)(R17G,K94N)
VH]::huIgG1z SEQ ID NO: 803
QVQLVESGGGVVQPGGSLRLSCAASGFTFSSYGMHWVRQAPGKGLEWVAFIWYDGSNKYYADSVKD
RFTISRDNSKNTLYLQMNSLRAEDTAVYYCARRAGIIGTIGYYYGMDVWGQGTTVTVSSASTKGPS
VFPLAPSSKSTSGGTAALGCLVKDYFPEPVTVSWNSGALTSGVHTFPAVLQSSGLYSLSSVVTVPS
SSLGTQTYICNVNHKPSNTKVDKKVEPKSCDKTHTCPPCPAPELLGGPSVFLFPPKPKDTLMISRT
PEVTCVVVDVSHEDPEVKFNWYVDGVEVHNAKTKPREEQYNSTYRVVSVLTVLHQDWLNGKEYKCK
VSNKALPAPIEKTISKAKGQPREPQVYTLPPSREEMTKNQVSLTCLVKGFYPSDIAVEWESNGQPE
NNYKTTPPVLDSDGSFFLYSKLTVDKSRWQQGNVFSCSVMHEALHNHYTQKSLSLSPGK
14303_HC [hu anti-<huCDH19> 2G6 (1-477)(D61E,D72E)
VH]::huIgG1z SEQ ID NO: 804
QVQLVESGGGVVQPGRSLRLSCAASGFTFSSYGMHWVRQAPGKGLEWVAFIWYEGSNKYYAESVKD
RFTISRDNSKNTLYLQMKSLRAEDTAVYYCARRAGIIGTIGYYYGMDVWGQGTTVTVSSASTKGPS
VFPLAPSSKSTSGGTAALGCLVKDYFPEPVTVSWNSGALTSGVHTFPAVLQSSGLYSLSSVVTVPS
SSLGTQTYICNVNHKPSNTKVDKKVEPKSCDKTHTCPPCPAPELLGGPSVFLFPPKPKDTLMISRT
PEVTCVVVDVSHEDPEVKFNWYVDGVEVHNAKTKPREEQYNSTYRVVSVLTVLHQDWLNGKEYKCK
VSNKALPAPIEKTISKAKGQPREPQVYTLPPSREEMTKNQVSLTCLVKGFYPSDIAVEWESNGQPE
NNYKTTPPVLDSDGSFFLYSKLTVDKSRWQQGNVFSCSVMHEALHNHYTQKSLSLSPGK
14304_HC [hu anti-<huCDH19> 2G6 (1-477)(R17G) VH]::huIgG1z
SEQ ID NO: 805
QVQLVESGGGVVQPGGSLRLSCAASGFTFSSYGMHWVRQAPGKGLEWVAFIWYDGSNKYYADSVKD
RFTISRDNSKNTLYLQMKSLRAEDTAVYYCARRAGIIGTIGYYYGMDVWGQGTTVTVSSASTKGPS
VFPLAPSSKSTSGGTAALGCLVKDYFPEPVTVSWNSGALTSGVHTFPAVLQSSGLYSLSSVVTVPS
SSLGTQTYICNVNHKPSNTKVDKKVEPKSCDKTHTCPPCPAPELLGGPSVFLFPPKPKDTLMISRT
PEVTCVVVDVSHEDPEVKFNWYVDGVEVHNAKTKPREEQYNSTYRVVSVLTVLHQDWLNGKEYKCK
VSNKALPAPIEKTISKAKGQPREPQVYTLPPSREEMTKNQVSLTCLVKGFYPSDIAVEWESNGQPE
NNYKTTPPVLDSDGSFFLYSKLTVDKSRWQQGNVFSCSVMHEALHNHYTQKSLSLSPGK
TABLE-US-00017 TABLE IIId Light Chain Variable and Contant Region
Polynucleotide and Amino acid Sequences 13586 LC [hu
anti-<huCDH19> 4F3 VL]::huKLC
EIVLTQSPGTLSLSPGERATLSCRASQSVSSSYLA
WYQQKPGQAPRLLIYGASSRATGIPDRFSGSGSGT
DFTLTISRLEPEDFAVYYCQQYGSSWTFGQGTKVE
IKRTVAAPSVFIFPPSDEQLKSGTASVVCLLNNFY
PREAKVQWKVDNALQSGNSQESVTEQDSKDSTYSL
SSTLTLSKADYEKHKVYACEVTHQGLSSPVTKSFN RGEC SEQ ID NO: 806 13589 LC
[hu anti-<huCDH19> 4A9 VL]::huLLC-C1
QSVLTQPPSVSGAPGQRVTISCTGSSSNIGTGYAV
HWYQQFPGTAPKLLIYGNNNRPSGVPDRFSGSKSG
TSASLAITGLQAEDEADYYCQSYDSRLSGWVFGGG
TKLTVLGQPKANPTVTLFPPSSEELQANKATLVCL
ISDFYPGAVTVAWKADGSPVKAGVETTKPSKQSNN
KYAASSYLSLTPEQWKSHRSYSCQVTHEGSTVEKT VAPTECS SEQ ID NO: 807 13590 LC
[hu anti-<huCDH19> 4B10 VL]::huKLC
EIVLTQSPGTLSLSPGERATLSCRASQSVSNTYLA
WYHQRPGQAPRLLIYGASSRATGIPDRFSGSGSGT
DFALTISSLEPEDFAVYYCQQYSNSWTFGQGTKVE
IKRTVAAPSVFIFPPSDEQLKSGTASVVCLLNNFY
PREAKVQWKVDNALQSGNSQESVTEQDSKDSTYSL
SSTLTLSKADYEKHKVYACEVTHQGLSSPVTKSFN RGEC SEQ ID NO: 808 13874 LC
[hu anti-<huCDH19> 17118.2 VL]::huKLC
DIVLTQSPGTLSLSPGERATLSCRASQSVAGSYLA
WYQQKPGQAPRLLISGASSRATGIPDRFSGSGSGT
DFTLTISRLEPEDFAVYYCQQYGKSPITFGQGTRL
EMKGTVAAPSVFIFPPSDEQLKSGTASVVCLLNNF
YPREAKVQWKVDNALQSGNSQESVTEQDSKDSTYS
LSSTLTLSKADYEKHKVYACEVTHQGLSSPVTKSF NRGEC SEQ ID NO: 809 13875 LC
[hu anti-<huCDH19> 16C1.1 VL]::huKLC
EIVLTQSPGTLSLSPGERATLSCRASQSVSSSYLA
WYQQKPGQAPRLLIFGASSRATGIPDRFSGSGSGT
DFTLTISGLEPEDFAVYHCQQYGNSPLTFGGGTKV
EIKRTVAAPSVFIFPPSDEQLKSGTASVVCLLNNF
YPREAKVQWKVDNALQSGNSQESVTEQDSKDSTYS
LSSTLTLSKADYEKHKVYACEVTHQGLSSPVTKSF NRGEC SEQ ID NO: 810 13876 LC
[hu anti-<huCDH19> 16A4.1 VL]::huKLC
EIVLTQSPGTLSLSPGERATLSCRASQSVSSSYLA
WYQQKPGQAPRLLIYGTSSRATGIPDRFSGSGSGT
DFTLTISRLEPEDFAVYYCQQYGSSPFTFGGGTKV
EIKRTVAAPSVFIFPPSDEQLKSGTASVVCLLNNF
YPREAKVQWKVDNALQSGNSQESVTEQDSKDSTYS
LSSTLTLSKADYEKHKVYACEVTHQGLSSPVTKSF NRGEC SEQ ID NO: 811 13877 LC
[hu anti-<huCDH19> 22G10.1 VL]::huKLC
EIVMTQSPVTLSLSLGERATLSCRASQSISSNLAW
FQQKPGQAPRLLIYGAFTRATGIPARVSGSGSGTE
FTLTISSLQSEDFAVYYCQQYNYWPLTFGGGTKVE
IKRTVAAPSVFIFPPSDEQLKSGTASVVCLLNNFY
PREAKVQWKVDNALQSGNSQESVTEQDSKDSTYSL
SSTLTLSKADYEKHKVYACEVTHQGLSSPVTKSFN RGEC SEQ ID NO: 812 13878 LC
[hu anti-<huCDH19> 20D3.1 VL]::huLLC-C2
QSALTQPPSATGTPGQRVTISCSGSSSNIGSNFVN
WYKQLPGTAPKVLIYTNNQRPSGVPDRFSGSKSGT
SASLAISGLQSEDESDYYCATWDDSLNGWVFGGGT
KLTVLGQPKAAPSVTLFPPSSEELQANKATLVCLI
SDFYPGAVTVAWKADSSPVKAGVETTTPSKQSNNK
YAASSYLSLTPEQWKSHRSYSCQVTHEGSTVEKTV APTECS SEQ ID NO: 813 13879 LC
[hu anti-<huCDH19> 22D1.1 VL]::huLLC-C2
QSALTQPPSATGTPGQRVTISCSGSSSNIGSNFVN
WYKQLPGTAPKVLIYTNNQRPSGVPDRFSGSKSGT
SASLAISGLQSEDESDYYCATWDDSMNGWVFGGGT
KLTVLGQPKAAPSVTLFPPSSEELQANKATLVCLI
SDFYPGAVTVAWKADSSPVKAGVETTTPSKQSNNK
YAASSYLSLTPEQWKSHRSYSCQVTHEGSTVEKTV APTECS SEQ ID NO: 814 13880 LC
[hu anti-<huCDH19> 25F8.1 VL]::huLLC-C2
QSALTQPPSATGTPGQRVTISCSGSSSNIGRNFVN
WYKQLPGTAPKVLIYTNNQRPSGVPDRFSGSKSGT
SASLAISGLQSEDESDYYCAAWDDSLNGWVFGGGT
KLTVLGQPKAAPSVTLFPPSSEELQANKATLVCLI
SDFYPGAVTVAWKADSSPVKAGVETTTPSKQSNNK
YAASSYLSLTPEQWKSHRSYSCQVTHEGSTVEKTV APTECS SEQ ID NO: 815 13881 LC
[hu anti-<huCDH19> 26F12.1 VL]::huLLC-C2
QSVLTQSPSASGTPGQKVTISCSGSRSNIGSNFVN
WYQQLPGTAPKLLIYTNYQRPSGVPDRFSGSKSGT
SASLAISGLQSEDEADYYCAVWDDSLNGWVFGGGT
KLTVLGQPKAAPSVTLFPPSSEELQANKATLVCLI
SDFYPGAVTVAWKADSSPVKAGVETTTPSKQSNNK
YAASSYLSLTPEQWKSHRSYSCQVTHEGSTVEKTV APTECS SEQ ID NO: 816 13882 LC
[hu anti-<huCDH19> 26D1.1 VL]::huLLC-C2
HSVLTQSPSASGTPGQRVTISCSGSRSNIGSNFVN
WYQQLPGTAPKLLIYTNNQRPSGVPDRFSGSKSGT
SASLAISGLQSEDEADYYCAVWDDSLNGWVFGGGT
KLTVLGQPKAAPSVTLFPPSSEELQANKATLVCLI
SDFYPGAVTVAWKADSSPVKAGVETTTPSKQSNNK
YAASSYLSLTPEQWKSHRSYSCQVTHEGSTVEKTV APTECS SEQ ID NO: 817 13883 LC
[hu anti-<huCDH19> 25G10.1 VL]::huKLC
EIVLTQSPGTLSLSPGERATLSCRASQSVSSSYLA
WYQQKPGQAPRLLIFGASSRATGIPDRFSGSGSGT
DFTLTISRLEPEDFAVYHCQQYGNSPLTFGGGTKV
EIKRTVAAPSVFIFPPSDEQLKSGTASVVCLLNNF
YPREAKVQWKVDNALQSGNSQESVTEQDSKDSTYS
LSSTLTLSKADYEKHKVYACEVTHQGLSSPVTKSF NRGEC SEQ ID NO: 818 13885 LC
[hu anti-<huCDH19> 19B5.1 VL]::huLLC-C2
QSALTQPPSTTGTPGQRVTISCSGSRSNIGSNFVN
WYKQLPGTAPKVLIYTNNQRPSGVPDRFSGSKSGT
SASLAISGLQSEDESDYYCATWDDSMNGWVFGGGT
ICLTVLGQPICAAPSVTLFPPSSEELQANKATLVC
LISDFYPGAVTVAWKADSSPVKAGVETTTPSKQSN
NKYAASSYLSLTPEQWKSHRSYSCQVTHEGSTVEK TVAPTECS SEQ ID NO: 819 14022
LC [hu anti-<huCDH19> 4A2 (1-236)(N30Q) VL]::huKLC
EIVLTQSPGTLSLSPGERATLSCRASRQISSSYLAWY
QQKPGQAPRLLIYGPSSRATGIPDRFSGSGSGTDFTL
TISRLEPEDFTVYYCQQYGSSFTFGPGTKVDIKRT
VAAPSVFIFPPSDEQLKSGTASVVCLLNNFYPREA
KVQWKVDNALQSGNSQESVTEQDSKDSTYSLSSTL
TLSKADYEKHKVYACEVTHQGLSSPVTKSFNRGEC SEQ ID NO: 820 14024 LC [hu
anti-<huCDH19> 4A2 (1-236)(N30Q, T102A, P141Q) VL]::huKLC
EIVLTQSPGTLSLSPGERATLSCRASRQISSSYLA
WYQQKPGQAPRLLIYGPSSRATGIPDRFSGSGSGT
DFTLTISRLEPEDFAVYYCQQYGSSFTFGQGTKVD
IKRTVAAPSVFIFPPSDEQLKSGTASVVCLLNNFY
PREAKVQWKVDNALQSGNSQESVTEQDSKDSTYSL
SSTLTLSICADYEKHKVYACEVTHQGLSSPVTKSF NRGEC SEQ ID NO: 821 14025 LC
[hu anti-<huCDH19> 4A2 (1-236)(N30Q, T102A) VL]::huKLC
EIVLTQSPGTLSLSPGERATLSCRASRQISSSYLA
WYQQKPGQAPRLLIYGPSSRATGIPDRFSGSGSGT
DFTLTISRLEPEDFAVYYCQQYGSSFTFGPGTKVD
IKRTVAAPSVFIFPPSDEQLKSGTASVVCLLNNFY
PREAKVQWKVDNALQSGNSQESVTEQDSKDSTYSL
SSTLTLSKADYEKHKVYACEVTHQGLSSPVTKSFN RGEC SEQ ID NO: 822 14026 LC
[hu anti-<huCDH19> 4A2 (1-236)(N30Q, T102A) VL]::huKLC
EIVLTQSPGTLSLSPGERATLSCRASRQISSSYLA
WYQQKPGQAPRLLIYGPSSRATGIPDRFSGSGSGT
DFTLTISRLEPEDFAVYYCQQYGSSFTFGPGTKVD
IKRTVAAPSVFIFPPSDEQLKSGTASVVCLLNNFY
PREAKVQWKVDNALQSGNSQESVTEQDSKDSTYSL
SSTLTLSKADYEKHKVYACEVTHQGLSSPVTKSFN RGEC SEQ ID NO: 823 14027 LC
[hu anti-<huCDH19> 4A2 (1-236)(N30Q, T102A, P141Q) VL]::huKLC
EIVLTQSPGTLSLSPGERATLSCRASRQISSSYLA
WYQQKPGQAPRLLIYGPSSRATGIPDRFSGSGSGT
DFTLTISRLEPEDFAVYYCQQYGSSFTFGQGTKVD
IKRTVAAPSVFIFPPSDEQLKSGTASVVCLLNNFY
PREAKVQWKVDNALQSGNSQESVTEQDSKDSTYSL
SSTLTLSKADYEKHKVYACEVTHQGLSSPVTKSFN RGEC SEQ ID NO: 824 14028 LC
[hu anti-<huCDH19> 4A2 (1-236)(N30Q, T102A, P141Q) VL]::huKLC
EIVLTQSPGTLSLSPGERATLSCRASRQISSSYLAW
YQQKPGQAPRLLIYGPSSRATGIPDRFSGSGSGTD
FTLTISRLEPEDFAVYYCQQYGSSFTFGQGTKVDI
KRTVAAPSVFIFPPSDEQLKSGTASVVCLLNNFYP
REAKVQWKVDNALQSGNSQESVTEQDSKDSTYSLS
STLTLSKADYEKHKVYACEVTHQGLSSPVTKSFNR GEC SEQ ID NO: 825 14029 LC [hu
anti-<huCDH19> 4A2 (1-236)(R290, N30S) VL]::huKLC
EIVLTQSPGTLSLSPGERATLSCRASQSISSSYLA
WYQQKPGQAPRLLIYGPSSRATGIPDRFSGSGSGT
DFTLTISRLEPEDFTVYYCQQYGSSFTFGPGTKVD
IKRTVAAPSVFIFPPSDEQLKSGTASVVCLLNNFY
PREAKVQWKVDNALQSONSQESVTEQDSKDSTYSL
SSTLTLSKADYEKHKVYACEVTHQGLSSPVTKSFN RGEC SEQ ID NO: 826 14030 LC
[hu anti-<huCDH19> 4F3 VL]::huKLC
EIVLTQSPGTLSLSPGERATLSCRASQSVSSSYLA
WYQQKPGQAPRLLIYGASSRATGIPDRFSGSGSGT
DFTLTISRLEPEDFAVYYCQQYGSSWTFGQGTKVE
IKRTVAAPSVFIFPPSDEQLKSGTASVVCLLNNFY
PREAKVQWKVDNALQSGNSQESVTEQDSKDSTYSL
SSTLTLSKADYEKEKVYACEVTHQGLSSPVTKSFN RGEC SEQ ID NO: 827 14031 LC
[hu anti-<huCDH19> 4F3
VL]::huKLC EIVLTQSPGTLSLSPGERATLSCRASQSVSSSYLA
WYQQICPGQAPRLLIYGASSRATGIPDRFSGSGSG
TDFTLTISRLEPEDFAVYYCQQYGSSWTFGQGTKV
EIKRTVAAPSVFIFPPSDEQLKSGTASVVCLLNNF
YPREAKVQWKVDNALQSGNSQESVTEQDSKDSTYS
LSSTLTLSKADYEKHKVYACEVTHQGLSSPVTKSF NRGEC SEQ ID NO: 828 14032 LC
[hu anti-<huCDH19> 4F3 VL]::huKLC
EIVLTQSPGTLSLSPGERATLSCRASQSVSSSYLA
WYQQKPGQAPRLLIYGASSRATGIPDRFSGSGSGT
DFTLTISRLEPEDFAVYYCQQYGSSWTFGQGTKVEI
KRTVAAPSVFIFPPSDEQLKSGTASVVCLLNNFYP
REAKVQWKVDNALQSGNSQESVTEQDSKDSTYSLS
STLTLSKADYEKHKVYACEVTHQGLSSPVTKSFNR GEC SEQ ID NO: 829 14033 LC [hu
anti-<huCDH19> 4F3 VL]::huKLC
EIVLTQSPGTLSLSPGERATLSCRASQSVSSSYLAWY
QQKPGQAPRLLIYGASSRATGIPDRFSGSGSGTDFTL
TISRLEPEDFAVYYCQQYGSSWTFGQGTKVEIKRT
VAAPSVFIFPPSDEQLKSGTASVVCLLNNFYPREA
KVQWKVDNALQSONSQESVTEQDSKDSTYSLSSTL
TLSKADYEKHKVYACEVTHQGLSSPVTKSFNRGEC SEQ ID NO: 830 14034 LC [hu
anti-<huCDH19> 4F3 VL]::huKLC
EIVLTQSPGTLSLSPGERATLSCRASQSVSSSYLA
WYQQKPGQAPRLLIYGASSRATGIPDRFSGSGSGT
DFTLTISRLEPEDFAVYYCQQYGSSWTFGQGTKVE
IKRTVAAPSVFIFPPSDEQLKSGTASVVCLLNNFY
PREAKVQWKVDNALQSGNSQESVTEQDSKDSTYSL
SSTLTLSKADYEKHKVYACEVTHQGLSSPVTKSFN RGEC SEQ ID NO: 831 14039 LC
[hu anti-<huCDH19> 2G6 (1-234)(C42S, D110E) VL]::huLLC-C1
SYELTQPPSVSVSPGQTASITCSGDRLGEKYTSWY
QQRPGQSPLLVIYQDTKRPSGIPERFSGSNSGNTA
TLTISGTQAMDEADYYCQAWESSTVVFGGGTKLTV
LGQPKANPTVTLFPPSSEELQANKATLVCLISDFY
PGAVTVAWKADGSPVKAGVETTKPSKQSNNKYAAS
SYLSLTPEQWKSHRSYSCQVTHEGSTVEKTVAPTE CS SEQ ID NO: 832 14040 LC [hu
anti-<huCDH19> 16C1.1 (1-235)(H105Y) VL]::huKLC
EIVLTQSPGTLSLSPGERATLSCRASQSVSSSYLA
WYQQKPGQAPRLLIFGASSRATGIPDRFSGSGSGT
DFTLTISGLEPEDFAVYYCQQYGNSPLTFGGGTKV
EIKRTVAAPSVFIFPPSDEQLKSGTASVVCLLNNF
YPREAKVQWKVDNALQSGNSQESVTEQDSKDSTYS
LSSTLTLSKADYEKHKVYACEVTHQGLSSPVTKSF NRGEC SEQ ID NO: 833 14041 LC
[hu anti-<huCDH19> 16C1.1 (1-235)(H105Y) VL]::hul(LC
EIVLTQSPGTLSLSPGERATLSCRASQSVSSSYLA
WYQQKPGQAPRLLIFGASSRATGIPDRFSGSGSGT
DFTLTISGLEPEDFAVYYCQQYGNSPLTFGGGTKV
EIKRTVAAPSVFIFPPSDEQLKSGTASVVCLLNNF
YPREAKVQWKVDNALQSGNSQESVTEQDSKDSTYS
LSSTLTLSKADYEKHKVYACEVTHQGLSSPVTKSF NRGEC SEQ ID NO: 834 14042 LC
[hu anti-<huCDH19> 16C1.1 (1-235)(H105Y) VL]::hul(LC
EIVLTQSPGTLSLSPGERATLSCRASQSVSSSYLA
WYQQKPGQAPRLLIFGASSRATGIPDRFSGSGSGT
DFTLTISGLEPEDFAVYYCQQYGNSPLTFGGGTKV
EIKRTVAAPSVFIFPPSDEQLKSGTASVVCLLNNF
YPREAKVQWKVDNALQSGNSQESVTEQDSKDSTYS
LSSTLTLSKADYEKHKVYACEVTHQGLSSPVTKSF NRGEC SEQ ID NO: 835 14043 LC
[hu anti-<huCDH19> 16C1.1 (1-235)(H105Y) VL]::huKLC
EIVLTQSPGTLSLSPGERATLSCRASQSVSSSYLA
WYQQKPGQAPRLLIFGASSRATGIPDRFSGSGSGT
DFTLTISGLEPEDFAVYYCQQYGNSPLTFGGGTKV
EIKRTVAAPSVFIFPPSDEQLKSGTASVVCLLNNF
YPREAKVQWKVDNALQSGNSQESVTEQDSKDSTYS
LSSTLTLSKADYEKHKVYACEVTHQGLSSPVTKSF NRGEC SEQ ID NO: 836 14044 LC
[hu anti-<huCDH19> 16C1.1 (1-235)(G95R, H105Y, G141Q)
VL]::hul(LC EIVLTQSPGTLSLSPGERATLSCRASQSVSSSYLA
WYQQKPGQAPRLLIFGASSRATGIPDRFSGSGSGT
DFTLTISRLEPEDFAVYYCQQYGNSPLTFGQGTKV
EIKRTVAAPSVFIFPPSDEQLKSGTASVVCLLNNF
YPREAKVQWKVDNALQSGNSQESVTEQDSKDSTYS
LSSTLTLSKADYEKHKVYACEVTHQGLSSPVTKSF NRGEC SEQ ID NO: 837 14045 LC
[hu anti-<huCDH19> 17H8.2 (1-235)(G149R) VL]::huKLC
DIVLTQSPGTLSLSPGERATLSCRASQSVAGSYLA
WYQQKPGQAPRLLISGASSRATGIPDRFSGSGSGT
DFTLTISRLEPEDFAVYYCQQYGKSPITFGQGTRL
EMKRTVAAPSVFIFPPSDEQLKSGTASVVCLLNNF
YPREAKVQWKVDNALQSGNSQESVTEQDSKDSTYS
LSSTLTLSKADYEKHKVYACEVTHQGLSSPVTKSF NRGEC SEQ ID NO: 838 14046 LC
[hu anti-<huCDH19> 17H8.2 (1-235)(G149R) VL]::huKLC
DIVLTQSPGTLSLSPGERATLSCRASQSVAGSYLA
WYQQKPGQAPRLLISGASSRATGIPDRFSGSGSGT
DFTLTISRLEPEDFAVYYCQQYGKSPITFGQGTRL
EMKRTVAAPSVFIFPPSDEQLKSGTASVVCLLNNF
YPREAKVQWKVDNALQSGNSQESVTEQDSKDSTYS
LSSTLTLSKADYEKHKVYACEVTHQGLSSPVTKSF NRGEC SEQ ID NO: 839 14047 LC
[hu anti-<huCDH19> 17118.2 (1-235)(G149R) VL]::huKLC
DIVLTQSPGTLSLSPGERATLSCRASQSVAGSYLA
WYQQKPGQAPRLLISGASSRATGIPDRFSGSGSGT
DFTLTISRLEPEDFAVYYCQQYGKSPITFGQGTRL
EMKRTVAAPSVFIFPPSDEQLKSGTASVVCLLNNF
YPREAKVQWKVDNALQSGNSQESVTEQDSKDSTYS
LSSTLTLSKADYEKHKVYACEVTHQGLSSPVTKSF NRGEC SEQ ID NO: 840 14048 LC
[hu anti-<huCDH19> 17118.2 (1-235)(S57Y, G149R) VL]::huKLC
DIVLTQSPOTLSLSPGERATLSCRASQSVAGSYLA
WYQQKPGQAPRLLIYGASSRATGIPDRFSGSGSGT
DFTLTISRLEPEDFAVYYCQQYGKSPITFGQGTRL
EMKRTVAAPSVFIFPPSDEQLKSGTASVVCLLNNF
YPREAKVQWKVDNALQSGNSQESVTEQDSKDSTYS
LSSTLTLSKADYEKHKVYACEVTHQGLSSPVTKSF NRGEC SEQ ID NO: 841 14049 LC
[hu anti-<huCDH19> 4F7 (1-239)(H57Y) VL]::huLLC-C2
QSVLTQPPSVSGAPGQRVTISCTGSSSNIGTGYDV
HWYQQLPGTAPKLLIYGNSNRPSGVPDRFSGSKSG
TSASLAITGLQAEDEADYYCQSYDSSLSGWVFGGG
TRLTVLGQPKANPTVTLFPPSSEELQANKATLVCL
ISDFYPGAVTVAWKADGSPVKAGVETTKPSKQSNN
KYAASSYLSLTPEQWKSHRSYSCQVTHEGSTVEKT VAPTECS SEQ ID NO: 842 14050 LC
[hu anti-<huCDH19> 4F7 (1-239)(1157Y, D110E) VL]::huLLC-C2
QSVLTQPPSVSGAPGQRVTISCTGSSSNIGTGYDV
HWYQQLPGTAPKLLIYGNSNRPSGVPDRFSGSKSG
TSASLAITGLQAEDEADYYCQSYESSLSGWVFGGG
TRLTVLGQPKANPTVTLFPPSSEELQANKATLVCL
ISDFYPGAVTVAWKADGSPVKAGVETTKPSKQSNN
KYAASSYLSLTPEQWKSHRSYSCQVTHEGSTVEKT VAPTECS SEQ ID NO: 843 14051 LC
[hu anti-<huCDH19> 4F7 (1-239)(D110E) VL]::huLLC-C2
QSVLTQPPSVSGAPGQRVTISCTGSSSNIGTGYDV
HWYQQLPGTAPKLLIHGNSNRPSGVPDRFSGSKSG
TSASLAITGLQAEDEADYYCQSYESSLSGWVFGGG
TRLTVLGQPKANPTVTLFPPSSEELQANKATLVCL
ISDFYPGAVTVAWKADGSPVKAGVETTKPSKQSNN
KYAASSYLSLTPEQWKSHRSYSCQVTHEGSTVEKT VAPTECS SEQ ID NO: 844 14052 LC
[hu anti-<huCDH19> 4B10 (1-236)(H45Q, A90T) VL]::huKLC
EIVLTQSPGTLSLSPGERATLSCRASQSVSNTYLA
WYQQRPGQAPRLLIYGASSRATGIPDRFSGSGSGT
DFTLTISSLEPEDFAVYYCQQYSNSWTFGQGTKVE
IKRTVAAPSVFIFPPSDEQLKSGTASVVCLLNNFY
PREAKVQWKVDNALQSGNSQESVTEQDSKDSTYSL
SSTLTLSKADYEKHKVYACEVTHQGLSSPVTKSFN RGEC SEQ ID NO: 845 14053 LC
[hu anti-<huCDH19> 4B10 (1-236)(11450, A90T) VL]::huKLC
EIVLTQSPOTLSLSPGERATLSCRASQSVSNTYLA
WYQQRPGQAPRLLIYGASSRATGIPDRFSGSGSGT
DFTLTISSLEPEDFAVYYCQQYSNSWTFGQGTKVE
IKRTVAAPSVFIFPPSDEQLKSGTASVVCLLNNFY
PREAKVQWKVDNALQSGNSQESVTEQDSKDSTYSL
SSTLTLSKADYEKHKVYACEVTHQGLSSPVTKSFN RGEC SEQ ID NO: 846 14054 LC
[hu anti-<huCDH19> 4B10 (1-236)(11450, A90T) VL]::huKLC
EIVLTQSPGTLSLSPGERATLSCRASQSVSNTYLA
WYQQRPGQAPRLLIYGASSRATGIPDRFSGSGSGT
DFTLTISSLEPEDFAVYYCQQYSNSWTFGQGTKVE
IKRTVAAPSVFIFPPSDEQLKSGTASVVCLLNNFY
PREAKVQWKVDNALQSGNSQESVTEQDSKDSTYSL
SSTLTLSKADYEKHKVYACEVTHQGLSSPVTKSFN RGEC SEQ ID NO: 847 14055 LC
[hu anti-<huCDH19> 4B10 (1-236)(H45Q, A90T) VL]::huKLC
EIVLTQSPGTLSLSPGERATLSCRASQSVSNTYLA
WYQQRPGQAPRLLIYGASSRATGIPDRFSGSGSGT
DFTLTISSLEPEDFAVYYCQQYSNSWTFGQGTKVE
IKRTVAAPSVFIFPPSDEQLKSGTASVVCLLNNFY
PREAKVQWKVDNALQSGNSQESVTEQDSKDSTYSL
SSTLTLSKADYEKHKVYACEVTHQGLSSPVTKSFN RGEC SEQ ID NO: 848 14056 LC
[hu anti-<huCDH19> 4A9 (1-239)(F47L) VL]::huLLC-C1
QSVLTQPPSVSGAPGQRVTISCTGSSSNIGTGYAV
HWYQQLPGTAPKLLIYGNNNRPSGVPDRFSGSKSG
TSASLAITGLQAEDEADYYCQSYDSRLSGWVFGGG
TKLTVLGQPKANPTVTLFPPSSEELQANKATLVCL
ISDFYPGAVTVAWKADGSPVKAGVETTKPSKQSNN
KYAASSYLSLTPEQWKSHRSYSCQVTHEGSTVEKT VAPTECS SEQ ID NO: 849 14057 LC
[hu anti-<huCDH19> 4A9 (1-239)(F47L) VL]::huLLC-C1
QSVLTQPPSVSGAPGQRVTISCTGSSSNIGTGYAV
HWYQQLPGTAPKLLIYGNNNRPSGVPDRFSGSKSG
TSASLAITGLQAEDEADYYCQSYDSRLSGWVFGGG
TKLTVLGQPKANPTVTLFPPSSEELQANKATLVCL
ISDFYPGAVTVAWKADOSPVKAGVETTKPSKQSNN
KYAASSYLSLTPEQWKSHRSYSCQVTHEGSTVEKT VAPTECS SEQ ID NO: 850
14058 LC [hu anti-<huCDH19> 4A9 (1-239)(F47L, D110E)
VL]::huLLC-C1 QSVLTQPPSVSGAPGQRVTISCTGSSSNIGTGYAV
HWYQQLPGTAPKLLIYGNNNRPSGVPDRFSGSKSG
TSASLAITGLQAEDEADYYCQSYESRLSGWVEGGG
TKLTVLGQPKANPTVTLEPPSSEELQANKATLVCL
ISDFYPGAVTVAWKADGSPVKAGVETTKPSKQSNN
KYAASSYLSLTPEQWKSHRSYSCQVTHEGSTVEKT VAPTECS SEQ ID NO: 851 14059 LC
[hu anti-<huCDH19> 4A9 (1-239)(F47L, D110E) VL]::huLLC-C1
QSVLTQPPSVSGAPGQRVTISCTGSSSNIGTGYAV
HWYQQLPGTAPKWYGNNNRPSGVPDRFSGSKSGTS
ASLAITGLQAEDEADYYCQSYESRLSGWVFGGGTK
LTVLGQPKANPTVTLFPPSSEELQANKATLVCLIS
DFYPGAVTVAWKADGSPVKAGVETTKPSKQSNNKY
AASSYLSLTPEQWKSHRSYSCQVTHEGSTVEKTVA PTECS SEQ ID NO: 852 14060 LC
[hu anti-<huCDH19> 20D3.1 (1-235)(S102A) VL]::huLLC-C2
QSALTQPPSATGTPGQRVTISCSGSSSNIGSNFVN
WYKQLPGTAPKVLIYTNNQRPSGVPDRFSGSKSGT
SASLAISGLQSEDEADYYCATWDDSLNGWVFGGGT
KLTVLGQPKAAPSVTLFPPSSEELQANKATLVCLI
SDFYPGAVTVAWKADSSPVKAGVETTTPSKQSNNK
YAASSYLSLTPEQWKSHRSYSCQVTHEGSTVEKTV APTECS SEQ ID NO: 853 14061 LC
[hu anti-<huCDH19> 20D3.1 (1-235)(K45Q, S102A) VL]::huLLC-C2
QSALTQPPSATGTPGQRVTISCSGSSSNIGSNFVN
WYQQLPGTAPKVLIYTNNQRPSGVPDRFSGSKSGT
SASLAISGLQSEDEADYYCATWDDSLNGWVFGGGT
KLTVLGQPICAAPSVTLFPPSSEELQANKATLVCL
ISDFYPGAVTVAWKADSSPVKAGVETTTPSKQSNN
KYAASSYLSLTPEQWKSHRSYSCQVTHEGSTVEKT VAPTECS SEQ ID NO: 854 14062 LC
[hu anti-<huCDH19> 20D3.1 (1-235)(K45Q, S102A) VL]::huLLC-C2
QSALTQPPSATGTPGQRVTISCSGSSSNIGSNFVN
WYQQLPGTAPKVLIYTNNQRPSGVPDRFSGSKSGT
SASLAISGLQSEDEADYYCATWDDSLNGWVEGGGT
KLTVLGQPKAAPSVTLFPPSSEELQANKATLVCLI
SDFYPGAVTVAWKADSSPVKAGVETTTPSKQSNNK
YAASSYLSLTPEQWKSHRSYSCQVTHEGSTVEKTV APTECS SEQ ID NO: 855 14063 LC
[hu anti-<huCDH19> 20D3.1 (1-235)(K45Q, S102A, D111E, N135Q)
VL]::huLLC-C2 QSALTQPPSATGTPGQRVTISCSGSSSNIGSNFVN
WYQQLPGTAPKVLIYTNNQRPSGVPDRFSGSKSGT
SASLAISGLQSEDEADYYCATWDESLQGWVFGGGT
KLTVLGQPKAAPSVTLFPPSSEELQANKATLVCLI
SDFYPGAVTVAWKADSSPVKAGVETTTPSKQSNNK
YAASSYLSLTPEQWKSHRSYSCQVTHEGSTVEKTV APTECS SEQ ID NO: 856 14064 LC
[hu anti-<huCDH19> 20D3.1 (1-235)(W109Y) VL]::huLLC-C2
QSALTQPPSATGTPGQRVTISCSGSSSNIGSNFVN
WYKQLPGTAPKVLIYTNNQRPSGVPDRFSGSKSGT
SASLAISGLQSEDESDYYCATYDDSLNGWVFGGGT
KLTVLGQPKAAPSVTLFPPSSEELQANKATLVCLI
SDFYPGAVTVAWKADSSPVKAGVETTTPSKQSNNK
YAASSYLSLTPEQWKSHRSYSCQVTHEGSTVEKTV APTECS SEQ ID NO: 857 14065 LC
[hu anti-<huCDH19> 22G10.1 VL]::huKLC
EIVMTQSPVTLSLSLGERATLSCRASQSISSNLAW
FQQKPGQAPRLLIYGAFTRATGIPARVSGSGSGTE
FTLTISSLQSEDFAVYYCQQYNYWPLTFGGGTKVE
IKRTVAAPSVFIFPPSDEQLKSGTASVVCLLNNFY
PREAKVQWKVDNALQSGNSQESVTEQDSKDSTYSL
SSTLTLSKADYEKHKVYACEVTHQGLSSPVTKSFN RGEC SEQ ID NO: 858 14066 LC
[hu anti-<huCDH19> 22G10.1 VL]::huKLC
EIVMTQSPVTLSLSLGERATLSCRASQSISSNLAW
FQQKPGQAPRLLIYGAFTRATGIPARVSGSGSGTE
FTLTISSLQSEDFAVYYCQQYNYWPLTFGGGTKVE
IKRTVAAPSVFIFPPSDEQLKSGTASVVCLLNNFY
PREAKVQWKVDNALQSGNSQESVTEQDSKDSTYSL
SSTLTLSKADYEKHKVYACEVTHQGLSSPVTKSFN RGEC SEQ ID NO: 859 14067 LC
[hu anti-<huCDH19> 22G10.1 (1-234)(097E, S981P) VL]::huKLC
EIVMTQSPVTLSLSLGERATLSCRASQSISSNLAW
FQQKPGQAPRLLIYGAFTRATGIPARVSGSGSGTE
FTLTISSLEPEDFAVYYCQQYNYWPLTFGGGTKVE
IKRTVAAPSVFIFPPSDEQLKSGTASVVCLLNNFY
PREAKVQWKVDNALQSGNSQESVTEQDSKDSTYSL
SSTLTLSKADYEKHKVYACEVTHQGLSSPVTKSFN RGEC SEQ ID NO: 860 14068 LC
[hu anti-<huCDH19> 22G10.1 (1-234)(V78F, 097E, S98P)
VL]::huKLC EIVMTQSPVTLSLSLGERATLSCRASQSISSNLAW
FQQKPGQAPRLLIYGAFTRATGIPARFSGSGSGTE
FTLTISSLEPEDFAVYYCQQYNYWPLTFGGGTKVE
IKRTVAAPSVFIFPPSDEQLKSGTASVVCLLNNEY
PREAKVQWKVDNALQSGNSQESVTEQDSKDSTYSL
SSTLTLSKADYEKHKVYACEVTHQGLSSPVTKSFN RGEC SEQ ID NO: 861 14069 LC
[hu anti-<huCDH19> 22G10.1 (1-234)(V78F, 097E, S98P)
VL]::huKLC EIVMTQSPVTLSLSLGERATLSCRASQSISSNLAW
FQQKPGQAPRLLIYGAFTRATGIPARFSGSGSGTE
FTLTISSLEPEDFAVYYCQQYNYWPLTFGGGTKVE
IKRTVAAPSVFIFPPSDEQLKSGTASVVCLLNNFY
PREAKVQWKVDNALQSGNSQESVTEQDSKDSTYSL
SSTLTLSKADYEKHKVYACEVTHQGLSSPVTKSFN RGEC SEQ ID NO: 862 14070 LC
[hu anti-<huCDH19> 22G10.1 VL]::huKLC
EIVMTQSPVTLSLSLGERATLSCRASQSISSNLAW
FQQKPGQAPRLLIYGAFTRATGIPARVSGSGSGTE
FTLTISSLQSEDFAVYYCQQYNYWPLTEGGOTKVE
IKRTVAAPSVFIFPPSDEQLKSGTASVVCLLNNEY
PREAKVQWKVDNALQSGNSQESVTEQDSKDSTYSL
SSTLTLSKADYEKHKVYACEVTHQGLSSPVTKSFN RGEC SEQ ID NO: 863 14071 LC
[hu anti-<huCDH19> 16A4.1 (1-235)(G141Q) VL]::huKLC
EIVLTQSPGTLSLSPGERATLSCRASQSVSSSYLA
WYQQKPGQAPRLLIYGTSSRATGIPDRFSGSGSGT
DFTLTISRLEPEDFAVYYCQQYGSSPFTFGQGTKV
EIKRTVAAPSVFIFPPSDEQLKSGTASVVCLLNNF
YPREAKVQWKVDNALQSGNSQESVTEQDSKDSTYS
LSSTLTLSKADYEKHKVYACEVTHQGLSSPVTKSF NRGEC SEQ ID NO: 864 14072 LC
[hu anti-<huCDH19> 19B5.1 (1-235)(K45Q, S102A) VL]::huLLC-C2
QSALTQPPSTTGTPGQRVTISCSGSRSNIGSNFVN
WYQQLPGTAPKVLIYTNNQRPSGVPDRFSGSKSGT
SASLAISGLQSEDEADYYCATWDDSMNGWVFGGGT
KLTVLGQPKAAPSVTLFPPSSEELQANKATLVCLI
SDFYPGAVTVAWKADSSPVKAGVETTTPSKQSNNK
YAASSYLSLTPEQWKSHRSYSCQVTHEGSTVEKTV APTECS SEQ ID NO: 865 14073 LC
[hu anti-<huCDH19> 19B5.1 (1-235)(K450, S102A) VL]::huLLC-C2
QSALTQPPSTTGTPGQRVTISCSGSRSNIGSNEVN
WYQQLPGTAPKVLIYTNNQRPSGVPDRFSGSKSGT
SASLAISGLQSEDEADYYCATWDDSMNGWVFGGGT
KLTVLGQPKAAPSVTLFPPSSEELQANKATLVCLI
SDFYPGAVTVAWKADSSPVKAGVETTTPSKQSNNK
YAASSYLSLTPEQWKSHRSYSCQVTHEGSTVEKTV APTECS SEQ ID NO: 866 14074 LC
[hu anti-<huCDH19> 19B5.1 (1-235)(T11V, K450, S102A)
VL]::huLLC-C2 QSALTQPPSVTGTPGQRVTISCSGSRSNIGSNFVN
WYQQLPGTAPKVLIYTNNQRPSGVPDRFSGSKSGT
SASLAISGLQSEDEADYYCATWDDSMNGWVFGGOT
KLTVLGQPKAAPSVTLFPPSSEELQANKATLVCLI
SDFYPGAVTVAWKADSSPVKAGVETTTPSKQSNNK
YAASSYLSLTPEQWKSHRSYSCQVTHEGSTVEKTV APTECS SEQ ID NO: 867 14075 LC
[hu anti-<huCDH19> 19B5.1 (1-235)(T11V, K45Q, S102A, D111E,
N135Q) VL]::huLLC-C2 QSALTQPPSVTGTPGQRVTISCSGSRSNIGSNFVN
WYQQLPGTAPKVLIYTNNQRPSGVPDRFSGSKSGT
SASLAISGLQSEDEADYYCATWDESMQGWVEGGGT
KLTVLGQPKAAPSVTLEPPSSEELQANKATLVCLI
SDFYPGAVTVAWKADSSPVKAGVETTTPSKQSNNK
YAASSYLSLTPEQWKSHRSYSCQVTHEGSTVEKTV APTECS SEQ ID NO: 868 14076 LC
[hu anti-<huCDH19> 19B5.1 (1-235)(T11V, K45Q, S102A, W109Y,
D111E, N135Q) VL]::huLLC-C2 QSALTQPPSVTGTPGQRVTISCSGSRSNIGSNFVN
WYQQLPGTAPKVLIYTNNQRPSGVPDRFSGSKSGT
SASLAISGLQSEDEADYYCATYDESMQGWVFGGGT
KLTVLGQPKAAPSVTLFPPSSEELQANKATLVCLI
SDFYPGAVTVAWKADSSPVKAGVETTTPSKQSNNK
YAASSYLSLTPEQWKSHRSYSCQVTHEGSTVEKTV APTECS SEQ ID NO: 869 14077 LC
[hu anti-<huCDH19> 23A10.3 (1-231)(C42S) VL]::huLLC-C2
SYELTQPPSVSVSPGQTASITCSGDRLGEKYVSWY
QQKPGQSPILVIYQDNKWPSGIPERFSGSNSGNTA
TLTISGTQAMDEADYYCQAWDSSTVVFGGGTKLTV
LGQPKAAPSVTLFPPSSEELQANKATLVCLISDFY
PGAVTVAWKADSSPVKAGVETTTPSKQSNNKYAAS
SYLSLTPEQWKSHRSYSCQVTHEGSTVEKTVAPTE CS SEQ ID NO: 870 14078 LC [hu
anti-<huCDH19> 23A10.3 (1-231)(C42S) VL]::huLLC-C2
SYELTQPPSVSVSPGQTASITCSGDRLGEKYVSWY
QQKPGQSPILVIYQDNKWPSGIPERFSGSNSGNTA
TLTISGTQAMDEADYYCQAWDSSTVVFGGGTKLTV
LGQPKAAPSVTLFPPSSEELQANKATLVCLISDFY
PGAVTVAWKADSSPVKAGVETTTPSKQSNNKYAAS
SYLSLTPEQWKSHRSYSCQVTHEGSTVEKTVAPTE CS SEQ ID NO: 871 14079 LC [hu
anti-<huCDH19> 23A10.3 (1-231)(C42S, D110E) VL]::huLLC-C2
SYELTQPPSVSVSPGQTASITCSGDRLGEKYVSWY
QQKPGQSPILVIYQDNKWPSGIPERFSGSNSGNTA
TLTISGTQAMDEADYYCQAWESSTVVFGGGTKLTV
LGQPKAAPSVTLFPPSSEELQANKATLVCLISDFY
PGAVTVAWKADSSPVKAGVETTTPSKQSNNKYAAS
SYLSLTPEQWKSHRSYSCQVTHEGSTVEKTVAPTE CS SEQ ID NO: 872 14080 LC [hu
anti-<huCDH19> 23A10.3 (1-231)(C42Y) VL]::huLLC-C2
SYELTQPPSVSVSPGQTASITCSGDRLGEKYVYWY
QQKPGQSPILVIYQDNKWPSGIPERFSGSNSGNTA
TLTISGTQAMDEADYYCQAWDSSTVVFOGGTKLTV
LGQPKAAPSVTLFPPSSEELQANKATLVCLISDFY
PGAVTVAWKADSSPVKAGVETTTPSKQSNNKYAAS
SYLSLTPEQWKSHRSYSCQVTHEGSTVEKTVAPTE CS SEQ ID NO: 873 14081 LC [hu
anti-<huCDH19> 25G10.1 (1-235)(H105Y) VL]::hul(LC
EIVLTQSPGTLSLSPGERATLSCRASQSVSSSYLA
WYQQKPGQAPRLLIFGASSRATGIPDRFSGSGSGT
DFTLTISRLEPEDFAVYYCQQYGNSPLTFGGGTKV
EIKRTVAAPSVFIFPPSDEQLKSGTASVVCLLNNF
YPREAKVQWKVDNALQSGNSQESVTEQDSKDSTYS
LSSTLTLSKADYEKHKVYACEVTHQGLSSPVTKSF NRGEC SEQ ID NO: 874 14082 LC
[hu anti-<huCDH19> 25G10.1 (1-235)(H105Y) VL]::hul(LC
EIVLTQSPGTLSLSPGERATLSCRASQSVSSSYLA
WYQQKPGQAPRLLIFGASSRATGIPDRFSGSGSGT
DFTLTISRLEPEDFAVYYCQQYGNSPLTFGGGTKV
EIKRTVAAPSVFIFPPSDEQLKSGTASVVCLLNNF
YPREAKVQWKVDNALQSGNSQESVTEQDSKDSTYS
LSSTLTLSKADYEKHKVYACEVTHQGLSSPVTKSF NRGEC SEQ ID NO: 875 14083 LC
[hu anti-<huCDH19> 26D1.1 (1-235)(S7P) VL]::huLLC-C2
HSVLTQPPSASGTPGQRVTISCSGSRSNIGSNFVN
WYQQLPGTAPKLLIYTNNQRPSGVPDRFSGSKSGT
SASLAISGLQSEDEADYYCAVWDDSLNGWVFGGGT
KLTVLGQPKAAPSVTLFPPSSEELQANKATLVCLI
SDFYPGAVTVAWKADSSPVKAGVETTTPSKQSNNK
YAASSYLSLTPEQWKSHRSYSCQVTHEGSTVEKTV APTECS SEQ ID NO: 876 14084 LC
[hu anti-<huCDH19> 26D1.1 (1-235)(H1Q, S7P) VL]::huLLC-C2
QSVLTQPPSASGTPGQRVTISCSGSRSNIGSNFVN
WYQQLPGTAPKLLIYTNNQRPSGVPDRFSGSKSGT
SASLAISGLQSEDEADYYCAVWDDSLNGWVFGGGT
KLTVLGQPKAAPSVTLFPPSSEELQANKATLVCLI
SDFYPGAVTVAWKADSSPVKAGVETTTPSKQSNNK
YAASSYLSLTPEQWKSHRSYSCQVTHEGSTVEKTV APTECS SEQ ID NO: 877 14085 LC
[hu anti-<huCDH19> 26D1.1 (1-235)(H1Q, S7P, W109Y)
VL]::huLLC-C2 QSVLTQPPSASGTPGQRVTISCSGSRSNIGSNFVN
WYQQLPGTAPKLLIYTNNQRPSGVPDRFSGSKSGT
SASLAISGLQSEDEADYYCAVYDDSLNGWVFGGGT
KLTVLGQPKAAPSVTLFPPSSEELQANKATLVCLI
SDFYPGAVTVAWKADSSPVKAGVETTTPSKQSNNK
YAASSYLSLTPEQWKSHRSYSCQVTHEGSTVEKTV APTECS SEQ ID NO: 878 14086 LC
[hu anti-<huCDH19> 26D1.1 (1-235)(H1Q, S7P, W109Y, D111E,
N135Q) VL]::huLLC-C2 QSVLTQPPSASGTPGQRVTISCSGSRSNIGSNFVN
WYQQLPGTAPKLLIYTNNQRPSGVPDRFSGSKSGT
SASLAISGLQSEDEADYYCAVYDESLQGWVFGGGT
KLTVLGQPKAAPSVTLFPPSSEELQANKATLVCLI
SDFYPGAVTVAWKADSSPVKAGVETTTPSKQSNNK
YAASSYLSLTPEQWKSHRSYSCQVTHEGSTVEKTV APTECS SEQ ID NO: 879 14087 LC
[hu anti-<huCDH19> 26D1.1 (1-235)(H1Q, S7P, W109Y, D111E,
N1350) VL]::huLLC-C2 QSVLTQPPSASGTPGQRVTISCSGSRSNIGSNFVN
WYQQLPGTAPKLLIYTNNQRPSGVPDRFSGSKSGT
SASLAISGLQSEDEADYYCAVYDESLQGWVFGGGT
KLTVLGQPKAAPSVTLFPPSSEELQANKATLVCLI
SDFYPGAVTVAWKADSSPVKAGVETTTPSKQSNNK
YAASSYLSLTPEQWKSHRSYSCQVTHEGSTVEKTV APTECS SEQ ID NO: 880 14088 LC
[hu anti-<huCDH19> 26D1.1 (1-235)(H1Q, S7P) VL]::huLLC-C2
QSVLTQPPSASGTPGQRVTISCSGSRSNIGSNFVN
WYQQLPGTAPKLLIYTNNQRPSGVPDRFSGSKSGT
SASLAISGLQSEDEADYYCAVWDDSLNGWVFGGGT
KLTVLGQPKAAPSVTLFPPSSEELQANKATLVCLI
SDFYPGAVTVAWKADSSPVKAGVETTTPSKQSNNK
YAASSYLSLTPEQWKSHRSYSCQVTHEGSTVEKTV APTECS SEQ ID NO: 881 14089 LC
[hu anti-<huCDH19> 26E12.1 (1-235)(S7P) VL]::huLLC-C2
QSVLTQPPSASGTPGQKVTISCSGSRSNIGSNFVN
WYQQLPGTAPKLLIYTNYQRPSGVPDRFSGSKSGT
SASLAISGLQSEDEADYYCAVWDDSLNGWVFGGGT
KLTVLGQPKAAPSVTLFPPSSEELQANKATLVCLI
SDFYPGAVTVAWKADSSPVKAGVETTTPSKQSNNK
YAASSYLSLTPEQWKSHRSYSCQVTHEGSTVEKTV APTECS SEQ ID NO: 882 14090 LC
[hu anti-<huCDH19> 26F12.1 (1-235)(S7P, D111E) VL]::huLLC-C2
QSVLTQPPSASGTPGQKVTISCSGSRSNIGSNFVN
WYQQLPGTAPKLLIYTNYQRPSGVPDRFSGSKSGT
SASLAISGLQSEDEADYYCAVWDESLNGWVFGGGT
KLTVLGQPKAAPSVTLFPPSSEELQANKATLVCLI
SDFYPGAVTVAWKADSSPVKAGVETTTPSKQSNNK
YAASSYLSLTPEQWKSHRSYSCQVTHEGSTVEKTV APTECS SEQ ID NO: 883 14091 LC
[hu anti-<huCDH19> 26E12.1 (1-235)(S7P, D111E) VL]::huLLC-C2
QSVLTQPPSASGTPGQKVTISCSGSRSNIGSNFVN
WYQQLPGTAPKLLIYTNYQRPSGVPDRFSGSKSGT
SASLAISGLQSEDEADYYCAVWDESLNGWVFGGGT
KLTVLGQPKAAPSVTLFPPSSEELQANKATLVCLI
SDFYPGAVTVAWKADSSPVKAGVETTTPSKQSNNK
YAASSYLSLTPEQWKSHRSYSCQVTHEGSTVEKTV APTECS SEQ ID NO: 884 14092 LC
[hu anti-<huCDH19> 26E12.1 (1-235)(S7P, W109Y, D111E, N1350)
VL]::huLLC-C2 QSVLTQPPSASGTPGQKVTISCSGSRSNIGSNFVN
WYQQLPGTAPKLLIYTNYQRPSGVPDRFSGSKSGT
SASLAISGLQSEDEADYYCAVYDESLQGWVFGGGT
KLTVLGQPKAAPSVTLFPPSSEELQANKATLVCLI
SDFYPGAVTVAWKADSSPVKAGVETTTPSKQSNNK
YAASSYLSLTPEQWKSHRSYSCQVTHEGSTVEKTV APTECS SEQ ID NO: 885 14093 LC
[hu anti-<huCDH19> 25E8.1 (1-235)(K45Q) VL]::huLLC-C2
QSALTQPPSATGTPGQRVTISCSGSSSNIGRNFVN
WYQQLPGTAPKVLIYTNNQRPSGVPDRFSGSKSGT
SASLAISGLQSEDESDYYCAAWDDSLNGWVFGGGT
KLTVLGQPKAAPSVTLFPPSSEELQANKATLVCLI
SDFYPGAVTVAWKADSSPVKAGVETTTPSKQSNNK
YAASSYLSLTPEQWKSHRSYSCQVTHEGSTVEKTV APTECS SEQ ID NO: 886 14094 LC
[hu anti-<huCDH19> 25E8.1 (1-235)(K45Q, S102A) VL]::huLLC-C2
QSALTQPPSATGTPGQRVTISCSGSSSNIGRNFVN
WYQQLPGTAPKVLIYTNNQRPSGVPDRFSGSKSGT
SASLAISGLQSEDEADYYCAAWDDSLNGWVFGGGT
KLTVLGQPKAAPSVTLFPPSSEELQANKATLVCLI
SDFYPGAVTVAWKADSSPVKAGVETTTPSKQSNNK
YAASSYLSLTPEQWKSHRSYSCQVTHEGSTVEKTV APTECS SEQ ID NO: 887 14095 LC
[hu anti-<huCDH19> 25F8.1 (1-235)(K450, S102A) VL]::huLLC-C2
QSALTQPPSATGTPGQRVTISCSGSSSNIGRNFVN
WYQQLPGTAPKVLIYTNNQRPSGVPDRFSGSKSGT
SASLAISGLQSEDEADYYCAAWDDSLNGWVFGGGT
KLTVLGQPKAAPSVTLFPPSSEELQANKATLVCLI
SDFYPGAVTVAWKADSSPVKAGVETTTPSKQSNNK
YAASSYLSLTPEQWKSHRSYSCQVTHEGSTVEKTV APTECS SEQ ID NO: 888 14096 LC
[hu anti-<huCDH19> 25E8.1 (1-235)(K450, S102A, D111E)
VL]::huLLC-C2 QSALTQPPSATGTPGQRVTISCSGSSSNIGRNFVN
WYQQLPGTAPKVLIYTNNQRPSGVPDRFSGSKSGT
SASLAISGLQSEDEADYYCAAWDESLNGWVFGGGT
KLTVLGQPKAAPSVTLFPPSSEELQANKATLVCLI
SDFYPGAVTVAWKADSSPVKAGVETTTPSKQSNNK
YAASSYLSLTPEQWKSHRSYSCQVTHEGSTVEKTV APTECS SEQ ID NO: 889 14097 LC
[hu anti-<huCDH19> 25E8.1 (1-235)(K45Q, S102A, D111E, N135Q)
VL]::huLLC-C2 QSALTQPPSATGTPGQRVTISCSGSSSNIGRNFVN
WYQQLPGTAPKVLIYTNNQRPSGVPDRFSGSKSGT
SASLAISGLQSEDEADYYCAAWDESLQGWVFGGGT
KLTVLGQPKAAPSVTLFPPSSEELQANKATLVCLI
SDFYPGAVTVAWKADSSPVKAGVETTTPSKQSNNK
YAASSYLSLTPEQWKSHRSYSCQVTHEGSTVEKTV APTECS SEQ ID NO: 890 14098 LC
[hu anti-<huCDH19> 22D1.1 (1-235)(K450, S102A) VL]::huLLC-C2
QSALTQPPSATGTPGQRVTISCSGSSSNIGSNFVN
WYQQLPGTAPKVLIYTNNQRPSGVPDRFSGSKSGT
SASLAISGLQSEDEADYYCATWDDSMNGWVFGGGT
KLTVLGQPKAAPSVTLFPPSSEELQANKATLVCLI
SDFYPGAVTVAWKADSSPVKAGVETTTPSKQSNNK
YAASSYLSLTPEQWKSHRSYSCQVTHEGSTVEKTV APTECS SEQ ID NO: 891 14099 LC
[hu anti-<huCDH19> 22D1.1 (1-235)(K45Q, S102A, D111E, N135Q)
VL]::huLLC-C2 QSALTQPPSATGTPGQRVTISCSGSSSNIGSNFVN
WYQQLPGTAPKVLIYTNNQRPSGVPDRFSGSKSGT
SASLAISGLQSEDEADYYCATWDESMQGWVFGGGT
KLTVLGQPKAAPSVTLFPPSSEELQANKATLVCLI
SDFYPGAVTVAWKADSSPVKAGVETTTPSKQSNNK
YAASSYLSLTPEQWKSHRSYSCQVTHEGSTVEKTV APTECS SEQ ID NO: 892 14100 LC
[hu anti-<huCDH19> 22D1.1 (1-235)(K45Q, S102A, W109Y, D111E,
N1350) VL]::huLLC-C2 QSALTQPPSATGTPGQRVTISCSGSSSNIGSNFVN
WYQQLPGTAPKVLIYTNNQRPSGVPDRFSGSKSGT
SASLAISGLQSEDEADYYCATYDESMQGWVFOGGT
KLTVLGQPKAAPSVTLFPPSSEELQANKATLVCLI
SDFYPGAVTVAWKADSSPVKAGVETTTPSKQSNNK
YAASSYLSLTPEQWKSHRSYSCQVTHEGSTVEKTV APTECS SEQ ID NO: 893 14101 LC
[hu anti-<huCDH19> 22D1.1 (1-235)(K450, S102A, W109Y)
VL]::huLLC-C2 QSALTQPPSATGTPGQRVTISCSGSSSNIGSNFVN
WYQQLPGTAPKVLIYTNNQRPSGVPDRFSGSKSGT
SASLAISGLQSEDEADYYCATYDDSMNGWVFGGGT
KLTVLGQPKAAPSVTLFPPSSEELQANKATLVCLI
SDFYPGAVTVAWKADSSPVKAGVETTTPSKQSNNK
YAASSYLSLTPEQWKSHRSYSCQVTHEGSTVEKTV APTECS SEQ ID NO: 894 14102 LC
[hu anti-<huCDH19> 22D1.1 (1-235)(K45Q, S102A) VL]::huLLC-C2
QSALTQPPSATGTPGQRVTISCSGSSSNIGSNFVN
WYQQLPGTAPKVLIYTNNQRPSGVPDRFSGSKSGT
SASLAISGLQSEDEADYYCATWDDSMNGWVFGGGT
KLTVLGQPKAAPSVTLFPPSSEELQANKATLVCLI
SDFYPGAVTVAWKADSSPVKAGVETTTPSKQSNNK
YAASSYLSLTPEQWKSHRSYSCQVTHEGSTVEKTV APTECS SEQ ID NO: 895 13591 LC
[hu anti-<huCDH19> 4F7 VL]::huLLC-C1
QSVLTQPPSVSGAPGQRVTISCTGSSSNIGTGYDV
HWYQQLPGTAPKLLIHGNSNRPSGVPDRFSGSKSG
TSASLAITGLQAEDEADYYCQSYDSSLSGWVFGGG
TRLTVLGQPKANPTVTLFPPSSEELQANKATLVCL
ISDFYPGAVTVAWKADGSPVKAGVETTKPSKQSNN
KYAASSYLSLTPEQWKSHRSYSCQVTHEGSTVEKT VAPTECS SEQ ID NO: 896 14301 LC
[hu anti-<huCDH19> 2G6 (1-234)(D110E) VL]::huLLC-C1
SYELTQPPSVSVSPGQTASITCSGDRLGEKYTCWY
QQRPGQSPLLVIYQDTKRPSGIPERFSGSNSGNTA
TLTISGTQAMDEADYYCQAWESSTVVFGGGTKLTV
LGQPKANPTVTLFPPSSEELQANKATLVCLISDFY
PGAVTVAWKADGSPVKAGVETTKPSKQSNNKYAAS
SYLSLTPEQWKSHRSYSCQVTHEGSTVEKTVAPIE CS SEQ ID NO: 897 14302 LC [hu
anti-<huCDH19> 2G6 (1-234)(C42S, D110E) VL]::huLLC-C1
SYELTQPPSVSVSPGQTASITCSGDRLGEKYTSWY
QQRPGQSPLLVIYQDTKRPSGIPERFSGSNSGNTA
TLTISGTQAMDEADYYCQAWESSTVVFGGGTKLTV
LGQPKANPTVTLFPPSSEELQANKATLVCLISDFY
PGAVTVAWKADGSPVKAGVETTKPSKQSNNKYAAS
SYLSLTPEQWKSHRSYSCQVTHEGSTVEKTVAPIE CS SEQ ID NO: 898 14303 LC [hu
anti-<huCDH19> 2G6 (1-234)(C42S, D110E) VL]::huLLC-C1
SYELTQPPSVSVSPGQTASITCSGDRLGEKYTSWY
QQRPGQSPLLVIYQDTKRPSGIPERFSGSNSGNTA
TLTISGTQAMDEADYYCQAWESSTVVFGGGTKLTV
LGQPKANPTVTLFPPSSEELQANKATLVCLISDFY
PGAVTVAWKADGSPVKAGVETTKPSKQSNNKYAAS
SYLSLTPEQWKSHRSYSCQVTHEGSTVEKTVAPIE CS SEQ ID NO: 899 14304 LC [hu
anti-<huCDH19> 23A10.3 (1-231)(C42S) VL]::huLLC-C2
SYELTQPPSVSVSPGQTASITCSGDRLGEKYVSWY
QQKPGQSPILVIYQDNKWPSGIPERFSGSNSGNTA
TLTISGTQAMDEADYYCQAWDSSTVVFGGGTKLTV
LGQPKAAPSVTLFPPSSEELQANKATLVCLISDFY
PGAVTVAWKADSSPVKAGVETTTPSKQSNNKYAAS
SYLSLTPEQWKSHRSYSCQVTHEGSTVEKTVAPTE CS SEQ ID NO: 900
TABLE-US-00018 TABLE Iva HEAVY CHAIN CDRs Ab Type CDR 1 CDR 2 CDR 3
14039 AA SYGMH FIWYE RAGIIGT 14303 SEQ ID GSNKY IGYYYGM NO: 28
YAESV DV KD SEQ ID SEQ ID NO: 30 NO: 901 14027 AA SSGYY YIYYT
EGSSGW WS GSAYY YFQY SEQ ID NPSLK SEQ ID NO: 46 S NO: 902 SEQ ID
NO: 47 14028 AA SSGYY YIYYT EGSSGY WS GSAYY YFQY SEQ ID NPSLK SEQ
ID NO: 46 S NO: 903 SEQ ID NO: 47 14059 AA GYYWS YFSYS NYAFHF SEQ
ID GSTNY DF NO: 52 NPSLK SEQ ID S NO: 904 SEQ ID NO: 53 14052 AA
SYDMH VISYE ERYFD SEQ ID GTNEY YSFDY NO: 58 YAESV SEQ ID KG NO: 906
SEQ ID NO: 905 14055 AA SYDMH VISYE ERYFDW SEQ ID GTNEY SFDY NO: 58
YAESV SEQ ID KG NO: 60 SEQ ID NO: 905 14033 AA SYDMD VIWYE ETGEGW
SEQ ID GSNKY YFDL NO: 70 YAESV SEQ ID RG NO: 72 SEQ ID NO: 907
14034 AA SYDMD VIWYE ETGEGY SEQ ID GSNKY YFDL NO: 70 YAESV SEQ ID
RG NO: 908 SEQ ID NO: 907 14051 AA SYSWS YIYYS NYAFH SEQ ID GSTNY
FDY NO: 82 NPSLK SEQ ID S NO: 909 SEQ ID NO: 83 14046 AA SYYWS
YIYYI ESRYRS 14048 SEQ ID GSTNY GWYDAF NO: 94 NPSLK DI S SEQ ID SEQ
ID NO: 910 NO: 95 14047 AA SYYWS YIYYI ESRYRS SEQ ID GSTNY GYYDAF
NO: 94 NPSLK DI S SEQ ID SEQ ID NO: 911 NO: 95 14042 AA GYYWS YIYYI
EGSSGW SEQ ID GSTNY YRWFDP NO: 100 NPSLK SEQ ID S NO: 912 SEQ ID
NO: 101 14043 AA GYYWS YIYYI DGSSGY SEQ ID GSTNY YRYFDP NO: 100
NPSLK SEQ ID S NO: 913 SEQ ID NO: 101 14069 AA SYAMN TISGG GGMGGY
SEQ ID GANTY YYGMDV NO: 118 YAESV SEQ ID KG NO: 120 SEQ ID NO: 914
14062 AA SYFIH IINPI GGIQLY 14063 SEQ ID SVSTS LHFDY 14064 NO: 124
YAQKF SEQ ID QG NO: 915 SEQ ID NO: 125 14100 AA SYFIH IINPI GGIQLY
14101 SEQ ID SVSTS LHLDY NO: 130 YAQKF SEQ ID QG NO: 916 SEQ ID NO:
131 14097 AA SYYIH IINPS GGIQLY SEQ ID GGSTR LHFDY NO: 136 YAQKF
SEQ ID QG NO: 917 SEQ ID NO: 137 14091 AA NYYMS IINPS GGIQL 14092
SEQ ID GGDST YLHFDY NO: 142 YAQKF SEQ ID QG NO: 918 SEQ ID NO: 143
14087 AA SYYMS IIHPS GGIKLY SEQ ID GGDTT LHFDY NO: 148 YAQKF SEQ ID
QG NO: 919 SEQ ID NO: 149 14082 AA GYYWS YIYYI EGSSGY SEQ ID GSTNY
YRYFDP NO: 154 NPSLK S SEQ ID NO: 155 SEQ ID NO: 920 14079 AA RYGIH
VIWYE RAGIPGT SEQ ID GSNKY TGYYYGM NO: 160 YAESV DV KG SEQ ID SEQ
ID NO: 162 NO: 921 14073 AA SYFIH IINPI GGIQLY 14076 SEQ ID SVSTS
LHLDY NO: 1 YAQKF SEQ ID QG NO: 3 SEQ ID NO: 2 AA SYGMH VIWYD
RAGIIG SEQ ID GSNKY TTGYYY NO: 4 YADSV GMDV KG SEQ ID SEQ ID NO: 6
NO: 5
TABLE-US-00019 TABLE IVb LIGHT CHAIN CDRs Ab Type CDR 1 CDR 2 CDR 3
14039 AA SGDRL QDTKR QAWES 14302 GEKYT PS STW 14303 S SEQ ID SEQ ID
SEQ ID NO: 197 NO: 923 NO: 922 14301 AA SGDRL QDTKR QAWES GEKYT PS
STW C SEQ ID SEQ ID SEQ ID NO: 197 NO: 923 NO: 196 14022 AA RASRQ
GPSSR QQYGS 14024 ISSSY AT SFT 14025 LA SEQ ID SEQ ID 14026 SEQ ID
NO: 215 NO: 216 14027 NO: 924 14028 14029 AA RASQS GPSSR QQYGS
ISSSY AT SFT LA SEQ ID SEQ ID SEQ ID NO: 215 NO: 216 NO: 925 14058
AA TGSSS GNNNR QSYES 14059 NIGTG PS RLSGW YAVH SEQ ID V SEQ ID NO:
221 SEQ ID NO: 220 NO: 926 14050 AA TGSSS GNSNR QSYES 14051 NIGTG
PS SLSGW YDVH SEQ ID V SEQ ID NO: 251 SEQ ID NO: 250 NO: 927 14063
AA SGSSS TNNQR ATWDE NIGSN PS SLQGW FVN SEQ ID V SEQ ID NO: 293 SEQ
ID NO: 292 NO: 928 14064 AA SGSSS TNNQR ATYDD NIGSN PS SLNGW FVN
SEQ ID V SEQ ID NO: 293 SEQ ID NO: 292 NO: 929 14099 AA SGSSS TNNQR
ATWDE NIGSN PS SMQGW FVN SEQ ID V SEQ ID NO: 299 SEQ ID NO: 298 NO:
930 14100 AA SGSSS TNNQR ATYDE NIGSN PS SMQGW FVN SEQ ID V SEQ ID
NO: 299 SEQ ID NO: 298 NO: 931 14101 AA SGSSS TNNQR ATYDD NIGSN PS
SMNGW FVN SEQ ID V SEQ ID NO: 299 SEQ ID NO: 298 NO: 932 14096 AA
SGSSS TNNQR AAWDE NIGRN PS SLNGW FVN SEQ ID V SEQ ID NO: 305 SEQ ID
NO: 304 NO: 933 14097 AA SGSSS TNNQR AAWDE NIGRN PS SLQGW FVN SEQ
ID V SEQ ID NO: 305 SEQ ID NO: 304 NO: 934 14090 AA SGSRS TNYQR
AVWDE 14091 NIGSN PS SLNGW FVN SEQ ID V SEQ ID NO: 311 SEQ ID NO:
310 NO: 935 14092 AA SGSRS TNYQR AVYDE NIGSN PS SLQGW FVN SEQ ID V
SEQ ID NO: 311 SEQ ID NO: 310 NO: 936 14085 AA SGSRS TNNQR AVYDD
NIGSN PS SLNGW FVN SEQ ID V SEQ ID NO: 317 SEQ ID NO: 316 NO: 937
14086 AA SGSRS TNNQR AVYDE 14087 NIGSN PS SLQGW FVN SEQ ID V SEQ ID
NO: 317 SEQ ID NO: 316 NO: 938 14077 AA SGDRL QDNKW QAWDS 14078
GEKYV PS STW 14304 S SEQ ID SEQ ID SEQ ID NO: 329 NO: 330 NO: 939
14079 AA SGDRL QDNKW QAWES GEKYV PS STW S SEQ ID SEQ ID SEQ ID NO:
329 NO: 940 NO: 939 14080 AA SGDRL QDNKW QAWDS GEKYV PS STW Y SEQ
ID SEQ ID SEQ ID NO: 329 NO: 330 NO: 941 14075 AA SGSRS TNNQR ATWDE
NIGSN PS SMQGW FVN SEQ ID V SEQ ID NO: 335 SEQ ID NO: 334 NO: 942
14076 AA SGSRS TNNQR ATYDE NIGSN PS SMQGW FVN SEQ ID V SEQ ID NO:
335 SEQ ID NO: 334 NO: 943
[0431] Human and Cynomologous Monkey Cadherin-19 Sequences
TABLE-US-00020 TABLE V SEQ ID DESIG- NO. NATION SOURCE TYPE
SEQUENCE 944 Human Human aa MNCYLLLRFMLGIPLLWPCL Cadherin-
GATENSQTKKVKQPVRSHLR 19 VKRGWVWNQFFVPEEMNTTS HHIGQLRSDLDNGNNSFQYK
LLGAGAGSTFIIDERTGDIY AIQKLDREERSLYILRAQVI DIATGRAVEPESEFVIKVSD
INDNEPKFLDEPYEAIVPEM SPEGTLVIQVTASDADDPSS GNNARLLYSLLQGQPYFSVE
PTTGVIRISSKMDRELQDEY WVIIQAKDMIGQPGALSGTT SVLIKLSDVNDNKPIFKESL
YRLTVSESAPTGTSIGTIMA YDNDIGENAEMDYSIEEDDS QTFDIITNHETQEGIVILKK
KVDFEHQNHYGIRAKVKNHH VPEQLMKYHTEASTTFIKIQ VEDVDEPPLFLLPYYVFEVF
EETPQGSFVGVVSATDPDNR KSPIRYSITRSKVFNINDNG TITTSNSLDREISAWYNLSI
TATEKYNIEQISSIPLYVQV LNINDHAPEFSQYYETYVCE NAGSGQVIQTISAVDRDESI
EEHHFYFNLSVEDTNNSSFT IIDNQDNTAVILTNRTGFNL QEEPVFYISILIADNGIPSL
TSTNTLTIHVCDCGDSGSTQ TCQYQELVLSMGFKTEVIIA ILICIMIIFGFIFLTLGLKQ
RRKQILFPEKSEDFRENIFQ YDDEGGGEEDTEAFDIAELR SSTIMRERKTRKTTSAEIRS
LYRQSLQVGPDSAIFRKFIL EKLEEANTDPCAPPFDSLQT YAFEGTGSLAGSLSSLESAV
SDQDESYDYLNELGPRFKRL ACMFGSAVQSNN 945 Human Human nt
atgaactgttatttactgct Cadherin- gcgttttatgttgggaattc 19
ctctcctatggccttgtctt ggagcaacagaaaactctca aacaaagaaagtcaagcagc
cagtgcgatctcatttgaga gtgaagcgtggctgggtgtg gaaccaattttttgtaccag
aggaaatgaatacgactagt catcacatcggccagctaag atctgatttagacaatggaa
acaattctttccagtacaag cttttgggagctggagctgg aagtacttttatcattgatg
aaagaacaggtgacatatat gccatacagaagcttgatag agaggagcgatccctctaca
tcttaagagcccaggtaata gacatcgctactggaagggc tgtggaacctgagtctgagt
ttgtcatcaaagtttcggat atcaatgacaatgaaccaaa attcctagatgaaccttatg
aggccattgtaccagagatg tctccagaaggaacattagt tatccaggtgacagcaagtg
atgctgacgatccctcaagt ggtaataatgctcgtctcct ctacagcttacttcaaggcc
agccatatttttctgttgaa ccaacaacaggagtcataag aatatcttctaaaatggata
gagaactgcaagatgagtat tgggtaatcattcaagccaa ggacatgattggtcagccag
gagcgttgtctggaacaaca agtgtattaattaaactttc agatgttaatgacaataagc
ctatatttaaagaaagttta taccgcttgactgtctctga atctgcacccactgggactt
ctacaggaacaatcatggca tatgataatgacataggaga gaatgcagaaatggattaca
gcattgaagaggatgattcg caaacatttgacattattac taatcatgaaactcaagaag
gaatagttatattaaaaaag aaagtggatcttgagcacca gaaccactacggtattagag
caaaagttaaaaaccatcat gttcctgagcagctcatgaa gtaccacactgaggcttcca
ccactttcattaagatccag gtggaagatgttgatgagcc tcctcttttcctccttccat
attatgtatttgaagttttt gaagaaaccccacagggatc atttgtaggcgtggtgtctg
ccacagacccagacaatagg aaatctcctatcaggtattc tattactaggagcaaagtgt
tcaatatcaatgataatggt acaatcactacaagtaactc actgcatcgtgaaatcagtg
cttggtacaacctaagtatt acagccacagaaaaatacaa tatagaacagatctcttcga
tcccactgtatgtgcaagtt cttaacatcaatgatcatgc tcctgagttctctcaatact
atgagacttatgtttgtgaa aatgcaggctccggtcaggt aattcagactatcagtgcag
tggatagagatgaatccata gaagagcaccatttttactt taatctatctgtagaagaca
ctaacaattcaagttttaca atcatagataaccaagataa cacagctgtcattttgacta
atagaactggttttaacctt caagaagaacctgtcttcta catctccatcttaattgccg
acaatggaatcccgtcactt acaagtacaaacacccttac catccatgtctgtgactgtg
gtgacagtgggagcacacag acctgccagtaccaggagct tgtgctttccatgggattca
agacagaagtcatcattgct attctcatttgcattatgat catatttgggtttatttttt
tgactttgggtttaaaacaa cggagaaaacagattctatt tcctgagaaaag
tgaagatttcagagagaata tattccaatatgatgatgaa gggggtggagaagaagatac
agaggcctttgatatagcag agctgaggagtagtaccata atgcgggaacgcaagactcg
gaaaaccacaagcgctgaga tcaggagcctatacaggcag tctttgcaagttggccccga
cagtgccatattcaggaaat tcattctggaaaagctcgaa gaagctaatactgatccgtg
tgcccctccttttgattccc tccagacctacgcttttgag ggaacagggtcattagctgg
atccctgagctccttagaat cagcagtctctgatcacgat gaaagctatgattaccttaa
tgagttgggacctcgcttta aaagattagcatgcatgttt ggttctgcagtgcagtcaaa
taattag 946 Cyno Macaca aa MNCYLLLPFMLGIPLLWPCL Cadherin- fasci-
GATENSQTKKVQQPVGSHLR 19 cularis VKRGWVWNQFFVPEEMNTTS
HHVGRLRSDLDNGNNSFQYK LLGAGAGSTFIIDERTGDIY AIEKLDREERSLYILRAQVI
DITTGRAVEPESEFVIKVSD INDNEPKFLDEPYEAIVPEM SPEGTLVIQVTASDADDPSS
GNNARLLYSLLQGQPYFSVE PTTGVIRISSKMDRELQDEY WVIIQAKDMIGQPGALSGTT
SVLIKLSDVNDNKPIFKESL YRLTVSESAPTGTSIGTIMA YDNDIGENAEMDYSIEEDDS
QTFDIITNHETQEGIVILKK KVNFEHQNHYGIRAKVKNHH VDEQLMKYHTEASTTFIKIQ
VEDVDEPPLFLLPYYIFEIF EETPQGSFVGVVSATDPDNR KSPIRYSITRSKVFNIDDNG
TITTTNSLDREISAWYNLSI TATEKYNIEQISSIPVYVQV LNINDHAPEFSQYYESYVCE
NAGSGQVIQTISAVDRDESI EEHHFYFNLSVEDTNSSSFT IIDNQDNTAVILTNRTGFNL
QEEPIFYISILIADNGIPSL TSTNTLTIHVCDCDDSGSTQ TCQYQELMLSMGFKTEVIIA
ILICIMVIFGFIFLTLGLKQ RRKQILFPEKSEDFRENIFR YDDEGGGEEDTEAFDVAALR
SSTIMRERKTRKTTSAEIRS LYRQSLQVGPDSAIFRKFIL EKLEEADTDPCAPPFDSLQT
YAFEGTGSLAGSLSSLESAV SDQDESYDYLNELGPRFKRL ACMFGSAVQSNN 947 Cyno
Macaca nt ATGAATTGTTATTTACTGCT Cadherin- fasci-
GCCTTTTATGTTGGGAATTC 19 cularis CTCTCCTATGGCCTTGTCTT
GGAGCAACAGAAAACTCTCA AACAAAGAAAGTCCAGCAGC CAGTAGGATCTCATCTGAGA
GTGAAGCGTGGCTGGGTGTG GAACCAATTTTTTGTACCAG AGGAAATGAATACGACTAGT
CATCACGTTGGCCGGCTAAG ATCTGATTTAGACAATGGAA ACAATTCTTTCCAGTACAAG
CTTTTGGGAGCTGGAGCTGG AAGTACTTTTATCATTGATG AAAGAACAGGTGACATATAT
GCCATAGAGAAGCTTGATAG AGAGGAGCGATCCCTCTACA TCTTAAGAGCCCAGGTAATA
GACATCACTACTGGAAGGGC TGTGGAACCTGAGTCTGAGT TTGTCATCAAAGTTTCGGAT
ATCAATGACAATGAACCAAA ATTCCTAGATGAACCTTATG AGGCCATTGTACCAGAGATG
TCTCCAGAAGGAACATTAGT CATCCAGGTGACAGCAAGTG ATGCTGATGACCCTTCAAGT
GGTAATAATGCTCGTCTCCT CTACAGCTTATTACAAGGCC AGCCATATTTTTCTGTTGAA
CCAACAACAGGAGTCATAAG AATATCTTCTAAAATGGATA GAGAACTGCAAGATGAGTAT
TGGGTAATCATTCAAGCCAA GGACATGATTGGTCAGCCAG GAGCGTTGTCTGGAACAACG
AGTGTATTAATTAAACTTTC AGATGTTAATGACAATAAGC CTATATTTAAAGAAAGTTTA
TACCGCCTGACGGTCTCTGA ATCTGCACCCACTGGGACTT CTATAGGAACAATCATGGCA
TATGATAATGACATAGGAGA GAATGCAGAAATGGATTACA GCATTGAAGAGGATGATTCA
CAGACATTTGACATTATTAC
TAATCATGAAACTCAAGAAG GAATAGTTATATTAAAAAAG AAAGTGAATTTTGAGCACCA
GAACCACTATGGTATTAGAG CAAAAGTTAAAAACCATCAT GTTGATGAGCAGCTCATGAA
ATACCACACTGAAGCTTCCA CCACTTTCATTAAGATCCAG GTGGAAGATGTTGATGAGCC
TCCTCTTTTCCTCCTTCCGT ATTACATATTTGAAATTTTT GAAGAAACCCCACAAGGATC
ATTTGTAGGCGTGGTGTCTG CCACAGACCCAGACAATAGG AAATCTCCTATCAGGTATTC
TATTACTAGGAGCAAAGTGT TCAATATCGATGATAATGGT ACAATCACTACAACTAACTC
ACTGGATCGGGAAATCAGTG CTTGGTACAACCTAAGTATT ACAGCCACAGAAAAATACAA
TATAGAGCAGATCTCTTCGA TCCCAGTGTATGTGCAAGTT CTTAATATCAATGATCATGC
TCCTGAGTTCTCTCAATACT ATGAGAGTTATGTTTGTGAA AATGCAGGCTCTGGTCAGGT
AATTCAGACTATCAGTGCAG TGGATAGAGATGAATCCATA GAAGAGCACCATTTTTACTT
TAATCTATCTGTAGAAGACA CTAACTCTTCAAGTTTTACA ATCATAGACAATCAAGATAA
CACAGCTGTCATTTTGACTA ATAGAACTGGTTTTAACCTT CAAGAAGAGCCCATCTTCTA
CATCTCCATCTTAATTGCCG ACAATGGAATCCCGTCACTT ACAAGTACAAACACCCTTAC
CATCCATGTCTGTGACTGTG ATGACAGTGGGAGCACACAG ACCTGCCAGTACCAGGAGCT
TATGCTTTCCATGGGATTCA AGACAGAAGTCATCATTGCT ATTCTCATTTGCATTATGGT
AATATTTGGGTTTATTTTTT TGACTTTGGGTTTAAAACAA CGGAGAAAACAGATTCTATT
TCCTGAGAAAAG TGAAGATTTCAGAGAGAATA TATTCCGATATGATGACGAA
GGGGGTGGAGAAGAAGATAC AGAGGCCTTTGACGTAGCAG CGCTGAGGAGTAGCACCATA
ATGCGGGAACGCAAGACTCG GAAAACCACCAGCGCTGAGA TCAGGAGCCTATACAGGCAG
TCTTTGCAAGTTGGCCCCGA CAGTGCCATATTCAGGAAGT TCATCCTGGAAAAGCTCGAA
GAAGCTGATACTGATCCGTG TGCCCCTCCTTTTGATTCCC TCCAGACCTACGCTTTTGAG
GGAACAGGGTCATTAGCTGG ATCCCTGAGCTCCTTAGAAT CAGCTGTCTCTGATCAGGAT
GAAAGCTATGATTACCTTAA CGAGTTGGGACCTCGCTTTA AAAGATTAGCATGCATGTTT
GGTTCTGCAGTGCAGTCAAA TAATTAG 948 secreted Human aa
MNCYLLLRFMLGIPLLWPCL Cadherin- GATENSQTKKVKQPVRSHLR 19
VKRGWVWNQFFVPEEMNTTS ecto- HHIGQLRSDLDNGNNSFQYK domain
LLGAGAGSTFIIDERTGDIY (amino AIQKLDREERSLYILRAQVI acids
DIATGRAVEPESEFVIKVSD 1-596) INDNEPKFLDEPYEAIVPEM
SPEGTLVIQVTASDADDPSS GNNARLLYSLLQGQPYFSVE PTTGVIRISSKMDRELQDEY
WVIIQAKDMIGQPGALSGTT SVLIKLSDVNDNKPIFKESL YRLTVSESAPTGTSIGTIMA
YDNDIGENAEMDYSIEEDDS QTFDIITNHETQEGIVILKK KVDFEHQNHYGIRAKVKNHH
VPEQLMKYHTEASTTFIKIQ VEDVDEPPLFLLPYYVFEVF EETPQGSFVGVVSATDPDNR
KSPIRYSITRSKVFNINDNG TITTSNSLDREISAWYNLSI TATEKYNIEQISSIPLYVQV
LNINDHAPEFSQYYETYVCE NAGSGQVIQTISAVDRDESI EEHHFYFNLSVEDTNNSSFT
IIDNQDNTAVILTNRTGFNL QEEPVFYISILIADNGIPSL TSTNTLTIHVCDCGDSGSTQ
TCQYQELVLSMGFKTE 949 secreted Human nt atgaactgttatttactgct
Cadherin- gcgttttatgttgggaattc 19 ctctcctatggccttgtctt ecto-
ggagcaacagaaaactctca domain aacaaagaaagtcaagcagc (amino
cagtgcgatctcatttgaga acids gtgaagcgtggctgggtgtg 1-596)
gaaccaattttttgtaccag aggaaatgaatacgactagt catcacatcggccagctaag
atctgatttagacaatggaa acaattctttccagtacaag cttttgggagctggagctgg
aagtacttttatcattgatg aaagaacaggtgacatatat gccatacagaagcttgatag
agaggagcgatccctctaca tcttaagagcccaggtaata gacatcgctactggaagggc
tgtggaacctgagtctgagt ttgtcatcaaagtttcggat atcaatgacaatgaaccaaa
attcctagatgaaccttatg aggccattgtaccagagatg tctccagaaggaacattagt
tatccaggtgacagcaagtg atgctgacgatccctcaagt ggtaataatgctcgtctcct
ctacagcttacttcaaggcc agccatatttttctcttgaa ccaacaacaggagtcataag
aatatcttctaaaatggata gagaactgcaagatgagtat tgggtaatcattcaagccaa
ggacatgattggtcagccag gagcgttgtctggaacaaca agtgtattaattaaactttc
agatgttaatgacaataagc ctatttttaaagaaagttta taccgcttgactgtctctga
atctgcacccactgggactt ctataggaacaatcatggca tatgataatgacataggaga
gaatgcagaaatggattaca gcattgaagaggatgattcg caaacatttgacattattac
taatcatgaaactcaagaag gaatagttatattaaaaaag aaagtggattttgagcacca
gaaccactacggtattagag caaaagttaaaaaccatcat gttcctgagcagctcatgaa
gtaccacactgaggcttcca ccactttcattaagatccag gcggaagatgttgatgagcc
tcctcttttcctccttccat attatgtatttgaagttttt gaagaaaccccacagggatc
atttgtaggcgtggtgtctg ccacagacccagacaatagg aaatctcctatcaggtattc
tattactaggagcaaagtgt tcaatatcaatgacaatggt acaatcactacaagtaactc
actggatcgtgaaatcagtg cttggtacaacctaagtatt acagccacagaaaaatacaa
tatagaacagatctcttcga tcccactgtatgtgcaagtt cttaacatcaatgatcatgc
tcctgagttctctcaatact atgagacttatgtttgtgaa aatgcaggctctggtcaggt
aattcagactatcagtgcag tggatagagatgaatccata gaagagcaccatttttactt
taatctatctgtagaagaca ctaacaattcaagttttaca atcatagataatcaagataa
cacagctgtcattttgacta atagaactggttttaacctt caagaagaacctgtcttcta
catctccatcttaattgccg acaatggaatcccgtcactt acaagtacaaacacccttac
catccatgtctgtgactgtg gtgacagtgggagcacacag acctgccagtaccaggagct
tgtgctttccatgggattca agacagaa 950 truncated Human aa
MNCYLLLRFMLGIPLLWPCL membrane GATENSQTKKVKQPVRSHLR bound
VKRGWVWNQFFVPEEMNTTS form HHIGQLRSDLDNGNNSFQYK of human
LLGAGAGSTFIIDERTGDIY cadherin- AIQKLDREERSLYILRAQVI 19
DIATGRAVEPESEFVIKVSD (amino INDNEPKFLDEPYEAIVPEM acids
SPEGTLVIQVTASDADDPSS 1-624) GNNARLLYSLLQGQPYFSVE
PTTGVIRISSKMDRELQDEY WVIIQAKDMIGQPGALSGTT SVLIKLSDVNDNKPIFKE
SLYRLTVSESAPTGTSIGTI MAYDNDIGENAEMDYSIEED DSQTFDIITNHETQEGIVIL
KKKVDFEHQNHYGIRAKVKN KHVPEQLMKYHTEASTTFIK IQVEDVDEPPLFLLPYYVFE
VFEETPQGSFVGVVSATDPD NRKSPIRYSITRSKVFNIND NGTITTSNSLDREISAWYNL
SITATEKYNIEQISSIPLYV QVLNINDHAPEFSQYYETYV CENAGSGQVIQTISAVDRDE
SIEEHHFYFNLSVEDTNNSS FTIIDNQDNTAVILTNRTGF NLQEEPVFYISILIADNGIP
SLTSTNTLTIHVCDCGDSGS TQTCQYQELVLSMGFKTEVI IAILICIMIIFGFIFLTLGL
KQRRKQ 951 truncated Humanl nt atgaactgttatttactgct membrane
gcgttttatgttgggaattc bound ctctcctatggccttgtctt form of
ggagcaacagaaaactctca human aacaaagaaagtcaagcagc cadherin-
cagtgcgatctcatttgaga 19 gtgaagcgtggctgggtgtg (amino
gaaccaattttttgtaccag acids aggaaatgaatacgactagt 1-624)
catcacatcggccagctaag atctgatttagacaatggaa acaattctttccagtacaag
cttttgggagctggagctgg aagtacttttatcattgatg aaagaacaggtgacatatat
gccatacagaagcttgatag agaggagcgatccctctaca tcttaagagcccaggtaata
gacatcgctactggaagggc tgtggaacctgagtctgagt ttgtcatcaaagtttcggat
atcaatgacaatgaaccaaa attcctagatgaaccttatg aggccattgtaccagagatg
tctccagaaggaacattagt tatccaggtgacagcaagtg atgctgacgatccctcaagt
ggtaataatgctcgtctcct ctacagcttacttcaaggcc agccatatttttctgttgaa
ccaacaacaggagtcataag aatatcttctaaaatggata gagaactgcaagatgagtat
tgggtaatcattcaagccaa ggacatgattggtcagccag gagcgttgtctggaacaaca
agtgtattaattaaactttc agatgttaatgacaataagc ctatatttaaagaaagttta
taccgcttgactgtctctga atctgcacccactgggactt ctataggaacaatcatggca
tatgataatgacataggaga gaatgcagaaatggattaca gcattgaagaggatgattcg
caaacatttgacattattac taatcatgaaactcaagaag gaatagttatattaaaaaag
aaagtggattttgagcacca gaaccactacggtattagag caaaagttaaaaaccatcat
gttcctgagcagctcatgaa gtaccacactgaggcttcca ccactttcattaagatccag
gtggaagatgttgatgagcc tcctcttttcctccttccat attatgtatttgaagttttt
gaagaaaccccacagggatc atttgtaggcgtggtgtctg ccacagacccagacaatagg
aaatctcctatcaggtattc tattactaggagcaaagtgt tcaatatcaatgataatggt
acaatcactacaagtaactc actggatcgtgaaatcagtg cttggtacaacctaagtatt
acagccacagaaaaatacaa tatagaacagatctcttcga tcccactgtatgtgcaagtt
cttaacatcaatgatcatgc tcctgagttctctcaatact atgagacttatgtttgtgaa
aatgcaggctctggtcaggt aattcagactatcagtgcag tggatagacatgaatccaLa
gaagagcaccatttttactt taatctatctgtagaagaca ctaacaattcaagttttaca
atcatagataatcaagataa cacagctgtcattttgacta atagaactggttttaacctt
caagaagaacctgtcttcta catctccatcttaattgccg acaatggaatcccgtcactt
acaagtacaaacacccttac catccatgtctgtgactgtg gtgacagtgggagcacacag
acctgccagtaccaggagct tgtgctttccatgggattca agacagaagtcatcattgct
attctcatttgcattatgat catatttgggtttatttttt tgactttgggtttaaaacaa
cggagaaaacag 952 C137897 artifi- aa GWVWNQFFVPEEMNTTSHHI huCDH19
cial GQLRSDLDNGNNSFQYKLLG (44-141) AGAGSTFIIDERTGDIYAIQ muCDH19
KLDREERSLYILRAQVIDIA (140-770) TGRAVEPESEFVIKVSDIND
NEPRFLDEPYEAIVPEMSPE GTFVIKVTANDADDPSTGYH ARILYNLERGQPYFSVEPTT
GVIRISSKMDRELQDTYCVI IQAKDMLGQPGALSGTTTVS IKLSDINDNKPIFKESFYRF
TISESAPIGTSIGKIMAYDD DIGENAEMEYSIEDDDSKIF DIIIDMDTQEGIVILKKKVD
FEQQSYYGIRAKVKNCHVDE ELAPAHVNASTTYIKVQVED EDEPPVFLLPYYILEIPEGK
PYGTIVGTVSATDPDRRQSP MRYYLTGSKMFDINDNGTII TTNMLDREVSAWYNLTVTAT
ETYNVQQISSAHVYVQVFNI NDNAPEFSQFYETYVCENAE SGEIVQIISAIDRDESIEDH
HFYFNHSLEDTNNSSFMLTD NQDNTAVILSNRTGFNLKEE PVFYMIILIADNGIPSLTST
NTLTIQVCDCGDSRNTETCA NKGLLFIMGFRTEAIIAIMI CVMVIFGFFFLILALKQRRK
ETLFPEKTEDFRENIFCYDD EGGGEEDSEAFDIVELRQST VMRSRKPQRSKSAEIRSLYR
QSLQVGPDSAIFRKFILEKL SEAMTDPCAPPFDSLQTFAY EGTGSSAGSLSSLASRDTDQ
EDDFDYLNDLGPRFKRLASM FGSAVQPNN 953 C137897 artifi- nt
ggctgggtgtggaaccaatt huCDH19 cial ttttgtaccagaggaaatga (44-141)
atacgactagtcatcacatc muCDH19 ggccagctaagatctgattt (140-770)
agacaatggaaacaattctt tccagtacaagcttttggga gctggagctggaagtacttt
tatcattgatgaaagaacag gtgacatatatgccatacag aagcttgatagagaggagcg
atccctctacatcttaagag cccaggtaatagacatcgct actggaagggctgtggaacc
tgagtctgagtttgtcatca aagtttcggatatcaatgac aatgaacccagattcctaga
tgaaccatatgaggccattg tacctgagatgtctccagaa ggaacatttgtcatcaaggt
gacagccaatgacgcagatg atccttcaactggctatcat gctcgcatcctatacaactt
agaacgaggtcaaccatact tttctgttgagccaacaaca ggagtcataaggatatcttc
taagatggatagagagttgc aagatacatactgtgtaatt attcaagccaaggacatgct
cggtcagcctggagccttgt ctggaacaacaaccgtatca attaagctgtcagatattaa
tgacaacaagccaatattca aagaaagtttctaccgcttc actatatctgaatctgcacc
cattggaacatcaataggga aaattatggcatatgatgat gacataggggagaatgcaga
gatggagtacagcattgaag atgatgattcaaaaatattt gacataatcattgacaatga
cacccaagaagggatagtta tacttaaaaagaaagttgat tttgagcagcagagctatta
tggcattagagctaaggtta aaaactgccatgtggatgaa gagcttgcacctgcccatgt
taacgcttccacaacctaca ttaaagttcaagtagaagat gaagatgaacctcctgtttt
cctcttaccatattacatac ttgaaattcctgaaggaaaa ccatatggaacaattgtggg
gacggtttctgccacagacc cagatcgaagacaatctcct atgagatattatctcactgg
aagcaaaatgtttgatatca atgacaatggaacaataatc accactaacatgcttgacag
agaggtcagtgcttggtaca acttgactgtcacagctact gaaacatacaatgtacaaca
gatctcttcagcccatgttt atgtacaagtctttaacatt aacgacaatgctccagagtt
ctctcaattctatgagactt atgtttgtgaaaatgctgaa tctggtgagatagttcagat
catcagtgcaattgatagag atgagtccatagaagatcac catttttactttaatcactc
tctggaagacacaaacaact caagttttatgctaacagac aatcaagataacacagctgt
aattctgagtaatagaactg gtttcaatcttaaagaagag cctgtcttctacattgatca
tcttgattgctgataacggga tcccatctctcacaagcaca aacactctcactatccaagt
ctgtgactgtggagacagta gaaacacagaaacttgtgct aacaagggacttctctttat
catgggattcagaacagagg caataattgccatcatgata tgtgttatggtaatatttgg
gtttttctttttgattcttg ctctgaaacagcgaagaaag gagactctatttccagagaa
gactgaagactttagggaga atatattttgctatgatgat gaaggcggcggggaagaaga
ctcggaagcctttgacatcg tagagctgagacaaagtaca gtaatgagagaaagaaagcc
tcagagaagcaagagtgcgg agatcaggagcttgtacagg cagtccctgcaggtgggccc
agacagtgccatatttcgaa aatttatcccagagaagctt gaagaagccaacacagaccc
atgtgctcccccctttgatt cactacagacgtttgcctat gagggaacagggtcaicagc
tggctctctgagctccttgg catccagagacactgatcag gaggatgacttcgactacct
taatgacctgggacctcgtt ttaaaagattagcaagcatg tttggctctgcagtacaacc
caacaattag 954 C137896 artifi- aa GWVWNQFFVPEEMNTTSHHI huCDH19 cial
GQLRSDLDNGNNSFQYKLLG (44-249) AGAGSTFIIDERTGDIYAIQ muCDH19
KLDREERSLYILRAQVIDIA (248-770) TGRAVEPESEFVIKVSDIND
NEPKFLDSPYEAIVPEMSPE GTLVIQVTASDADDPSSGNN ARLLYSLLQGQPYFSVEPTT
GVIRISSKMDRELQDEYWVI IQAKDMIGQPGALSGTTSVL IKLSDVNDNKPIFKESFYRF
TISESAPIGTSIGKIMAYDD DIGENAEMEYSIEDDDSKIF DIIIDNDTQEGIVILKKKVD
FEQQSYYGIRAKVKNCHVDE ELAPAHVNASTTYIKVQVED EDEPPVFLLPYYILEIPEGK
PYGTIVGTVSATDPDRRQSP MRYYLTGSKMFDINDNGTII TTNMLDREVSAWYNLTVTAT
ETYNVQQISSAHVYVQVFNI NDNAPEFSQFYETYVCENAE SGEIVQIISAIDRDESIEDH
HFYFNHSLEDTNNSSFMLTD NQDNTAVILSNRTGFNLKEE PVFYMIILIADNGIPSLTST
NTLTIQVCDCGDSRNTETCA NKGLLFIMGFRTEAIIAIMI CVMVIFGFFFLILALKQRRK
ETLFPEKTEDFRENIFCYDD EGGGEEDSEAFDIVELRQST
VMRERKPQRSKSAEIRSLYR QSLQVGPDSAIFRKFILEKL SEANTDPCAPPFDSLQTFAY
EGTGSSAGSLSSLASRDTDQ EDDFDYLNDLGPRFKRLASM FGSAVQPNH 955 C137896
artifi- nt ggctgggtgtggaaccaatt huCDH19 cial ttttgtaccagaggaaatga
(44-249) atacgactagtcatcacatc muCDH19 ggccagctaagatctgattt
(248-770) agacaa tggaaacaattctttccagt acaagcttttgggagctgga
gctggaagtacttttatcat tgatgaaagaacaggttgac atatatgccatacagaagct
tgatagagaggagcgatccc tctacatcttaagagcccag gtaatagacatcgctactgg
aagggctgtggaacctgagt ctgagtttgtcatcaaagtt tcggatatcaatgacaatga
accaaaattcctagatgaac cttatgaggccattgtacca gagatgtctccagaaggaac
attagttatccaggtgacag caagtgatgctgacgatccc tcaagtggtaataatgctcg
tctcctctacagcttacttc aaggccagccatatttttct gttgaaccaacaacaggagt
cataagaatatcttctaaaa tggatagagaactgcaagat gagtattgggtaatcattca
agccaaggacatgattggtc agccaggagcgttgtctgga acaacaagtgtattaattaa
actttcagatgttaatgaca acaagccaatattcaaagaa agtttctaccgcttcactat
atctgaatctgcacccattg gaacatcaatagggaaaatt atggcatatgatgatgacat
aggggagaatgcagagatgg agtacagcattgaagatgat gattcaaaaatatttgacat
aatcattgacaatgacaccc aagaagggatagttatactt aaaaagaaagttgattttga
gcagcagagctattatggca ttagagctaaggttaaaaac tgccatgtggatgaagagct
tgcacctgcccatgttaacg cttccacaacctacattaaa gttcaagtagaagatgaaga
tgaacctcctgttttcctct taccatattacatacttgaa attcctgaaggaaaacca~a
tggaacaattgtggggacgg tttctgccacagacccagat cgaagacaatctcctatgag
atattatctcactggaagca aaatgtttgatatcaatgac aatggaacaataatcaccac
taacatgcttgacagagagg tcagtgcttggtacaacttg actgtcacagctactgaaac
atacaatgtacaacagatct cttcagcccatgtttatgta caagtctttaacattaacga
caatgctccagagttctctc aattctatgagacttatgtt tgtgaaaatgctgaatctgg
tgagatagttcagatcatca gtgcaattgatagagatgag tccatagaagatcaccattt
ttactttaatcactctctgg aagacacaaacaactcaagt tttatgctaacagacaatca
agataacacagctgtaattc tgagtaatagaactggtttc aatcttaaagaagagcctgt
cttctacatgatcatcttga ttgctgataacgggatccca tctctcacaagcacaaacac
tctcactatccaagtctgtg actgtggagacagtacaaac acagaaacttgtgctaacaa
gcgacttctctttatcatgg gattcagaacagaggcaata attgccatcatgatatgtgt
tatggtaatatttgggtttt tctttttgattcttgctctg aaacagcgaagaaaggagac
tctatttccagagaagactg aagactttagggagaatata ttttgctatgatgatgaagg
cggcggggaagaagactcgg aagcctttgacatcgtagag ctgagacaaagtacagtaat
gagagaaagaaagcctcaga gaagcaagagtgcggagatc aggagcttgtacaggcagtc
cctgcaggtgggcccagaca gtgccatatttcgaaaattt atcctagagaagcttgaaga
agccaacacagacccatgtg ctcccccctttgattcacta cagacgtttgcctatgaggg
aacagggtcatcagctggct ctctgagctccttggcatcc agagacactgatcaggagga
tgacttcgactaccttaatg acctgggacctcgttttaaa agattagcaagcatgtttgg
ctctgcagtacaacccaaca attag 956 C137913 artifi- aa
AWVWRPFVVLEEMDDIQCVG muCDH19 cial KLRSDLDNGNNSFQYKLLGI (44-139)
GAGSFSINERTGEICAIQKL huCDH19 DREEKSLYILRAQVIDTTIG (142-249)
KAVETESEFVIRVLDINDNE muCDH19 PKFLDEPYEAIVPEMSPEGT (248-770)
LVIQVTASDADDPSSGNNAR LLYSLLQGQPYFSVEPTTGV IRISSKMDRELQDEYWVIIQ
AKDMIGQPGALSGTTSVLIK LSDVNDNKPIFKESFYRFTI SESAPIGTSIGKIMAYDDDI
GENAEMEYSIEDDDSKIFDI IIDNDTQEGIVILKKKVDFE QQSYYGIRAKVKNCHVDEEL
APAHVNASTTYIKVQVEDED EPPVFLLPYYILEIPEGKPY GTIVGTVSATDPDRRQSPMR
YYLTGSKMFDINDNGTIITT NMLDREVSAWYNLTVTATET YNVQQISSAHVYVQVFNIND
NAPEFSQFYETYVCENAESG EIVQIISAIDRDESIEDHHF YFNHSLEDTNNSSFMLTDNQ
DNTAVILSNRTGFNLKEEPV FYMIILIADNGIPSLTSTNT LTIQVCDCGDSRNTETCANK
GLLFIMGFRTEAIIAIMICV MVIFGFFFLILALKQRRKET LFPEKTEDFRENIFCYDDEG
GGEEDSEAFDIVELRQSTVM RERKPQRSKSAEIRSLYRQS LQVGPDSAIFRKFILEKLEE
ANTDPCAPPFDSLQTFAYEG TGSSAGSLSSLASRDTDQED DFDYLNDLGPRFKRLASMFG
SAVQPNN 957 C137913 artifi- nt gcctgggtgtggagaccatt muCDH19 cial
tgttgttctagaagaaatgg (44-139) atgatatacaatgtgttgga huCDH19
aagctaagatctgacttaga (142-249) caatggaaacaactctttcc muCDH19
agtacaagctactggggatt (248-770) ggcgctggaagctttagcat
taatgaaagaacaggtgaaa tatgtgccatac agaagcttgatagagaggaa
aaatccctctacattctgag agcccaggtaatagacacca ctattgggaaggctgtggaa
actgaatccgagtttgtcat cagagttttggatatcaatg acaatgaaccaaaattccta
gatgaaccttatgaggccat tgtaccagagatgtctccag aaggaacattagttatccag
gtgacagcaagtgatgctga cgatccctcaagtggtaata atgctcgtctcctctacagc
ttacttcaaggccagccata tttttctgttgaaccaacaa caggagtcataagaatatct
tctaaaatggatagagaact gcaagatgagtattgggtaa tcattcaagccaaggacatg
attggtcagccaggagcgtt gtctggaacaacaagtgtat taattaaactttcagatgtt
aatgacaacaagccaatatt caaagaaagtttctaccgct tcactatatctgaatctgca
cccattggaacatcaatagg gaaaattatggcatatgatg atgacataggggagaatgca
gagatggagtacagcattga agatgatgattcaaaaatat ttgacataatcattgacaat
gacacccaagaagggatagt tatacttaaaaagaaagttg attttgagcagcagagctat
tatggcattagagctaaggt taaaaactgccatgtggatg aagagcttgcacctgcccat
gttaacgcttccacaaccta cattaaagttcaagtagaag atgaagatgaacctcctgtt
ttcctcttaccatattacat acttgaaattcctgaaggaa aaccatatggaacaattgtg
gggacggtttctgccacaga cccagatcgaagacaatctc ctatgagatattatctcact
ggaagcaaaatgtttgatat caatgacaatggaacaataa tcaccactaacatgcttgac
agagaggtcagtgcttggta caacttgactgtcacagcta ctgaaacatacaatgtacaa
cagatctcttcagcccatgt ttatgtacaagtctttaaca ttaacgacaatgctccagag
ttctctcaa-tctatgagac ttatgtttgtgaaaatgctg aatctggtgagatagttcag
atcatcagtgcaattgatag agatgagtccatagaagatc accatttttactttaatcac
tctctggaagacacaaacaa ctcaagttttatgctaacag acaatcaagataacacagct
gtaattctgagtaatagaac tggtttcaatcttaaagaag agcctgtcttctacatgatc
atcttgattgctgataacgg gatcccatctctcacaagca caaacactctcactatccaa
gtctgtgactgtggagacag tagaaacacagaaacttgtg ctaacaagggacttctcttt
atcatgggattcagaacaga ggcaacaattgccatcatga tatgtgttatggtaatattt
gggtttttctttttgattct tgctctgaaacagcgaagaa aggagactctacttccagag
aagactgaagactttaggga gaatatattttgctatgatg atgaaggcggcggggaagaa
gactcggaagcctttgacat cgtagagctgagacaaagta cagcaatgagagaaagaaag
cctcagagaagcaagagtgc ggagatcaggagcttgtaca ggcagtccctgcaggtgggc
ccagacagtgccatatttcg aaaatttatcctagagaagc ttgaagaagccaacacagac
ccatgtgctcccccctttga ttcactacagacgtttgcct atgagggaacagggtcatca
gctggctctctgagctcctt ggcatccagagacactgatc aggaggatgacttcgactac
cttaatgacctgggacctcg ttttaaaagattagcaagca tgtttggctctgcagtacaa
cccaacaattag 958 C137847 artifi- aa AWVWRPFVVLEEMDDIQCVG muCDH19
cial KLRSDLDNGNNSFQYKLLGI (44-139) GAGSFSINERTGEICAIQKL huCDH19
DREEKSLYILRAQVIOTTIG (142-364) KAVETESEFVIRVLDINDNE muCDH19
PKFLDEPYEAIVPEMSPEGT (363-770) LVIQVTASDADDPSSGNNAR
LLYSLLQGQPYFSVEPTTGV IRISSKMDRELQDEYWVIIQ AKDMIGQPGALSGTTSVLIK
LSDVNDNKPIFKESLYRLTV SESAPTGTSIGTIMAYDNDI GENAEMDYSIEEDDSQTFDI
ITNHETQEGIVILKKKVDFE HQNHYGIRAKVKNHHVPEQL MKYHTEASTTFIKIQVEDVD
EPPVFLLPYYILEIPEGKPY GTIVGTVSATDPDRRQSPMR YYLTGSKMFDINDNGTIITT
NMLDREVSAWYNLTVTATET YNVQQISSAHVYVQVFNIND NAPEFSQFYETYVCENAESG
EIVQIISAIDRDESIEDHHF YFNHSLEDTNNSSFMLTDNQ DNTAVILSNRTGFNLKEEPV
FYMIILIADNGIPSLTSTNT LTIQVCDCGDSRNTETCANK GLLFIMGFRTEAIIAIMICV
MVIFGFFFLILALKQRRKET LFPEKTEDFRENIFCYDDEG GGEEDSEAFDIVELRQSTVM
RERKPQRSKSAEIRSLYRQS LQVGPDSAIFRKFILEKLEE ANTDPCAPPFDSLQTFAYEG
TGSSAGSLSSLASRDTDQED DFDYLNDLGPRFKRLASMFG SAVQPNN 959 C137847
artifi- nt gcctgggtgtggagaccatt muCDH19 cial tgttgttctagaagaaatgg
(44-139) atgatatacaatgtgttgga huCDH19 aagctaagatctgacttaga
(142-364) caatggaaacaactctttcc muCDH19 agtacaagctactggggatt
(363-770) ggcgctggaagctttagcat taatgaaagaacaggtgaaa
tatgtgccatacagaagctt gatagagaggaaaaatccct ctacattctgagagcccagg
taatagacaccactattggg aaggctgtggaaactgaatc cgagtttgtcatcagagttt
tggatatcaatgacaatgaa ccaaaattcctagatgaacc ttatgaggccattgtaccag
agatgtctccagaaggaaca ttagttatccaggtgacagc aagtgatgctgacgatccct
caagtggtaataatgctcgt ctcctctacagcttacttca aggccagccatatttttctg
ttgaaccaacaacaggagtc ataagaatatcttctaaaat ggatagagaactgcaagatg
agtattgggtaatcattcaa gccaaggacatgattggtca gccaggagcgttgtctggaa
caacaagtgtattaattaaa ctttcagatgttaatgacaa taagcctatatttaaagaaa
gtttataccgcttgactgtc tctgaatctgcacccactgg gacttctataggaacaatca
tggcatatgataatgacata ggagagaatgcagaaatgga ttacagcattgaagaggatg
attcgcaaacatttgacatt attactaatcatgaaactca agaaggaatagttatattaa
aaaagaaagtggattttgag caccagaaccactacggtat tagagcaaaagttaaaaacc
atcatgttcctgagcagctc atgaagtaccacactgaggc ttccaccactttcattaaga
tccaggtggaagatgttgat gaacctcctgttttcctctt accatattacatacttgaaa
ttcctgaaggaaaaccatat ggaacaattgtggggacggt ttctgccacagacccagatc
gaagacaatctcctatgaga tattatctcactggaagcaa aatgtttgatatcaatgaca
atggaacaataatcaccact aacatgcttgacagagaggt cagtgcttggtacaacttga
ctgtcacagctactgaaaca tacaatgtacaacagatctc ttcagcccatgtttatgtac
aagtctttaacattaacgac aatgctccagagttctctca attctatgagacttatgttt
gtgaaaatgctgaatctggt gagatagttcagatcatcag tgcaattgatagagatgagt
ccatagaagatcaccatttt tactttaatcactctctgga agacacaaacaactcaagtt
ttatgctaacagacaatcaa gataacacagctgtaattct gagtaatagaactggtttca
atcttaaagaagagcctgtc ttctacatgatcatcttgat tgctgataacgggatcccat
ctctcacaagcacaaacact ctcactatccaagtctgtga ctgtggagacagtagaaaca
cagaaacttgtgctaacaag ggacttctctttatcatggg attcagaacagaggcaataa
ttgccatcatgatatgtgtt atggtaatatttgggttttt ctttttgattcttgctctga
aacagcgaagaaaggagact ctatttccagagaagactga agactttagggagaatatat
tttgctatgatgatgaaggc ggcggggaagaagactcgga agcctttgacatcgtagagc
tgagacaaagtacagtaatg agagaaagaaagcctcagag aagcaagagtgcggagatca
ggagcttgtacaggcagtcc ctgcaggtgggcccagacag tgccatatttcgaaaattta
tcctagagaagcttgaagaa gccaacacagacccatgtgc tcccccctttgattcactac
agacgtttgcctatgaggga acagggtcatcagctggctc tctgagctccttggcatcca
gagacactgatcaggaggat gacttcgactaccttaatga cctgggacctcgttttaaaa
gattagcaagcatgtttggc tctgcagtacaacccaacaa ttag 960 C137911 artifi-
aa AWVWRPFVVLEEMDDIQCVG muCDH19 cial KLRSDLDNGNNSFQYKLLGI (44-247)
GAGSFSINERTGEICAIQKL huCDH19 DREEKSLYILRAQVIDTTIG (250-364)
KAVETESEFVIRVLDINDNE muCDH19 PRFLDEPYEAIVPEMSPEGT (363-770)
FVIKVTANDADDPSTGYHAR ILYNLERGQPYFSVEPTTGV IRISSKMDRELQDTYCVIIQ
AKDMLGQPGALSGTTTVSIK LSDINDNKPIFKESLYRLTV SESAPTGTSIGTIMAYDNDI
GENAEMDYSIEEDDSQTFDI ITNHETQEGIVILKKKVDFE HQNHYGIRAKVKNHHVPEQL
MKYHTEASTTFIKIQVEDVD EPPVFLLPYYILEIPEGKPY GTIVGTVSATDPDRRQSPMR
YYLTGSKMFDINDNGTIITT NMLDREVSAWYNLTVTATET YNVQQISSAHVYVQVFNIND
NAPEFSQFYETYVCENAESG EIVQIISAIDRDESIEDHHF YFNHSLEDTNNSSFMLTDNQ
DNTAVILSNRTGFNLKEEPV FYMIILIADNGIPSLTSTNT LTIQVCDCGDSRNTETCANK
GLLFIMGFRTEAIIAIMICV MVIFGFFFLILALKQRRKET LFPEKTEDFRENIFCYDDEG
GGEEDSEAFDIVELRQSTVM RERKPQRSKSAEIRSLYRQS LQVGPDSAIFRKFILEKLEE
ANTDPCAPPFDSLQTFAYEG TGSSAGSLSSLASRDTDQED DFDYLNDLGPRF 961 C137911
artifi- nt gcctgggtgtggagaccatt muCDH19 cial tgttgttctagaagaaatgg
(44-247) atgatatacaatgtgttgga huCDH19 aagctaagatctgacttaga
(250-364) caatggaaacaactctttcc muCDH19 agtacaagctactggggatt
(363-770) ggcgctggaagctttagcat taatgaaagaacaggtgaaa
tatgtgccatacagaagctt gatagagaggaaaaatccct ctacattctgagagcccagg
taatagacaccactattggg aaggctgtggaaactgaatc cgagtttgtcatcagagttt
tggatatcaatgacaatgaa cccagattcctagatgaacc atatgaggccattgtacctg agat
gtctccagaaggaacatttg tcatcaaggtgacagccaat gacgcagatgatccttcaac
tggctatcatgctcgcatcc tatacaacttagaacgaggt caaccatacttttctgttga
gccaacaacaggagtcataa ggatatcttctaagatggat agagagttgcaagatacata
ctgtgtaattattcaagcca aggacatgctcggtcagcct ggagccttgtctggaacaac
aaccgtatcaattaagctgt cagatattaatgacaataag cctatatttaaagaaagttt
ataccgcttgactgtctctg aatctgcacccactgggact tctataggaacaatcatggc
atatgataatgacataggag agaatgcagaaatggattac agcattgaagaggatgattc
gcaaacatttgacattatta ctaatcatgaaactcaagaa ggaatagttatattaaaaaa
gaaagtggattttgagcacc agaaccactacggtattaga gcaaaagttaaaaaccatca
tgttcctgagcagctcatga agtaccacactgaggcttcc accactttcattaagatcca
ggtggaagatgttgatgaac ctcctgttttcctcttacca tattacatacttgaaattcc
tgaaggaaaaccatatggaa caattgtggggacggtttct gccacagacccagatcgaag
acaatctcctatgagatatt atctcactggaagcaaaatg tttgatatcaatgacaatgg
aacaataatcaccactaaca tgcttgacagagaggtcagt gcttggtacaacttgactgt
cacagctactgaaacataca atgtacaacagatctcttca gcccatgtttatgtacaagt
ctttaacattaacgacaatg ctccagagttctctcaattc tatgagacttatgtttgtga
aaatgctgaatctggtgaga tagttcagatcatcagtgca attgatagagatgagtccat
agaagatcaccatttttact ttaatctatctgtagaagac actaacaattcaagttttac
aatcatagataatcaagata acacagctgtcattttgagt aatagaactggtttcaatct
taaagaagagcctgtcttct acatgatcatcttgattgct gataacgggatcccatctct
cacaagcacaaacactctca ctatccaagtctgtgactgt ggagacagtagaaacacaga
aacttgtgctaacaagggac ttctctttatcatgggattc agaacagaggcaataattgc
catcatgatatgtgttatgg taatatttgggtttttcttt ttgattcttgctctgaaaca
gcgaagaaaggagactctat ttccagagaagactgaagac tttagggagaatatattttg
ctatgatgatgaaggcggcg gggaagaagatacagaggcc tttgatatagcagagctgag
gagtagtaccataatgcggg aacgcaagactcggaaaacc acaagcgcggagatcaggag
cttgtacaggcagtccctgc aggtgggcccagacagtgcc atatttcgaaaatttatcct
agagaagcttgaagaagcca acacagacccatgtgctccc ccctttgattcactacagac
gtttgcctatgagggaacag ggtcatcagctggctctctg agctccttagaatcagcagt
ctctgatcaggatgaaagct atgattaccttaatgagttg ggacctcgctttaaaagatt
agcatgcatgtttggctctg cagtacaacccaacaattag 962 C137917 artifi- aa
AWVWRPFvvLEEMDDIQCVG muCDH19 cial KLRSDLDNGNNSFQYKLLGI (44-362)
GAGSFSINERTGEICAIQKL huCDH19 DREEKSLYILRAQVIDTTIG (365-772)
KAVETESEFVIRVLDINDNE PRFLDEPYEAIVPEMSPEGT FVIKVTANDADDPSTGYHAR
ILYNLERGQPYFSVEPTTGV IRISSKMDRELQDTYCVIIQ AKDMLGQPGALSGTTTVSIK
LSDINDNKPIFKESFYRFTI SESAPIGTSIGKIMAYDDDI GENAEMEYSIEDDDSKIFDI
IIDNDTQEGIVILKKKVDFE QQSYYGIRAKVKNCHVDEEL APAHVNASTTYIKVQVEDED
EPPLFLLPYYVFEVFEETPQ GSFVGvvSATDPDNRKSPIR YSITRSKVFNINDNGTITTS
NSLDREISAWYNLSITATEK YNIEQISSIPLYVQVLNIND HAPEFSQYYETYVCENAGSG
QVIQTISAVDRDESIEEHHF YFNLSVEDTNNSSFTIIDNQ DNTAVILTNRTGFNLQEEPV
FYISILIADNGIPSLTSTNT LTIHVCDCGDSGSTQTCQYQ ELVLSMGFKTEVIIAILICI
MIIFGFIFLTLGLKQRRKQI LFPEKSEDFRENIFQYDDEG GGEEDTEAFDIAELRSSTIM
RERKTRKTTSAEIRSLYRQS LQVGPDSAIFRKFILEKLEE ANTDPCAPPFDSLQTYAFEG
TGSLAGSLSSLESAVSDQDE SYDYLNELGPRFKRLACMFG SAVQSNN 963 C137917
artifi- nt gcctgggtgtggagaccatt muCDH19 cial tgtcgttctagaagaaatgg
(44-362) atgatatacaatgtgttgga huCDH19 aagctaagatctgacttaga
(365-772) caatggaaacaactctttcc agtacaagctactggggatt
ggcgctggaagctttagcat taatgaaagaacaggtgaaa tatgtgccatacagaagctt
gatagagaggaaaaatccct ctacattctgagagcccagg taatagacaccactattggg
aaggctgtggaaactgaatc cgagtttgtcatcagagttt tggatatcaatgacaatgaa
cccagattcctagatgaacc atatgaggccattgtacctg agatgtctccagaaggaaca
tttgtcatcaaggtgacagc caatgacgcagatgatcctt caactggctatcatgctcgc
atcctataca acttagaacgaggtcaacca tacttttctgttgagccaac
aacaggagtcataaggatat cttctaagatggatagagag ttgcaagatacatactgtgt
aattattcaagccaaggaca tgctcggtcagcctggagcc ttgtctggaacaacaaccgt
atcaattaagctgtcagata ttaatgacaacaagccaata ttcaaagaaagtttctaccg
cttcactatatctgaatctg cacccattggaacatcaata gggaaaattatggcatatga
tgatgacataggggagaatg cagagatggagtacagcatt gaagatgatgattcaaaaat
atttgacataatcattgaca atgacacccaagaagggata gttatacttaaaaagaaagt
tgattttgagcagcagagct attatggcattagagctaag gttaaaaactgccatgtgga
tgaagagcttgcacctgccc atgttaacgcttccacaacc tacattaaagttcaagtaga
agatgaagatgagcctcctc ttttcctccttccatattat gtatttgaagtttttgaaga
aaccccacagggaLcatttg taggcgtggtgtctgccaca gacccagacaataggaaatc
tcctatcaggtattctatta ctaggagcaaagtgttcaat atcaatgataatggtacaat
cactacaagtaactcactgg atcgtgaaatcagtgct~gg tacaacctaagtattacagc
cacagaaaaatacaatatag aacagatctcttcgatccca ctgtatgtgcaagttcttaa
catcaatgatcatgctcctg agttctctcaatactatgag acttatgtttgtgaaaatgc
aggctctggtcaggtaattc agactatcagtgcagtggat agagatgaatccatagaaga
gcaccatttttactttaatc tatctgtagaagacactaac aattcaagttttacaatcat
agataatcaagataacacag ctgtcattttgactaataga actggttttaaccttcaaga
agaacctgtcttctacatct ccattcttaattgccgacaat ggaatcccgtcacttacaag
tacaaacacccttaccatcc atgtctgtgactgtggtgac agtgggagcacacagacctg
ccagtaccaggagcttgtgc tttccatgggattcaagaca gaagtcatcattgctattct
catttgcattatgatcatat ttgggtttatttttttgact ttgggtttaaaacaacggag
aaaacagattctatttcctg agaaaagtgaagatttcaga gagaatatattccaatatga
tgatgaagggggtggagaag aagatacagaggcctttgat atagcagagctgaggagtag
taccataatgcgggaacgca agactcggaaaaccacaagc gctgagatcaggagcctata
caggcagtctttgcaagttg gccccgacagtgccatattc aggaaattcattctggaaaa
gctcgaagaagctaatactg atccgtgtgcccctcctttt gattccctccagacctacgc
ttttgagggaacagggtcat tagctggatccctgagctcc ttagaatcagcagtctctga
tcaggatgaaagctatgatt accttaatgagttgggacct cgctttaaaagattagcatg
catgtttggttctgcagtgc agtcaaataattag 964 C137915 artifi- aa
AWVWRPFWLEEMDDIQCVGK muCDH19 cial LRSDLDNGNNSFQYKLLGIG (44-461)
AGSFSINERTGEICAIQKLD huCDH19 REEKSLYILRAQVIDTTIGK (464-772)
AVETESEFVIRVLDINDNEP RFLDSPYEAIVPEMSPEGTF VIKVTANDADDPSTGYHARI
LYNLERGQPYFSVEPTTGVI RISSKMDRELQDTYCVIIQA KDMLGQPGALSGTTTVSIKL
SDINDNKPIFKESFYRFTIS ESAPIGTSIGKIMAYDDDIG ENAEMEYSIEDDDSKIFDil
iDNDTQEGIVILKKKVDFSQ QSYYGIRAKVKNCHVDEELA PAHVNASTTYIKVQVEDEDE
PPVFLLPYYILEIPEGKPYG TIVGTVSATDPDRRQSPMRY YLTGSKMFDINDN3TIITTN
MLDREVSAWYNLTVTATETY NVQQISSAHVYVQVFNINDH APEFSQYYETYVCENAGSGQ
VIQTISAVDRDESIEEHHFY FNLSVEDTNNSSFTIIDNQD NTAVILTNRTGFNLQEEPVF
YISILIADNGIPSLTSTNTL TIHVCDCGDSGSTQTCQYQE LVLSMGFKTEVIIAILICIM
IIFGFIFLTLGLKQRRKQIL FPEKSEDFRENIFQYDDEGG GEEDTEAFDIAELRSSTIMR
ERKTRKTTSAEIRSLYRQSL QVGPDSAIFRKFILEKLEEA NTDPCAPPFDSLQTYAFEGT
GSLAGSLSSLESAVSDQDES YDYLNELGPRFKRLACMFGS AVQSNN 965 C137915
artifi- nt gcctgggtgtggagaccatt
muCDH19 cial tgttgttctagaagaaatgg (44-461) atgatatacaatgtgttgga
huCDH19 aagctaagatctgacttaga (464-772) caatggaaacaactctttcc
agtacaagctactggggatt ggcgctggaagctttagcat taatgaaagaacaggtgaaa
tatgtgccatacagaagctt gatagagaggaaaaatccct ctacattctgagagcccagg
taatagacaccactattggg aaggctgtggaaactgaatc cgagtttgtcatcagagttt
tggatatcaatgacaatgaa cccagattcctagatgaacc atatgaggccattgtacctg
agatgtctccagaaggaaca tttgtcatcaaggtgacagc caatgacgcagatgatcctt
caactggctatcatgctcgc atcctatacaacttagaacg aggtcaaccatacttttctg
ttgagccaacaacaggagtc ataaggatatcttctaagat ggatagagagttgcaa
gatacatactgtgtaattat tcaagccaaggacatgctcg gtcagcctggagccttgtct
ggaacaacaaccgtatcaat taagctgtcagatattaatg acaacaagccaatattcaaa
gaaagtttctaccgcttcac tatatctgaatctgcaccca ttggaacatcaatagggaaa
attatggcatatgatgatga cataggggagaatgcagaga tggactacagcattgaagat
gatgattcaaaaatatttga cataatcattgacaatgaca cccaagaagggatagttata
cttaaaaagaaagttgattt tgagcagcagagctattatg gcattagagctaaggttaaa
aactgccatgtggatgaaga gcttgcacctgcccatgtta acgcttccacaacctacatt
aaagttcaagtagaagatga agatgaacctcctgttttcc tcttaccatattacatactt
gaaattcctgaaggaaaacc atatggaacaattgtgggga cggtttctgccacagaccca
gatcgaagacaatctcctat gagatattatctcactggaa gcaaaatgtttgaLatcaat
gacaatggaacaataatcac cactaacatgcttgacagag aggtcagtgcttggtacaac
ttgactgtcacagctactga aacatacaatgtacaacaga tctcttcagcccatgtttat
gtacaagtctttaacattaa tgatcatgctcctgagttct ctcaatactatgagacttat
gtttgtgaaaatgcaggctc tggtcaggtaattcagacta tcagtgcagtggatagagat
gaatccatagaacagcacca tttttactttaatctatctg tagaagacactaacaattca
agttttacaatcatagataa tcaagataacacagctgtca ttttgactaatagaactggt
tttaaccttcaagaagaacc tgtcttctacatctccatct taattgccgacaatggaatc
ccgtcacttacaagtacaaa cacccttaccatccaLgtct gtgactgtggtgacagtggg
agcacacagacctgccagta ccaggagctttgtgctttcca tgggattcaagacagaagtc
atcattgctattctcatttg cattatgatcatatttgggt ttatttttttgactttgggt
ttaaaacaacggagaaaaca gattctatttcctgagaaaa gtgaagatttcagagagaat
atattccaatatgatgatga agggcgtggagaagaagata cagaggcctttgatatagca
gagctgaggagtagtaccat aatgcgggaacgcaagactc ggaaaaccacaagcgctgag
atcaggagcctatacaggca gtctttgcaagttggccccg acagtgccatattcaggaaa
ttcattctggaaaagctcga agaagctaatactgatccgt gtgcccctccttttgattcc
ctccagacctacgcttttga gggaacagggtcattagctg catccctgagctccttagaa
tcagcagtctctgatcagga tgaaagctatgattacctta atgagttgggacctcgcttt
aaaagattagcatgcatgtt tggttctgcagtgcagtcaa ataattag 966 C71144
artifi- aa AWVWRPFVVLEEMDDIQCVG muCDH19 cial KLRSDLDNGNNSFQYKLLGI
(44-770) GAGSFSINERTGEICAIQKL DREEKSLYILRAQVIDTTIG
KAVETESEFVIRVLDINDNE PRFLDEPYEAIVPEMSPEGT FVIKVTANDADDPSTGYHAR
ILYNLERGQPYFSVEPTTGV IRISSKMDRELQDTYCVIIQ AKDMLGQPGALSGTTTVSIK
LSDINDNKPIFKESFYRFTI SESAPIGTSIGKIMAYDDDI GENAEMEYSIEDDDSKIFDI
IIDNDTQEGIVILKKKVDFE QQSYYGIRAKVKNCHVDEEL APAHVNASTTYIKVQVEDED
EPPVFLLPYYILEIPEGKPY GTIVGTVSATDPDRRQSPMR YYLTGSKMFDINDNSTIITT
NMLDREVSAWYNLTVTATET YNVQQISSAHVYVQVFNIND NAPEFSQFYETYVCENAESG
EIVQIISAIDRDESIEDHHF YFNHSLEDTNNSSFMLTDNQ DNTAVILSNRTGFNLKEEPV
FYMIILIADNGIPSLTSTNT LTIQVCDCGDSRNTETCANK GLLFIMGFRTEAIIAIMICV
MVIFGFFFLILALKQRRKET LFPEKTEDFRENIFCYDDEG GGEEDSEAFDIVELRQSTVM
RERKPQRSKSAEIRSLYRQS LQVGPDSAIFRKFILEKLEE ANTDPCAPPFDSLQTFAYEG
TGSSAGSLSSLASRDTDQED DFDYLNDLGPRFKRLASMFG SAVQPNN 967 C71144
artifi- nt gcctgggtgtggagaccatt muCDH19 cial tgttgttctagaagaaatgg
(44-770) atgatatacaatgtgttgga aagctaagatctgacttaga
caatggaaacaactctttcc agtacaagctactggggatt ggcgctggaagctttagcat
taatgaaagaacaggtgaaa tatgtgccatacagaagctt gatagagaggaaaaatccct
ctacattctgagagcccagg taatagacaccactattggg aaggctgcggaaactgaatc
cgagtttgtcatcagagttt tggatatcaatgacaatgaa cccagattcctagatgaacc
atatgaggccattgtacctg agatgtctccagaaggaaca tttgtcatcaaggtgacagc
caatgacgcagatgatcctt caactggctatcatgctcgc atcctatacaacttagaacg
aggtcaaccatacttttctg ttgagccaacaacaggagtc ataaggatatcttctaagat
ggatagagagttgcaagata catactgtgtaattattcaa gccaaggacatgctcggtca
gcctggagccttgtctggaa caacaaccgtatcaattaag ctgtcagatattaatgacaa
caagccaatattcaaagaaa gtttctaccgcttcactata tctgaatctgcacccattgg
aacatcaatagggaaaatta tggcatatgatgatgacata ggggagaatgcagagatgga
gtacagcattgaagatgatg attcaaaaatatttgacata atcattgacaatgacaccca
agaagggatagttatactta aaaagaaagttgattttgag cagcagagccaitatggcat
tagagctaaggttaaaaact gccatgtggatgaagagctt gcacctgcccatgttaacgc
ttccacaacctacattaaag ttcaagtagaagatgaagat gaacctcctgttttcctctt
accatattacatacttgaaa ttcctgaaggaaaaccatat ggaacaattgtggggacggt
ttctgccacagacccagatc gaagacaatctcctatgaga tattatctcactggaagcaa
aatgtttgatatcaatgaca atggaacaataatcaccact aacatgcttgacagagaggt
cagtgcttggtacaacttga ctgtcacagctacLgaaaca tacaatgtacaacagatctc
ttcagcccatgtttatgtac aagtctttaacattaacgac aatgctccagagttctctca
attctatgagacttatgttt gtgaaaatgctgaatctggt gagatagttcagatcatcag
tgcaattgatagagatgagt ccatagaagatcaccatttt tactttaatcactctctgga
agacacaaacaactcaagtt ttatgctaacagacaatcaa gataacacagctgtaattct
gagtaatagaactggtttca atcttaaagaagagcctgtc ttctacatgatcatcttgat
tgctgataacgggatcccat ctctcacaagcacaaacact ctcactatccaagtctgtga
ctgtggagacagtagaaaca cagaaacttgtgctaacaag ggacttctctttatcatggg
attcagaacagaggcaataa ttgccatcatgatatgtgtt atggtaatatttgggttttt
ctttttgatttctttgctctg aaacagcgaagaaaggagact ctatttccagagaagactga
agactttagggagaatatat tttgctatgatgatgaaggc ggcggggaagaagactcgga
agcctttgacatcgtagagc tgagacaaagtacagtaatg agagaaagaaagcctcagag
aagcaagagtgcggagatca ggagcttgtacaggcagtcc ctgcaggtgggcccagacag
tgccatatttcgaaaattta tcctagagaagcttgaagaa gccaacacagacccatgtgc
tcccccctttgattcactac agacgtttgcctatgaggga acagggtcatcagctggctc
tctgagctccttggcatcca gagacaccgatcaggaggat gacttcgactaccttaatga
cctgggacctcgttttaaaa gattagcaagcatgtttggc tctgcagtacaacccaacaa ttag
968 Flag Tag artifi- aa DYKDDDDK cial 969 Flag Tag artifi- nt
gactacaaagacgatgacga cial caag 970 ckCDH19 artifi- aa
MNCSTFLSLVLALVQLQLCS (1-43):: cial PTTQIFSAQKTDQSYTTIRR FLAG::ckC
VKRDYKDDDDKGWVWEPLFV DH19 TEEETSTMPMYVGQLKSDLD (44-776)
KEDGSLQYILTGEGADSIFF INEHGKIYVRQKLDREKKSF YILRAQVINRKTRHPIEPDS
EFIIKVRDINDHEPQFLDGP YVATVPEMSPEGTSVTQVTA TDGDDPSYGNNARLLYSLIQ
GQPYFSVEPKTGVIRMTSQM DRETKDQYLVVIQAKDMVGQ AGAFSATATVTINLSDVNDN
PPKFQQRLYYLNVSEEAPVG TTVGRLLAEDSDIGENAAMN YFIEEDSSDVFGIITDRETQ
EGIIILKKRVDYESKRKHSV RVKAVNRYIDDRFLKEGPFE DITIVQISVVDADEPPVFTL
ESYVMEIAEGVVSGSLVGTV SARDLDNDDSSVRYSIVQGL HLKRLFSINEHNGTIITTEP
LDREKASWHNITVTATETRN PEKISEANVYIQVLDVNDHA PEFSKYYETFVCENAVPGQL
IQNISAVDKDDSAENHRFYF SLAQATNSSHFTVKDNQDNT AGIFTA3SGFSRKEQFYFFL
PILILDNGSPPLTSTNTLTV TVCDCDTEVNTLYCRYGAFL YSIGLSTEALVAVLACLLIL
LVFFLAIIGIRQQRKKTLFS EKVEEFRENIVRYDDEGGGE EDTEAFDISALRTRAVLRTH
KPRKKITTEIHSLYRQSLQV GPDSAIFRQFISEKLEEANT DPSVPPYDSLQTYAFEGTGS
LAGSLSSLGSNTSDVDQNYE YLVGWGPPFKQLAGMYTSQR STRD 971 huCDH19(1-
MNCYLLLRFMLGIPLLWPCL 43)::FLAG:: GATENSQTKKVKQPVRSHLR hu(44-
VKRDYKDDDDKGWVWNQFFV 141):: PEEMNTTSHHIGQLRSDLDN ckCDH1
GNNSFQYKLLGAGAGSTFII 9(142-776) DERTGDIYAIQKLDREERSL
YILRAQVIDIATGRAVEPES EFVIKVSDINDHEPQFLDGP YVATVPEMSPEGTSVTQVTA
TDGDDPSYGKNARLLYSLIQ GQPYFSVEPKTGVIRKTSQM DRETKDQYLVVIQAKDMVGQ
AGAFSATATVTIKLSDVNDN PPKFQQRLYYLNVSEEAPVG TTVGRLLAEDSDIGENAAMN
YFIEEDSSDVFGIITDRETQ EGIIILKKRVDYESKRKHSV RVKAVNRYIDDRFLKEGPFE
DITIVQISVVDADEPPVFTL ESYVMEIAEGVVSGSLVGTV SARDLDNDDSSVRYSIVQGL
HLKRLFSINE HNGTIITTEPLDREKASWHN ITVTATETRNPEKISEANVY
IQVLDVNDHAPEFSKYYETF VCENAVPGQLIQNISAVDKD DSAENHRFYFSLAQATNSSH
FTVKDNQDNTAGIFTAGSGF SRKEQFYFFLPILILDNGSP PLTSTNTLTVTVCDCDTEVN
TLYCRYGAFLYSIGLSTEAL VAVLACLLILLVFFLAIIGI RQQRKKTLFSEKVEEFRENI
VRYDDEGGGEEDTEAFDISA LRTRAVLRTHKPRKKITTEI HSLYRQSLQVGPDSAIFRQF
ISEKLEEANTDPSVPPYDSL QTYAFEGTGSLAGSLSSLGS NTSDVDQNYEYLVGWGPPFK
QLAGMYTSQRSTRD 972 ckCDH19(1- MNCSTFLSLVLALVQLQLCS 43)::
PTTQIFSAQKTDQSYTTIRR FLAG::ckC VKRDYKDDDDKGWVWEPLFV DH19(44-
TEEETSTMPMYVGQLKSDLD 141):: KEDGSLQYILTGEGADSIFF huCDH1
INEHGKIYVRQKLDREKKSF 9(142- YILRAQVINRKTRHPIEPDS 249)::
EFIIKVRDINDNEPKFLDEP ckCDH1 YEAIVPEMSPEGTLVIQVTA 9(250-776)
SDADDPSSGNNARLLYSLLQ GQPYFSVEPTTGVIRISSKM DRELQDEYWVIIQAKDMIGQ
PGALSGTTSVLIKLSDVNDN PPKFQQRLYYLNVSEEAPVG TTVGRLLAEDSDIGENAAMN
YFIEEDSSDVFGIITDRETQ EGIIILKKRVDYESKRKHSV RVKAVNRYIDDRFLKEGPFE
DITIVQISVVDADEPPVFTL ESYVMEIAEGVVSGSLVGTV SARDLDNDDSSVRYSIVQGL
HLKRLFSINEHNGTIITTEP LDREKASWHNITVTATETRN PEKISEANVYIQVLDVNDHA
PEFSKYYETFVCENAVPGQL IQNISAVDKDDSAENHRFYF SLAQATNSSHFTVKDNQDNT
AGIFTAGSGFSRKEQFYFFL PILILDNGSPPLTSTNTLTV TVCDCDTEVNTLYCRYGAFL
YSIGLSTEALVAVLACLLIL LVFFLAIIGIRQQRKKTLFS EKVEEFRENIVRYDDEGGGE
EDTEAFDISALRTRAVLRTH KPRKKITTEIHSLYRQSLQV GPDSAIFRQFISEKLEEANT
DPSVPPYDSLQTYAFEGTGS LAGSLSSLGSNTSDVDQNYE YLVGWGPPFKQLAGMYTSQR STRD
973 ckCDH19(1- MNCSTFLSLVLALVQLQLCS 43):: PTTQIFSAQKTDQSYTTIRR
FLAG::ckC VKRDYKDDDDKGWVWEPLFV DH19(44- TEEETSTMPMYVGQLKSDLD 249)::
KEDGSLQYILTGEGADSIFF huCDH1 INEHGKIYVRQKLDREKKSF 9(250-
YILRAQVINRKTRHPIEPDS 364):: EFIIKVRDINDHEPQFLDGP ckCDH1
YVATVPEMSPEGTSVTQVTA 9(365-776) TDGDDPSYGKNARLLYSLIQ
GQPYFSVEPKTGVIRKTSQM DRETKDQYLWIQAKDMVGQA GAFSATATVTINLSDVNDNK
PIFKESLYRLTVSESAPTGT SIGTIMAYDNDIGENAEMDY SIEEDDSQTFDIITNHETQE
GIVILKKKVDFEHQNHYGIR AKVKNHHVPEQLMKYHTEAS TTFIKIQVEDVDEPPVFTLE
SYVMEIAEGWSGSLVGTVSA RDLDNDDSSVRYSIVQGLHL KRLFSINEHNGTIITTEPLD
REKASWHNITVTATETRNPE KISEANVYIQVLDVNDHAPE FSKYYETFVCENAVPGQLIQ
NISAVDKDDSAENHRFYFSL AQATNSSHFTVKDNQDNTAG IFTAGSGFSRKEQFYFFLPI
LILDNGSPPLTSTNTLTVTV CDCDTEVNTLYCRYGAFLYS IGLSTEALVAVLACLLILLV
FFLAIIGIRQQRKKTLFSEK VEEFRENIVRYDDEGGGEED TEAFDISALRTRAVLRTHKP
RKKITTEIHSLYRQSLQVGP DSAIFRQFISEKLEEANTDP SVPPYDSLQTYAFEGTGSLA
GSLSSLGSNTSDVDQNYEYL VGWGPPFKQLAGMYTSQRST RD 974 ckCDH19(1-
MNCSTFLSLVLALVQLQLCS 43):: PTTQIFSAQKTDQSYTTIRR FLAG::ckC
VKRDYKDDDDKGWVWEPLFV DH19(44- TEEETSTMPMYVGQLKSDLD 364)::
KEDGSLQYILTGEGADSIFF huCDH1 INEHGKIYVRQKLDREKKSF 9(365-
YILRAQVINRKTRHPIEPDS 463):: EFIIKVRDINDHEPQFLDGP ckCDH1
YVATVPEMSPEGTSVTQVTA 9(469-776) TDGDDPSYGNNARLLYSLIQ
GQPYFSVEPKTGVIRMTSQM DRETKDQYLVVIQAKDMVGQ AGAFSATATVTINLSDVNDN
PPKFQQRLYYLNVSEEAPVG TTVGRLLAEDSDIGENAAMN YFIEEDSSDVFGIITDRETQ
EGIIILKKRVDYESKRKHSV RVKAVNRYIDDRFLKEGPFE DITIVQISVVDADEPPLFLL
PYYVFEVFEETPQGSFVGVV SATDPDNRKSPIRYSITRSK VFNINDNGTITTSNSLDREI
SAWYNLSITATEKYNIEQIS SIPLYVQVLNINDHAPEFSK YYETFVCENAVPGQLIQNIS
AVDKDDSAENHRFYFSLAQA TNSSHFTVKDNQDNTAGIFT AGSGFSRKEQFYFFLPILIL
DNGSPPLTSTNTLTVTVCDC DTEVNTLYCRYGAFLYSIGL STEALVAVLACLLILLVFFL
AIIGIRQQRKKTLFSEKVEE FRENIVRYDDEGGGEEDTEA FDISALRTRAVLRTHKPRKK
ITTEIHSLYRQSLQVGPDSA IFRQFISEKLEEANTDPSVP PYDSLQTYAFEGTGSLAGSL
SSLGSNTSDVDQNYEYLVGW GPPFKQLAGMYTSQRSTRD 975 (1-
MNCSTFLSLVLALVQLQLCS 43):: PTTQIFSAQKTDQSYTTIRR FLAG::ckC
VKRDYKDDDDKGWVWEPLFV DH19(44- TEEETSTMPMYVGQLKSDLD 468):: KEDGSL
huCDH1 QYILTGEGADSIFFIKEHGK 9(464-772) IYVRQKLDREKKSFYILRAQ
VINRKTRHPIEPDSEFIIKV RDINDHEPQFLEGPYVATVP EMSPEGTSVTQVTATDGDDP
SYGNNARLLYSLIQGQPYFS VEPKTGVIRMTSQMDRETKD QYLVVIQAKDMVGQAGAFSA
TATVTINLSDVNDNPPKFQQ RLYYLNVSEEAPVGTTVGRL LAEDSDIGENAAMNYFIEED
SSDVFGIITDRETQEGIIIL KKRVDYESKRKHSVRVKAVN RYIDDRFLKEGPFEDITIVQ
ISVVDADEPPVFTLESYVME IAEGVVSGSLVGTVSARDLD MDDSSVRYSIVQGLHLKRLF
SINEHNGTIITTEPLDREKA SWHNITVTATETRNPEKISE ANVYIQVLDVNDHAPEFSQY
YETYVCENAGSGQVIQTISA VDRDESIEEHHFYFNLSVED TNNSSFTIIDNQDNTAVILT
NRTGFNLQEEPVFYISILIA DNGIPSLTSTNTLTIHVCDC GDSGSTQTCQYQELVLSMGF
KTEVIIAILICIMIIFGFIF LTLGLKQRRKQILFPEKSED
FRENIFQYDDEGGGEEDTEA FDIAELRSSTIMRERKTRKT TSAEIRSLYRQSLQVGPDSA
IFRKFILEKLEEANTDPCAP PFDSLQTYAFEGTGSLAGSL SSLESAVSDQDESYDYLNEL
GPRFKRLACMFGSAVQSNN 976 rhCDH19(1- MNCYLLLPFMLGIPLLKPCL 43)::
GATENSQTKKVQQPVGSHLR FLAG::rhC VKRDYKDDDDKGWVWNQFFV DH19
PEEMNTTSHHVGRLRSDIDN (44-772) GNNSFQYKLLGAGAGSTFII
DERTGDIYAIEKLDREERSL YILRAQVIDITTGRAVEPES EFVIKVSDINDNEPKFLDEP
YEAIVPEMSPEGTLVIQVTA SDADDPSSGNNARLLYSLLQ GQPYFSVEPTTGVIRISSKM
DRELQDEYWVIIQAKDMIGQ PGALSGTTSVLIKLSDVNDN KPIFKESLYRLTVSESAPTG
TSIGTIMAYDNDIGENAEMD YSIEEDDSQTFDIITNHETQ EGIVILKKKVNFEHQNHYGI
RAKVKNHHVDEQLMKYHTEA STTFIKIQVEDVDEPPLFLL PYYIFEIFEETPQGSFVGVV
SATDPDNRKSPIRYSITRSK VFNIDDNGTITTTNSLDREI SAWYNLSITATEKYNIEQIS
SIPVYVQVLNINDHAPEFSQ YYESYVCENAGSGQVIQTIS AVDRDESIEEHHFYFNLSVE
DTNSSSFTIIDNQDNTAVIL TNRTGFNLQEEPIFYISILI ADNGIPSLTSTNTLTIHVCD
CDDSGSTQTCQYQELMLSMG FKTEVIIAILICIMVIFGFI FLTLGLKQRRKQILFPEKSE
DFRENIFRYDDEGGGEEDTE AFDVAALRSSTIMRERKTRK TTSAEIRSLYRQSLQVGPDS
AIFRKFILEKLEEADTDPCA PPFDSLQTYAFEGTGSLAGS LSSLESAVSDQDESYDYLNE
LGPRFKRLACMFGSAVQSNM 977 caCDH19(1- QFFVPEEMNKTDYHIGQLRS 42)::
DLDNGNNSFQYKLLGAGAGS FLAG::caC IFVIDERTGDIYAIQKLDRE DH19
ERSLYTLRAQVIDSTTGRAV (43-770) EPESEFVIRVSDINDNEPKF
LDEPYEAIVPEMSPEGTLVI QVTATDADDPASGNNARLLY SLLQGQPYFSIEPTTGVIRI
SSKMDRELQDEYWVIIQAKD MIGLPGALSGTTSVLIKLSD VNDNKPIFKERLYRLTVSES
APTGTSIGRIMAYDNDIGEN AEMDYSIEDDSQTFDIITNN ETQEGIVILKKKVDFEHQNH
YLIRANVKNRHVAEHLMEYH VEASTTFVRVQVEDEDEPPV FLLPYYLFEILEESPHGSFV
GMVSATDPDQRKSPIRYSIT RSKVFSIDDNGTIITTNPLD REISAWYNLSITATEKYNVQ
QISAVPVYVQVLNINDHAPE FSEYYDSYVCENAGSGQVIQ TISAVDRDESVEDHHFYFNL
SVEDTKNSSFIIIDNEDNTA VILTNRTGFSLQEEPVFYIS VLIADNGIPSLTSTNTLTIH
ICDCDDYGSTQTCRDKDLLL SMGFRTEVILAILISIMIIF GFIFLILGLKQRRKPTLFPE
KGEDFRENIFRYDDEGGGEE DTEAFDIVQLRSSTIMRERK TRKTAAAEIRSLYRQSLQVG
PDSAIFRKFILEKLEEANTD PCAPPFDSLQTYAFEGTGSL AGSLSSLGSAVSDQDENYDY
LNELGPRFKRLACMFGSAMQ SNN 978 rhCDH19(1- MNCYLLLPFMLGIPLLWPCL 43):
GATENSQTKKVQQPVGSHLR FLAG::rhC VKRDYKDDDDKGWVWNQFFV DH19(44-
PEEMNTTSHHVGRLRSDLDN 141):: GNNSFQYKLLGAGAGSTFII caCDH1
DERTGDIYAIEKLDREERSL 9(141-770) YILRAQVIDITTGRAVEPES
EFVIKVSDINDNEPKFLDEP YEAIVPEMSPEGTLVIQVTA TDADDPASGNNARLLYSLLQ
GQPYFSIEPTTGVIRISSKM DRELQDEYKVIIQAKDMIGL PGALSGTTSVLIKLSDVNDN
KPIFKERLYRITVSESAPTG TSIGRIMAYDNDIGENAEMD YSIEDDSQTFDIITNNETQE
GIVILKKKVDFEHQNHYLIR ANVKNRHVAEHLMEYHVEAS TTFVRVQVEDEDEPPVFLLP
YYLFEILEESPHGSFVGMVS ATDPDQRKSPIRYSITRSKV FSIDDNGTIITTNPLDREIS
AWYNLSITATEKYNVQQISA VPVYVQVLNINDHAPEFSEY YDSYVCENAGSGQVIQTISA
VDRDESVEDHHFYFNLSVED TKNSSFIIIDNEDNTAVILT NRTGFSLQEEPVFYISVLIA
DNGIPSLTSTNTLTIHICDC DDYGSTQTCRDKDLLLSMGF RTEVILAILISIMIIFGFIF
LILGLKQRRKPTLFPEKGED FRENIFRYDDEGGGEEDTEA FDIVQLRSSTIMRERKTRKT
AAAEIRSL YRQSLQVGPDSAIFRKFILE KLEEANTDPCAPPFDSLQTY
AFEGTGSLAGSLSSLGSAVS DQDENYDYLNELGPRFKRLA CMFGSAMQSNN 979
rhCDH19(1- MNCYLLLPFMLGIPLLWPCL 43):: GATENSQTKKVQQPVGSHLR
FLAG::rhC VKRDYKDDDOKGWVWNQFFV DH19(44- PEEMNTTSHHVGRLRSDLDN 65)::
GNNSFQYKLLGAGAGSIFVI caCDH19 DERTGDIYAIQKLDREERSL (65-770)
YTLRAQVIDSTTGRAVEPES EFVIRVSDINDNEPKFLDEP YEAIVPEMSPEGTLVIQVTA
TDADDPASGNNARLLYSLLQ GQPYFSIEPTTGVIRISSKM DRELQDEYWVIIQAKDMIGL
PGALSGTTSVLIKLSDVNDN KPIFKERLYRLTVSESAPTG TSIGRIMAYDNDIGENAEMD
YSIEDDSQTFDIITNNETQE GIVILKKKVDFEHQNHYLIR ANVKNRHVAEHLMEYHVEAS
TTFVRVQVEDEDEPPVFLLP YYLFEILEESPHGSFVGMVS ATDPDQRKSPIRYSITRSKV
FSIDDNGTIITTNPLDREIS AWYNLSITATEKYNVQQISA VPVYVQVLNINDHAPEFSEY
YDSYVCENAGSGQVIQTISA VDRDESVEDHKFYFNLSVED TKNSSFIIIDNEDNTAVILT
NRTGFSLQEEPVFYISVLIA DNGIPSLTSTNTLTIHICDC DDYGSTQTCRDKDLLLSMGF
RTEVILAILISIMIIFGFIF LILGLKQRRKPTLFPEKGED FRENIFRYDDEGGGEEDTEA
FDIVQLRSSTIMRERKTRKT AAAEIRSLYRQSLQVGPDSA IFRKFILEKLEEANTDPCAP
PFDSLQTYAFEGTGSLAGSL SSLGSAVSDQDENYDYLNEL GPRFKRLACMFGSAMQSNN 980
caCDH19(1- MNYCFLLPLMLGIPLIWPCF 43):: TASESSKTEVKHQAGSHLRV
FLAG::caC KRDYKDDDDKGWMWNQFFVP DH19(44- EEMNKTDYHIGQLRSDLDNG 87)::
NNSFQYKLLGAGAGSTFIID rhCDH19(89- ERTGDIYAIEKLDREERSLY 114)::
ILRAQVIDSTTGRAVEPESE caCDH1 FVIRVSDINDNEPKFLDEPY 9(115-770)
EAIVPEMSPEGTLVIQVTAT DADDPASGNNARLLYSLLQG QPYFSIEPTTGVIRISSKMD
RELQDEYWVIIQAKDMIGLP GALSGTTSVLIKLSDVNDNK PIFKERLYRLTVSESAPTGT
SIGRIMAYDNDIGENAEMDY SIEDDSQTFDIITNNETQEG IVILKKKVDFEHQNHYLIRA
KVKNRHVAEHLMEYHVEAST TFVRVQVEDEDEPPVFLLPY YLFEILEESPHGSFVGMVSA
TDPDQRKSPIRYSITRSKVF SIDDNGTIITTNPLDREISA WYNLSITATEKYNVQQISAV
PVYVQVLNINDHAPEFSEYY DSYVCENAGSGQVIQTISAV DRDESVEDHHFYFNLSVEDT
KNSSFIIIDNEDNTAVILTN RTGFSLQEEPVFYISVLIAD NGIPSLTSTNTLTIHICDCD
DYGSTQTCRDKDLLLSMGFR TEVILAILISIMIIFGFIFL ILGLKQRRKPTLFPEKGEDF
RENIFRYDDEGGGEEDTEAF DIVQLRSSTIMRERKTRKTA AAEIRSLYRQSLQVGPDSAI
FRKFILEKLEEANTDPCAPP FDSLQTYAFEGTGSLAGSLS SLGSAVSDQDENYDYLNELG
PRFKRLACMFGSAMQSNN 981 caCDH19(1- MNYCFLLPLMLGIPLIWPCF 43)::
TASESSKTEVKHQAGSHLRV FLAG::caC KRDYKDDDDKGWMWNQFFVP DH19(44-
EEMNKTDYHIGQLRSDLDNG 120):: NNSFQYKLLGAGAGSIFVID rhCDH1
ERTGDIYAIQKLDREERSLY 9(122- TLRAQVIDITTGRAVEPESE 137)::
FVIKVSDINDNEPKFLDEPY caCDH1 EAIVPEMSPEGTLVIQVTAT 9(137-770)
DADDPASGNNARLLYSLLQG QPYFSIEPTTGVIRISSKMD RELQDEYWVIIQAKDMIGLP
GALSGTTSVLIKLSDVNDNK PIFKERLYRLTVSESAPTGT SIGRIMAYDNDIGENAEMDY
SIEDDSQTFDIITNNETQEG IVILKKKVDFEHQNHYLIRA NVKNRHVAEHLMEYHVEAST
TFVRVQVEDEDEPPVFLLPY YLFEILEESPHGSFVGMVSA TDPDQRKSPIRYSITRSKVF
SIDDNGTIITTNPLDREISA WYNLSITATEKYNVQQISAV PVYVQVLNINDHAPEFSEYY
DSYVCENAGSGQVIQTISAV DRDESVEDEHFYFNLSVEDT KNSSFIIIDNEDNTAVILTN
RTGFSLQEEPVFYISVLIAD NGIPSLTSTNTLTIHICDCD DYGSTQTCRDKDLLLSMGFR
TEVILAILISIMIIFGFIFL ILGLKQRRKPTLFPEKGEDF RENIFRYDDEGGGEEDTEAF
DIVQLRSSTIMRERKTRKTA AAEIRSLYRQSLQVGPDSAI FRKFILEKLEEANTDPCAPP
FDSLQTYAFEGTGSLAGSLS SLGSAVSDQDENYDYLNELG PRFKRLACMFGSAMQSNN 982
rhCDH19(1- MNCYLLLPFMLGIPLLWPCL 43):: GATENSQTKKVQQPVGSHLR
FLAG::rhC VKRDYKDDDDKGWVWNQFFV DH19(44- PEEMNTTSHHVGRLRSDLDN
141):: GNNSFQYKLLGAGAGSTFII raCDH19 DERTGDIYAIEKLDREERSL (140-
YILRAQVIDITTGRAVEPES 247):: EFVIKVSDINDNEPRFLDEP rhCDH1
YEAIVPEMSPEGTFVIKVTA 9(250-772) NDADDPTSGYHARILYNLEQ
GQPYFSVEPTTGVIRISSKM DRELQDTYCVIIQAKDMLGQ PGALSGTTTISIKLSDINDN
KPIFKESLYRLTVSESAPTG TSIGTIMAYDNDIGENAEMD YSIEEDDSQTFDIITNHETQ
EGIVILKKKVNFEHQNHYGI RAKV KNHHVDEQLMKYHTEASTTF IKIQVEDVDEPPLFLLPYYI
FEIFEETPQGSFVGVVSATD PDNRKSPIRYSITRSKVFNI DDNGTITTTNSLDREISAWY
NLSITATEKYNIEQISSIPV YVQVLNINDHAPEFSQYYES YVCENAGSGQVIQTISAVDR
DESIEEKHFYFNLSVEDTNS SSFTIIDNQDNTAVILTNRT GFNLQEEPIFYISILIADNG
IPSLTSTNTLTIHVCDCDDS GSTQTCQYQELMLSMGFKTE VIIAILICIMVIFGFIFLTL
GLKQRRKQILFPEKSEDFRE NIFRYDDEGGGEEDTEAFDV AALRSSTIMRERKTRKTTSA
EIRSLYRQSLQVGPDSAIFR KFILEKLEEADTDPCAPPFD SLQTYAFEGTGSLAGSLSSL
ESAVSDQDESYDYLNELGPR FKRLACMFGSAVQSNN 983 raCDH19(1-
MNHYFLKYWILMVPLIWPCL 43):: KVAETLKIEKAQRAVPSLGR FLAG::raC
AKRDYKDDDDKGWVWKQFVV DH19 PEEMDTIQHVGRLRSDLDNG (44-770)
NNSFQYKLLGTGDGSFSIDE KTGDIFAMQKLDREKQSLYI LRAQVIDTTIGKAVEPESEF
VIRVSDVNDNEPRFLDEPYE AIVPEMSPEGTFVIKVTAND ADDPTSGYHARILYNLEQGQ
PYFSVEPTTGVIRISSKMDR ELQDTYCVIIQAKDMLGQPG ALSGTTTISIKLSDINDNKP
IFKESFYRFTISESAPSGTT IGKIMAYDDDIGENAEMDYS IEDDESQIFDIVIDNETQEG
IVILKKKVDFEHQNHYGIRV KVKNCHVDEELAPAHVNAST TYIKVQVEDEDEPPTFLLPY
YIFEIPEGKPYGTMVGTVSA VDPDRRQSPMRYSLIGSKMF DINGNGTIVTTNLLDREVSA
WYNLSVTATETYNVQQISSA HVYVQVLNINDHAPEFSQLY ETYVCENAESGEIIQTISAI
DRDESIEDHHFYFNHSVEDT NNSSFILTDNQDNTAVILSN RAGFSLKEETVFYMIILIAD
NGIPPLTSTNTLTIQVCDCG DSRSTETCTSKELLFIMGFK AEAIIAIVICVMVIFGFIFL
ILALKQRRKETLFPEKTEDF RENIFCYDDEGGGEEDSEAF DIIELRQSTVMRERKPRKSR
SAEIRSLYRQSLQVGPDSAI FRKFILEKLEEANTDSSAPP FDSLQTFAYEGTGSSAGSLS
SLGSSVTDQEDDFDYLNDLG PCFKRLANMFGSAVQPDN 984 (1-
MNYCFLKHWILMIPLLWPCL 43):: KVSETLKAEKARRTVPSTWR FLAG::mu
AKRDYKDDDDKAWVWRPFVV CDH 19 LEEMDDIQCVGKLRSDLDNG (44-323)::
NNSFQYKLLGIGAGSFSINE raCDH19 RTGEICAIQKLDREEKSLYI (324-
LRAQVIDTTIGKAVETESEF 327):: VIRVLDINDNEPRFLDEPYE muCDH1
AIVPEMSPEGTFVIKVTAND 9(328-770) ADDPSTGYHARILYNLERGQ
PYFSVEPTTGVIRISSKMDR ELQDTYCVIIQAKDMLGQPG ALSGTTTVSIKLSDINDNKP
IFKESFYRFTISESAPIGTS IGKIMAYDDDIGENAEMEYS IEDDDSKIFDIIIDNDTQEG
IVILKKKVDFEHQNHYGIRA KVKNCHVDEELAPAHVNAST TYIKVQVEDEDEPPVFLLPY
YILEIPEGKPYGTIVGTVSA TDPDRRQSPMRYYLTGSKMF DINDNGTIITTNMLDREVSA
WYNLTVTATETYNVQQISSA HVYVQVFNINDNAPEFSQFY ETYVCENAESGEIVQIISAI
DRDESIEDEHFYFNHSLEDT NNSSFMLTDNQDNTAVILSN RTGFNLKEEPVFYMIILIAD
NGIPSLTSTNTLTIQVCDCG DSRNTETCANKGLLFIMGFR TEAIIAIMICVMVIFGFFFL
ILALKQRRKETLFPEKTEDF RENIFCYDDEGGGEEDSEAF DIVELRQSTVMRERKPQRSK
SAEIRSLYRQSLQVGPDSAI FRKFILEKLEEANTDPCAPP FDSLQTFAYEGTGSSAGSLS
SLASRDTDQEDDFDYLNDLG PRFKRLASMFGSAVQPNN 985 muCDH19(1-
MNYCFLKHWILMIPLLWPCL 43):: KVSETLKAEKARRTVPSTWR FLAG::mu
AKRDYKDDDDKAWVWRPFVV CDH19(44- LEEMDDIQCVGKLRSDLDNG 770)::
NNSFQYKLLGIGAGSFSINE raCDH19 RTGEICAIQKLDREEKSLYI (290, 299,
LRAQYIDTTIGKAVETESEF 308) VIRVLDINDNEPRFLDEPYE AIVPEMSPEGTFVIKVTAND
ADDPSTGYHARILYNLERGQ PYFSVEPTTGVIRISSKMDR ELQDTYCVIIQAKDMLGQPG
ALSGTTTVSIKLSDINDNKP IFKESFYRFTISESAPIGTS IGKIMAYDDDIGENAEMEYS
IEDDDSKIFDIIIDNDTQEG IVILKKKVDFEQQSYYGIRA KVKNCHVDEELAPAHVNAST
TYIKVQVEDEDEPFVFLLPY YILEIPEGKPYGTIVGTVSA TDPDRRQSPMRYYLTGSKMF
DINDNGTIITTMMLDREVSA WYNLTVTATETYNVQQISSA HVYVQVFNINDNAPEFSQFY
ETYVCENAESGEIVQIISAI DRDESIEDKHFYFNHSLEDT NNSSFMLTDNQDNIAVILSN
RTGFNLKEEPVFYMIILIAD NGIPSLTSTNTLTIQVCDCG DSRNTETCANKGLLFIMGFR
TEAIIAIMICVMVIFGFFFL ILALKQRRKETLFPEKTEDF RENIFCYDDEGGGEEDSEAF
DIVELRQSTVMRERKPQRSK SAEIRSLYRQSLQVGPDSAI FRKFILEKLEEANTDPCAPP
FDSLQTFAYEGTGSSAGSLS SLASRDTDQEDDFDYLNDLG PRFKRLASMFGSAVQPNN 986
muCDH19(1- MNYCFLKHWILMIPLLWPCL 43):: KVSETLKAEKARRTVPSTWR FLAG::mu
AKRDYKDDDDKAWVWRPFVV CDH19(44- LEEMDDIQCVGKLRSDLDNG 770)::
NNSPQYKLLGIGAGSFSINE huCDH1 RTGEICAIQKLDREEKSLYI 9(271)
LRAQVIDTTIGKAVETESEF VIRVLDINDNEPRFLDEPYE AIVPEMSPEGTFVIKVTAND
ADDPSTGYHARILYNLERGQ PYFSVEPTTGVIRISSKMDR ELQDTYCVIIQAKDMLGQPG
ALSGTTTVSIKLSDINDNKP IFKESFYRFTISESAPTGTS IGKIMAYDDDIGENAEMEYS
IEDDDSKIFDIIIDNDTQEG IVILKKKVDFEQQSYYGIRA KVKNCHVDEELAPAHVNAST
TYIKVQVEDEDEPPVFLLPY YILEIPEGKPYGTIVGTVSA TDPDRRQSPMRYYLTGSKMF
DINDNGTIITTNMLDREVSA WYNLTVTATETYNVQQISSA HVYVQVFNINDNAPEFSQFY
ETYVCENAESGEIVQIISAI DRDESIEDHHFYFNHSLEDT NNSSFMLTDNQDNTAVILSN
RTGFNLKEEPVFYMIILIAD NGIPSLTSTNTLTIQVCDCG DSRNTETCANKGLLFIMGFR
TEAIIAIMICVMVIFGFFFL ILALKQRRKETLFPEKTEDF RENIFCYDDEGGGEEDSEAF
DIVELRQSTVMRERKPQRSK SAEIRSLYRQSLQVGPDSAI FRKFILEKLEEANTDPCAPP
FDSLQTFAYEGTGSSAGSLS SLASRDTDQEDDFDYLNDLG PRFKRLASMFGSAVQPNN
Sequence CWU 0 SQTB SEQUENCE LISTING The patent application
contains a lengthy "Sequence Listing" section. A copy of the
"Sequence Listing" is available in electronic form from the USPTO
web site
(https://seqdata.uspto.gov/?pageRequest=docDetail&DocID=US20220127354A1).
An electronic copy of the "Sequence Listing" will also be available
from the USPTO upon request and payment of the fee set forth in 37
CFR 1.19(b)(3).
0 SQTB SEQUENCE LISTING The patent application contains a lengthy
"Sequence Listing" section. A copy of the "Sequence Listing" is
available in electronic form from the USPTO web site
(https://seqdata.uspto.gov/?pageRequest=docDetail&DocID=US20220127354A1).
An electronic copy of the "Sequence Listing" will also be available
from the USPTO upon request and payment of the fee set forth in 37
CFR 1.19(b)(3).
* * * * *
References