U.S. patent application number 16/357541 was filed with the patent office on 2019-09-12 for antigen binding proteins.
The applicant listed for this patent is GLAXOSMITHKLINE INTELLECTUAL PROPERTY DEVELOPMENT LIMITED. Invention is credited to Paul Andrew HAMBLIN, Alan Peter Lewis, Thomas Matthew WEBB.
Application Number | 20190276535 16/357541 |
Document ID | / |
Family ID | 50272641 |
Filed Date | 2019-09-12 |
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United States Patent
Application |
20190276535 |
Kind Code |
A1 |
HAMBLIN; Paul Andrew ; et
al. |
September 12, 2019 |
ANTIGEN BINDING PROTEINS
Abstract
Antigen binding proteins that bind Lymphocyte Activation Gene 3
(LAG-3), and more particularly to antigen binding proteins that
cause depletion of LAG-3+ activated T cells.
Inventors: |
HAMBLIN; Paul Andrew;
(Stevenage, GB) ; Lewis; Alan Peter; (Stevenage,
GB) ; WEBB; Thomas Matthew; (Brentford, GB) |
|
Applicant: |
Name |
City |
State |
Country |
Type |
GLAXOSMITHKLINE INTELLECTUAL PROPERTY DEVELOPMENT LIMITED |
Brentford |
|
GB |
|
|
Family ID: |
50272641 |
Appl. No.: |
16/357541 |
Filed: |
March 19, 2019 |
Related U.S. Patent Documents
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Application
Number |
Filing Date |
Patent Number |
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14774728 |
Sep 11, 2015 |
10280221 |
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PCT/EP2014/054967 |
Mar 13, 2014 |
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16357541 |
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61789325 |
Mar 15, 2013 |
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Current U.S.
Class: |
1/1 |
Current CPC
Class: |
A61P 35/00 20180101;
C07K 16/2803 20130101; A61P 17/06 20180101; A61P 19/02 20180101;
A61K 39/39558 20130101; A61P 1/04 20180101; A61P 37/06 20180101;
C07K 2317/24 20130101; C07K 2317/92 20130101; A61K 39/39541
20130101; A61P 1/00 20180101; A61P 37/04 20180101; A61P 37/02
20180101; A61P 37/00 20180101; A61P 1/16 20180101; A61P 25/00
20180101; A61P 29/00 20180101; A61P 37/08 20180101; C07K 2317/56
20130101; C07K 2317/732 20130101; A61P 31/00 20180101; A61P 43/00
20180101; C07K 2317/565 20130101 |
International
Class: |
C07K 16/28 20060101
C07K016/28 |
Claims
1. A method of treatment, e.g., of a disease associated with the
involvement of pathogenic T cells, of a human or animal subject
comprising administering a therapeutically effective amount of an
antigen binding protein which is capable of binding Lymphocyte
Activation Gene 3 (LAG-3) and which comprises CDRL1, CDRL2 and
CDRL3 from SEQ ID NO:5 and CDRH1, CDRH2 and CDRH3 from SEQ ID
NO:10.
2. The method of claim 1, wherein the disease is an autoimmune
disease, infectious disease, allergic disease or cancer.
3. The method of claim 2, wherein the disease is an autoimmune
disease and the autoimmune disease is selected from the group
consisting of psoriasis, Crohn's disease, rheumatoid arthritis,
primary biliary cirrhosis, systemic lupus erythematosus (SLE),
Sjogren's syndrome, multiple sclerosis, ulcerative colitis and
autoimmune hepatitis.
4. The method of claim 1, wherein the antigen binding protein
comprises the following CDRs: CDRL1: SEQ ID NO:1 CDRL2: SEQ ID NO:2
CDRL3: SEQ ID NO:3 CDRH1: SEQ ID NO:6 CDRH2: SEQ ID NO:7 CDRH3: SEQ
ID NO:8.
5. The method of claim 1, wherein the antigen binding protein
comprises a) the variable light chain (VL) of SEQ ID NO:4 and b)
the variable heavy chain (VH) of SEQ ID NO:9.
6. The method of claim 1, wherein the antigen binding protein is
capable of binding LAG-3 expressed on activated T-cells.
7. The method of claim 1, wherein the antigen binding protein is
capable of depleting LAG-3+ activated human T cells.
8. The method of claim 1, wherein the antigen binding protein is a
humanised antibody.
9. The method of claim 8, wherein the humanised antibody comprises
a human IgG1 constant region.
10. The method of claim 8, wherein the antigen binding protein
comprises a) a light chain sequence with at least 97% identity to
SEQ ID NO:5, and b) a heavy chain sequence with at least 97%
identity to SEQ ID NO:10.
11. The method of claim 8, wherein the humanised antibody comprises
a) a light chain sequence of SEQ ID NO:5, and b) a heavy chain
sequence of SEQ ID NO:10.
12. The method of claim 8, wherein the humanised antibody is
non-fucosylated.
13. A method of treatment, e.g., of a disease associated with the
involvement of pathogenic T cells, of a human or animal subject
comprising administering a therapeutically effective amount of a
humanised antibody that comprises the variable light chain (VL) of
SEQ ID NO:4 and the variable heavy chain (VH) of SEQ ID NO:9,
wherein the antibody does not comprise fucose on the core
carbohydrate structure attached to Asn297.
14. An isolated nucleic acid molecule which encodes an antigen
binding protein which is capable of binding Lymphocyte Activation
Gene 3 (LAG-3) and which comprises CDRL1, CDRL2 and CDRL3 from SEQ
ID NO:5 and CDRH1, CDRH2 and CDRH3 from SEQ ID NO:10.
15. An expression vector comprising the nucleic acid molecule
according to claim 14.
16. A host cell comprising the expression vector according to claim
15.
17. An antigen binding protein as produced by the host cell of
claim 16.
18. A method of producing an antigen binding protein, comprising a)
culturing a host cell according to claim 16 under conditions
suitable to express the antigen binding protein and b) isolating
the antigen binding protein.
19. A host cell comprising the expression vector according to claim
15, wherein the FUT8 gene encoding alpha-1,6-fucosyltransferase has
been inactivated in the host cell.
Description
FIELD OF THE INVENTION
[0001] The present invention is directed to antigen binding
proteins, particularly antibodies that bind Lymphocyte Activation
Gene (LAG-3) and cause depletion of activated T cells expressing
LAG-3, polynucleotides encoding such antigen binding proteins,
pharmaceutical compositions containing said antigen binding
proteins, and to the use of said antigen binding proteins in the
treatment and/or prevention of diseases associated with the
involvement of pathogenic T cells.
BACKGROUND TO THE INVENTION
[0002] Lymphocyte Activation Gene-3 (LAG-3) is a negative
co-stimulatory receptor that modulates T cell homeostasis,
proliferation and activation (Sierro S et al; Expert Opin. Ther.
Targets (2010) 15: 91-101). An immunoglobulin superfamily member,
LAG-3 is a CD4-like protein which, like CD4, binds to MHC class II
molecules, but with two-fold higher affinity and at a distinct site
from CD4 (Huard B et al., (1997) Proc Natl Acad Sci USA 94:
5744-9). In addition to exerting very distinct functions (CD4 is a
positive co-stimulatory molecule) the two receptors are also
differentially regulated. CD4 is constitutively expressed on the
surface of all mature CD4+ T cells, with only a small fraction
residing intracellularly, whereas a large proportion of LAG-3
molecules are retained in the cell close to the
microtubule-organizing centre, and only induced following antigen
specific T cell activation (Woo S R et al., (2010) Eur J Immunol
40: 1768-77). The role of LAG-3 as a negative regulator of T cell
responses is based on studies with LAG-3 knockout mice and use of
blocking anti-LAG-3 antibodies in model in vitro and in vivo
systems (Sierro S et al., Expert Opin. Ther. Targets (2010) 15:
91-101; Hannier S et al (1998), J Immunol 161: 4058-65;
Macon-Lemaitre L et al (2005), Immunology 115: 170-8; Workman C J
et al (2003), Eur J Immunol 33:970-9).
[0003] At the cell surface, LAG-3 is expressed as a dimer, which is
required for formation of stable MHC class II binding sites (Huard
B et al. (1997) Proc Natl Acad Sci USA 94: 5744-9). LAG-3, in
soluble form, also occurs in serum of healthy donors and patients
with tuberculosis and cancer (Lienhardt C et al. (2002), Eur J
Immunol 32: 1605-13; Triebel F et al (2006). Cancer Left 235:
147-53), and this form may correlate with the number of LAG-3+ T
cells (Siawaya J et al. (2008). J of Infection 56: 340-7). The key
attribute of LAG-3 as a target antigen for an enhanced lymphocyte
depletion agent is its relatively selective expression profile when
compared with other agents currently in the clinic, i.e.
Campath.TM. (T/B cells), Amevive (most CD45R0+ T-cells) or Rituxan
(B-cells). Few molecules have been identified as sustained markers
of in vivoT cell activation in humans. These include LAG-3, OX40,
MHC class II, CD69, CD38, ICOS and CD40L. However, apart from LAG-3
and OX40 the majority of these molecules are also constitutively
expressed on human natural T regs or on other cell types. LAG-3 is
expressed on a small proportion of T-cells in healthy humans (ca.
1-4%), and in a similar proportion of NK cells (Baixeras E et al.
(1992), J Exp Med 176: 327-37; Huard B et al (1994), Immunogenetics
39: 213-7). Upon activation with anti-CD3 ca. 30-80% of both CD4+
and CD8+ T cells express LAG-3 within 24 to 48 h; this percentage
is increased in presence of IL2, IL7 and IL12 (Sierro S et al,
Expert Opin. Ther. Targets (2010) 15: 91-101; Bruniquel D et al
(1998), Immunogenetics 48: 116-24). Following antigen-specific
stimulation with recall antigen (i.e. CMV or Tetanus toxoid) the
majority of activated T cells are LAG-3+. In addition, in humans,
LAG-3 is expressed on a sub-population (1-10%) of CD4+ CD25+ FoxP3+
T regs in healthy human blood. This population appears to be
functionally suppressive in vitro by cell contact and IL10
dependent mechanisms and therefore may represent a population of
recently activated natural or induced T regs [Camisaschi C, Casati
C, Rini F et al. (2010). LAG-3 expression defines a subset of
CD4+CD25highFox3P+ regulatory T cells that are expanded at tumour
sites. J. Immunol 184: 6545-51). LAG-3 has been detected on other
cell types of hematopoietic lineage, such as plasmacytoid dendritic
cells, B-cells, and NKT-cells, but only in the mouse, and mostly
following activation (Sierro S, Romero P & Speiser D; Expert
Opin. Ther. Targets (2010) 15: 91-101).
[0004] Depletion of LAG-3+ T cells may be used to treat or prevent
T cell driven immunoinflammatory disorders. In auto-immune diseases
where the majority of auto-reactive cells are chronically activated
by self antigens at the disease site and/or re-circulate in the
periphery, a short course of a depleting antigen binding protein
may selectively deplete this auto-immune T cell repertoire
providing long term remission. The precedence for this approach has
been demonstrated with the pan-lymphocyte depleting antibody
Campath.TM., in which a single 12 mg injection reduced the rate of
relapse by 74% compared to standard treatment in a multiple
sclerosis trial (The CAMMS223 Trial Investigators (2008), N Engl J
Med. 359:1786-801). Due to the more selective expression of LAG-3
compared with CD52, the target for Campath.TM., the impact on the
naive and resting memory T cell and natural T regs repertoire
should be reduced. This is expected to lead to an improved
therapeutic index, maintaining efficacy, but with reduced risk of
infection and malignancy as well as onset of auto-immunity
associated with Campath.TM.. Additionally, in a baboon tuberculin
skin challenge model, the LAG-3 targeting chimeric antibody IMP731
mediated depletion of LAG-3+ T-cells, both in the periphery and at
the skin challenge site, resulting in a reduction in the tuberculin
skin challenge response (Poirier N et al. (2011), Clin Exp Immunol
164: 265-74). In a further study, a LAG-3 polyclonal antibody
depleted LAG-3+ infiltrating T-cells from a rat cardiac allograft
and prolonged the survival of these grafts (Haudebourg T et al.
(2007), Transplantation 84: 1500-1506).
[0005] There exists a need in the art for antigen binding proteins,
particularly humanised antibodies, that bind LAG-3 and cause
deletion of LAG-3+ activated T cells, and which may have use in the
treatment of auto-immune diseases, such as psoriasis, Crohn's
disease, rheumatoid arthritis, primary biliary cirrhosis, systemic
lupus erythematosus (SLE), Sjogren's syndrome, multiple sclerosis,
ulcerative colitis and autoimmune hepatitis; infectious diseases,
allergic diseases and cancer.
SUMMARY OF THE INVENTION
[0006] The present invention is broadly directed to antigen binding
proteins, such as humanised antibodies, which bind Lymphocyte
Activation Gene 3 (LAG-3) and which may be able to cause depletion
of LAG-3+ activated T cells. More particularly, antigen binding
proteins of the present invention may comprise CDRL1, CDRL2 and
CDRL3 of SEQ ID No. 5.
[0007] Antigen binding proteins described herein may have use in
the treatment or prevention of diseases associated with the
involvement of pathogenic T cells, for example auto-immune
diseases, such as psoriasis, Crohn's disease, rheumatoid arthritis,
primary biliary cirrhosis, systemic lupus erythematosus (SLE),
Sjogren's syndrome, multiple sclerosis, ulcerative colitis and
autoimmune hepatitis; infectious diseases, allergic diseases and
cancer. Accordingly, the invention is further directed to
pharmaceutical compositions comprising an antigen binding protein
according to the invention and optionally one or more
pharmaceutically acceptable excipients and/or carriers.
DESCRIPTION OF THE FIGURES
[0008] FIG. 1: Antibody binding to LAG-3 expressing EL4 (A) and
activated human CD3+ T cells (B). Synagis, a monoclonal antibody
against an unrelated target, was used as negative control.
[0009] FIG. 2: Effect of afucosylated antibody H5L7BW administered
intra-peritoneally on co-administered, activated human PBMCs
retrieved from the peritoneal cavity 24 hours post-injection. A)
Quantification of human CD4.sup.+LAG-3.sup.+ and
CD8.sup.+LAG-3.sup.+ T cells 24 hours after co-administration of
1.times.10.sup.7 activated human PBMCs and 5 mg/kg Control
antibody, H5L7BW or Campath.TM. (Donor A: Control n=2; H5L7BW n=2,
MabCampath n=1; Donor B: Control n=2; H5L7BW n=3, Campath.TM. n=2).
B) Quantification of total CD4.sup.+ and CD8.sup.+ T cells.
(*p<0.001).
[0010] FIG. 3: Effect of afucosylated antibody H5L7BW and its
non-ADCC enhanced variant H5L7 on activated human PBMCs
co-administered intra-peritoneally and retrieved from the
peritoneal cavity 5 hours post-injection. A) Quantification of
human CD4.sup.+LAG-3.sup.+ and CD8.sup.+LAG-3.sup.+ T cells 5 hours
after co-administration of 1.times.10.sup.7 activated human PBMCs
and 5 mg/kg Control antibody, H5L7BW or H5L7 (n=3 per group). B)
Quantification of total CD4.sup.+ and CD8.sup.+ T cells.
(*p<0.001).
[0011] FIG. 4: Effect of afucosylated antibody H5L7BW administered
intravenously 18 hours pre-administration of human activated PBMCs
into the peritoneum of SCID mice. A) Quantification of human
CD4.sup.+LAG-3.sup.+ and CD8.sup.+LAG-3.sup.+ T cells 5 hours after
i.p. injection of 5.times.10.sup.6 (n=1 per group) or
1.times.10.sup.7 O/N (n=4 per group) activated human PBMCs. B)
Quantification of total CD4.sup.+ and CD8.sup.+ T cells. 5 mg/kg
H5L7BW or control antibody was injected intravenously 18 hours
pre-injection of activated human PBMCs. (*p<0.001, #
p=0.0052).
[0012] FIG. 5: Effect of H5L7BW, H5L7 or IMP731 (5 mg/kg)
administered intravenously 18 hours pre-administration of activated
human PBMCs into the peritoneum of SCID mice. A) Quantification of
human CD4.sup.+LAG-3.sup.+ and CD8.sup.+LAG-3.sup.+ T cells 5 hours
after i.p. injection of 1.times.10.sup.7 (n=4 per group) activated
human PBMCs. 5 mg/kg H5L7BW, H5L7, IMP731 or control antibody were
injected intravenously 18 hours pre injection of human PBMCs. B)
Quantification of total CD4.sup.+ and CD8.sup.+ T cells. 5 mg/kg
LAG-3 depleting antibodies or control antibody were injected
intravenously 18 hours pre-injection of activated human PBMCs.
(*p<0.001).
DETAILED DESCRIPTION OF THE INVENTION
[0013] The present invention is broadly directed to antigen binding
proteins that bind Lymphocyte Activation Gene 3 (LAG-3), and more
particularly to antigen binding proteins that may cause depletion
of LAG-3+ activated T cells.
[0014] The term "antigen binding protein" as used herein refers to
antibodies and fragments thereof which are capable of binding to
LAG-3. Unless otherwise specified, the term "LAG-3" as used herein
refers to Lymphocyte Activation Gene 3. The term "LAG-3" includes
within its scope, but is not limited to LAG-3 expressed as a dimer
on the surface of, for example, activated T cells, NK cells and B
cells (also known in the art as, for example, CD223) and a soluble
form of LAG-3 found, for example, in human serum, referred to
herein as "SLAG-3" . . . . Unless otherwise specified, references
herein to "sLAG-3" and "LAG-3" are to human polypeptides. In a
particular embodiment, the present invention provides antigen
binding proteins capable of binding the form of LAG-3 expressed as
a dimer on the surface of, for example, activated T cells, NK cells
and B cells (also known in the art as, for example, CD223). More
particularly, the present invention is directed to antigen binding
proteins that are capable of binding LAG-3 expressed on activated
T-cells and are able to cause depletion of said activated T
cells.
[0015] In one aspect, the present invention provides an antigen
binding protein capable of binding LAG-3 and which comprises CDRL1
from SEQ ID No. 5, wherein position 27E is proline.
[0016] In a further aspect, the present invention provides an
antigen binding protein, which comprises CDRL1 of SEQ ID NO. 1.
[0017] In a further aspect, the present invention provides an
antigen binding protein which is capable of binding LAG-3 and which
comprises CDRL1 from SEQ ID NO.5, wherein the antigen binding
protein further comprises CDRL2 and/or CDRL3 from SEQ ID NO. 5, or
a CDR variant thereof.
[0018] In a further aspect, the present invention provides an
antigen binding protein further comprising CDRL2 of SEQ ID NO. 2
and/or CDRL3 of SEQ ID NO. 3 or a CDR variant thereof.
[0019] In a further aspect, the present invention provides an
antigen binding protein which is capable of binding LAG-3 and which
comprises CDRL1, CDRL2 and CDRL3 from SEQ ID NO.5.
[0020] In a further aspect, the present invention provides an
antigen binding protein comprising one or more of CDRH1, CDRH2 and
CDRH3, or a CDR variant thereof, from SEQ ID NO 10.
[0021] In another aspect, the invention provides an antigen binding
protein comprising a CDRL1, CDRL2 and CDRL3 from SEQ ID NO:5, and
CDRH1, CDRH2 and CDRH3 from SEQ ID NO:10.
[0022] In a further aspect, the present invention provides an
antigen binding protein comprising one or more CDRs, or a CDR
variant thereof, selected from the group comprising CDRH1 of SEQ ID
NO. 6, CDRH2 of SEQ ID NO. 7 and CDRH3 of SEQ ID NO. 8.
[0023] In a further aspect, the present invention provides an
antigen binding protein comprising the following CDRs: [0024]
CDRL1: SEQ ID NO. 1 [0025] CDRL2: SEQ ID NO. 2 [0026] CDRL3: SEQ ID
NO. 3 [0027] CDRH1: SEQ ID NO. 6 [0028] CDRH2: SEQ ID NO. 7 [0029]
CDRH3: SEQ ID NO. 8.
[0030] In another aspect, the invention provides an antigen binding
protein comprising a variable light chain comprising CDRL1, CDRL2
and CDRL3 from SEQ ID NO:5, and a variable heavy chain comprising
CDRH1, CDRH2 and CDRH3 from SEQ ID NO:10.
[0031] In a particular aspect, the antigen binding protein is a
humanised antibody, optionally an IgG.
[0032] The term "CDR" as used herein, refers to the complementarity
determining region amino acid sequences of an antigen binding
protein. These are the hypervariable regions of immunoglobulin
heavy and light chains. There are three heavy chain and three light
chain CDRs (or CDR regions) in the variable portion of an
immunoglobulin.
[0033] It will be apparent to those skilled in the art that there
are various numbering conventions for CDR sequences; Chothia
(Chothia et al. (1989) Nature 342: 877-883), Kabat (Kabat et al.,
Sequences of Proteins of Immunological Interest, 4th Ed., U.S.
Department of Health and Human Services, National Institutes of
Health (1987)), AbM (University of Bath) and Contact (University
College London). The minimum overlapping region using at least two
of the Kabat, Chothia, AbM and contact methods can be determined to
provide the "minimum binding unit". The minimum binding unit may be
a sub-portion of a CDR. The structure and protein folding of the
antibody may mean that other residues are considered part of the
CDR sequence and would be understood to be so by a skilled
person.
[0034] Unless otherwise stated and/or in absence of a specifically
identified sequence, references herein to "CDR", "CDRL1", "CDRL2",
"CDRL3", "CDRH1", "CDRH2", "CDRH3" refer to amino acid sequences
numbered according to any of the known conventions identified in
Table 1. In a particular embodiment, the numbering convention
utilised is the Kabat convention. References herein to "position
27E" are to the amino acid present at position 27E in the light
chain variable domain defined using the Kabat numbering convention.
The skilled person will understand that this position has an
equivalent under other known conventions, such as, for example,
Chothia where position 27E is equivalent to position 30B.
[0035] Table 1 below represents one definition using each numbering
convention for each CDR or binding unit. It should be noted that
some of the CDR definitions may vary depending on the individual
publication used.
TABLE-US-00001 TABLE 1 Kabat Chothia AbM Contact Minimum CDR CDR
CDR CDR binding unit H1 31-35/ 26-32/ 26-35/ 30-35/ 31-32 35A/35B
33/34 35A/35B 35A/35B H2 50-65 52-56 50-58 47-58 52-56 H3 95-102
95-102 95-102 93-101 95-101 L1 24-34 24-34 24-34 30-36 30-34 L2
50-56 50-56 50-56 46-55 50-55 L3 89-97 89-97 89-97 89-96 89-96
[0036] The term "CDR variant" as used herein, refers to a CDR that
has been modified by at least one, for example 1, 2 or 3, amino
acid substitution(s), deletion(s) or addition(s), wherein the
modified antigen binding protein comprising the CDR variant
substantially retains the biological characteristics of the antigen
binding protein pre-modification. It will be appreciated that each
CDR that can be modified may be modified alone or in combination
with another CDR. In one aspect, the modification is a
substitution, particularly a conservative substitution, for example
as shown in Table 2.
TABLE-US-00002 TABLE 2 Side chain Members Hydrophobic Met, Ala,
Val, Leu, Ile Neutral hydrophilic Cys, Ser, Thr Acidic Asp, Glu
Basic Asn, Gln, His, Lys, Arg Residues that influence chain
orientation Gly, Pro Aromatic Trp, Tyr, Phe
[0037] For example, in a variant CDR, the amino acid residues of
the minimum binding unit may remain the same, but the flanking
residues that comprise the CDR as part of the Kabat or Chothia
definition(s) may be substituted with a conservative amino acid
residue.
[0038] Such antigen binding proteins comprising modified CDRs or
minimum binding units as described above may be referred to herein
as "functional CDR variants" or "functional binding unit
variants".
[0039] Antigen binding proteins of the present invention may be
capable of binding sLAG-3. In one aspect, the equilibrium
dissociation constant (KD) of the antigen binding protein-sLAG-3
interaction is 10 nM or less, such as 1 nM or less, for example
between 1 pM and 300, 400, 500 pM or between 500 pM and 1 nM. A
skilled person will appreciate that the smaller the KD numerical
value, the stronger the binding. The reciprocal of KD (i.e. 1/KD)
is the equilibrium association constant (KA) having units M.sup.-1.
A skilled person will appreciate that the larger the KA numerical
value, the stronger the binding.
[0040] In one aspect, the present invention provides antigen
binding proteins that are capable of binding recombinant LAG-3 with
a KD of less than 1 nM, for example between 1 pM and 300 pM, when
determined by Biacore.TM. surface Plasmon resonance analysis using
recombinant human, or cynomolgus macaque LAG-3 extracellular
domains (ECDs) of SEQ ID NOs:51 and 52, respectively.
[0041] Furthermore, antigen bingeing proteins of the present
invention may also be capable of binding LAG-3 expressed on, for
example, EL4 cells or activated human CD3+ T cells.
[0042] Antigen binding proteins of the present invention may also
be capable of depleting LAG-3+ activated T cells, in particular,
CD4+LAG-3+ and CD8+LAG-3+ T cells. Depletion of LAG-3+ T cells may
occur by, for example, antibody dependent cell mediated cytotoxic
activity (ADCC) and/or complement-dependent cytotoxic activity
(CDC).
[0043] In one aspect, the present invention provides antigen
binding proteins that are capable of causing greater than 40%
depletion of antigen specific CD4 and/or CD8 LAG-3.sup.+ human T
cells by ADCC in an in-vitro assay using primary human T cells.
[0044] In a further aspect, the present invention provides antigen
binding proteins that, at a concentration of 0.1 .mu.g/mL, are
capable of causing greater than 50% depletion in an in vitro ADCC
assay using europium-labelled LAG-3 expressing EL4 cells as target
cells and human PBMCs as effector cells, wherein the
effector:target ratio is no greater than 50:1 and the assay is run
for a period of 2 hours. % cell lysis is calculated based on
europium release from LAG-3 expressing EL4 cells.
[0045] The interaction between the constant region of an antigen
binding protein and various Fc receptors (FcR) including
Fc.gamma.RI (CD64), Fc.gamma.RII (CD32) and Fc.gamma.RIII (CD16) is
believed to mediate the effector functions, such as ADCC and CDC,
of the antigen binding protein. Significant biological effects can
be a consequence of effector functionality. Usually, the ability to
mediate effector function requires binding of the antigen binding
protein to an antigen and not all antigen binding proteins will
mediate every effector function.
[0046] Effector function can be measured in a number of ways
including for example via binding of the antigen binding protein,
for example antibody, of the present invention via Fc.gamma.RIII to
Natural Killer cells or via Fc.gamma.RI to monocytes/macrophages to
measure for ADCC effector function. For example an antigen binding
protein of the present invention can be assessed for ADCC effector
function in a Natural Killer cell assay. Examples of such assays
can be found in Shields et al, 2001 The Journal of Biological
Chemistry, Vol. 276, p 6591-6604; Chappel et al, 1993 The Journal
of Biological Chemistry, Vol 268, p 25124-25131; Lazar et al, 2006
PNAS, 103; 4005-4010.
[0047] Examples of assays to determine CDC function include those
described in 1995 J Imm Meth 184:29-38.
[0048] In one aspect of the present invention, the antigen binding
protein is an antibody.
[0049] The term "antibody" as used herein refers to molecules with
an immunoglobulin-like domain and includes monoclonal (for example
IgG, IgM, IgA, IgD or IgE), recombinant, polyclonal, chimeric,
humanised, bispecific and heteroconjugate antibodies; a single
variable domain (e.g., VL), a domain antibody (dAb.RTM.), antigen
binding fragments, immunologically effective fragments, Fab,
F(ab').sub.2, Fv, disulphide linked Fv, single chain Fv, closed
conformation multispecific antibody, disulphide-linked scFv,
diabodies, TANDABS.TM., etc. and modified versions of any of the
foregoing (for a summary of alternative "antibody" formats see
Holliger and Hudson, Nature Biotechnology, 2005, Vol 23, No. 9,
1126-1136). Alternative antibody formats include alternative
scaffolds in which the one or more CDRs of any molecules in
accordance with the disclosure can be arranged onto a suitable
non-immunoglobulin protein scaffold or skeleton, such as an
affibody, a SpA scaffold, an LDL receptor class A domain, an avimer
(see, e.g., U.S. Patent Application Publication Nos. 2005/0053973,
2005/0089932, 2005/0164301) or an EGF domain.
[0050] In a further aspect, the antigen binding protein is a
humanised antibody.
[0051] A "humanised antibody" refers to a type of engineered
antibody having its CDRs derived from a non-human donor
immunoglobulin, the remaining immunoglobulin-derived parts of the
molecule being derived from one (or more) human immunoglobulin(s).
In addition, framework support residues may be altered to preserve
binding affinity (see, e.g., Queen et al., Proc. Natl Acad Sci USA,
86:10029-10032 (1989), Hodgson et al., Bio/Technology, 9:421
(1991)). A suitable human acceptor antibody may be one selected
from a conventional database, e.g., the KABAT.RTM. database, Los
Alamos database, and Swiss Protein database, by homology to the
nucleotide and amino acid sequences of the donor antibody. A human
antibody characterized by a homology to the framework regions of
the donor antibody (on an amino acid basis) may be suitable to
provide a heavy chain constant region and/or a heavy chain variable
framework region for insertion of the donor CDRs. A suitable
acceptor antibody capable of donating light chain constant or
variable framework regions may be selected in a similar manner. It
should be noted that the acceptor antibody heavy and light chains
are not required to originate from the same acceptor antibody. The
prior art describes several ways of producing such humanised
antibodies--see for example EP-A-0239400 and EP-A-054951.
[0052] In yet a further aspect, the humanised antibody has a human
antibody constant region that is an IgG1, for example, the heavy
chain constant region of SEQ ID No. 46.
[0053] It will be understood that the present invention further
provides humanised antibodies which comprise a) a light chain
sequence of SEQ ID NO. 5 or a light chain sequence with at least
75%, 80%, 85%, 90%, 95%, 96%, 97%, 98% or 99% identity to any of
SEQ ID NO. 5 and b) a heavy chain sequence of SEQ ID NO. 10 or a
heavy chain sequence with at least 75%, 80%, 85%, 90%, 95%, 96%,
97%, 98% or 99% identity to any of SEQ ID NO. 10.
[0054] In a further aspect, the present invention provides a
humanised antibody, which comprises a) a light chain sequence with
at least 90% identity to SEQ ID NO. 5, and b) a heavy chain
sequence with at least 90% identity to SEQ ID NO. 10.
[0055] In a further aspect, the present invention provides a
humanised antibody, which comprises a) a light chain sequence with
at least 95% identity to SEQ ID NO. 5, and b) a heavy chain
sequence with at least 95% identity to SEQ ID NO. 10.
[0056] In yet a further aspect, the present invention provides a
humanised antibody, which comprises a) a light chain sequence with
at least 97% identity to SEQ ID NO. 5, and b) a heavy chain
sequence with at least 97% identity to SEQ ID NO. 10.
[0057] In yet a further aspect, the present invention provides a
humanised antibody, which comprises a) a light chain sequence of
SEQ ID NO. 5, and b) a heavy chain sequence of SEQ ID NO. 10.
[0058] It will be understood that the present invention further
provides humanised antibodies which comprise a) a light chain
sequence of SEQ ID NO. 35 or a light chain sequence with at least
75%, 80%, 85%, 90%, 95%, 96%, 97%, 98% or 99% identity to any of
SEQ ID NO. 35 and b) a heavy chain sequence of SEQ ID NO. 36 or a
heavy chain sequence with at least 75%, 80%, 85%, 90%, 95%, 96%,
97%, 98% or 99% identity to any of SEQ ID NO. 36.
[0059] In a further aspect, the present invention provides antigen
binding proteins comprising CDRL1-L3 and CDRH1-H3 of SEQ ID NO: 35
and 36, respectively.
[0060] For nucleotide and amino acid sequences, the term
"identical" or "identity" indicates the degree of identity between
two nucleic acid or two amino acid sequences when optimally aligned
and compared with appropriate insertions or deletions.
[0061] The percent identity between two sequences is a function of
the number of identical positions shared by the sequences (i.e., %
identity=number of identical positions/total number of positions
multiplied by 100), taking into account the number of gaps, and the
length of each gap, which need to be introduced for optimal
alignment of the two sequences. The comparison of sequences and
determination of percent identity between two sequences can be
accomplished using a mathematical algorithm, as described
below.
[0062] Percent identity between a query nucleic acid sequence and a
subject nucleic acid sequence is the "Identities" value, expressed
as a percentage, which is calculated by the BLASTN algorithm when a
subject nucleic acid sequence has 100% query coverage with a query
nucleic acid sequence after a pair-wise BLASTN alignment is
performed. Such pair-wise BLASTN alignments between a query nucleic
acid sequence and a subject nucleic acid sequence are performed by
using the default settings of the BLASTN algorithm available on the
National Center for Biotechnology Institute's website with the
filter for low complexity regions turned off. Importantly, a query
nucleic acid sequence may be described by a nucleic acid sequence
identified in one or more claims herein.
[0063] Percent identity between a query amino acid sequence and a
subject amino acid sequence is the "Identities" value, expressed as
a percentage, which is calculated by the BLASTP algorithm when a
subject amino acid sequence has 100% query coverage with a query
amino acid sequence after a pair-wise BLASTP alignment is
performed. Such pair-wise BLASTP alignments between a query amino
acid sequence and a subject amino acid sequence are performed by
using the default settings of the BLASTP algorithm available on the
National Center for Biotechnology Institute's website with the
filter for low complexity regions turned off. Importantly, a query
amino acid sequence may be described by an amino acid sequence
identified in one or more claims herein.
Production
[0064] The antigen binding proteins, for example antibodies, such
as humanised antibodies of the present invention may be produced by
transfection of a host cell with an expression vector comprising
the coding sequence(s) for the antigen binding protein of the
invention. An expression vector or recombinant plasmid is produced
by placing these coding sequences for the antigen binding protein
in operative association with conventional regulatory control
sequences capable of controlling the replication and expression in,
and/or secretion from, a host cell. Regulatory sequences include
promoter sequences, e.g., CMV promoter, and signal sequences which
can be derived from other known antibodies. Similarly, a second
expression vector can be produced having a DNA sequence which
encodes a complementary antigen binding protein light or heavy
chain. In certain embodiments this second expression vector is
identical to the first except insofar as the coding sequences and
selectable markers are concerned, so to ensure as far as possible
that each polypeptide chain is functionally expressed.
Alternatively, the heavy and light chain coding sequences for the
antigen binding protein may reside on a single vector.
[0065] A selected host cell is co-transfected by conventional
techniques with both the first and second vectors (or simply
transfected by a single vector) to create the transfected host cell
of the invention comprising both the recombinant or synthetic light
and heavy chains. The transfected cell is then cultured by
conventional techniques to produce the engineered antigen binding
protein of the invention. The antigen binding protein which
includes the association of both the recombinant heavy chain and/or
light chain is screened from culture by appropriate assay, such as
ELISA or RIA. Similar conventional techniques may be employed to
construct other antigen binding proteins.
[0066] Suitable vectors for the cloning and subcloning steps
employed in the methods and construction of the compositions of
this invention may be selected by one of skill in the art. For
example, the conventional pUC series of cloning vectors may be
used. One vector, pUC19, is commercially available from supply
houses, such as Amersham (Buckinghamshire, United Kingdom) or
Pharmacia (Uppsala, Sweden). Additionally, any vector which is
capable of replicating readily, has an abundance of cloning sites
and selectable genes (e.g., antibiotic resistance), and is easily
manipulated may be used for cloning. Thus, the selection of the
cloning vector is not a limiting factor in this invention.
[0067] The expression vectors may also be characterized by genes
suitable for amplifying expression of the heterologous DNA
sequences, e.g., the mammalian dihydrofolate reductase gene (DHFR).
Other preferable vector sequences include a poly A signal sequence,
such as from bovine growth hormone (BGH) and the betaglobin
promoter sequence (betaglopro). The expression vectors useful
herein may be synthesized by techniques well known to those skilled
in this art.
[0068] The components of such vectors, e.g. replicons, selection
genes, enhancers, promoters, signal sequences and the like, may be
obtained from commercial or natural sources or synthesized by known
procedures for use in directing the expression and/or secretion of
the product of the recombinant DNA in a selected host. Other
appropriate expression vectors of which numerous types are known in
the art for mammalian, bacterial, insect, yeast, and fungal
expression may also be selected for this purpose.
[0069] The present invention also encompasses a cell line
transfected with a recombinant plasmid containing the coding
sequences of the antigen binding proteins of the present invention.
Host cells useful for the cloning and other manipulations of these
cloning vectors are also conventional. However, cells from various
strains of E. coli may be used for replication of the cloning
vectors and other steps in the construction of antigen binding
proteins of this invention.
[0070] Suitable host cells or cell lines for the expression of the
antigen binding proteins of the invention include mammalian cells
such as NS0, Sp2/0, CHO (e.g. DG44), COS, HEK, a fibroblast cell
(e.g., 3T3), and myeloma cells, for example it may be expressed in
a CHO or a myeloma cell. Human cells may be used, thus enabling the
molecule to be modified with human glycosylation patterns.
Alternatively, other eukaryotic cell lines may be employed. The
selection of suitable mammalian host cells and methods for
transformation, culture, amplification, screening and product
production and purification are known in the art. See, e.g.,
Sambrook et al., cited above.
[0071] Bacterial cells may prove useful as host cells suitable for
the expression of the recombinant Fabs or other embodiments of the
present invention (see, e.g., Pluckthun, A., Immunol. Rev.,
130:151-188 (1992)). However, due to the tendency of proteins
expressed in bacterial cells to be in an unfolded or improperly
folded form or in a non-glycosylated form, any recombinant Fab
produced in a bacterial cell would have to be screened for
retention of antigen binding ability. If the molecule expressed by
the bacterial cell was produced in a properly folded form, that
bacterial cell would be a desirable host, or in alternative
embodiments the molecule may express in the bacterial host and then
be subsequently re-folded. For example, various strains of E. coli
used for expression are well-known as host cells in the field of
biotechnology. Various strains of B. subtilis, Streptomyces, other
bacilli and the like may also be employed in this method.
[0072] Where desired, strains of yeast cells known to those skilled
in the art are also available as host cells, as well as insect
cells, e.g. Drosophila and Lepidoptera and viral expression
systems. See, e.g. Miller et al., Genetic Engineering, 8:277-298,
Plenum Press (1986) and references cited therein.
[0073] The general methods by which the vectors may be constructed,
the transfection methods required to produce the host cells of the
invention, and culture methods necessary to produce the antigen
binding protein of the invention from such host cell may all be
conventional techniques. Typically, the culture method of the
present invention is a serum-free culture method, usually by
culturing cells serum-free in suspension. Likewise, once produced,
the antigen binding proteins of the invention may be purified from
the cell culture contents according to standard procedures of the
art, including ammonium sulfate precipitation, affinity columns,
column chromatography, gel electrophoresis and the like. Such
techniques are within the skill of the art and do not limit this
invention. For example, preparations of altered antibodies are
described in WO 99/58679 and WO 96/16990.
[0074] Yet another method of expression of the antigen binding
proteins may utilize expression in a transgenic animal, such as
described in U.S. Pat. No. 4,873,316. This relates to an expression
system using the animals casein promoter which when transgenically
incorporated into a mammal permits the female to produce the
desired recombinant protein in its milk.
[0075] In a further aspect of the invention there is provided a
method of producing an antigen binding protein (e.g. a humanised
antibody) of the invention which method comprises the step of
culturing a host cell transformed or transfected with a vector
encoding the light and/or heavy chain of the antibody of the
invention and recovering the antigen binding protein thereby
produced.
[0076] In accordance with the present invention there is provided a
method of producing an anti-LAG-3 antigen binding protein (e.g. a
humanised antibody) of the present invention which binds to human
LAG-3, which method comprises the steps of; [0077] (a) providing a
first vector encoding a heavy chain of the antibody; [0078] (b)
providing a second vector encoding a light chain of the antibody;
[0079] (c) transforming a mammalian host cell (e.g. CHO) with said
first and second vectors; [0080] (d) culturing the host cell of
step (c) under conditions conducive to the secretion of the
antibody from said host cell into said culture media; [0081] (e)
recovering the secreted antibody of step (d).
[0082] Once expressed by the desired method, the antigen binding
protein may then be examined for in vitro activity by use of an
appropriate assay, such as Biacore.TM. surface Plasmon resonance
analysis, to assess binding of the antigen binding protein to
LAG-3. Additionally, other in vitro and in vivo assays may also be
used to determine an antigen binding protein's ability to cause
depletion of cells expressing LAG-3, such as activated human T cell
populations.
[0083] The skilled person will appreciate that, upon production of
an antigen binding protein such as an antibody, in particular
depending on the cell line used and particular amino acid sequence
of the antigen binding protein, post-translational modifications
may occur. For example, this may include the cleavage of certain
leader sequences, the addition of various sugar moieties in various
glycosylation and phosphorylation patterns, deamidation, oxidation,
disulfide bond scrambling, isomerisation, C-terminal lysine
clipping, and N-terminal glutamine cyclisation. The present
invention encompasses the use of antigen binding proteins which
have been subjected to, or have undergone, one or more
post-translational modifications. Thus an "antigen binding protein"
or "antibody" of the invention includes an "antigen binding
protein" or "antibody", respectively, as defined earlier which has
undergone a post-translational modification such as described
herein.
[0084] Glycosylation of antibodies at conserved positions in their
constant regions is known to have a profound effect on antibody
function, particularly effector functioning, see for example, Boyd
et al. (1996) Mol. Immunol. 32: 1311-1318. Glycosylation variants
of the antigen binding proteins of the invention wherein one or
more carbohydrate moiety is added, substituted, deleted or modified
are contemplated. Introduction of an asparagine-X-serine or
asparagine-X-threonine motif creates a potential site for enzymatic
attachment of carbohydrate moieties and may therefore be used to
manipulate the glycosylation of an antibody. In Raju et al. (2001)
Biochemistry 40: 8868-8876 the terminal sialyation of a TNFR-IgG
immunoadhesin was increased through a process of regalactosylation
and/or resialylation using beta-1, 4-galactosyltransferace and/or
alpha, 2,3 sialyltransferase. Increasing the terminal sialylation
is believed to increase the half-life of the immunoglobulin.
Antibodies, in common with most glycoproteins, are typically
produced as a mixture of glycoforms. This mixture is particularly
apparent when antibodies are produced in eukaryotic, particularly
mammalian cells. A variety of methods have been developed to
manufacture defined glycoforms, see Zhang et al. (2004) Science
303: 371: Sears et al. (2001) Science 291: 2344; Wacker et al.
(2002) Science 298: 1790; Davis et al. (2002) Chem. Rev. 102: 579;
Hang et al. (2001) Acc. Chem. Res 34: 727. The antibodies (for
example of the IgG isotype, e.g. IgG1) as herein described may
comprise a defined number (e.g. 7 or less, for example 5 or less,
such as two or a single) of glycoform(s).
[0085] Deamidation is an enzymatic reaction primarily converting
asparagine (N) to iso-aspartic acid and aspartic acid (D) at
approximately 3:1 ratio. To a much lesser degree, deamidation can
occur with glutamine residues in a similar manner. Deamidation in a
CDR results in a change in charge of the molecule, but typically
does not result in a change in antigen binding, nor does it impact
on PK/PD.
[0086] Oxidation can occur during production and storage (i.e. in
the presence of oxidizing conditions) and results in a covalent
modification of a protein, induced either directly by reactive
oxygen species or indirectly by reaction with secondary by-products
of oxidative stress. Oxidation happens primarily with methionine
residues, but occasionally can occur at tryptophan and free
cysteine residues.
[0087] Disulfide bond scrambling can occur during production and
basic storage conditions. Under certain circumstances, disulfide
bonds can break or form incorrectly, resulting in unpaired cysteine
residues (--SH). These free (unpaired) sulfhydryls (--SH) can
promote shuffling.
[0088] Isomerization typically occurs during production,
purification, and storage (at acidic pH) and usually occurs when
aspartic acid is converted to isoaspartic acid through a chemical
process.
[0089] N-terminal glutamine in the heavy chain and/or light chain
is likely to form pyroglutamate (pGlu). Most pGlu formation happens
in the production bioreactor, but it can be formed
non-enzymatically, depending on pH and temperature of processing
and storage conditions. pGlu formation is considered as one of the
principal degradation pathways for recombinant mAbs.
[0090] C-terminal lysine clipping is an enzymatic reaction
catalyzed by carboxypeptidases, and is commonly observed in
recombinant mAbs. Variants of this process include removal of
lysine from one or both heavy chains. Lysine clipping does not
appear to impact bioactivity and has no effect on mAb effector
function.
Effector Function Enhancement
[0091] The interaction between the constant region of an antigen
binding protein and various Fc receptors (FcR) including
Fc.gamma.RI (CD64), Fc.gamma.RII (CD32) and Fc.gamma.RIII (CD16) is
believed to mediate the effector functions, such as ADCC and CDC,
of the antigen binding protein.
[0092] The term "Effector Function" as used herein is meant to
refer to one or more of Antibody dependant cell mediated cytotoxic
activity (ADCC), Complement-dependant cytotoxic activity (CDC)
mediated responses, Fc-mediated phagocytosis or antibody dependant
cellular phagocytosis (ADCP) and antibody recycling via the FcRn
receptor.
[0093] The ADCC or CDC properties of antigen binding proteins of
the present invention may be enhanced in a number of ways.
[0094] Human IgG1 constant regions containing specific mutations or
altered glycosylation on residue Asn297 have been shown to enhance
binding to Fc receptors. In some cases these mutations have also
been shown to enhance ADCC and CDC (Lazar et al. PNAS 2006, 103;
4005-4010; Shields et al. J Biol Chem 2001, 276; 6591-6604;
Nechansky et al. Mol Immunol, 2007, 44; 1815-1817).
[0095] In one embodiment of the present invention, such mutations
are in one or more of positions selected from 239, 332 and 330
(IgG1), or the equivalent positions in other IgG isotypes. Examples
of suitable mutations are S239D and I332E and A330L. In one
embodiment, the antigen binding protein of the invention herein
described is mutated at positions 239 and 332, for example S239D
and I332E or in a further embodiment it is mutated at three or more
positions selected from 239 and 332 and 330, for example S239D and
I332E and A330L. (EU index numbering).
[0096] In one embodiment of the present invention, there is
provided an antigen binding protein comprising a chimeric heavy
chain constant region for example an antigen binding protein
comprising a chimeric heavy chain constant region with at least one
CH2 domain from IgG3 such that the antigen binding protein has
enhanced effector function, for example wherein it has enhanced
ADCC or enhanced CDC, or enhanced ADCC and CDC functions. In one
such embodiment, the antigen binding protein may comprise one CH2
domain from IgG3 or both CH2 domains may be from IgG3.
[0097] Also provided is a method of producing an antigen binding
protein according to the invention comprising the steps of: [0098]
a) culturing a recombinant host cell comprising an expression
vector comprising an isolated nucleic acid as described herein
wherein the expression vector comprises a nucleic acid sequence
encoding a Fc region containing domains derived from human germline
IgG1 and IgG3 sequences; and [0099] b) recovering the antigen
binding protein.
[0100] Such methods for the production of antigen binding proteins
can be performed, for example, using the COMPLEGENT.TM. technology
system available from BioWa, Inc. (La Jolla, Calif., USA) and Kyowa
Hakko Kogyo (now, Kyowa Hakko Kirin Co., Ltd.) Co., Ltd. in which a
recombinant host cell comprising an expression vector in which a
nucleic acid sequence encoding a Fc region containing domains
derived from human germline IgG1 and IgG3 sequences is expressed to
produce an antigen binding protein having enhanced complement
dependent cytotoxicity (CDC) activity that is increased relative to
an otherwise identical antigen binding protein lacking such a
chimeric Fc domain. Aspects of the COMPLEGENT.TM. technology system
are described in WO2007011041 and US20070148165 each of which are
incorporated herein by reference. In an alternative embodiment CDC
activity may be increased by introducing sequence specific
mutations into the Fc region of an IgG chain. Those of ordinary
skill in the art will also recognize other appropriate systems.
[0101] In an alternative embodiment of the present invention, there
is provided an antigen binding protein comprising a heavy chain
constant region with an altered glycosylation profile such that the
antigen binding protein has enhanced effector function. For
example, wherein the antigen binding protein has enhanced ADCC or
enhanced CDC or wherein it has both enhanced ADCC and CDC effector
function. Examples of suitable methodologies to produce antigen
binding proteins with an altered glycosylation profile are
described in WO2003011878, WO2006014679 and EP1229125, all of which
can be applied to the antigen binding proteins of the present
invention.
[0102] The present invention also provides a method for the
production of an antigen binding protein according to the invention
comprising the steps of: [0103] a) culturing a recombinant host
cell comprising an expression vector comprising the isolated
nucleic acid as described herein under conditions suitable to
express the antigen binding protein, wherein the FUT8 gene encoding
alpha-1,6-fucosyltransferase has been inactivated in the
recombinant host cell; and [0104] b) isolating the antigen binding
protein produced by the recombinant host cell.
[0105] The present invention also provides a method for the
production of an antigen binding protein according to the invention
comprising the steps of: [0106] a) expressing an antigen binding
protein according to the invention in a recombinant host cell,
wherein the FUT8 gene encoding alpha-1,6-fucosyltransferase is been
inactivated in the recombinant host cell; and [0107] b) isolating
the antigen binding protein produced by the recombinant host
cell.
[0108] Such methods for the production of antigen binding proteins
can be performed, for example, using the POTELLIGENT.TM. technology
system available from BioWa, Inc. (La Jolla, Calif., USA) in which
CHOK1SV cells lacking a functional copy of the FUT8 gene produce
monoclonal antibodies having enhanced antibody dependent cell
mediated cytotoxicity (ADCC) activity that is increased relative to
an identical monoclonal antibody produced in a cell with a
functional FUT8 gene. Aspects of the POTELLIGENT.TM. technology
system are described in U.S. Pat. Nos. 7,214,775, 6,946,292,
WO0061739 and WO0231240 all of which are incorporated herein by
reference. Those of ordinary skill in the art will also recognize
other appropriate systems.
[0109] In a further aspect, the present invention provides
non-fucosylated antibodies. References herein to "non-fucosylated"
or "afucosylated" antibodies refer to antibodies that harbour a
tri-mannosyl core structure of complex-type N-glycans of Fc without
fucose residue. Non-fucosylated or afucosylated antibodies of the
present invention do not comprise fucose on the core carbohydrate
structure attached to Asn297. These glycoengineered antibodies that
lack core fucose residue from the Fc N-glycans may exhibit stronger
ADCC than fucosylated equivalents due to enhancement of
Fc.gamma.RIIIa binding capacity.
[0110] It will be apparent to those skilled in the art that such
modifications may not only be used alone but may be used in
combination with each other in order to further enhance effector
function.
[0111] In one such embodiment of the present invention there is
provided an antigen binding protein comprising a heavy chain
constant region which comprises a mutated and chimeric heavy chain
constant region. For example, wherein an antigen binding protein
comprising at least one CH2 domain from human IgG3 and one CH2
domain from human IgG1, wherein the IgG1 CH2 domain has one or more
mutations at positions selected from 239 and 332 and 330 (for
example the mutations may be selected from S239D and I332E and
A330L) such that the antigen binding protein has enhanced effector
function. In this context, enhanced effector function may equate
to, for example, having enhanced ADCC or enhanced CDC, for example
wherein it has enhanced ADCC and enhanced CDC. In one embodiment
the IgG1 CH2 domain has the mutations S239D and I332E.
[0112] In an alternative embodiment of the present invention there
is provided an antigen binding protein comprising a chimeric heavy
chain constant region and which has an altered glycosylation
profile. In one such embodiment the heavy chain constant region
comprises at least one CH2 domain from IgG3 and one CH2 domain from
IgG1 and has an altered glycosylation profile such that the ratio
of fucose to mannose is 0.8:3 or less, for example wherein the
antigen binding protein is defucosylated so that said antigen
binding protein has an enhanced effector function in comparison
with an equivalent antigen binding protein with an immunoglobulin
heavy chain constant region lacking said mutations and altered
glycosylation profile, for example wherein it has one or more of
the following functions, enhanced ADCC or enhanced CDC, for example
wherein it has enhanced ADCC and enhanced CDC.
[0113] In an alternative embodiment the antigen binding protein has
at least one human IgG3 CH2 domain and at least one heavy chain
constant domain from human IgG1 wherein both IgG CH2 domains are
mutated in accordance with the limitations described herein.
[0114] In one aspect of the invention there is provided a method of
producing an antigen binding protein according to the invention
described herein comprising the steps of: [0115] a) culturing a
recombinant host cell containing an expression vector containing an
isolated nucleic acid as described herein, said expression vector
further comprising a Fc nucleic acid sequence encoding a Fc region
containing domains derived from human germline IgG1 and IgG3
sequences, and wherein the FUT8 gene encoding
alpha-1,6-fucosyltransferase has been inactivated in the
recombinant host cell; and [0116] b) recovering the antigen binding
protein.
[0117] Such methods for the production of antigen binding proteins
can be performed, for example, using the AccretaMab.TM. technology
system available from BioWa, Inc. (La Jolla, Calif., USA) which
combines the POTELLIGENT.TM. and COMPLEGENT.TM. technology systems
to produce an antigen binding protein having both ADCC and CDC
enhanced activity that is increased relative to an otherwise
identical monoclonal antibody lacking a chimeric Fc domain and
which has fucose on the oligosaccharide
[0118] In yet another embodiment of the present invention there is
provided an antigen binding protein comprising a mutated and
chimeric heavy chain constant region wherein said antigen binding
protein has an altered glycosylation profile such that the antigen
binding protein has enhanced effector function, for example wherein
it has one or more of the following functions, enhanced ADCC or
enhanced CDC. In one embodiment the mutations are selected from
positions 239 and 332 and 330, for example the mutations are
selected from S239D and I332E and A330L. In a further embodiment
the heavy chain constant region comprises at least one CH2 domain
from human IgG3 and one Ch2 domain from human IgG1. In one
embodiment the heavy chain constant region has an altered
glycosylation profile such that the ratio of fucose to mannose is
0.8:3 or less for example the antigen binding protein is
defucosylated, so that said antigen binding protein has an enhanced
effector function in comparison with an equivalent non-chimeric
antigen binding protein or with an immunoglobulin heavy chain
constant region lacking said mutations and altered glycosylation
profile.
Half-Life Extension
[0119] Increased half-life, or half-life extension, can be useful
in in vivo applications of antigen binding proteins, especially
antibodies and most especially antibody fragments of small size.
Such fragments (Fvs, disulphide bonded Fvs, Fabs, scFvs, dAbs) are
generally rapidly cleared from the body. Antigen binding proteins
in accordance with the disclosure can be adapted or modified to
provide increased serum half-life in vivo and consequently longer
persistence, or residence, times of the functional activity of the
antigen binding protein in the body. Suitably, such modified
molecules have a decreased clearance and increased Mean Residence
Time compared to the non-adapted molecule. Increased half-life can
improve the pharmacokinetic and pharmacodynamic properties of a
therapeutic molecule and can also be important for improved patient
compliance.
[0120] The phrases, "half-life" ("t.sub.1/2") and "serum half
life", refer to the time taken for the serum (or plasma)
concentration of an antigen binding protein in accordance with the
disclosure to reduce by 50%, in vivo, for example due to
degradation of the antigen binding protein and/or clearance or
sequestration of the antigen binding protein by natural
mechanisms.
[0121] The antigen binding proteins of the disclosure can be
stabilized in vivo and their half-life increased by binding to
molecules which resist degradation and/or clearance or
sequestration ("half-life extending moiety" or "half-life extending
molecule"). Half-life extension strategies are reviewed, for
example, in "Therapeutic Proteins: Strategies to Modulate Their
Plasma Half-Lives", Edited by Roland Kontermann, Wiley-Blackwell,
2012, ISBN: 978-3-527-32849-9. Suitable half-life extension
strategies include: PEGylation, polysialylation, HESylation,
recombinant PEG mimetics, N-glycosylation, O-glycosylation, Fc
fusion, engineered Fc, IgG binding, albumin fusion, albumin
binding, albumin coupling and nanoparticles.
[0122] In one embodiment, the half-life extending moiety or
molecule is a polyethylene glycol moiety or a PEG mimetic. In one
embodiment, the antigen binding protein comprises (optionally
consists of) a single variable domain of the disclosure linked to a
polyethylene glycol moiety (optionally, wherein said moiety has a
size of about 20 to about 50 kDa, optionally about 40 kDa linear or
branched PEG). Reference is made to WO04081026 for more detail on
PEGylation of domain antibodies and binding moieties. In one
embodiment, the antagonist consists of a domain antibody monomer
linked to a PEG, wherein the domain antibody monomer is a single
variable domain according to the disclosure. Suitable PEG mimetics
are reviewed, for example in Chapter 4, pages 63-80, "Therapeutic
Proteins: Strategies to Modulate Their Plasma Half-Lives" Edited by
Roland Kontermann, Wiley-Blackwell, 2012, ISBN:
978-3-527-32849-9.
[0123] The interaction between the Fc region of an antibody and
various Fc receptors (Fc.gamma.R) is believed to mediate
phagocytosis and half-life/clearance of an antibody or antibody
fragment. The neonatal FcRn receptor is believed to be involved in
both antibody clearance and the transcytosis across tissues (see
Junghans (1997) Immunol. Res 16: 29-57; and Ghetie et al. (2000)
Annu. Rev. Immunol. 18: 739-766). In one embodiment, the half-life
extending moiety may be an Fc region from an antibody. Such an Fc
region may incorporate various modifications depending on the
desired property. For example, a salvage receptor binding epitope
may be incorporated into the antibody to increase serum half life,
see U.S. Pat. No. 5,739,277.
[0124] Human IgG1 residues determined to interact directly with
human FcRn includes Ile253, Ser254, Lys288, Thr307, Gln311, Asn434
and His435. Accordingly, substitutions at any of the positions
described in this section may enable increased serum half-life
and/or altered effector properties of the antibodies.
[0125] Half-life extension by fusion to the Fc region is reviewed,
for example, in Chapter 9, pages 157-188, "Therapeutic Proteins:
Strategies to Modulate Their Plasma Half-Lives" Edited by Roland
Kontermann, Wiley-Blackwell, 2012, ISBN: 978-3-527-32849-9.
[0126] Typically, a polypeptide that enhances serum half-life in
vivo, i.e. a half-life extending molecule, is a polypeptide which
occurs naturally in vivo and which resists degradation or removal
by endogenous mechanisms which remove unwanted material from the
organism (e.g., human). Typically, such molecules are naturally
occurring proteins which themselves have a long half-life in
vivo.
[0127] For example, a polypeptide that enhances serum half-life in
vivo can be selected from proteins from the extracellular matrix,
proteins found in blood, proteins found at the blood brain barrier
or in neural tissue, proteins localized to the kidney, liver,
muscle, lung, heart, skin or bone, stress proteins,
disease-specific proteins, or proteins involved in Fc transport.
Suitable polypeptides are described, for example, in
WO2008/096158.
[0128] Such an approach can also be used for targeted delivery of
an antigen binding protein, e.g. a single variable domain, in
accordance with the disclosure to a tissue of interest. In one
embodiment targeted delivery of a high affinity single variable
domain in accordance with the disclosure is provided.
[0129] In one embodiment, an antigen binding protein, e.g. single
variable domain, in accordance with the disclosure can be linked,
i.e. conjugated or associated, to serum albumin, fragments and
analogues thereof. Half-life extension by fusion to albumin is
reviewed, for example in Chapter 12, pages 223-247, "Therapeutic
Proteins: Strategies to Modulate Their Plasma Half-Lives" Edited by
Roland Kontermann, Wiley-Blackwell, 2012, ISBN:
978-3-527-32849-9.
[0130] Examples of suitable albumin, albumin fragments or albumin
variants are described, for example, in WO2005077042 and
WO2003076567.
[0131] In another embodiment, a single variable domain, polypeptide
or ligand in accordance with the disclosure can be linked, i.e.
conjugated or associated, to transferrin, fragments and analogues
thereof.
[0132] In one embodiment, half-life extension can be achieved by
targeting an antigen or epitope that increases half-live in vivo.
The hydrodynamic size of an antigen binding protein and its serum
half-life may be increased by conjugating or associating an antigen
binding protein of the disclosure to a binding domain that binds a
naturally occurring molecule and increases half-live in vivo.
[0133] For example, the antigen binding protein in accordance with
the invention can be conjugated or linked to an anti-serum albumin
or anti-neonatal Fc receptor antibody or antibody fragment, e.g. an
anti-SA or anti-neonatal Fc receptor dAb, Fab, Fab' or scFv, or to
an anti-SA affibody or anti-neonatal Fc receptor Affibody or an
anti-SA avimer, or an anti-SA binding domain which comprises a
scaffold selected from, but not limited to, the group consisting of
CTLA-4, lipocallin, SpA, an affibody, an avimer, GroEl and
fibronectin (see WO2008096158 for disclosure of these binding
domains). Conjugating refers to a composition comprising
polypeptide, dAb or antagonist of the disclosure that is bonded
(covalently or noncovalently) to a binding domain such as a binding
domain that binds serum albumin.
[0134] In another embodiment, the binding domain may be a
polypeptide domain such as an Albumin Binding Domain (ABD) or a
small molecule which binds albumin (reviewed, for example in
Chapter 14, pages 269-283 and Chapter 15, pages 285-296,
"Therapeutic Proteins: Strategies to Modulate Their Plasma
Half-Lives" Edited by Roland Kontermann, Wiley-Blackwell, 2012,
ISBN: 978-3-527-32849-9).
[0135] In one embodiment, there is provided a fusion protein
comprising an antigen binding protein in accordance with the
invention and an anti-serum albumin or anti-neonatal Fc receptor
antibody or antibody fragment.
[0136] The long half-life of IgG antibodies is reported to be
dependent on its binding to FcRn. Therefore, substitutions that
increase the binding affinity of IgG to FcRn at pH 6.0 while
maintaining the pH dependence of the interaction by engineering the
constant region have been extensively studied (Ghetie et al.,
Nature Biotech. 15: 637-640, 1997; Hinton et al., JBC 279:
6213-6216, 2004; Dall'Acqua et al.,
[0137] 10 J Immunol 117: 1129-1138, 2006). Another means of
modifying antigen binding proteins of the present invention
involves increasing the in-vivo half life of such proteins by
modification of the immunoglobulin constant domain or FcRn (Fc
receptor neonate) binding domain.
[0138] In adult mammals, FcRn, also known as the neonatal Fc
receptor, plays a key role in maintaining serum antibody levels by
acting as a protective receptor that binds and salvages antibodies
of the IgG isotype from degradation. IgG molecules are endocytosed
by endothelial cells, and if they bind to FcRn, are recycled out
into circulation. In contrast, IgG molecules that do not bind to
FcRn enter the cells and are targeted to the lysosomal pathway
where they are degraded.
[0139] The neonatal FcRn receptor is believed to be involved in
both antibody clearance and the transcytosis across tissues (see
Junghans R. P (1997) Immunol. Res 16. 29-57 and Ghetie et al (2000)
Annu. Rev. Immunol. 18, 739-766). Human IgG1 residues determined to
interact directly with human FcRn includes Ile253, Ser254, Lys288,
Thr307, Gln311, Asn434 and His435. Switches at any of these
positions described in this section may enable increased serum
half-life and/or altered effector properties of antigen binding
proteins of the invention.
[0140] Antigen binding proteins of the present invention may have
amino acid modifications that increase the affinity of the constant
domain or fragment thereof for FcRn. Increasing the half-life of
therapeutic and diagnostic IgG's and other bioactive molecules has
many benefits including reducing the amount and/or frequency of
dosing of these molecules. In one embodiment there is therefore
provided an antigen binding according to the invention provided
herein or a fusion protein comprising all or a portion (an FcRn
binding portion) of an IgG constant domain having one or more of
these amino acid modifications and a non-IgG protein or non-protein
molecule conjugated to such a modified IgG constant domain, wherein
the presence of the modified IgG constant domain increases the in
vivo half life of the antigen binding protein.
[0141] PCT Publication No. WO 00/42072 discloses a polypeptide
comprising a variant Fc region with altered FcRn binding affinity,
which polypeptide comprises an amino acid modification at any one
or more of amino acid positions 238, 252, 253, 254, 255, 256, 265,
272, 286, 288, 303, 305, 307, 309, 311, 312, 317, 340, 356, 360,
362, 376, 378, 380, 386, 388, 400, 413, 415, 424, 433, 434, 435,
436, 439, and 447 of the Fc region, wherein the numbering of the
residues in the Fc region is that of the EU index (Kabat et
al).
[0142] PCT Publication No. WO 02/060919 A2 discloses a modified IgG
comprising an IgG constant domain comprising one or more amino acid
modifications relative to a wild-type IgG constant domain, wherein
the modified IgG has an increased half-life compared to the
half-life of an IgG having the wild-type IgG constant domain, and
wherein the one or more amino acid modifications are at one or more
of positions 251, 253, 255, 285-290, 308-314, 385-389, and
428-435.
[0143] Shields et al. (2001, J Biol Chem; 276:6591-604) used
alanine scanning mutagenesis to alter residues in the Fc region of
a human IgG1 antibody and then assessed the binding to human FcRn.
Positions that effectively abrogated binding to FcRn when changed
to alanine include 1253, S254, H435, and Y436. Other positions
showed a less pronounced reduction in binding as follows:
E233-G236, R255, K288, L309, 5415, and H433. Several amino acid
positions exhibited an improvement in FcRn binding when changed to
alanine; notable among these are P238, T256, E272, V305, T307,
Q311, D312, K317, D376, E380, E382, S424, and N434. Many other
amino acid positions exhibited a slight improvement (D265, N286,
V303, K360, Q362, and A378) or no change (S239, K246, K248, D249,
M252, E258, T260, S267, H268, S269, D270, K274, N276, Y278, D280,
V282, E283, H285, T289, K290, R292, E293, E294, Q295, Y296, N297,
S298, R301, N315, E318, K320, K322, S324, K326, A327, P329, P331,
E333, K334, T335, S337, K338, K340, Q342, R344, E345, Q345, Q347,
R356, M358, T359, K360, N361, Y373, S375, S383, N384, Q386, E388,
N389, N390, K392, L398, S400, D401, K414, R416, Q418, Q419, N421,
V422, E430, T437, K439, S440, S442, S444, and K447) in FcRn
binding.
[0144] The most pronounced effect was found for combination
variants with improved binding to FcRn. At pH 6.0, the E380A/N434A
variant showed over 8-fold better binding to FcRn, relative to
native IgG1, compared with 2-fold for E380A and 3.5-fold for N434A.
Adding T307A to this effected a 12-fold improvement in binding
relative to native IgG1. In one embodiment the antigen binding
protein of the invention comprises the E380A/N434A mutations and
has increased binding to FcRn.
[0145] Dall'Acqua et al. (2002, J Immunol.; 169:5171-80) described
random mutagenesis and screening of human IgG1 hinge-Fc fragment
phage display libraries against mouse FcRn. They disclosed random
mutagenesis of positions 251, 252, 254-256, 308, 309, 311, 312,
314, 385-387, 389, 428, 433, 434, and 436. The major improvements
in IgG1-human FcRn complex stability occur in substituting residues
located in a band across the Fc-FcRn interface (M252, S254, T256,
H433, N434, and Y436) and to lesser extend substitutions of
residues at the periphery like V308, L309, Q311, G385, Q386, P387,
and N389. The variant with the highest affinity to human FcRn was
obtained by combining the M252Y/S254T/T256E and H433K/N434F/Y436H
mutations and exhibited a 57-fold increase in affinity relative to
the wild-type IgG1. The in vivo behaviour of such a mutated human
IgG1 exhibited a nearly 4-fold increase in serum half-life in
cynomolgus monkey as compared to wild-type IgG1.
[0146] The present invention therefore provides a variant of an
antigen binding protein with optimized binding to FcRn. In a
preferred embodiment, the said variant of an antigen binding
protein comprises at least one amino acid modification in the Fc
region of said antigen binding protein, wherein said modification
is selected from the group consisting of 226, 227, 228, 230, 231,
233, 234, 239, 241, 243, 246, 250, 252, 256, 259, 264, 265, 267,
269, 270, 276, 284, 285, 288, 289, 290, 291, 292, 294, 297, 298,
299, 301, 302, 303, 305, 307, 308, 309, 311, 315, 317, 320, 322,
325, 327, 330, 332, 334, 335, 338, 340, 342, 343, 345, 347, 350,
352, 354, 355, 356, 359, 360, 361, 362, 369, 370, 371, 375, 378,
380, 382, 384, 385, 386, 387, 389, 390, 392, 393, 394, 395, 396,
397, 398, 399, 400, 401 403, 404, 408, 411, 412, 414, 415, 416,
418, 419, 420, 421, 422, 424, 426, 428, 433, 434, 438, 439, 440,
443, 444, 445, 446 and 447 of the Fc region as compared to said
parent polypeptide, wherein the numbering of the amino acids in the
Fc region is that of the EU index in Kabat.
[0147] In a further aspect of the invention the modifications are
M252Y/S254T/T256E.
[0148] Additionally, various publications describe methods for
obtaining physiologically active molecules whose half-lives are
modified either by introducing an FcRn-binding polypeptide into the
molecules (WO 97/43316; U.S. Pat. Nos. 5,869,046; 5,747,035; WO
96/32478; WO 91/14438) or by fusing the molecules with antibodies
whose FcRn-binding affinities are preserved but affinities for
other Fc receptors have been greatly reduced (WO 99/43713) or
fusing with FcRn binding domains of antibodies (WO 00/09560; U.S.
Pat. No. 4,703,039).
[0149] Although substitutions in the constant region are able to
significantly improve the functions of therapeutic IgG antibodies,
substitutions in the strictly conserved constant region have the
risk of immunogenicity in human (Presta, supra, 2008; De Groot and
Martin, Clin Immunol 131: 189-201, 2009) and substitution in the
highly diverse variable region sequence might be less immunogenic.
Reports concerned with the variable region include engineering the
CDR residues to improve binding affinity to the antigen (Rothe et
al., Expert Opin Biol Ther 6: 177-187, 2006; Bostrom et al.,
Methods Mol Bioi 525: 353-376, 2009; Thie et al., Methods Mol Biol
525: 309-322, 2009) and engineering the CDR and framework residues
to improve stability (Worn and Pluckthun, J Mol Biol 305: 989-1010,
2001; Ewert et al., Methods 34: 184-199, 2004) and decrease
immunogenicity risk (De Groot and Martin, supra, 2009; Jones et
al., Methods Mol Biol 525: 405-423, xiv, 2009). As reported,
improved affinity to the antigen can be achieved by affinity
maturation using the phage or ribosome display of a randomized
library.
[0150] Improved stability can be rationally obtained from sequence-
and structure-based rational design. Decreased immunogenicity risk
(deimmunization) can be accomplished by various humanization
methodologies and the removal of T-cell epitopes, which can be
predicted using in silico technologies or determined by in vitro
assays. Additionally, variable regions have been engineered to
lower pI. A longer half life was observed for these antibodies as
compared to wild type antibodies despite comparable FcRn binding.
Engineering or selecting antibodies with pH dependent antigen
binding to modify antibody and/or antigen half life eg IgG2
antibody half life can be shortened if antigen-mediated clearance
mechanisms normally degrade the antibody when bound to the antigen.
Similarly, the antigen:antibody complex can impact the half-life of
the antigen, either extending half-life by protecting the antigen
from the typical degradation processes, or shortening the half-life
via antibody-mediated degradation. One embodiment relates to
antibodies with higher affinity for antigen at pH 7.4 as compared
to endosomal pH (i.e., pH 5.5-6.0) such that the KD ratio at
pH5.5/pH 7.4 or at pH 6.0/pH 7.4 is 2 or more. For example to
enhance the pharmacokinetic (PK) and pharmacodynamic (PD)
properties of the antibody, it is possible to engineer pH-sensitive
binding to the antibody by introducing histidines into CDR
residues.
Pharmaceutical Compositions
[0151] The antigen binding proteins of the present invention will
normally, but not necessarily, be formulated into pharmaceutical
compositions prior to administration to a patient. Accordingly, in
another aspect of the invention there is provided a pharmaceutical
composition comprising an antigen binding protein according to the
invention and one or more pharmaceutically acceptable excipients
and/or carriers.
[0152] Methods for the preparation of such pharmaceutical
compositions are well known to those skilled in the art (e.g.
Remingtons Pharmaceutical Sciences, 16th edition (1980) Mack
Publishing Co and Pharmaceutical Biotechnology; Plenum publishing
corporation; Volumes 2, 5 and 9).
[0153] The antigen binding proteins of the present invention may be
formulated for administration in any convenient way. Pharmaceutical
compositions may, for example, be administered by injection or
continuous infusion (examples include, but are not limited to,
intravenous, intraperitoneal, intradermal, subcutaneous,
intramuscular and intraportal). In one embodiment, the composition
is suitable for subcutaneous injection.
[0154] Pharmaceutical compositions may be suitable for topical
administration (which includes, but is not limited to,
epicutaneous, inhaled, intranasal or ocular administration) or
enteral administration (which includes, but is not limited to, oral
or rectal administration).
[0155] Pharmaceutical compositions may comprise between 0.0001
mg/kg to 10 mg/kg of antigen binding protein, for example between
0.1 mg/kg and 5 mg/kg of antigen binding protein. Alternatively,
the composition may comprise between 1.0 mg/kg and 3.0 mg/kg.
[0156] Pharmaceutical compositions may comprise, in addition to an
antigen binding protein of the present invention, one or more other
therapeutic agents. Additional therapeutic agents that may be
combined with an antigen binding protein of the present invention
include, but are not limited to, anti-CTLA-4 (e.g. ipilimumab and
tremelimumab), anti-TIM-3, anti-OX40, anti-OX40L, anti-PD1 (e.g.
nivolumab, lambrolizumab), anti-PD1L, anti-GITR, anti-IL-5 (e.g.
mepolizumab), anti-B-Lymphocyte cell activating (BLyS) factor (e.g.
belimumab), anti-GITRL, anti-IL-7, anti-IL-7R, anti-CD20,
anti-CCL20, anti-TNF.alpha., anti-OSM and anti-IL-6 antibodies, as
well as inhibitors of JAK, CCR9, RIP kinases, BET proteins,
ROR.gamma.1 and thiopurines.
[0157] The antigen binding proteins of the present invention and
one or more other therapeutic agents for combination therapy may be
formulated together in the same composition or presented in
separate compositions. Separately presented compositions may be
administered simultaneously or sequentially.
Methods of Use
[0158] The antigen binding proteins described herein may have use
in therapy. Antigen binding proteins of the present invention that
bind Lymphocyte Activation Gene 3 (LAG-3) and cause depletion of
LAG-3+ activated T cells may have use in the treatment or
prevention of diseases associated with the involvement of
pathogenic T cells, such as auto-immune diseases, infectious
diseases, allergic diseases and cancer.
[0159] Examples of disease states in which the antigen binding
proteins have potentially beneficial effects include auto-immune
diseases including, but not limited to psoriasis, inflammatory
bowel disease (for example Crohn's disease and/or ulcerative
colitis), rheumatoid arthritis, primary biliary cirrhosis, systemic
lupus erythematosus (SLE), Sjogren's syndrome, multiple sclerosis,
autoimmune hepatitis, uveitis, type I diabetes ankylosing
spondylitis, psoriatic arthritis, Grave's disease, graft versus
host disease, treatment and/or prevention of organ transplant
rejection, e.g. renal or liver transplant rejection, primary
sclerosing cholangitis, sarcoidosis, vasculitis, nephritis,
autoimmune thrombocytopenic purpura, systemic sclerosis, celiac
disease, anti-phosopholipid antibody syndrome, alopecia areata and
myasthenia gravis; infectious diseases including, but not limited
to, hepatitis C, hepatitis B, HIV, tuberculosis and malaria; and
allergic diseases including, but not limited to, asthma, atopic
dermatitis and COPD.
[0160] The antigen binding proteins of the present invention may
also have use in the treatment of cancer, including, but not
limited to ovarian cancer, melanoma (e.g. metastatic malignant
melanoma), prostate cancer, bowel cancer (e.g. colon cancer and
cancer of the small intestine), stomach cancer, oesophageal cancer,
breast cancer, lung cancer, renal cancer (e.g. clear cell
carcinoma), pancreatic cancer, uterine cancer, liver cancer,
bladder cancer, cervical cancer, oral cancer, brain cancer,
testicular cancer, skin cancer, thyroid cancer, and haematological
malignancies including myelomas and chronic and acute
leukaemias.
[0161] It will be appreciated by those skilled in the art that
references herein to "treatment" or "therapy" may, depending on the
condition, extend to prophylaxis in addition to the treatment of an
established condition.
[0162] There is thus provided as a further aspect of the invention
an antigen binding protein of the present invention for use in
therapy.
[0163] There is also therefore provided an antigen binding protein
of the present invention for use in the treatment of psoriasis,
Crohn's disease, rheumatoid arthritis, primary biliary cirrhosis,
SLE, Sjogren's syndrome, multiple sclerosis, ulcerative colitis or
autoimmune hepatitis.
[0164] In a further embodiment, there is provided an antigen
binding protein of the present invention for use in the treatment
of psoriasis.
[0165] In a further embodiment, there is provided an antigen
binding protein of the present invention for use in the treatment
of Crohn's disease.
[0166] In a further embodiment, there is provided an antigen
binding protein of the present invention for use in the treatment
of ulcerative colitis.
[0167] There is further provided the use of an antigen binding
protein of the present invention in the manufacture of a medicament
for the treatment of psoriasis, Crohn's disease, rheumatoid
arthritis, primary biliary cirrhosis, systemic lupus erythematosus
(SLE), Sjogren's syndrome, multiple sclerosis, ulcerative colitis
or autoimmune hepatitis.
[0168] In a further embodiment, there is provided the use of an
antigen binding protein of the present invention in the manufacture
of a medicament for the treatment of psoriasis.
[0169] In a further embodiment, there is provided the use of an
antigen binding protein of the present invention in the manufacture
of a medicament for the treatment of Crohn's disease.
[0170] In a further embodiment, there is provided the use of an
antigen binding protein of the present invention in the manufacture
of a medicament for the treatment of ulcerative colitis.
[0171] There is further provided a method of treatment of a human
or animal subject, which method comprises administering a
therapeutically effective amount of an antigen binding protein of
the present invention.
[0172] There is further provided a method of treatment of a disease
associated with the involvement of pathogenic T cells in a human or
animal subject comprising administering a therapeutically effective
amount of an antigen binding protein of the present invention.
[0173] There is further provided a method of treatment of
psoriasis, Crohn's disease, rheumatoid arthritis, primary biliary
cirrhosis, systemic lupus erythematosus (SLE), Sjogren's syndrome,
multiple sclerosis, ulcerative colitis or autoimmune hepatitis,
which method comprises administering to a human subject in need
thereof, a therapeutically effective amount of an antigen binding
protein of the present invention.
[0174] In a further embodiment, there is provided a method of
treatment of psoriasis, which method comprises administering to a
human subject in need thereof, a therapeutically effective amount
of an antigen binding protein of the present invention.
[0175] In a further embodiment, there is provided a method of
treatment of Crohn's disease, which method comprises administering
to a human subject in need thereof, a therapeutically effective
amount of an antigen binding protein of the present invention.
[0176] In a further embodiment, there is provided a method of
treatment of ulcerative colitis, which method comprises
administering to a human subject in need thereof, a therapeutically
effective amount of an antigen binding protein of the present
invention.
[0177] The phrase "therapeutically effective amount" as used herein
is an amount of an antigen binding protein of the present invention
required to ameliorate or reduce one or more symptoms of, or to
prevent or cure, the disease.
EXAMPLES
[0178] The following Examples illustrate but do not limit the
invention.
Example 1: Biacore.TM. SPR Analysis of Purified Anti-LAG-3
Humanised Antibodies
[0179] A9H12 (IMP731), as disclosed in WO 2008/132601, was
humanised by grafting murine CDRs onto two heavy and two light
chain human acceptor frameworks. A number of heavy and light chain
humanised anti-LAG-3 variants were prepared, containing human to
murine back mutations and CDR modifications. Heavy chain variants
were numbered H0 to H8, and J0, J7 to J13 and light chain variants
were numbered L0 to L10 and M0 to M1. Tissue culture supernatants
containing all combinations of heavy and light chain humanised
anti_LAG-3 variants were analysed for binding to Fc-tagged
recombinant soluble LAG-3 (IMP321). The data was analysed using a
1:1 model inherent to the Biacore.TM. 4000 software. Antibodies
were selected based on calculated affinities and also by visual
comparison of binding sensorgrams with the chimeric antibody
IMP731. A total of 54 constructs that exhibited equivalent or
improved binding for IMP321 were identified for re-analysis using a
Biacore.TM. 3000. Data was fitted to both the 1:1 and bivalent
models, inherent to the BiaCore 3000 analysis software, and binding
data was compared by normalising the binding curves at maximal
association and comparing off-rates against IMP731 visually. This
enabled antibodies that demonstrated improved off-rates in
comparison to IMP731 to be discerned. A total of 18 humanised
anti-LAG-3 antibodies were selected for further analysis on the
basis of either equivalent or improved binding kinetics to
recombinant sLAG-3 in comparison to IMP731. These 18 humanised
antibodies were re-expressed and analysed as follows:
[0180] Anti-LAG-3 humanised antibodies were expressed in HEK 293 6E
cells and purified by affinity chromatography as follows:
[0181] 100 ml Scale HEK 293 6E Expression
[0182] Expression plasmids encoding heavy and light chains of the
humanised antibodies identified in Table 3 were transiently
co-transfected into HEK 293 6E cells and expressed at 100 ml scale
to produce antibody.
[0183] Purification of Humanised Antibodies
[0184] The expressed antibody molecules were purified by affinity
chromatography. Protein A sepharose beads (GE Healthcare Cat No
17-5280-04), were added to the cell culture supernatants and mixed
at room temperature for 30-60 minutes. The protein A sepharose
beads were then centrifuged and washed in PBS. The mixture was then
added into a 10 ml disposable column (Pierce Cat No: 29924) and the
PBS allowed to drain. The column was washed 3 times with 10 ml PBS
before elution of the antibody with IgG Elution buffer (Pierce Cat
No: 21009). The antibody eluted was immediately neutralized using
1M Trizma.RTM. hydrochloride buffer (T2819) and was then buffer
exchanged into PBS with a Vivaspin 6 mwco 5000 column (Cat. No.:
FDP-875-105D). The yield was determined by measurement of
absorbance at 280 nm. The level of aggregated protein in the
purified sample was determined by size exclusion
chromatography.
[0185] Binding Kinetics
[0186] The binding kinetics of the purified antibodies for a sLAG-3
molecule were assessed by SPR using a Biacore.TM. 3000. A goat
anti-human kappa antibody (Southern Biotech, Catalogue No. 2060-01)
was immobilised on a CM5 chip by primary amine coupling. Humanised
anti-LAG3 antibodies were captured on this surface and the LAG3-Ig
molecule IMP321 (Chrystelle Brignone, Caroline Grygar, Manon Marcu,
Knut Schakel, Frederic Triebel, The Journal of Immunology, 2007,
179: 4202-4211) used as the analyte at 64 nM with a buffer
injection (i.e. 0 nM) used to double reference the binding curves.
Regeneration was with 10 mM Glycine, pH1.5. The run was carried out
on the Biacore.TM. 3000, using HBS-EP as running buffer and at
25.degree. C. Sensorgrams were normalised for binding at maximal
association and off-rates compared against IMP731 by visual
inspection of the sensorgram profiles.
[0187] The results show that the purified humanised anti-LAG-3
antibodies can be categorised into 3 groups; group 1 with humanised
variants that appear to be better at binding to IMP321 than the
chimeric IMP731, group 2 with variants that appear to bind in a
very similar manner to IMP731 and group 3 with variants that
demonstrate worse binding than IMP731.
[0188] 10 humanised variants fall within group 1 and demonstrate
improved (i.e. reduced) off-rates when compared to IMP731 by visual
inspection of the Biacore.TM. sensorgrams. All of these molecules
contained the L7 light chain, which contains a glycine to proline
substitution at position 27e in light chain CDR1. This data
indicates that proline at position 27e improves the off-rate for
IMP321 of the humanised anti-LAG-3 antibodies when paired with
numerous humanised heavy chains.
[0189] Of the remaining antibodies tested, 4 molecules fall within
group 2 and had similar off-rates to the chimeric IMP731 antibody,
while 4 other molecules fall within group 3 and exhibit worse
off-rates than IMP731. Table 3 provides an approximate ranking of
those molecules in comparison to IMP731. H5L7 exhibits the best
off-rate (i.e. lowest) in this experiment by visual inspection of
the Biacore.TM. sensorgrams.
TABLE-US-00003 TABLE 3 Comparison of off-rates with IMP731 Off-rate
comparison Rank order of Humanised Variant with IMP731 off-rates
H5L7 better 1 H1L7 better 2 J7L7 better 3 H4L7 better 4 J11L7
better 5 H2L7 better 6 J13L7 better 7 H7L7 better 8 J0L7 better 9
H0L7 better 10 H1L1 same H5L1 same J7L1 same J11L1 same J13L1 worse
H7L1 worse J0L1 worse H0L1 worse
Example 2: Binding Analysis of Wild Type Fucosylated and
Afucosylated Humanised Anti-LAG-3 Antibodies for Binding to
Recombinant Human LAG-3-his Using the Biacore.TM. T100
[0190] Afucosylated antibody H5L7BW was generated by expression of
plasmids encoding H5L7 in the BioWa POTELLIGENT.RTM. (FUT8
knock-out CHO) cell line. Afucosylated antibodies produced using
POTELLIGENT.RTM. technology have been shown to exhibit increased
antibody dependent cell-mediated cytotoxicity (ADCC) compared to
equivalent highly-fucosylated conventional antibodies through
increased affinity to Fc.gamma.RIIIa (CD16).
[0191] Wild type fucosylated and afucosylated antibodies were
compared for their ability to bind to recombinant human LAG-3 ECD
with a C-terminal His6 (SEQ ID NO:51) using the Biacore.TM. T100
(GE Healthcare.TM.). Protein A was immobilised on a CM5 chip by
primary amine coupling. This surface was then used to capture the
humanised antibodies. Recombinant human LAG-3 ECD-His6 was then
passed over the captured antibodies at 32, 8, 2, 0.5 and 0.125 nM
and regeneration was carried out using 50 mM NaOH. The binding
curves were double referenced with buffer injection (i.e. 0 nM) and
the data was fitted to the T100 analysis software using the 1:1
model. The run was carried out at 25.degree. C., using HBS-EP as
the running buffer.
[0192] In order to investigate the statistical significance of this
kinetic data, this experiment was repeated 3 times with the same
batch of the four antibodies and the chimeric control. KD, ka and
kd parameters were each log (base 10) transformed prior to separate
statistical analyses. For each parameter, a mixed model analysis of
variance (`Anova`) was performed on transformed data, including
terms for Run (random block effect) and Antibody.
[0193] From the Anova, geometric means were predicted for each
antibody, along with statistically plausible ranges (95% confidence
intervals) for each mean. Planned comparisons of antibodies were
performed within the Anova. Comparisons are presented as ratios of
the two antibodies compared, again with 95% confidence intervals
and p values. The ratios may also be interpreted as a fold change,
e.g. a ratio of 0.1 corresponds to a 90% decrease.
[0194] Geometric means were derived for each of the humanised
antibodies and the chimeric control IMP731 for the binding affinity
(KD), shown in Table 4. The mean KD for H5L7 was 0.2075 nM, a
significant decrease of 92% (i.e. 10 fold decrease) with
p<0.0001 when compared with IMP731. IMP731 exhibited a mean KD
of 2.76 nM. Afucosylated H5L7BW exhibits equivalent binding as
fucosylated H5L7, with a geometric KD of 0.2179 nM, with no
significant difference (p=0.1790).
[0195] The improvement in affinity observed for H5L7 in comparison
to IMP731 is predominantly driven by differences in the off-rates
of the antibodies for LAG-3-ECD-His6, shown in Table 5. There is an
approximate 85% decrease (i.e. almost 10 fold decrease) in kd for
H5L7 in comparison IMP731 which is highly statistically
significant. There is no significant difference between
afucosylated H5L7BW and H5L7 (p=0.4408).
TABLE-US-00004 TABLE 4 Statistical evaluation for the KD of
fucosylated and afucosylated anti-LAG-3 variants binding to
recombinant human LAG-3-His Geometric Means for KD (nM) Geometric
Lower Upper Antibody Batch No mean 95% CI 95% CI H5L7 GRITS42382
2.08E-10 1.89E-10 2.28E-10 H5L7BW GRITS42760 2.18E-10 1.98E-10
2.40E-10 IMP731 020909 2.76E-09 2.51E-09 3.04E-09 Comparisons of KD
Lower Upper KD comparison Ratio 95% CI 95% CI P value H5L7BW-H5L7
1.0502 0.97268 1.13389 0.179 H5L7-IMP731 0.07736 0.0715 0.0837
<.0001
TABLE-US-00005 TABLE 5 Statistical evaluation for the kd of
fucosylated and afucosylated anti-LAG-3 variants binding to
recombinant human LAG-3-His Geometric Means for kd (1/s) Geometric
Lower Upper Antibody Batch No mean 95% CI 95% CI H5L7 GRITS42382
3.95E-03 3.16E-03 4.94E-03 H5L7BW GRITS42760 4.41E-03 3.53E-03
5.51E-03 IMP731 020909 2.75E-02 2.20E-02 3.44E-02 Comparisons of kd
Lower Upper KD comparison Ratio 95% CI 95% CI P value H5L7BW-H5L7
1.11715 0.81531 1.53073 0.4408 H5L7-IMP731 0.15478 0.11157 0.21471
<.0001
Example 3: Evaluation of the LAG-3-his Binding Epitope of
Anti-LAG-3 Humanised Variants in Comparison with Chimeric Antibody
IMP731 Using the ProteOn.TM.
[0196] An epitope binning experiment was performed with H5L7 to
evaluate whether the LAG-3 epitope within which IMP731 binds was
conserved upon humanisation. Furthermore, the binding epitope of
fucosylated and afucosylated humanised variants was also
compared.
[0197] Epitope binding was evaluated using the ProteOn.TM. XPR36
(BioRad.TM.) biosensor machine, by assessing whether anti-LAG-3
antibodies were able to simultaneously bind to LAG-3-His in complex
with antibody captured on the ProteOn.TM. chip surface. IMP731 and
non-competitive murine antibody 17B4 were utilised as controls in
this assay.
[0198] The antibodies to be tested were biotinylated using
Ez-Link-sulfo-NHS biotinylation kit. Each biotinylated antibody was
captured on a separate flow cell on a neutravidin NLC chip using a
vertical injection. After antibody capture, the surface was blocked
with biocytin at 2.5 mg/ml. Using the co-inject facility inherent
to the ProteOn run software, LAG-3 ECD-His6 was injected over the
coupled antibodies at 100 nM, followed by the un-biotinylated
antibodies at 100 nM with both injections being horizontal so that
the LAG-3-His and the antibodies cross all 6 neutravidin captured
antibodies. The assay was run at 25.degree. C. and in HBS-EP on the
ProteOn XPR36 Protein Interaction Array System.
[0199] Data analysis was carried out using report points taken
after the LAG-3-His injection and report points taken after the
un-biotinylated antibody analyte injection. The overall response
was calculated by subtracting the response seen with the antibody
binding from the response seen with LAG-3 ECD-His6 binding. A
positive resonance unit (RU) value meant that antibody analyte
injection had bound to LAG-3 ECD-His6 complexed with the
biotinylated antibody on the neutravidin capture surface,
indicative of binding at non-competitive epitopes. No response or a
negative response meant that antibody analyte injection had not
bound to LAG-3 ECD-His6 complexed with the biotinylated antibody on
the neutravidin capture surface, indicating antibodies bind at
competitive epitopes.
[0200] Anti-LAG-3 humanised variants (fucosylated and afucosylated)
are unable to bind to human LAG-3 ECD-His6 in complex with IMP731,
indicative that the epitope for LAG-3 ECD-His6 is shared and thus
conserved. Murine antibody 17B4 is able to bind to human LAG-3
ECD-His6 in complex with IMP731 substantiating that this antibody
is non-competitive for LAG-3 ECD-His6 binding with IMP731.
Conversely, the humanised antibodies are able to bind to human
LAG-3 ECD-His6 in complex with 17B4.
[0201] The results confirm that there has been no alteration in
epitope between the chimeric IMP731 and the humanised variant of
IMP731 tested in this experiment. The experiment also shows that
there is no difference between fucosylated and afucosylated
antibodies for binding.
Example 4: Binding Analysis of Anti-LAG-3 Humanised Antibodies to
Recombinant Cynomolgus Macaque and Baboon LAG-3 ECD-His6 Using the
Biacore.TM. T100
[0202] The binding cross reactivity of anti-LAG-3 humanised
antibodies for both cynomolgus macaque (cyno) and baboon
recombinant LAG-3 ECD-His6 (SEQ ID NOs 52 and 53, respectively) was
assessed using the Biacore.TM. T100 (GE Healthcare.TM.).
[0203] Protein A was immobilised on a CM5 chip by primary amine
coupling. This surface was then used to capture the humanised
antibodies. In-house generated recombinant cynomolgus macaque and
baboon LAG-3 ECD-His6 were then passed over the captured antibodies
and regeneration was carried out using 50 mM NaOH. LAG-3 ECD-His6
was passed over at 16, 4, 1, 0.25 and 0.0625 nM. The binding curves
were double referenced with buffer injection (i.e. 0 nM) and the
data was fitted to the T100 analysis software using the 1:1 model.
The run was carried out at 37.degree. C. using HBS-EP as the
running buffer.
[0204] H5L7, H5L7BW and IMP731 bind with comparable affinity to
both cynomolgus macaque and baboon recombinant LAG-3 ECD-His6. Data
was generated from separate experiments, however chimeric antibody
IMP731 was utilised as a control between experiments.
[0205] This data indicates that both non-human primate recombinant
LAG-3 orthologues bind to the H5L7 derived antibodies with a 10
fold improvement in affinity in comparison with human recombinant
LAG-3 ECD-His6 (SEQ ID NO: 51) (H5L7: human LAG-3 0.208 nM, cyno
LAG-3 0.017 nM and baboon LAG-3 0.022 nM; H5L7BW human LAG-3 0.218
nM, cyno LAG-3 0.021 nM and baboon LAG-3 0.024 nM). Whilst both
non-human primate recombinant LAG-3 orthologues bind to IMP731
derived antibodies with an improvement in affinity of approximately
100 fold in comparison with human recombinant LAG-3 ECD-His6 (SEQ
ID NO: 51) (IMP731: human LAG-3 2.76 nM, cyno LAG-3 0.021 nM and
baboon LAG-3 0.019 nM).
Example 5: Binding Profiles of H5L7BW, H5L7 and IMP731 to Human
LAG-3 Expressing EL4 Cells, and Human Primary Activated CD3+ T
Cells
[0206] Human LAG-3 expressing EL4 cells were incubated with either
IMP731, H5L7 or H5L7BW Alexa647-conjugated antibodies at varying
concentrations of up to 50 .mu.g/ml for 30 minutes at room
temperature. Cells were washed with FACS buffer (PBS+0.5% BSA) to
remove unbound antibody.
[0207] CD3.sup.+ T cells were prepared from PBMCs by negative
selection using Untouched Human T cell Dynal beads. CD3.sup.+ T
cells were activated by incubation with immobilised anti-CD3 and
anti-CD28 and soluble recombinant human IL-12 for 3 days at
37.degree. C. Activated cells were incubated with Alexa
647-conjugated antibodies of varying concentrations up to 3
.mu.g/ml for 30 minutes at room temperature. Cells were washed with
FACS buffer (PBS+0.5% BSA).
[0208] EL4 cells and CD3.sup.+ T cells were analysed by FACS using
a Beckman Coulter FC 500 flow cytometer. FACS raw data were
analysed using CXP Analysis software (Beckman Coulter). The data
was initially plotted on a forward-scatter versus side-scatter plot
and the population of cells of interest were gated. This gated
population was then plotted as a histogram displaying fluorescence
intensity and the mean fluorescence intensity (MFI) calculated. MFI
values were then plotted in GraphPad Prism 5 software to generate
dose response curves.
[0209] Binding profiles of H5L7BW, H5L7 and IMP731 to human LAG-3
expressing EL4 cells, and human primary activated CD3+ T cells are
shown in FIG. 1. The three antibodies exhibited similar binding
characteristics to human LAG-3 expressing EL4 cells (FIG. 1A) and
activated human CD3+ T cells (FIG. 1B).
Example 6: Assessment of the Depleting Activity of H5L7BW and H5L7
by Antibody Dependent Cellular Cytotoxicity (ADCC) in Primary Human
T Cells
[0210] The donors used in these experiments were screened for
re-call responses to the CD4 antigens present in Revaxis,
(Diptheria, Tetanus and Poliomyelitis) and to either a CMVpp 65
peptide pool or to a CD8 peptide pool, which contained peptide
epitopes to CMV, EBV and Influenza. The antigen used to perform
initial studies was the CMVpp 65 peptide pool. However, due to the
limited number of donors that demonstrated a re-call response to
this antigen, Revaxis and the CD8 peptide pool were the antigens
used to generate the majority of the potency data for the anti-LAG3
antibodies.
[0211] Peripheral blood was collected from healthy human volunteers
on day 0 (25 mL) and day 5 (75 mL) of the experiment and was used
to prepare mononuclear cells by ficollplaque density gradient
centrifugation. The PBMCs prepared on day 0 were labeled using the
CellTrace.TM. Violet Cell Proliferation Kit, in accordance with the
manufacturer's instructions, after which they were washed, seeded
in 24-well flat bottomed tissue culture plates at a density of
2.times.106/mL in medium and stimulated with antigen (Revaxis and
the CD8 peptide pool were used at a dilution of 1 in 1000; the
CMVpp 65 peptide was used at a dilution of 1 in 100). The PBMCs
were incubated for 5 days at 37.degree. C. in a 5% CO2 humidified
incubator.
[0212] Autologous donor NK cells were purified from the PBMCs
prepared on day 5 of the experiment by negative selection using
kits from either Invitrogen or Miltenyi Biotec in accordance with
the specific instructions of each manufacturer. The purified NK
cells were counted and diluted to a density of 1.3.times.106/mL in
medium.
[0213] The cells that had been stimulated with antigen for 5 days
were washed, counted and diluted to a density of 2.times.106/viable
cells/mL in medium.
[0214] Autologous donor NK cells (80 .mu.L) and antigen activated
cells (100 .mu.L) were pipetted into round-bottomed 5 mL
polystyrene FACS tubes with test antibody or medium (20 .mu.L). The
final concentrations of the anti LAG-3 antibodies tested ranged
from 1000 to 0.015 ng/mL. The samples were incubated for 18 h at
37.degree. C. in a 5% CO2 humidified incubator. After 18 h the ADCC
assay samples were analysed for the presence of antigen specific
LAG-3 positive T cells using flow cytometry. Briefly, the samples
were washed in FACS buffer, blocked with human IgG (3 .mu.g/tube),
and incubated with mouse anti-human CD4, CD8, CD337, CD25 and LAG-3
fluorochrome conjugated antibodies for 30 minutes in the dark at
room temperature. After a further wash step in PBS the cells were
incubated in the presence of a fixable green dead cell for 30
minutes in the dark at room temperature. The samples were finally
washed with PBS, fixed and analysed by flow cytometry using a 60
second acquisition time at a flow rate of 1 .mu.L per second.
[0215] All sample data were acquired using the BD FACSCanto II Flow
Cytometer with FACS Diva software version 6.1.3 (BD BioSciences).
The Live/Dead fixable green dead cell stain was used as a dead cell
exclusion marker and appropriate isotype and FMO-1 controls were
used to define negative populations. Briefly dead cells were
omitted from the analysis using a plot of forward scatter (FSC-A)
against fluorescence in FL1 (Green dead cell stain). Doublets were
then excluded from the analysis by using a plot of FSC-W against
FSC-H. Viable single lymphocytes were subsequently identified and
gated using a plot of forward scatter (FSC-A) against side scatter
(SSC-A). CD4 antigen specific T cells were identified from this
gated population of cells using plots of CD4 fluorescence against
SSC-A and Violet Dye fluorescence against CD4 fluorescence
respectively. Antigen specific CD4 T cells were identified by a
reduction of Violet Dye fluorescence. A further plot of CD25
fluorescence against LAG-3 fluorescence was drawn to confirm the
activation state of this population of cells and that they
expressed LAG-3. Similar plots were drawn to identify antigen
specific CD8 T cells.
[0216] The percentages of antigen specific CD4 and CD8 T cells
present in each sample (as a percentage of the viable lymphocyte
population) were recorded. Nonlinear variable slope curve-fits of
these data were plotted and EC50 values were generated using
GraphPad Prism software (v5.03).
[0217] To calculate the maximum level of depletion observed in an
assay, at the highest concentration of antibody tested, the
following formula was used: (1-(% Antigen specific T cells
remaining after antibody treatment)/(% Antigen specific T cells
remaining in the absence of antibody))*100.
[0218] Potency data for the depletion of LAG3 positive antigen
specific CD8 and CD4 T cells by H5L7BW and H5L7 was generated using
the in vitro assay system detailed above. H5L7BW induced depletion
of LAG3 positive antigen specific CD4 and CD8 T cells by ADCC in
six of the seven donors studied for disappearance of the respective
cell types. The potency of H5L7BW in antigen specific CD4 T cells,
as quantified by EC50 values, ranged from 14 pg/mL to 3.4 ng/mL
with maximum levels of depletion ranging from 44 to 78%. The
potency of this antibody in antigen specific LAG-3 positive CD8 T
cells ranged from 122 pg/mL to 17.5 ng/mL, with maximum levels of
depletion ranging from 39 to 87%. H5L7 mediated low levels of
depletion, or was inactive, in the donors studied.
Example 7: Assessment of the Depleting Activity of H5L7BW and H5L7
in an In-Vivo Human PBMC/Mouse SCID Xenograft Model
[0219] This assay describes the use of a human PBMC/mouse SCID
xenograft model to assess in vivo depletion efficacy of the
monoclonal, fully humanised, afucosylated LAG-3 depleting antibody
H5L7BW on activated human T cells. Healthy volunteer peripheral
blood mononuclear cells (PBMCs) were isolated and stimulated
overnight (anti-CD3, IL-12) to induce LAG-3 expression prior to
injection into the peritoneum of immuno-compromised SCID mice.
LAG-3 depleting or control antibodies were either co-administered
into the peritoneum or injected intravenously.
[0220] Depletion of LAG-3 positive cells was assessed by flow
cytometry in peritoneal lavage samples 5 or 24 hours after cell
injection.
[0221] Mice were injected with activated huPBMCs
(4.times.106-2.times.107 cells in 0.4 ml of PBS) by the
intraperitoneal route. Depending on the particular study route,
LAG-3 antibodies or huIgG1 BioWa controls were either
co-administered i.p. with the huPBMCs or mice were pre-treated
intravenously 18 h prior to huPBMC injection. 5 or 24 hours
post-cell injection, mice were euthanized, a peritoneal lavage was
performed and the cellular content of the lavage buffer analysed by
flow cytometry. Briefly, peritoneal lavage involved 3.times.5 ml
washes of the intact peritoneal cavity using cold PBS containing 3
mM EDTA.
[0222] All sample data were acquired using the BD FACSCanto II Flow
Cytometer with FACS Diva software version 6.1.3 (BD BioSciences).
Approximately 1.times.106 cells (where possible) were added per
FACS tube, the cell suspensions centrifuged at 1500 rpm for 10
minutes, and the pellet then re-suspended in 3 ml PBS. The
supernatants were then carefully decanted and the cell pellets
re-suspended in 100p 1 cold FACS wash buffer. 15p 1 FcR Blocking
Reagent was then added per tube and the cells incubated for 10
minutes at room temperature. 5p 1 of each staining antibody (10p 1
of 1:100 pre-diluted anti-LAG-3 blocking/detection antibody
17134-PE) or isotype control were then added respectively and
incubated for 20 minutes at room temperature protected from light.
The cells were subsequently washed by addition of 4 ml FACS buffer
per tube and centrifugation at 1500 rpm for 5 minutes after which
the supernatant was carefully decanted. This washing step was
repeated. Finally the cells were re-suspended in 300p 1 FACS buffer
and analysed by flow cytometry. In addition to LAG-3 detection by
use of the fluorescently labeled LAG-3 blocking antibody 1764-PE,
the following T cell and activation markers were used for T cell
phenotyping: CD45, CD4, CD8, and CD25. Percentages of CD4 and CD8 T
cells were expressed as percentage of CD45 positive cells. LAG-3
positive T cell populations were expressed as percentages of their
parent populations CD4 and CD8.
[0223] FACS Diva software version 6.1.3 was used to generate batch
analyses of individual cell counts/events and cell population
percentages. Data were analysed with SAS version 9.2.2 software
using a generalized linear model for binomial data. This analysis
directly models the cell count as a proportion of the parent
population. In this way, the size of the parent population is taken
into account during the analysis. Means were calculated for
proportions of target cell type for each treatment, along with 95%
confidence intervals. These were expressed as percentages.
[0224] Planned comparisons of treatments versus Control were made
using odds ratios. This expresses the odds of having a target cell
type in one treatment as a ratio to the odds of having the target
cell type on control treatment. An odds ratio <1 would indicate
a reduced odds of having the cell type in the treatment of interest
compared to the control. An odds ratio <1 would indicate a
reduced odds of having the cell type in the treatment of interest
compared to the control.
[0225] All experiments were performed using PBMCs from individual
healthy blood donors and due to the large blood volumes required
per experiment, no donor was used more than once. LAG-3 expression
levels after overnight stimulation varied greatly between donors
(ranging from 2-73% cell surface expression) but these differences
in expression levels had no effect on the highly significant
depletion efficacy of the tested antibodies.
[0226] The human PBMC/mouse SCID in vivo model was successfully
used to show depletion of activated human, LAG-3 expressing T cells
in the peritoneum of immunocompromised SCID mice. Depending on
donor, route of administration and time point of analysis, between
84.22-99.71% of LAG-3 positive human CD4 T cells and between
84.64-99.62% of LAG-3 positive human CD8 T cells were depleted. As
shown in FIG. 2, co-administration of 5 mg/kg H5L7BW to activated
human PBMCs in the peritoneum of SCID mice led to highly
significant depletion of LAG-3 positive CD4 and CD8 positive T
cells 24 hours after injection compared to Control IgG injected
animals.
[0227] FIG. 3 highlights the comparison between 5 mg/kg H5L7BW and
H5L7 5 hours after co-i.p. administration to activated human PBMCs
as described before. Both antibodies induced highly significant
depletion of LAG-3 positive CD4 and CD8 T cells (FIG. 3A).
[0228] As shown in FIG. 4, administration of 5 mg/kg H5L7BW via the
intra-venous route resulted in a highly statistically significant
depletion of LAG-3 positive T cells after 5 hours (FIG. 4A),
similar to what was observed in the experiments with i.p.
co-administered LAG-3 depletion antibodies. The comparison between
i.v. administered H5L7BW, H5L7 and IMP731 (all at 5 mg/kg) 5 hours
after i.p. administration of activated human PBMCs revealed very
similar depletion efficacies between the 3 molecules compared to
control treated animals (FIG. 5). Each of the 3 tested LAG-3
depleting antibodies caused highly significant reduction in the
number of LAG-3 positive CD4 and CD8 T cells (FIG. 5A) with H5L7BW
demonstrating greater depletion capacity compared to H5L7 or
IMP731.
Example 8: Binding Analysis of Anti-LAG-3 Humanised Antibodies to
Recombinant Soluble Human Fc Gamma Receptors Using the
ProteOn.TM.
[0229] Human Fc.gamma.RIIIa binding was investigated in order to
assess the ability of H5L7 and H5L7BW to induce antibody dependent
cell-mediated cytotoxicity (ADCC). H5L7 and H5L7BW anti-LAG-3
antibodies were assessed for binding to recombinant soluble human
Fc.gamma.RIIIa in addition to Fc.gamma.RI and Fc.gamma.RII
receptors using the ProteOn.TM. XPR36 (BioRad.TM.) biosensor
machine, and were compared against chimeric antibody IMP731.
[0230] A goat anti-poly-histidine IgG was immobilised on a GLM
biosensor chip by primary amine coupling. This surface was used as
a capture surface for the poly-histidine tagged human Fc gamma
receptors. Antibodies to be tested were used as the analyte and
passed over at 2048 nM, 512 nM, 128 nM, 32 nM and 8 nM with an
injection of 0 nM (i.e. buffer alone) used to double reference the
binding curves. The goat anti-poly-histidine IgG surface was
regenerated with 100 mM phosphoric acid between interactions. The
run was carried out on the ProteOn XPR36 Protein Array Interaction
System at 25.degree. C. and using HBS-EP as running buffer. Data
was analysed for each receptor separately, setting a global R-max
and using the Equilibrium Model inherent to the ProteOn's analysis
software. Control molecules were run at the beginning and the end
of the set of samples to be tested to ensure comparability of
results. Data was compared from two experiments and hybrid control
antibodies used as controls between experiments.
[0231] The results show that H5L7BW bound both polymorphisms of
Fc.gamma.RIIIa (valine V158 and phenylalanine F158) with an
improved affinity of approximately 10 fold in comparison to H5L7
(see Table 6). Fucosylated antibody H5L7 bound to Fc.gamma.RIIIa
with a similar affinity as chimeric antibody IMP731.
[0232] No significant changes were observed between the binding of
the humanised fucosylated and afucosylated anti-LAG-3 antibodies
for the Fc.gamma.RI or Fc.gamma.RIIa receptors.
TABLE-US-00006 TABLE 6 Binding of H5L7 and H5L7BW to human Fc gamma
receptors Fc.gamma.RIIa Fc.gamma.RIIa Fc.gamma.RIIIa Fc.gamma.RIIIa
Fc.gamma.RI R131 H131 V158 F158 Antibody (nM) (nM) (nM) (nM) (nM)
IMP731 39.0 2620.0 1280.0 406.0 1750.0 H5L7 26.3 792.0 638.0 236.0
752.0 H5L7BW 26.4 1490.0 1430.0 21.8 81.1
Sequences
TABLE-US-00007 [0233] TABLE 7 Sequence Summary Sequence Identifier
(SEQ ID No.) Amino Poly- acid nucleotide Sequence Sequence Sequence
H5L7, CDRL1 (Kabat defined) 1 57 H5L7, CDRL2 (Kabat defined) 2 58
H5L7, CDRL3 (Kabat defined) 3 59 H5L7, VL 4 60 H5L7, light chain
humanized construct 5 61 H5L7, CDRH1 (Kabat defined) 6 62 H5L7,
CDRH2 (Kabat defined) 7 63 H5L7, CDRH3 (Kabat defined) 8 64 H5L7,
VH 9 65 H5L7, heavy chain humanised construct 10 66 H1L7, light
chain humanised construct 11 67 H1L7, heavy chain humanised
construct 12 68 J7L7, light chain humanised construct 13 69 J7L7,
heavy chain humanised construct 14 70 H4L7, light chain humanised
construct 15 71 H4L7, heavy chain humanised construct 16 72 J11L7,
light chain humanised construct 17 73 J11L7, heavy chain humanised
construct 18 74 H2L7, light chain humanised construct 19 75 H2L7,
heavy chain humanised construct 20 76 J13L7, light chain humanised
construct 21 77 J13L7, heavy chain humanised construct 22 78 H7L7,
light chain humanised construct 23 79 H7L7, heavy chain humanised
construct 24 80 J0L7, light chain humanised construct 25 81 J0L7,
heavy chain humanised construct 26 82 H0L7, light chain humanised
construct 27 83 H0L7, heavy chain humanised construct 28 84 H1L1,
light chain humanised construct 29 85 H1L1, heavy chain humanised
construct 30 86 H5L1, light chain humanised construct 31 87 H5L1,
heavy chain humanised construct 32 88 J7L1, light chain humanised
construct 33 89 J7L1, heavy chain humanised construct 34 90 J11L1,
light chain humanised construct 35 91 J11L1, heavy chain humanised
construct 36 92 J13L1, light chain humanised construct 37 93 J13L1,
heavy chain humanised construct 38 94 H7L1, light chain humanised
construct 39 95 H7L1, heavy chain humanised construct 40 96 J0L1,
light chain humanised construct 41 97 J0L1, heavy chain humanised
construct 42 98 H0L1, light chain humanised construct 43 99 H0L1,
heavy chain humanised construct 44 100 Human kappa chain constant
region 45 101 Human IgG1 constant region 46 102 IMP731, VH 47 103
IMP731, VL 48 104 IMP731, heavy chain sequence 49 105 IMP731, light
chain sequence 50 106 Recombinant human LAG-3-ECD-His6 51 107
Recombinant cynomolgus macaque 52 108 LAG-3 ECD-His6 Recombinant
baboon LAG-3 ECD-His6 53 109 Leader sequence used for humanised 54
110 variant heavy and light chain constructs IMP731 Leader sequence
55 111 Leader sequence used for soluble 56 112 LAG-3 constructs
TABLE-US-00008 SEQ ID NO. 1 KSSQSLLNPSNQKNYLA SEQ ID NO. 2 FASTRDS
SEQ ID NO. 3 LQHFGTPPT SEQ ID NO. 4
DIQMTQSPSSLSASVGDRVTITCKSSQSLLNPSNQKNYLAWYQQKPGKAPKLLVYFASTRDSGVPSRFSGSGSG
TDFTLTISSLQPEDFATYYCLQHFGTPPTFGQGTKLEIKR SEQ ID NO. 5
DIQMTQSPSSLSASVGDRVTITCKSSQSLLNPSNQKNYLAWYQQKPGKAPKLLVYFASTRDSGVPSRFSGSGSG
TDFTLTISSLQPEDFATYYCLQHFGTPPTFGQGTKLEIKRTVAAPSVFIFPPSDEQLKSGTASVVCLLNNFYPR
EAKVQWKVDNALQSGNSQESVTEQDSKDSTYSLSSTLTLSKADYEKHKVYACEVTHQGLSSPVTKSENRGEC
SEQ ID NO. 6 AYGVN SEQ ID NO. 7 MIWDDGSTDYDSALKS SEQ ID NO. 8
EGDVAFDY SEQ ID NO. 9
QVQLQESGPGLVKPSETLSLTCTVSGFSLTAYGVNWIRQPPGKGLEWIGMIWDDGSTDYDSALKSRVTISVDTS
KNQFSLKLSSVTAADTAVYYCAREGDVAFDYWGQGTLVTVSS SEQ ID NO. 10
QVQLQESGPGLVKPSETLSLTCTVSGFSLTAYGVNWIRQPPGKGLEWIGMIWDDGSTDYDSALKSRVTISVDTS
KNQFSLKLSSVTAADTAVYYCAREGDVAFDYWGQGTLVTVSSASTKGPSVFPLAPSSKSTSGGTAALGCLVKDY
FPEPVTVSWNSGALTSGVHTFPAVLQSSGLYSLSSVVTVPSSSLGTQTYICNVNHKPSNTKVDKKVEPKSCDKT
HTCPPCPAPELLGGPSVFLFPPKPKDTLMISRTPEVTCVVVDVSHEDPEVKFNWYVDGVEVHNAKTKPREEQYN
STYRVVSVLTVLHQDWLNGKEYKCKVSNKALPAPIEKTISKAKGQPREPQVYTLPPSRDELTKNQVSLTCLVKG
FYPSDIAVEWESNGQPENNYKTTPPVLDSDGSFFLYSKLTVDKSRWQQGNVFSCSVMHEALHNHYTQKSLSLSP
GK SEQ ID NO. 11
DIQMTQSPSSLSASVGDRVTITCKSSQSLLNPSNQKNYLAWYQQKPGKAPKLLVYFASTRDSGVPSRFSGSGSG
TDFTLTISSLQPEDFATYYCLQHFGTPPTFGQGTKLEIKRTVAAPSVFIFPPSDEQLKSGTASVVCLLNNFYPR
EAKVQWKVDNALQSGNSQESVTEQDSKDSTYSLSSTLTLSKADYEKHKVYACEVTHQGLSSPVTKSFNRGEC
SEQ ID NO. 12
QVQLQESGPGLVKPSETLSLTCTVSGFSLTAYGVNWIRQPPGKGLEWIGMIWDDGSTDYNSALKSRVTISVDTS
KNQFSLKLSSVTAADTAVYYCAREGDVAFDYWGQGTLVTVSSASTKGPSVFPLAPSSKSTSGGTAALGCLVKDY
FPEPVTVSWNSGALTSGVHTFPAVLQSSGLYSLSSVVTVPSSSLGTQTYICNVNHKPSNTKVDKKVEPKSCDKT
HTCPPCPAPELLGGPSVFLFPPKPKDTLMISRTPEVTCVVVDVSHEDPEVKFNWYVDGVEVHNAKTKPREEQYN
STYRVVSVLTVLHQDWLNGKEYKCKVSNKALPAPIEKTISKAKGQPREPQVYTLPPSRDELTKNQVSLTCLVKG
FYPSDIAVEWESNGQPENNYKTTPPVLDSDGSFFLYSKLTVDKSRWQQGNVFSCSVMHEALHNHYTQKSLSLSP
GK SEQ ID NO. 13
DIQMTQSPSSLSASVGDRVTITCKSSQSLLNPSNQKNYLAWYQQKPGKAPKLLVYFASTRDSGVPSRFSGSGSG
TDFTLTISSLQPEDFATYYCLQHFGTPPTFGQGTKLEIKRTVAAPSVFIFPPSDEQLKSGTASVVCLLNNFYPR
EAKVQWKVDNALQSGNSQESVTEQDSKDSTYSLSSTLTLSKADYEKHKVYACEVTHQGLSSPVTKSFNRGEC
SEQ ID NO. 14
QVQLVQSGAEVKKPGSSVKVSCKASGFSLTAYGVNWVRQAPGQGLEWMGMIWDDGSTDYNSALKSRVTITADKS
TSTAYMELSSLRSEDTAVYYCAREGDVAFDYWGQGTLVTVSSASTKGPSVFPLAPSSKSTSGGTAALGCLVKDY
FPEPVTVSWNSGALTSGVHTFPAVLQSSGLYSLSSVVTVPSSSLGTQTYICNVNHKPSNTKVDKKVEPKSCDKT
HTCPPCPAPELLGGPSVFLFPPKPKDTLMISRTPEVTCVVVDVSHEDPEVKFNWYVDGVEVHNAKTKPREEQYN
STYRVVSVLTVLHQDWLNGKEYKCKVSNKALPAPIEKTISKAKGQPREPQVYTLPPSRDELTKNQVSLTCLVKG
FYPSDIAVEWESNGQPENNYKTTPPVLDSDGSFFLYSKLTVDKSRWQQGNVFSCSVMHEALHNHYTQKSLSLSP
GK SEQ ID NO. 15
DIQMTQSPSSLSASVGDRVTITCKSSQSLLNPSNQKNYLAWYQQKPGKAPKLLVYFASTRDSGVPSRFSGSGSG
TDFTLTISSLQPEDFATYYCLQHFGTPPTFGQGTKLEIKRTVAAPSVFIFPPSDEQLKSGTASVVCLLNNFYPR
EAKVQWKVDNALQSGNSQESVTEQDSKDSTYSLSSTLTLSKADYEKHKVYACEVTHQGLSSPVTKSFNRGEC
SEQ ID NO. 16
QVQLQESGPGLVKPSETLSLTCTVSGFSLTAYGVNWIRQPPGKGLEWLGMIWDDGSTDYNSALKSRLTISKDNS
KNQVSLKLSSVTAADTAVYYCAREGDVAFDYWGQGTLVTVSSASTKGPSVFPLAPSSKSTSGGTAALGCLVKDY
FPEPVTVSWNSGALTSGVHTFPAVLQSSGLYSLSSVVTVPSSSLGTQTYICNVNHKPSNTKVDKKVEPKSCDKT
HTCPPCPAPELLGGPSVFLFPPKPKDTLMISRTPEVTCVVVDVSHEDPEVKFNWYVDGVEVHNAKTKPREEQYN
STYRVVSVLTVLHQDWLNGKEYKCKVSNKALPAPIEKTISKAKGQPREPQVYTLPPSRDELTKNQVSLTCLVKG
FYPSDIAVEWESNGQPENNYKTTPPVLDSDGSFFLYSKLTVDKSRWQQGNVFSCSVMHEALHNHYTQKSLSLSP
GK SEQ ID NO. 17
DIQMTQSPSSLSASVGDRVTITCKSSQSLLNPSNQKNYLAWYQQKPGKAPKLLVYFASTRDSGVPSRFSGSGSG
TDFTLTISSLQPEDFATYYCLQHFGTPPTFGQGTKLEIKRTVAAPSVFIFPPSDEQLKSGTASVVCLLNNFYPR
EAKVQWKVDNALQSGNSQESVTEQDSKDSTYSLSSTLTLSKADYEKHKVYACEVTHQGLSSPVTKSENRGEC
SEQ ID NO. 18
QVQLVQSGAEVKKPGSSVKVSCKASGFSLTAYGVNWVRQAPGQGLEWMGMIWDDGSTDYDSALKSRVTITADKS
TSTAYMELSSLRSEDTAVYYCAREGDVAFDYWGQGTLVTVSSASTKGPSVFPLAPSSKSTSGGTAALGCLVKDY
FPEPVTVSWNSGALTSGVHTFPAVLQSSGLYSLSSVVTVPSSSLGTQTYICNVNHKPSNTKVDKKVEPKSCDKT
HTCPPCPAPELLGGPSVFLFPPKPKDTLMISRTPEVTCVVVDVSHEDPEVKFNWYVDGVEVHNAKTKPREEQYN
STYRVVSVLTVLHQDWLNGKEYKCKVSNKALPAPIEKTISKAKGQPREPQVYTLPPSRDELTKNQVSLTCLVKG
FYPSDIAVEWESNGQPENNYKTTPPVLDSDGSFFLYSKLTVDKSRWQQGNVFSCSVMHEALHNHYTQKSLSLSP
GK SEQ ID NO. 19
DIQMTQSPSSLSASVGDRVTITCKSSQSLLNPSNQKNYLAWYQQKPGKAPKLLVYFASTRDSGVPSRFSGSGSG
TDFTLTISSLQPEDFATYYCLQHFGTPPTFGQGTKLEIKRTVAAPSVFIFPPSDEQLKSGTASVVCLLNNFYPR
EAKVQWKVDNALQSGNSQESVTEQDSKDSTYSLSSTLTLSKADYEKHKVYACEVTHQGLSSPVTKSENRGEC
SEQ ID NO. 20
QVQLQESGPGLVKPSETLSLTCTVSGFSLTAYGVNWIRQPPGKGLEWIGMIWDDGSTDYNSALKSRVTISKDNS
KNQVSLKLSSVTAADTAVYYCAREGDVAFDYWGQGTLVTVSSASTKGPSVFPLAPSSKSTSGGTAALGCLVKDY
FPEPVTVSWNSGALTSGVHTFPAVLQSSGLYSLSSVVTVPSSSLGTQTYICNVNHKPSNTKVDKKVEPKSCDKT
HTCPPCPAPELLGGPSVFLFPPKPKDTLMISRTPEVTCVVVDVSHEDPEVKFNWYVDGVEVHNAKTKPREEQYN
STYRVVSVLTVLHQDWLNGKEYKCKVSNKALPAPIEKTISKAKGQPREPQVYTLPPSRDELTKNQVSLTCLVKG
FYPSDIAVEWESNGQPENNYKTTPPVLDSDGSFFLYSKLTVDKSRWQQGNVFSCSVMHEALHNHYTQKSLSLSP
GK SEQ ID NO. 21
DIQMTQSPSSLSASVGDRVTITCKSSQSLLNPSNQKNYLAWYQQKPGKAPKLLVYFASTRDSGVPSRFSGSGSG
TDFTLTISSLQPEDFATYYCLQHFGTPPTFGQGTKLEIKRTVAAPSVFIFPPSDEQLKSGTASVVCLLNNFYPR
EAKVQWKVDNALQSGNSQESVTEQDSKDSTYSLSSTLTLSKADYEKHKVYACEVTHQGLSSPVTKSFNRGEC
SEQ ID NO. 22
QVQLVQSGAEVKKPGSSVKVSCKASGGTFSAYGVNWVRQAPGQGLEWMGMIWDDGSTDYDSALKSRVTITADKS
TSTAYMELSSLRSEDTAVYYCAREGDVAFDYWGQGTLVTVSSASTKGPSVFPLAPSSKSTSGGTAALGCLVKDY
FPEPVTVSWNSGALTSGVHTFPAVLQSSGLYSLSSVVTVPSSSLGTQTYICNVNHKPSNTKVDKKVEPKSCDKT
HTCPPCPAPELLGGPSVFLFPPKPKDTLMISRTPEVTCVVVDVSHEDPEVKFNWYVDGVEVHNAKTKPREEQYN
STYRVVSVLTVLHQDWLNGKEYKCKVSNKALPAPIEKTISKAKGQPREPQVYTLPPSRDELTKNQVSLTCLVKG
FYPSDIAVEWESNGQPENNYKTTPPVLDSDGSFFLYSKLTVDKSRWQQGNVFSCSVMHEALHNHYTQKSLSLSP
GK SEQ ID NO. 23
DIQMTQSPSSLSASVGDRVTITCKSSQSLLNPSNQKNYLAWYQQKPGKAPKLLVYFASTRDSGVPSRFSGSGSG
TDFTLTISSLQPEDFATYYCLQHFGTPPTFGQGTKLEIKRTVAAPSVFIFPPSDEQLKSGTASVVCLLNNFYPR
EAKVQWKVDNALQSGNSQESVTEQDSKDSTYSLSSTLTLSKADYEKHKVYACEVTHQGLSSPVTKSFNRGEC
SEQ ID NO. 24
QVQLQESGPGLVKPSETLSLTCTVSGGSISAYGVNWIRQPPGKGLEWIGMIWDDGSTDYDSALKSRVTISVDTS
KNQFSLKLSSVTAADTAVYYCAREGDVAFDYWGQGTLVTVSSASTKGPSVFPLAPSSKSTSGGTAALGCLVKDY
FPEPVTVSWNSGALTSGVHTFPAVLQSSGLYSLSSVVTVPSSSLGTQTYICNVNHKPSNTKVDKKVEPKSCDKT
HTCPPCPAPELLGGPSVFLFPPKPKDTLMISRTPEVTCVVVDVSHEDPEVKFNWYVDGVEVHNAKTKPREEQYN
STYRVVSVLTVLHQDWLNGKEYKCKVSNKALPAPIEKTISKAKGQPREPQVYTLPPSRDELTKNQVSLTCLVKG
FYPSDIAVEWESNGQPENNYKTTPPVLDSDGSFFLYSKLTVDKSRWQQGNVFSCSVMHEALHNHYTQKSLSLSP
GK SEQ ID NO. 25
DIQMTQSPSSLSASVGDRVTITCKSSQSLLNPSNQKNYLAWYQQKPGKAPKLLVYFASTRDSGVPSRFSGSGSG
TDFTLTISSLQPEDFATYYCLQHFGTPPTFGQGTKLEIKRTVAAPSVFIFPPSDEQLKSGTASVVCLLNNFYPR
EAKVQWKVDNALQSGNSQESVTEQDSKDSTYSLSSTLTLSKADYEKHKVYACEVTHQGLSSPVTKSFNRGEC
SEQ ID NO. 26
QVQLVQSGAEVKKPGSSVKVSCKASGGTFSAYGVNWVRQAPGQGLEWMGMIWDDGSTDYNSALKSRVTITADKS
TSTAYMELSSLRSEDTAVYYCAREGDVAFDYWGQGTLVTVSSASTKGPSVFPLAPSSKSTSGGTAALGCLVKDY
FPEPVTVSWNSGALTSGVHTFPAVLQSSGLYSLSSVVTVPSSSLGTQTYICNVNHKPSNTKVDKKVEPKSCDKT
HTCPPCPAPELLGGPSVFLFPPKPKDTLMISRTPEVTCVVVDVSHEDPEVKFNWYVDGVEVHNAKTKPREEQYN
STYRVVSVLTVLHQDWLNGKEYKCKVSNKALPAPIEKTISKAKGQPREPQVYTLPPSRDELTKNQVSLTCLVKG
FYPSDIAVEWESNGQPENNYKTTPPVLDSDGSFFLYSKLTVDKSRWQQGNVFSCSVMHEALHNHYTQKSLSLSP
GK SEQ ID NO. 27
DIQMTQSPSSLSASVGDRVTITCKSSQSLLNPSNQKNYLAWYQQKPGKAPKLLVYFASTRDSGVPSRFSGSGSG
TDFTLTISSLQPEDFATYYCLQHFGTPPTFGQGTKLEIKRTVAAPSVFIFPPSDEQLKSGTASVVCLLNNFYPR
EAKVQWKVDNALQSGNSQESVTEQDSKDSTYSLSSTLTLSKADYEKHKVYACEVTHQGLSSPVTKSENRGEC
SEQ ID NO. 28
QVQLQESGPGLVKPSETLSLTCTVSGGSISAYGVNWIRQPPGKGLEWIGMIWDDGSTDYNSALKSRVTISVDTS
KNQFSLKLSSVTAADTAVYYCAREGDVAFDYWGQGTLVTVSSASTKGPSVFPLAPSSKSTSGGTAALGCLVKDY
FPEPVTVSWNSGALTSGVHTFPAVLQSSGLYSLSSVVTVPSSSLGTQTYICNVNHKPSNTKVDKKVEPKSCDKT
HTCPPCPAPELLGGPSVFLFPPKPKDTLMISRTPEVTCVVVDVSHEDPEVKFNWYVDGVEVHNAKTKPREEQYN
STYRVVSVLTVLHQDWLNGKEYKCKVSNKALPAPIEKTISKAKGQPREPQVYTLPPSRDELTKNQVSLTCLVKG
FYPSDIAVEWESNGQPENNYKTTPPVLDSDGSFFLYSKLTVDKSRWQQGNVFSCSVMHEALHNHYTQKSLSLSP
GK SEQ ID NO. 29
DIQMTQSPSSLSASVGDRVTITCKSSQSLLNGSNQKNYLAWYQQKPGKAPKLLVYFASTRDSGVPSRFSGSGSG
TDFTLTISSLQPEDFATYYCLQHFGTPPTFGQGTKLEIKRTVAAPSVFIFPPSDEQLKSGTASVVCLLNNFYPR
EAKVQWKVDNALQSGNSQESVTEQDSKDSTYSLSSTLTLSKADYEKHKVYACEVTHQGLSSPVTKSENRGEC
SEQ ID NO. 30
QVQLQESGPGLVKPSETLSLTCTVSGFSLTAYGVNWIRQPPGKGLEWIGMIWDDGSTDYNSALKSRVTISVDTS
KNQFSLKLSSVTAADTAVYYCAREGDVAFDYWGQGTLVTVSSASTKGPSVFPLAPSSKSTSGGTAALGCLVKDY
FPEPVTVSWNSGALTSGVHTFPAVLQSSGLYSLSSVVTVPSSSLGTQTYICNVNHKPSNTKVDKKVEPKSCDKT
HTCPPCPAPELLGGPSVFLFPPKPKDTLMISRTPEVTCVVVDVSHEDPEVKFNWYVDGVEVHNAKTKPREEQYN
STYRVVSVLTVLHQDWLNGKEYKCKVSNKALPAPIEKTISKAKGQPREPQVYTLPPSRDELTKNQVSLTCLVKG
FYPSDIAVEWESNGQPENNYKTTPPVLDSDGSFFLYSKLTVDKSRWQQGNVFSCSVMHEALHNHYTQKSLSLSP
GK SEQ ID NO. 31
DIQMTQSPSSLSASVGDRVTITCKSSQSLLNGSNQKNYLAWYQQKPGKAPKLLVYFASTRDSGVPSRFSGSGSG
TDFTLTISSLQPEDFATYYCLQHFGTPPTFGQGTKLEIKRTVAAPSVFIFPPSDEQLKSGTASVVCLLNNFYPR
EAKVQWKVDNALQSGNSQESVTEQDSKDSTYSLSSTLTLSKADYEKHKVYACEVTHQGLSSPVTKSENRGEC
SEQ ID NO. 32
QVQLQESGPGLVKPSETLSLTCTVSGFSLTAYGVNWIRQPPGKGLEWIGMIWDDGSTDYDSALKSRVTISVDTS
KNQFSLKLSSVTAADTAVYYCAREGDVAFDYWGQGTLVTVSSASTKGPSVFPLAPSSKSTSGGTAALGCLVKDY
FPEPVTVSWNSGALTSGVHTFPAVLQSSGLYSLSSVVTVPSSSLGTQTYICNVNHKPSNTKVDKKVEPKSCDKT
HTCPPCPAPELLGGPSVFLFPPKPKDTLMISRTPEVTCVVVDVSHEDPEVKFNWYVDGVEVHNAKTKPREEQYN
STYRVVSVLTVLHQDWLNGKEYKCKVSNKALPAPIEKTISKAKGQPREPQVYTLPPSRDELTKNQVSLTCLVKG
FYPSDIAVEWESNGQPENNYKTTPPVLDSDGSFFLYSKLTVDKSRWQQGNVFSCSVMHEALHNHYTQKSLSLSP
GK SEQ ID NO. 33
DIQMTQSPSSLSASVGDRVTITCKSSQSLLNGSNQKNYLAWYQQKPGKAPKLLVYFASTRDSGVPSRFSGSGSG
TDFTLTISSLQPEDFATYYCLQHFGTPPTFGQGTKLEIKRTVAAPSVFIFPPSDEQLKSGTASVVCLLNNFYPR
EAKVQWKVDNALQSGNSQESVTEQDSKDSTYSLSSTLTLSKADYEKHKVYACEVTHQGLSSPVTKSFNRGEC
SEQ ID NO. 34
QVQLVQSGAEVKKPGSSVKVSCKASGFSLTAYGVNWVRQAPGQGLEWMGMIWDDGSTDYNSALKSRVTITADKS
TSTAYMELSSLRSEDTAVYYCAREGDVAFDYWGQGTLVTVSSASTKGPSVFPLAPSSKSTSGGTAALGCLVKDY
FPEPVTVSWNSGALTSGVHTFPAVLQSSGLYSLSSVVTVPSSSLGTQTYICNVNHKPSNTKVDKKVEPKSCDKT
HTCPPCPAPELLGGPSVFLFPPKPKDTLMISRTPEVTCVVVDVSHEDPEVKFNWYVDGVEVHNAKTKPREEQYN
STYRVVSVLTVLHQDWLNGKEYKCKVSNKALPAPIEKTISKAKGQPREPQVYTLPPSRDELTKNQVSLTCLVKG
FYPSDIAVEWESNGQPENNYKTTPPVLDSDGSFFLYSKLTVDKSRWQQGNVFSCSVMHEALHNHYTQKSLSLSP
GK SEQ ID NO. 35
DIQMTQSPSSLSASVGDRVTITCKSSQSLLNGSNQKNYLAWYQQKPGKAPKLLVYFASTRDSGVPSRFSGSGSG
TDFTLTISSLQPEDFATYYCLQHFGTPPTFGQGTKLEIKRTVAAPSVFIFPPSDEQLKSGTASVVCLLNNFYPR
EAKVQWKVDNALQSGNSQESVTEQDSKDSTYSLSSTLTLSKADYEKHKVYACEVTHQGLSSPVTKSFNRGEC
SEQ ID NO. 36
QVQLVQSGAEVKKPGSSVKVSCKASGFSLTAYGVNWVRQAPGQGLEWMGMIWDDGSTDYDSALKSRVTITADKS
TSTAYMELSSLRSEDTAVYYCAREGDVAFDYWGQGTLVTVSSASTKGPSVFPLAPSSKSTSGGTAALGCLVKDY
FPEPVTVSWNSGALTSGVHTFPAVLQSSGLYSLSSVVTVPSSSLGTQTYICNVNHKPSNTKVDKKVEPKSCDKT
HTCPPCPAPELLGGPSVFLFPPKPKDTLMISRTPEVTCVVVDVSHEDPEVKFNWYVDGVEVHNAKTKPREEQYN
STYRVVSVLTVLHQDWLNGKEYKCKVSNKALPAPIEKTISKAKGQPREPQVYTLPPSRDELTKNQVSLTCLVKG
FYPSDIAVEWESNGQPENNYKTTPPVLDSDGSFFLYSKLTVDKSRWQQGNVFSCSVMHEALHNHYTQKSLSLSP
GK SEQ ID NO. 37
DIQMTQSPSSLSASVGDRVTITCKSSQSLLNGSNQKNYLAWYQQKPGKAPKLLVYFASTRDSGVPSRFSGSGSG
TDFTLTISSLQPEDFATYYCLQHFGTPPTFGQGTKLEIKRTVAAPSVFIFPPSDEQLKSGTASVVCLLNNFYPR
EAKVQWKVDNALQSGNSQESVTEQDSKDSTYSLSSTLTLSKADYEKHKVYACEVTHQGLSSPVTKSFNRGEC
SEQ ID NO. 38
QVQLVQSGAEVKKPGSSVKVSCKASGGTFSAYGVNWVRQAPGQGLEWMGMIWDDGSTDYDSALKSRVTITADKS
TSTAYMELSSLRSEDTAVYYCAREGDVAFDYWGQGTLVTVSSASTKGPSVFPLAPSSKSTSGGTAALGCLVKDY
FPEPVTVSWNSGALTSGVHTFPAVLQSSGLYSLSSVVTVPSSSLGTQTYICNVNHKPSNTKVDKKVEPKSCDKT
HTCPPCPAPELLGGPSVFLFPPKPKDTLMISRTPEVTCVVVDVSHEDPEVKFNWYVDGVEVHNAKTKPREEQYN
STYRVVSVLTVLHQDWLNGKEYKCKVSNKALPAPIEKTISKAKGQPREPQVYTLPPSRDELTKNQVSLTCLVKG
FYPSDIAVEWESNGQPENNYKTTPPVLDSDGSFFLYSKLTVDKSRWQQGNVFSCSVMHEALHNHYTQKSLSLSP
GK SEQ ID NO. 39
DIQMTQSPSSLSASVGDRVTITCKSSQSLLNGSNQKNYLAWYQQKPGKAPKLLVYFASTRDSGVPSRFSGSGSG
TDFTLTISSLQPEDFATYYCLQHFGTPPTFGQGTKLEIKRTVAAPSVFIFPPSDEQLKSGTASVVCLLNNFYPR
EAKVQWKVDNALQSGNSQESVTEQDSKDSTYSLSSTLTLSKADYEKHKVYACEVTHQGLSSPVTKSFNRGEC
SEQ ID NO. 40
QVQLQESGPGLVKPSETLSLTCTVSGGSISAYGVNWIRQPPGKGLEWIGMIWDDGSTDYDSALKSRVTISVDTS
KNQFSLKLSSVTAADTAVYYCAREGDVAFDYWGQGTLVTVSSASTKGPSVFPLAPSSKSTSGGTAALGCLVKDY
FPEPVTVSWNSGALTSGVHTFPAVLQSSGLYSLSSVVTVPSSSLGTQTYICNVNHKPSNTKVDKKVEPKSCDKT
HTCPPCPAPELLGGPSVFLFPPKPKDTLMISRTPEVTCVVVDVSHEDPEVKFNWYVDGVEVHNAKTKPREEQYN
STYRVVSVLTVLHQDWLNGKEYKCKVSNKALPAPIEKTISKAKGQPREPQVYTLPPSRDELTKNQVSLTCLVKG
FYPSDIAVEWESNGQPENNYKTTPPVLDSDGSFFLYSKLTVDKSRWQQGNVFSCSVMHEALHNHYTQKSLSLSP
GK SEQ ID NO. 41
DIQMTQSPSSLSASVGDRVTITCKSSQSLLNGSNQKNYLAWYQQKPGKAPKLLVYFASTRDSGVPSRFSGSGSG
TDFTLTISSLQPEDFATYYCLQHFGTPPTFGQGTKLEIKRTVAAPSVFIFPPSDEQLKSGTASVVCLLNNFYPR
EAKVQWKVDNALQSGNSQESVTEQDSKDSTYSLSSTLTLSKADYEKHKVYACEVTHQGLSSPVTKSFNRGEC
SEQ ID NO. 42
QVQLVQSGAEVKKPGSSVKVSCKASGGTFSAYGVNWVRQAPGQGLEWMGMIWDDGSTDYNSALKSRVTITADKS
TSTAYMELSSLRSEDTAVYYCAREGDVAFDYWGQGTLVTVSSASTKGPSVFPLAPSSKSTSGGTAALGCLVKDY
FPEPVTVSWNSGALTSGVHTFPAVLQSSGLYSLSSVVTVPSSSLGTQTYICNVNHKPSNTKVDKKVEPKSCDKT
HTCPPCPAPELLGGPSVFLFPPKPKDTLMISRTPEVTCVVVDVSHEDPEVKFNWYVDGVEVHNAKTKPREEQYN
STYRVVSVLTVLHQDWLNGKEYKCKVSNKALPAPIEKTISKAKGQPREPQVYTLPPSRDELTKNQVSLTCLVKG
FYPSDIAVEWESNGQPENNYKTTPPVLDSDGSFFLYSKLTVDKSRWQQGNVFSCSVMHEALHNHYTQKSLSLSP
GK SEQ ID NO. 43
DIQMTQSPSSLSASVGDRVTITCKSSQSLLNGSNQKNYLAWYQQKPGKAPKLLVYFASTRDSGVPSRFSGSGSG
TDFTLTISSLQPEDFATYYCLQHFGTPPTFGQGTKLEIKRTVAAPSVFIFPPSDEQLKSGTASVVCLLNNFYPR
EAKVQWKVDNALQSGNSQESVTEQDSKDSTYSLSSTLTLSKADYEKHKVYACEVTHQGLSSPVTKSENRGEC
SEQ ID NO. 44
QVQLQESGPGLVKPSETLSLTCTVSGGSISAYGVNWIRQPPGKGLEWIGMIWDDGSTDYNSALKSRVTISVDTS
KNQFSLKLSSVTAADTAVYYCAREGDVAFDYWGQGTLVTVSSASTKGPSVFPLAPSSKSTSGGTAALGCLVKDY
FPEPVTVSWNSGALTSGVHTFPAVLQSSGLYSLSSVVTVPSSSLGTQTYICNVNHKPSNTKVDKKVEPKSCDKT
HTCPPCPAPELLGGPSVFLFPPKPKDTLMISRTPEVTCVVVDVSHEDPEVKFNWYVDGVEVHNAKTKPREEQYN
STYRVVSVLTVLHQDWLNGKEYKCKVSNKALPAPIEKTISKAKGQPREPQVYTLPPSRDELTKNQVSLTCLVKG
FYPSDIAVEWESNGQPENNYKTTPPVLDSDGSFFLYSKLTVDKSRWQQGNVFSCSVMHEALHNHYTQKSLSLSP
GK SEQ ID NO. 45
TVAAPSVFIFPPSDEQLKSGTASVVCLLNNFYPREAKVQWKVDNALQSGNSQESVTEQDSKDSTYSLSSTLTLS
KADYEKHKVYACEVTHQGLSSPVTKSFNRGEC SEQ ID NO. 46
ASTKGPSVFPLAPSSKSTSGGTAALGCLVKDYFPEPVTVSWNSGALTSGVHTFPAVLQSSGLYSLSSVVTVPSS
SLGTQTYICNVNHKPSNTKVDKKVEPKSCDKTHTCPPCPAPELLGGPSVFLEPPKPKDTLMISRTPEVTCVVVD
VSHEDPEVKFNWYVDGVEVHNAKTKPREEQYNSTYRVVSVLTVLHQDWLNGKEYKCKVSNKALPAPIEKTISKA
KGQPREPQVYTLPPSRDELTKNQVSLTCLVKGFYPSDIAVEWESNGQPENNYKTTPPVLDSDGSFFLYSKLTVD
KSRWQQGNVFSCSVMHEALHNHYTQKSLSLSPGK SEQ ID NO. 47
QVQLKESGPGLVAPSQSLSITCTVSGFSLTAYGVNWVRQPPGKGLEWLGMIWDDGSTDYNSALKSRLSISKDNS
KSQVFLKMNSLQTDDTARYYCAREGDVAFDYWGQGTTLTVSS SEQ ID NO. 48
DIVMTQSPSSLAVSVGQKVTMSCKSSQSLLNGSNQKNYLAWYQQKPGQSPKLLVYFASTRDSGVPDRFIGSGSG
TDFTLTISSVQAEDLADYFCLQHFGTPPTFGGGTKLEIKR (Note different leader
sequence used for chimeric antibodies) SEQ ID NO. 49
QVQLKESGPGLVAPSQSLSITCTVSGFSLTAYGVNWVRQPPGKGLEWLGMIWDDGSTDYNSALKSRLSISKDNS
KSQVFLKMNSLQTDDTARYYCAREGDVAFDYWGQGTTLTVSSASTKGPSVFPLAPSSKSTSGGTAALGCLVKDY
FPEPVTVSWNSGALTSGVHTFPAVLQSSGLYSLSSVVTVPSSSLGTQTYICNVNHKPSNTKVDKKVEPKSCDKT
HTCPPCPAPELLGGPSVFLFPPKPKDTLMISRTPEVTCVVVDVSHEDPEVKFNWYVDGVEVHNAKTKPREEQYN
STYRVVSVLTVLHQDWLNGKEYKCKVSNKALPAPIEKTISKAKGQPREPQVYTLPPSRDELTKNQVSLTCLVKG
FYPSDIAVEWESNGQPENNYKTTPPVLDSDGSFFLYSKLTVDKSRWQQGNVFSCSVMHEALHNHYTQKSLSLSP
GK SEQ ID NO. 50
DIVMTQSPSSLAVSVGQKVTMSCKSSQSLLNGSNQKNYLAWYQQKPGQSPKLLVYFASTRDSGVPDRFIGSGSG
TDFTLTISSVQAEDLADYFCLQHFGTPPTFGGGTKLEIKRTVAAPSVFIFPPSDEQLKSGTASVVCLLNNFYPR
EAKVQWKVDNALQSGNSQESVTEQDSKDSTYSLSSTLTLSKADYEKHKVYACEVTHQGLSSPVTKSENRGEC
SEQ ID NO. 51
LQPGAEVPVVWAQEGAPAQLPCSPTIPLQDLSLLRRAGVTWQHQPDSGPPAAAPGHPLAPGPHPAAPSSWGPRP
RRYTVLSVGPGGLRSGRLPLQPRVQLDERGRQRGDFSLWLRPARRADAGEYRAAVHLRDRALSCRLRLRLGQAS
MTASPPGSLRASDWVILNCSFSRPDRPASVHWERNRGQGRVPVRESPHHHLAESELFLPQVSPMDSGPWGCILT
YRDGFNVSIMYNLTVLGLEPPTPLTVYAGAGSRVGLPCRLPAGVGTRSFLTAKWTPPGGGPDLLVTGDNGDFTL
RLEDVSQAQAGTYTCHIHLQEQQLNATVTLAIITVTPKSFGSPGSLGKLLCEVTPVSGQERFVWSSLDTPSQRS
FSGPWLEAQEAQLLSQPWQCQLYQGERLLGAAVYFTELSSPHHHHHH SEQ ID NO. 52
PQPGAEISVVWAQEGAPAQLPCSPTIPLQDLSLLRRAGVTWQHQPDSGPPAPAPGHPPAPGHRPAAPYSWGPRP
RRYTVLSVGPGGLRSGRLPLQPRVQLDERGRQRGDFSLWLRPARRADAGEYRATVHLRDRALSCRLRLRVGQAS
MTASPPGSLRTSDWVILNCSFSRPDRPASVHWERSRGQGRVPVQGSPHHHLAESFLFLPHVGPMDSGLWGCILT
YRDGENVSIMYNLTVLGLEPATPLTVYAGAGSRVELPCRLPPAVGTQSFLTAKWAPPGGGPDLLVAGDNGDFTL
RLEDVSQAQAGTYICHIRLQGQQLNATVTLAIITVTPKSFGSPGSLGKLLCEVTPASGQEHFVWSPLNTPSQRS
FSGPWLEAQEAQLLSQPWQCQLHQGERLLGAAVYFTELSSPHHHHHH SEQ ID NO. 53
PQPGAEISVVWAQEGAPAQLPCSPTIPLQDLSLLRRAGVTWQHQPDSGPPAPAPGHPPAPGHRPAAPYSWGPRP
RRYTVLSVGPGGLRSGRLPLQPRVQLDERGRQRGDFSLWLRPARRADAGEYRATVHLRDRALSCRLRLRVGQAS
MTASPPGSLRTSDWVILNCSFSRPDRPASVHWERSRGQGQVPVQESPHHHLAESFLFLPHVGPMDSGLWGCILT
YRDGENVSIMYNLTVLGLEPTTPLTVYAGAGSRVELPCRLPPAVGTQSFLTAKWAPPGGGPDLLVVGDNGNFTL
RLEDVSQAQAGTYICHIRLQGQQLNATVTLAIITVTPKSFGSPGSLGKLLCEVTPASGQERFVWSPLNTPSQRS
FSGPWLEAQEAQLLSQPWQCQLHQGERLLGAAVYFTELSSPHHHHHH SEQ ID NO. 54
MGWSCIILFLVATATGVHS SEQ ID NO. 55 MESQTQVLMFLLLWVSGACA SEQ ID NO.
56 MPLLLLLPLL WAGALA SEQ ID NO. 57
AAGAGCAGCCAGAGCCTGCTGAACCCCAGCAACCAGAAGAACTACCTGGCC SEQ ID NO. 58
TTCGCCTCTACCAGGGATTCC SEQ ID NO. 59 CTGCAGCACTTCGGCACCCCTCCCACT SEQ
ID NO. 60
GACATCCAGATGACCCAGAGCCCCTCTAGCCTCAGCGCCAGCGTGGGCGACAGGGTGACCATCACCTGCAAGAG
CAGCCAGAGCCTGCTGAACCCCAGCAACCAGAAGAACTACCTGGCCTGGTACCAGCAGAAACCCGGCAAGGCCC
CCAAGCTGCTGGTCTACTTCGCCTCTACCAGGGATTCCGGCGTCCCCAGCAGGTTCAGCGGCAGCGGCAGCGGC
ACCGACTTCACACTGACCATCAGCAGCCTGCAGCCCGAGGACTTCGCCACCTACTACTGCCTGCAGCACTTCGG
CACCCCTCCCACTTTTGGCCAGGGCACCAAGCTGGAGATTAAGCGT SEQ ID NO. 61
GACATCCAGATGACCCAGAGCCCCTCTAGCCTCAGCGCCAGCGTGGGCGACAGGGTGACCATCACCTGCAAGAG
CAGCCAGAGCCTGCTGAACCCCAGCAACCAGAAGAACTACCTGGCCTGGTACCAGCAGAAACCCGGCAAGGCCC
CCAAGCTGCTGGTCTACTTCGCCTCTACCAGGGATTCCGGCGTCCCCAGCAGGTTCAGCGGCAGCGGCAGCGGC
ACCGACTTCACACTGACCATCAGCAGCCTGCAGCCCGAGGACTTCGCCACCTACTACTGCCTGCAGCACTTCGG
CACCCCTCCCACTTTTGGCCAGGGCACCAAGCTGGAGATTAAGCGTACGGTGGCCGCCCCCAGCGTGTTCATCT
TCCCCCCCAGCGATGAGCAGCTGAAGAGCGGCACCGCCAGCGTGGTGTGTCTGCTGAACAACTTCTACCCCCGG
GAGGCCAAGGTGCAGTGGAAGGTGGACAATGCCCTGCAGAGCGGCAACAGCCAGGAGAGCGTGACCGAGCAGGA
CAGCAAGGACTCCACCTACAGCCTGAGCAGCACCCTGACCCTGAGCAAGGCCGACTACGAGAAGCACAAGGTGT
ACGCCTGTGAGGTGACCCACCAGGGCCTGTCCAGCCCCGTGACCAAGAGCTTCAACCGGGGCGAGTGC
SEQ ID NO. 62 GCCTACGGCGTCAAC SEQ ID NO. 63
ATGATCTGGGACGACGGCAGCACCGACTACGACAGCGCCCTGAAGAGC SEQ ID NO. 64
GAGGGCGACGTGGCCTTCGATTAC SEQ ID NO. 65
CAGGTGCAGCTCCAGGAGAGCGGCCCCGGCCTGGTGAAGCCTAGCGAGACCCTGAGCCTGACCTGCACCGTGAG
CGGCTTCTCCCTGACCGCCTACGGCGTCAACTGGATCAGGCAGCCCCCCGGCAAAGGCCTGGAGTGGATTGGGA
TGATCTGGGACGACGGCAGCACCGACTACGACAGCGCCCTGAAGAGCAGGGTGACCATCAGCGTGGACACCAGC
AAGAACCAGTTCAGCCTGAAGCTGAGCAGCGTGACTGCCGCCGACACCGCCGTCTATTACTGCGCCAGGGAGGG
CGACGTGGCCTTCGATTACTGGGGCCAGGGCACACTAGTGACCGTGTCCAGC SEQ ID NO. 66
CAGGTGCAGCTCCAGGAGAGCGGCCCCGGCCTGGTGAAGCCTAGCGAGACCCTGAGCCTGACCTGCACCGTGAG
CGGCTTCTCCCTGACCGCCTACGGCGTCAACTGGATCAGGCAGCCCCCCGGCAAAGGCCTGGAGTGGATTGGGA
TGATCTGGGACGACGGCAGCACCGACTACGACAGCGCCCTGAAGAGCAGGGTGACCATCAGCGTGGACACCAGC
AAGAACCAGTTCAGCCTGAAGCTGAGCAGCGTGACTGCCGCCGACACCGCCGTCTATTACTGCGCCAGGGAGGG
CGACGTGGCCTTCGATTACTGGGGCCAGGGCACACTAGTGACCGTGTCCAGCGCCAGCACCAAGGGCCCCAGCG
TGTTCCCCCTGGCCCCCAGCAGCAAGAGCACCAGCGGCGGCACAGCCGCCCTGGGCTGCCTGGTGAAGGACTAC
TTCCCCGAACCGGTGACCGTGTCCTGGAACAGCGGAGCCCTGACCAGCGGCGTGCACACCTTCCCCGCCGTGCT
GCAGAGCAGCGGCCTGTACAGCCTGAGCAGCGTGGTGACCGTGCCCAGCAGCAGCCTGGGCACCCAGACCTACA
TCTGTAACGTGAACCACAAGCCCAGCAACACCAAGGTGGACAAGAAGGTGGAGCCCAAGAGCTGTGACAAGACC
CACACCTGCCCCCCCTGCCCTGCCCCCGAGCTGCTGGGAGGCCCCAGCGTGTTCCTGTTCCCCCCCAAGCCTAA
GGACACCCTGATGATCAGCAGAACCCCCGAGGTGACCTGTGTGGTGGTGGATGTGAGCCACGAGGACCCTGAGG
TGAAGTTCAACTGGTACGTGGACGGCGTGGAGGTGCACAATGCCAAGACCAAGCCCAGGGAGGAGCAGTACAAC
AGCACCTACCGGGTGGTGTCCGTGCTGACCGTGCTGCACCAGGATTGGCTGAACGGCAAGGAGTACAAGTGTAA
GGTGTCCAACAAGGCCCTGCCTGCCCCTATCGAGAAAACCATCAGCAAGGCCAAGGGCCAGCCCAGAGAGCCCC
AGGTGTACACCCTGCCCCCTAGCAGAGATGAGCTGACCAAGAACCAGGTGTCCCTGACCTGCCTGGTGAAGGGC
TTCTACCCCAGCGACATCGCCGTGGAGTGGGAGAGCAACGGCCAGCCCGAGAACAACTACAAGACCACCCCCCC
TGTGCTGGACAGCGATGGCAGCTTCTTCCTGTACAGCAAGCTGACCGTGGACAAGAGCAGATGGCAGCAGGGCA
ACGTGTTCAGCTGCTCCGTGATGCACGAGGCCCTGCACAATCACTACACCCAGAAGAGCCTGAGCCTGTCCCCT
GGCAAG SEQ ID NO. 67
GACATCCAGATGACCCAGAGCCCCTCTAGCCTCAGCGCCAGCGTGGGCGACAGGGTGACCATCACCTGCAAGAG
CAGCCAGAGCCTGCTGAACCCCAGCAACCAGAAGAACTACCTGGCCTGGTACCAGCAGAAACCCGGCAAGGCCC
CCAAGCTGCTGGTCTACTTCGCCTCTACCAGGGATTCCGGCGTCCCCAGCAGGTTCAGCGGCAGCGGCAGCGGC
ACCGACTTCACACTGACCATCAGCAGCCTGCAGCCCGAGGACTTCGCCACCTACTACTGCCTGCAGCACTTCGG
CACCCCTCCCACTTTTGGCCAGGGCACCAAGCTGGAGATTAAGCGTACGGTGGCCGCCCCCAGCGTGTTCATCT
TCCCCCCCAGCGATGAGCAGCTGAAGAGCGGCACCGCCAGCGTGGTGTGTCTGCTGAACAACTTCTACCCCCGG
GAGGCCAAGGTGCAGTGGAAGGTGGACAATGCCCTGCAGAGCGGCAACAGCCAGGAGAGCGTGACCGAGCAGGA
CAGCAAGGACTCCACCTACAGCCTGAGCAGCACCCTGACCCTGAGCAAGGCCGACTACGAGAAGCACAAGGTGT
ACGCCTGTGAGGTGACCCACCAGGGCCTGTCCAGCCCCGTGACCAAGAGCTTCAACCGGGGCGAGTGC
SEQ ID NO. 68
CAGGTGCAGCTCCAGGAGAGCGGCCCCGGCCTGGTGAAGCCTAGCGAGACCCTGAGCCTGACCTGCACCGTGAG
CGGCTTCTCCCTGACCGCCTACGGCGTCAACTGGATCAGGCAGCCCCCCGGCAAAGGCCTGGAGTGGATTGGGA
TGATCTGGGACGACGGCAGCACCGACTACAACAGCGCCCTGAAGAGCAGGGTGACCATCAGCGTGGACACCAGC
AAGAACCAGTTCAGCCTGAAGCTGAGCAGCGTGACTGCCGCCGACACCGCCGTCTATTACTGCGCCAGGGAGGG
CGACGTGGCCTTCGATTACTGGGGCCAGGGCACACTAGTGACCGTGTCCAGCGCCAGCACCAAGGGCCCCAGCG
TGTTCCCCCTGGCCCCCAGCAGCAAGAGCACCAGCGGCGGCACAGCCGCCCTGGGCTGCCTGGTGAAGGACTAC
TTCCCCGAACCGGTGACCGTGTCCTGGAACAGCGGAGCCCTGACCAGCGGCGTGCACACCTTCCCCGCCGTGCT
GCAGAGCAGCGGCCTGTACAGCCTGAGCAGCGTGGTGACCGTGCCCAGCAGCAGCCTGGGCACCCAGACCTACA
TCTGTAACGTGAACCACAAGCCCAGCAACACCAAGGTGGACAAGAAGGTGGAGCCCAAGAGCTGTGACAAGACC
CACACCTGCCCCCCCTGCCCTGCCCCCGAGCTGCTGGGAGGCCCCAGCGTGTTCCTGTTCCCCCCCAAGCCTAA
GGACACCCTGATGATCAGCAGAACCCCCGAGGTGACCTGTGTGGTGGTGGATGTGAGCCACGAGGACCCTGAGG
TGAAGTTCAACTGGTACGTGGACGGCGTGGAGGTGCACAATGCCAAGACCAAGCCCAGGGAGGAGCAGTACAAC
AGCACCTACCGGGTGGTGTCCGTGCTGACCGTGCTGCACCAGGATTGGCTGAACGGCAAGGAGTACAAGTGTAA
GGTGTCCAACAAGGCCCTGCCTGCCCCTATCGAGAAAACCATCAGCAAGGCCAAGGGCCAGCCCAGAGAGCCCC
AGGTGTACACCCTGCCCCCTAGCAGAGATGAGCTGACCAAGAACCAGGTGTCCCTGACCTGCCTGGTGAAGGGC
TTCTACCCCAGCGACATCGCCGTGGAGTGGGAGAGCAACGGCCAGCCCGAGAACAACTACAAGACCACCCCCCC
TGTGCTGGACAGCGATGGCAGCTTCTTCCTGTACAGCAAGCTGACCGTGGACAAGAGCAGATGGCAGCAGGGCA
ACGTGTTCAGCTGCTCCGTGATGCACGAGGCCCTGCACAATCACTACACCCAGAAGAGCCTGAGCCTGTCCCCT
GGCAAG SEQ ID NO. 69
GACATCCAGATGACCCAGAGCCCCTCTAGCCTCAGCGCCAGCGTGGGCGACAGGGTGACCATCACCTGCAAGAG
CAGCCAGAGCCTGCTGAACCCCAGCAACCAGAAGAACTACCTGGCCTGGTACCAGCAGAAACCCGGCAAGGCCC
CCAAGCTGCTGGTCTACTTCGCCTCTACCAGGGATTCCGGCGTCCCCAGCAGGTTCAGCGGCAGCGGCAGCGGC
ACCGACTTCACACTGACCATCAGCAGCCTGCAGCCCGAGGACTTCGCCACCTACTACTGCCTGCAGCACTTCGG
CACCCCTCCCACTTTTGGCCAGGGCACCAAGCTGGAGATTAAGCGTACGGTGGCCGCCCCCAGCGTGTTCATCT
TCCCCCCCAGCGATGAGCAGCTGAAGAGCGGCACCGCCAGCGTGGTGTGTCTGCTGAACAACTTCTACCCCCGG
GAGGCCAAGGTGCAGTGGAAGGTGGACAATGCCCTGCAGAGCGGCAACAGCCAGGAGAGCGTGACCGAGCAGGA
CAGCAAGGACTCCACCTACAGCCTGAGCAGCACCCTGACCCTGAGCAAGGCCGACTACGAGAAGCACAAGGTGT
ACGCCTGTGAGGTGACCCACCAGGGCCTGTCCAGCCCCGTGACCAAGAGCTTCAACCGGGGCGAGTGC
SEQ ID NO. 70
CAGGTGCAGCTCGTGCAGAGCGGGGCCGAAGTCAAGAAACCCGGCAGCTCCGTGAAGGTGAGCTGCAAGGCCAG
CGGCTTCTCTCTCACTGCCTACGGCGTGAACTGGGTGAGGCAGGCTCCCGGCCAGGGCCTGGAGTGGATGGGCA
TGATCTGGGACGACGGCAGCACCGACTACAACAGCGCCCTGAAGAGCAGGGTGACCATCACCGCCGACAAGAGC
ACCAGCACCGCCTACATGGAACTGAGCAGCCTGAGGAGCGAGGACACCGCCGTGTACTATTGCGCCAGGGAGGG
CGACGTGGCCTTCGATTACTGGGGCCAGGGCACACTAGTGACCGTGTCCAGCGCCAGCACCAAGGGCCCCAGCG
TGTTCCCCCTGGCCCCCAGCAGCAAGAGCACCAGCGGCGGCACAGCCGCCCTGGGCTGCCTGGTGAAGGACTAC
TTCCCCGAACCGGTGACCGTGTCCTGGAACAGCGGAGCCCTGACCAGCGGCGTGCACACCTTCCCCGCCGTGCT
GCAGAGCAGCGGCCTGTACAGCCTGAGCAGCGTGGTGACCGTGCCCAGCAGCAGCCTGGGCACCCAGACCTACA
TCTGTAACGTGAACCACAAGCCCAGCAACACCAAGGTGGACAAGAAGGTGGAGCCCAAGAGCTGTGACAAGACC
CACACCTGCCCCCCCTGCCCTGCCCCCGAGCTGCTGGGAGGCCCCAGCGTGTTCCTGTTCCCCCCCAAGCCTAA
GGACACCCTGATGATCAGCAGAACCCCCGAGGTGACCTGTGTGGTGGTGGATGTGAGCCACGAGGACCCTGAGG
TGAAGTTCAACTGGTACGTGGACGGCGTGGAGGTGCACAATGCCAAGACCAAGCCCAGGGAGGAGCAGTACAAC
AGCACCTACCGGGTGGTGTCCGTGCTGACCGTGCTGCACCAGGATTGGCTGAACGGCAAGGAGTACAAGTGTAA
GGTGTCCAACAAGGCCCTGCCTGCCCCTATCGAGAAAACCATCAGCAAGGCCAAGGGCCAGCCCAGAGAGCCCC
AGGTGTACACCCTGCCCCCTAGCAGAGATGAGCTGACCAAGAACCAGGTGTCCCTGACCTGCCTGGTGAAGGGC
TTCTACCCCAGCGACATCGCCGTGGAGTGGGAGAGCAACGGCCAGCCCGAGAACAACTACAAGACCACCCCCCC
TGTGCTGGACAGCGATGGCAGCTTCTTCCTGTACAGCAAGCTGACCGTGGACAAGAGCAGATGGCAGCAGGGCA
ACGTGTTCAGCTGCTCCGTGATGCACGAGGCCCTGCACAATCACTACACCCAGAAGAGCCTGAGCCTGTCCCCT
GGCAAG SEQ ID NO. 71
GACATCCAGATGACCCAGAGCCCCTCTAGCCTCAGCGCCAGCGTGGGCGACAGGGTGACCATCACCTGCAAGAG
CAGCCAGAGCCTGCTGAACCCCAGCAACCAGAAGAACTACCTGGCCTGGTACCAGCAGAAACCCGGCAAGGCCC
CCAAGCTGCTGGTCTACTTCGCCTCTACCAGGGATTCCGGCGTCCCCAGCAGGTTCAGCGGCAGCGGCAGCGGC
ACCGACTTCACACTGACCATCAGCAGCCTGCAGCCCGAGGACTTCGCCACCTACTACTGCCTGCAGCACTTCGG
CACCCCTCCCACTTTTGGCCAGGGCACCAAGCTGGAGATTAAGCGTACGGTGGCCGCCCCCAGCGTGTTCATCT
TCCCCCCCAGCGATGAGCAGCTGAAGAGCGGCACCGCCAGCGTGGTGTGTCTGCTGAACAACTTCTACCCCCGG
GAGGCCAAGGTGCAGTGGAAGGTGGACAATGCCCTGCAGAGCGGCAACAGCCAGGAGAGCGTGACCGAGCAGGA
CAGCAAGGACTCCACCTACAGCCTGAGCAGCACCCTGACCCTGAGCAAGGCCGACTACGAGAAGCACAAGGTGT
ACGCCTGTGAGGTGACCCACCAGGGCCTGTCCAGCCCCGTGACCAAGAGCTTCAACCGGGGCGAGTGC
SEQ ID NO. 72
CAGGTGCAGCTCCAGGAGAGCGGCCCCGGCCTGGTGAAGCCTAGCGAGACCCTGAGCCTGACCTGCACCGTGAG
CGGCTTCTCCCTGACCGCCTACGGCGTCAACTGGATCAGGCAGCCCCCCGGCAAAGGCCTGGAGTGGCTGGGGA
TGATCTGGGACGACGGCAGCACCGACTACAACAGCGCCCTGAAGAGCAGGCTGACCATCAGCAAGGACAACAGC
AAGAACCAGGTGAGCCTGAAGCTGAGCAGCGTGACTGCCGCCGACACCGCCGTCTATTACTGCGCCAGGGAGGG
CGACGTGGCCTTCGATTACTGGGGCCAGGGCACACTAGTGACCGTGTCCAGCGCCAGCACCAAGGGCCCCAGCG
TGTTCCCCCTGGCCCCCAGCAGCAAGAGCACCAGCGGCGGCACAGCCGCCCTGGGCTGCCTGGTGAAGGACTAC
TTCCCCGAACCGGTGACCGTGTCCTGGAACAGCGGAGCCCTGACCAGCGGCGTGCACACCTTCCCCGCCGTGCT
GCAGAGCAGCGGCCTGTACAGCCTGAGCAGCGTGGTGACCGTGCCCAGCAGCAGCCTGGGCACCCAGACCTACA
TCTGTAACGTGAACCACAAGCCCAGCAACACCAAGGTGGACAAGAAGGTGGAGCCCAAGAGCTGTGACAAGACC
CACACCTGCCCCCCCTGCCCTGCCCCCGAGCTGCTGGGAGGCCCCAGCGTGTTCCTGTTCCCCCCCAAGCCTAA
GGACACCCTGATGATCAGCAGAACCCCCGAGGTGACCTGTGTGGTGGTGGATGTGAGCCACGAGGACCCTGAGG
TGAAGTTCAACTGGTACGTGGACGGCGTGGAGGTGCACAATGCCAAGACCAAGCCCAGGGAGGAGCAGTACAAC
AGCACCTACCGGGTGGTGTCCGTGCTGACCGTGCTGCACCAGGATTGGCTGAACGGCAAGGAGTACAAGTGTAA
GGTGTCCAACAAGGCCCTGCCTGCCCCTATCGAGAAAACCATCAGCAAGGCCAAGGGCCAGCCCAGAGAGCCCC
AGGTGTACACCCTGCCCCCTAGCAGAGATGAGCTGACCAAGAACCAGGTGTCCCTGACCTGCCTGGTGAAGGGC
TTCTACCCCAGCGACATCGCCGTGGAGTGGGAGAGCAACGGCCAGCCCGAGAACAACTACAAGACCACCCCCCC
TGTGCTGGACAGCGATGGCAGCTTCTTCCTGTACAGCAAGCTGACCGTGGACAAGAGCAGATGGCAGCAGGGCA
ACGTGTTCAGCTGCTCCGTGATGCACGAGGCCCTGCACAATCACTACACCCAGAAGAGCCTGAGCCTGTCCCCT
GGCAAG SEQ ID NO. 73
GACATCCAGATGACCCAGAGCCCCTCTAGCCTCAGCGCCAGCGTGGGCGACAGGGTGACCATCACCTGCAAGAG
CAGCCAGAGCCTGCTGAACCCCAGCAACCAGAAGAACTACCTGGCCTGGTACCAGCAGAAACCCGGCAAGGCCC
CCAAGCTGCTGGTCTACTTCGCCTCTACCAGGGATTCCGGCGTCCCCAGCAGGTTCAGCGGCAGCGGCAGCGGC
ACCGACTTCACACTGACCATCAGCAGCCTGCAGCCCGAGGACTTCGCCACCTACTACTGCCTGCAGCACTTCGG
CACCCCTCCCACTTTTGGCCAGGGCACCAAGCTGGAGATTAAGCGTACGGTGGCCGCCCCCAGCGTGTTCATCT
TCCCCCCCAGCGATGAGCAGCTGAAGAGCGGCACCGCCAGCGTGGTGTGTCTGCTGAACAACTTCTACCCCCGG
GAGGCCAAGGTGCAGTGGAAGGTGGACAATGCCCTGCAGAGCGGCAACAGCCAGGAGAGCGTGACCGAGCAGGA
CAGCAAGGACTCCACCTACAGCCTGAGCAGCACCCTGACCCTGAGCAAGGCCGACTACGAGAAGCACAAGGTGT
ACGCCTGTGAGGTGACCCACCAGGGCCTGTCCAGCCCCGTGACCAAGAGCTTCAACCGGGGCGAGTGC
SEQ ID NO. 74
CAGGTGCAGCTCGTGCAGAGCGGGGCCGAAGTCAAGAAACCCGGCAGCTCCGTGAAGGTGAGCTGCAAGGCCAG
CGGCTTCTCTCTCACTGCCTACGGCGTGAACTGGGTGAGGCAGGCTCCCGGCCAGGGCCTGGAGTGGATGGGCA
TGATCTGGGACGACGGCAGCACCGACTACGACAGCGCCCTGAAGAGCAGGGTGACCATCACCGCCGACAAGAGC
ACCAGCACCGCCTACATGGAACTGAGCAGCCTGAGGAGCGAGGACACCGCCGTGTACTATTGCGCCAGGGAGGG
CGACGTGGCCTTCGATTACTGGGGCCAGGGCACACTAGTGACCGTGTCCAGCGCCAGCACCAAGGGCCCCAGCG
TGTTCCCCCTGGCCCCCAGCAGCAAGAGCACCAGCGGCGGCACAGCCGCCCTGGGCTGCCTGGTGAAGGACTAC
TTCCCCGAACCGGTGACCGTGTCCTGGAACAGCGGAGCCCTGACCAGCGGCGTGCACACCTTCCCCGCCGTGCT
GCAGAGCAGCGGCCTGTACAGCCTGAGCAGCGTGGTGACCGTGCCCAGCAGCAGCCTGGGCACCCAGACCTACA
TCTGTAACGTGAACCACAAGCCCAGCAACACCAAGGTGGACAAGAAGGTGGAGCCCAAGAGCTGTGACAAGACC
CACACCTGCCCCCCCTGCCCTGCCCCCGAGCTGCTGGGAGGCCCCAGCGTGTTCCTGTTCCCCCCCAAGCCTAA
GGACACCCTGATGATCAGCAGAACCCCCGAGGTGACCTGTGTGGTGGTGGATGTGAGCCACGAGGACCCTGAGG
TGAAGTTCAACTGGTACGTGGACGGCGTGGAGGTGCACAATGCCAAGACCAAGCCCAGGGAGGAGCAGTACAAC
AGCACCTACCGGGTGGTGTCCGTGCTGACCGTGCTGCACCAGGATTGGCTGAACGGCAAGGAGTACAAGTGTAA
GGTGTCCAACAAGGCCCTGCCTGCCCCTATCGAGAAAACCATCAGCAAGGCCAAGGGCCAGCCCAGAGAGCCCC
AGGTGTACACCCTGCCCCCTAGCAGAGATGAGCTGACCAAGAACCAGGTGTCCCTGACCTGCCTGGTGAAGGGC
TTCTACCCCAGCGACATCGCCGTGGAGTGGGAGAGCAACGGCCAGCCCGAGAACAACTACAAGACCACCCCCCC
TGTGCTGGACAGCGATGGCAGCTTCTTCCTGTACAGCAAGCTGACCGTGGACAAGAGCAGATGGCAGCAGGGCA
ACGTGTTCAGCTGCTCCGTGATGCACGAGGCCCTGCACAATCACTACACCCAGAAGAGCCTGAGCCTGTCCCCT
GGCAAG SEQ ID NO. 75
GACATCCAGATGACCCAGAGCCCCTCTAGCCTCAGCGCCAGCGTGGGCGACAGGGTGACCATCACCTGCAAGAG
CAGCCAGAGCCTGCTGAACCCCAGCAACCAGAAGAACTACCTGGCCTGGTACCAGCAGAAACCCGGCAAGGCCC
CCAAGCTGCTGGTCTACTTCGCCTCTACCAGGGATTCCGGCGTCCCCAGCAGGTTCAGCGGCAGCGGCAGCGGC
ACCGACTTCACACTGACCATCAGCAGCCTGCAGCCCGAGGACTTCGCCACCTACTACTGCCTGCAGCACTTCGG
CACCCCTCCCACTTTTGGCCAGGGCACCAAGCTGGAGATTAAGCGTACGGTGGCCGCCCCCAGCGTGTTCATCT
TCCCCCCCAGCGATGAGCAGCTGAAGAGCGGCACCGCCAGCGTGGTGTGTCTGCTGAACAACTTCTACCCCCGG
GAGGCCAAGGTGCAGTGGAAGGTGGACAATGCCCTGCAGAGCGGCAACAGCCAGGAGAGCGTGACCGAGCAGGA
CAGCAAGGACTCCACCTACAGCCTGAGCAGCACCCTGACCCTGAGCAAGGCCGACTACGAGAAGCACAAGGTGT
ACGCCTGTGAGGTGACCCACCAGGGCCTGTCCAGCCCCGTGACCAAGAGCTTCAACCGGGGCGAGTGC
SEQ ID NO. 76
CAGGTGCAGCTCCAGGAGAGCGGCCCCGGCCTGGTGAAGCCTAGCGAGACCCTGAGCCTGACCTGCACCGTGAG
CGGCTTCTCCCTGACCGCCTACGGCGTCAACTGGATCAGGCAGCCCCCCGGCAAAGGCCTGGAGTGGATTGGGA
TGATCTGGGACGACGGCAGCACCGACTACAACAGCGCCCTGAAGAGCAGGGTGACCATCAGCAAGGACAACAGC
AAGAACCAGGTGAGCCTGAAGCTGAGCAGCGTGACTGCCGCCGACACCGCCGTCTATTACTGCGCCAGGGAGGG
CGACGTGGCCTTCGATTACTGGGGCCAGGGCACACTAGTGACCGTGTCCAGCGCCAGCACCAAGGGCCCCAGCG
TGTTCCCCCTGGCCCCCAGCAGCAAGAGCACCAGCGGCGGCACAGCCGCCCTGGGCTGCCTGGTGAAGGACTAC
TTCCCCGAACCGGTGACCGTGTCCTGGAACAGCGGAGCCCTGACCAGCGGCGTGCACACCTTCCCCGCCGTGCT
GCAGAGCAGCGGCCTGTACAGCCTGAGCAGCGTGGTGACCGTGCCCAGCAGCAGCCTGGGCACCCAGACCTACA
TCTGTAACGTGAACCACAAGCCCAGCAACACCAAGGTGGACAAGAAGGTGGAGCCCAAGAGCTGTGACAAGACC
CACACCTGCCCCCCCTGCCCTGCCCCCGAGCTGCTGGGAGGCCCCAGCGTGTTCCTGTTCCCCCCCAAGCCTAA
GGACACCCTGATGATCAGCAGAACCCCCGAGGTGACCTGTGTGGTGGTGGATGTGAGCCACGAGGACCCTGAGG
TGAAGTTCAACTGGTACGTGGACGGCGTGGAGGTGCACAATGCCAAGACCAAGCCCAGGGAGGAGCAGTACAAC
AGCACCTACCGGGTGGTGTCCGTGCTGACCGTGCTGCACCAGGATTGGCTGAACGGCAAGGAGTACAAGTGTAA
GGTGTCCAACAAGGCCCTGCCTGCCCCTATCGAGAAAACCATCAGCAAGGCCAAGGGCCAGCCCAGAGAGCCCC
AGGTGTACACCCTGCCCCCTAGCAGAGATGAGCTGACCAAGAACCAGGTGTCCCTGACCTGCCTGGTGAAGGGC
TTCTACCCCAGCGACATCGCCGTGGAGTGGGAGAGCAACGGCCAGCCCGAGAACAACTACAAGACCACCCCCCC
TGTGCTGGACAGCGATGGCAGCTTCTTCCTGTACAGCAAGCTGACCGTGGACAAGAGCAGATGGCAGCAGGGCA
ACGTGTTCAGCTGCTCCGTGATGCACGAGGCCCTGCACAATCACTACACCCAGAAGAGCCTGAGCCTGTCCCCT
GGCAAG SEQ ID NO. 77
GACATCCAGATGACCCAGAGCCCCTCTAGCCTCAGCGCCAGCGTGGGCGACAGGGTGACCATCACCTGCAAGAG
CAGCCAGAGCCTGCTGAACCCCAGCAACCAGAAGAACTACCTGGCCTGGTACCAGCAGAAACCCGGCAAGGCCC
CCAAGCTGCTGGTCTACTTCGCCTCTACCAGGGATTCCGGCGTCCCCAGCAGGTTCAGCGGCAGCGGCAGCGGC
ACCGACTTCACACTGACCATCAGCAGCCTGCAGCCCGAGGACTTCGCCACCTACTACTGCCTGCAGCACTTCGG
CACCCCTCCCACTTTTGGCCAGGGCACCAAGCTGGAGATTAAGCGTACGGTGGCCGCCCCCAGCGTGTTCATCT
TCCCCCCCAGCGATGAGCAGCTGAAGAGCGGCACCGCCAGCGTGGTGTGTCTGCTGAACAACTTCTACCCCCGG
GAGGCCAAGGTGCAGTGGAAGGTGGACAATGCCCTGCAGAGCGGCAACAGCCAGGAGAGCGTGACCGAGCAGGA
CAGCAAGGACTCCACCTACAGCCTGAGCAGCACCCTGACCCTGAGCAAGGCCGACTACGAGAAGCACAAGGTGT
ACGCCTGTGAGGTGACCCACCAGGGCCTGTCCAGCCCCGTGACCAAGAGCTTCAACCGGGGCGAGTGC
SEQ ID NO. 78
CAGGTGCAGCTCGTGCAGAGCGGGGCCGAAGTCAAGAAACCCGGCAGCTCCGTGAAGGTGAGCTGCAAGGCCAG
CGGCGGCACCTTCAGCGCCTACGGCGTGAACTGGGTGAGGCAGGCTCCCGGCCAGGGCCTGGAGTGGATGGGCA
TGATCTGGGACGACGGCAGCACCGACTACGACAGCGCCCTGAAGAGCAGGGTGACCATCACCGCCGACAAGAGC
ACCAGCACCGCCTACATGGAACTGAGCAGCCTGAGGAGCGAGGACACCGCCGTGTACTATTGCGCCAGGGAGGG
CGACGTGGCCTTCGATTACTGGGGCCAGGGCACACTAGTGACCGTGTCCAGCGCCAGCACCAAGGGCCCCAGCG
TGTTCCCCCTGGCCCCCAGCAGCAAGAGCACCAGCGGCGGCACAGCCGCCCTGGGCTGCCTGGTGAAGGACTAC
TTCCCCGAACCGGTGACCGTGTCCTGGAACAGCGGAGCCCTGACCAGCGGCGTGCACACCTTCCCCGCCGTGCT
GCAGAGCAGCGGCCTGTACAGCCTGAGCAGCGTGGTGACCGTGCCCAGCAGCAGCCTGGGCACCCAGACCTACA
TCTGTAACGTGAACCACAAGCCCAGCAACACCAAGGTGGACAAGAAGGTGGAGCCCAAGAGCTGTGACAAGACC
CACACCTGCCCCCCCTGCCCTGCCCCCGAGCTGCTGGGAGGCCCCAGCGTGTTCCTGTTCCCCCCCAAGCCTAA
GGACACCCTGATGATCAGCAGAACCCCCGAGGTGACCTGTGTGGTGGTGGATGTGAGCCACGAGGACCCTGAGG
TGAAGTTCAACTGGTACGTGGACGGCGTGGAGGTGCACAATGCCAAGACCAAGCCCAGGGAGGAGCAGTACAAC
AGCACCTACCGGGTGGTGTCCGTGCTGACCGTGCTGCACCAGGATTGGCTGAACGGCAAGGAGTACAAGTGTAA
GGTGTCCAACAAGGCCCTGCCTGCCCCTATCGAGAAAACCATCAGCAAGGCCAAGGGCCAGCCCAGAGAGCCCC
AGGTGTACACCCTGCCCCCTAGCAGAGATGAGCTGACCAAGAACCAGGTGTCCCTGACCTGCCTGGTGAAGGGC
TTCTACCCCAGCGACATCGCCGTGGAGTGGGAGAGCAACGGCCAGCCCGAGAACAACTACAAGACCACCCCCCC
TGTGCTGGACAGCGATGGCAGCTTCTTCCTGTACAGCAAGCTGACCGTGGACAAGAGCAGATGGCAGCAGGGCA
ACGTGTTCAGCTGCTCCGTGATGCACGAGGCCCTGCACAATCACTACACCCAGAAGAGCCTGAGCCTGTCCCCT
GGCAAG SEQ ID NO. 79
GACATCCAGATGACCCAGAGCCCCTCTAGCCTCAGCGCCAGCGTGGGCGACAGGGTGACCATCACCTGCAAGAG
CAGCCAGAGCCTGCTGAACCCCAGCAACCAGAAGAACTACCTGGCCTGGTACCAGCAGAAACCCGGCAAGGCCC
CCAAGCTGCTGGTCTACTTCGCCTCTACCAGGGATTCCGGCGTCCCCAGCAGGTTCAGCGGCAGCGGCAGCGGC
ACCGACTTCACACTGACCATCAGCAGCCTGCAGCCCGAGGACTTCGCCACCTACTACTGCCTGCAGCACTTCGG
CACCCCTCCCACTTTTGGCCAGGGCACCAAGCTGGAGATTAAGCGTACGGTGGCCGCCCCCAGCGTGTTCATCT
TCCCCCCCAGCGATGAGCAGCTGAAGAGCGGCACCGCCAGCGTGGTGTGTCTGCTGAACAACTTCTACCCCCGG
GAGGCCAAGGTGCAGTGGAAGGTGGACAATGCCCTGCAGAGCGGCAACAGCCAGGAGAGCGTGACCGAGCAGGA
CAGCAAGGACTCCACCTACAGCCTGAGCAGCACCCTGACCCTGAGCAAGGCCGACTACGAGAAGCACAAGGTGT
ACGCCTGTGAGGTGACCCACCAGGGCCTGTCCAGCCCCGTGACCAAGAGCTTCAACCGGGGCGAGTGC
SEQ ID NO. 80
CAGGTGCAGCTCCAGGAGAGCGGCCCCGGCCTGGTGAAGCCTAGCGAGACCCTGAGCCTGACCTGCACCGTGAG
CGGCGGCTCCATCAGCGCCTACGGCGTCAACTGGATCAGGCAGCCCCCCGGCAAAGGCCTGGAGTGGATTGGGA
TGATCTGGGACGACGGCAGCACCGACTACGACAGCGCCCTGAAGAGCAGGGTGACCATCAGCGTGGACACCAGC
AAGAACCAGTTCAGCCTGAAGCTGAGCAGCGTGACTGCCGCCGACACCGCCGTCTATTACTGCGCCAGGGAGGG
CGACGTGGCCTTCGATTACTGGGGCCAGGGCACACTAGTGACCGTGTCCAGCGCCAGCACCAAGGGCCCCAGCG
TGTTCCCCCTGGCCCCCAGCAGCAAGAGCACCAGCGGCGGCACAGCCGCCCTGGGCTGCCTGGTGAAGGACTAC
TTCCCCGAACCGGTGACCGTGTCCTGGAACAGCGGAGCCCTGACCAGCGGCGTGCACACCTTCCCCGCCGTGCT
GCAGAGCAGCGGCCTGTACAGCCTGAGCAGCGTGGTGACCGTGCCCAGCAGCAGCCTGGGCACCCAGACCTACA
TCTGTAACGTGAACCACAAGCCCAGCAACACCAAGGTGGACAAGAAGGTGGAGCCCAAGAGCTGTGACAAGACC
CACACCTGCCCCCCCTGCCCTGCCCCCGAGCTGCTGGGAGGCCCCAGCGTGTTCCTGTTCCCCCCCAAGCCTAA
GGACACCCTGATGATCAGCAGAACCCCCGAGGTGACCTGTGTGGTGGTGGATGTGAGCCACGAGGACCCTGAGG
TGAAGTTCAACTGGTACGTGGACGGCGTGGAGGTGCACAATGCCAAGACCAAGCCCAGGGAGGAGCAGTACAAC
AGCACCTACCGGGTGGTGTCCGTGCTGACCGTGCTGCACCAGGATTGGCTGAACGGCAAGGAGTACAAGTGTAA
GGTGTCCAACAAGGCCCTGCCTGCCCCTATCGAGAAAACCATCAGCAAGGCCAAGGGCCAGCCCAGAGAGCCCC
AGGTGTACACCCTGCCCCCTAGCAGAGATGAGCTGACCAAGAACCAGGTGTCCCTGACCTGCCTGGTGAAGGGC
TTCTACCCCAGCGACATCGCCGTGGAGTGGGAGAGCAACGGCCAGCCCGAGAACAACTACAAGACCACCCCCCC
TGTGCTGGACAGCGATGGCAGCTTCTTCCTGTACAGCAAGCTGACCGTGGACAAGAGCAGATGGCAGCAGGGCA
ACGTGTTCAGCTGCTCCGTGATGCACGAGGCCCTGCACAATCACTACACCCAGAAGAGCCTGAGCCTGTCCCCT
GGCAAG SEQ ID NO. 81
GACATCCAGATGACCCAGAGCCCCTCTAGCCTCAGCGCCAGCGTGGGCGACAGGGTGACCATCACCTGCAAGAG
CAGCCAGAGCCTGCTGAACCCCAGCAACCAGAAGAACTACCTGGCCTGGTACCAGCAGAAACCCGGCAAGGCCC
CCAAGCTGCTGGTCTACTTCGCCTCTACCAGGGATTCCGGCGTCCCCAGCAGGTTCAGCGGCAGCGGCAGCGGC
ACCGACTTCACACTGACCATCAGCAGCCTGCAGCCCGAGGACTTCGCCACCTACTACTGCCTGCAGCACTTCGG
CACCCCTCCCACTTTTGGCCAGGGCACCAAGCTGGAGATTAAGCGTACGGTGGCCGCCCCCAGCGTGTTCATCT
TCCCCCCCAGCGATGAGCAGCTGAAGAGCGGCACCGCCAGCGTGGTGTGTCTGCTGAACAACTTCTACCCCCGG
GAGGCCAAGGTGCAGTGGAAGGTGGACAATGCCCTGCAGAGCGGCAACAGCCAGGAGAGCGTGACCGAGCAGGA
CAGCAAGGACTCCACCTACAGCCTGAGCAGCACCCTGACCCTGAGCAAGGCCGACTACGAGAAGCACAAGGTGT
ACGCCTGTGAGGTGACCCACCAGGGCCTGTCCAGCCCCGTGACCAAGAGCTTCAACCGGGGCGAGTGC
SEQ ID NO. 82
CAGGTGCAGCTCGTGCAGAGCGGGGCCGAAGTCAAGAAACCCGGCAGCTCCGTGAAGGTGAGCTGCAAGGCCAG
CGGCGGCACCTTCAGCGCCTACGGCGTGAACTGGGTGAGGCAGGCTCCCGGCCAGGGCCTGGAGTGGATGGGCA
TGATCTGGGACGACGGCAGCACCGACTACAACAGCGCCCTGAAGAGCAGGGTGACCATCACCGCCGACAAGAGC
ACCAGCACCGCCTACATGGAACTGAGCAGCCTGAGGAGCGAGGACACCGCCGTGTACTATTGCGCCAGGGAGGG
CGACGTGGCCTTCGATTACTGGGGCCAGGGCACACTAGTGACCGTGTCCAGCGCCAGCACCAAGGGCCCCAGCG
TGTTCCCCCTGGCCCCCAGCAGCAAGAGCACCAGCGGCGGCACAGCCGCCCTGGGCTGCCTGGTGAAGGACTAC
TTCCCCGAACCGGTGACCGTGTCCTGGAACAGCGGAGCCCTGACCAGCGGCGTGCACACCTTCCCCGCCGTGCT
GCAGAGCAGCGGCCTGTACAGCCTGAGCAGCGTGGTGACCGTGCCCAGCAGCAGCCTGGGCACCCAGACCTACA
TCTGTAACGTGAACCACAAGCCCAGCAACACCAAGGTGGACAAGAAGGTGGAGCCCAAGAGCTGTGACAAGACC
CACACCTGCCCCCCCTGCCCTGCCCCCGAGCTGCTGGGAGGCCCCAGCGTGTTCCTGTTCCCCCCCAAGCCTAA
GGACACCCTGATGATCAGCAGAACCCCCGAGGTGACCTGTGTGGTGGTGGATGTGAGCCACGAGGACCCTGAGG
TGAAGTTCAACTGGTACGTGGACGGCGTGGAGGTGCACAATGCCAAGACCAAGCCCAGGGAGGAGCAGTACAAC
AGCACCTACCGGGTGGTGTCCGTGCTGACCGTGCTGCACCAGGATTGGCTGAACGGCAAGGAGTACAAGTGTAA
GGTGTCCAACAAGGCCCTGCCTGCCCCTATCGAGAAAACCATCAGCAAGGCCAAGGGCCAGCCCAGAGAGCCCC
AGGTGTACACCCTGCCCCCTAGCAGAGATGAGCTGACCAAGAACCAGGTGTCCCTGACCTGCCTGGTGAAGGGC
TTCTACCCCAGCGACATCGCCGTGGAGTGGGAGAGCAACGGCCAGCCCGAGAACAACTACAAGACCACCCCCCC
TGTGCTGGACAGCGATGGCAGCTTCTTCCTGTACAGCAAGCTGACCGTGGACAAGAGCAGATGGCAGCAGGGCA
ACGTGTTCAGCTGCTCCGTGATGCACGAGGCCCTGCACAATCACTACACCCAGAAGAGCCTGAGCCTGTCCCCT
GGCAAG SEQ ID NO. 83
GACATCCAGATGACCCAGAGCCCCTCTAGCCTCAGCGCCAGCGTGGGCGACAGGGTGACCATCACCTGCAAGAG
CAGCCAGAGCCTGCTGAACCCCAGCAACCAGAAGAACTACCTGGCCTGGTACCAGCAGAAACCCGGCAAGGCCC
CCAAGCTGCTGGTCTACTTCGCCTCTACCAGGGATTCCGGCGTCCCCAGCAGGTTCAGCGGCAGCGGCAGCGGC
ACCGACTTCACACTGACCATCAGCAGCCTGCAGCCCGAGGACTTCGCCACCTACTACTGCCTGCAGCACTTCGG
CACCCCTCCCACTTTTGGCCAGGGCACCAAGCTGGAGATTAAGCGTACGGTGGCCGCCCCCAGCGTGTTCATCT
TCCCCCCCAGCGATGAGCAGCTGAAGAGCGGCACCGCCAGCGTGGTGTGTCTGCTGAACAACTTCTACCCCCGG
GAGGCCAAGGTGCAGTGGAAGGTGGACAATGCCCTGCAGAGCGGCAACAGCCAGGAGAGCGTGACCGAGCAGGA
CAGCAAGGACTCCACCTACAGCCTGAGCAGCACCCTGACCCTGAGCAAGGCCGACTACGAGAAGCACAAGGTGT
ACGCCTGTGAGGTGACCCACCAGGGCCTGTCCAGCCCCGTGACCAAGAGCTTCAACCGGGGCGAGTGC
SEQ ID NO. 84
CAGGTGCAGCTCCAGGAGAGCGGCCCCGGCCTGGTGAAGCCTAGCGAGACCCTGAGCCTGACCTGCACCGTGAG
CGGCGGCTCCATCAGCGCCTACGGCGTCAACTGGATCAGGCAGCCCCCCGGCAAAGGCCTGGAGTGGATTGGGA
TGATCTGGGACGACGGCAGCACCGACTACAACAGCGCCCTGAAGAGCAGGGTGACCATCAGCGTGGACACCAGC
AAGAACCAGTTCAGCCTGAAGCTGAGCAGCGTGACTGCCGCCGACACCGCCGTCTATTACTGCGCCAGGGAGGG
CGACGTGGCCTTCGATTACTGGGGCCAGGGCACACTAGTGACCGTGTCCAGCGCCAGCACCAAGGGCCCCAGCG
TGTTCCCCCTGGCCCCCAGCAGCAAGAGCACCAGCGGCGGCACAGCCGCCCTGGGCTGCCTGGTGAAGGACTAC
TTCCCCGAACCGGTGACCGTGTCCTGGAACAGCGGAGCCCTGACCAGCGGCGTGCACACCTTCCCCGCCGTGCT
GCAGAGCAGCGGCCTGTACAGCCTGAGCAGCGTGGTGACCGTGCCCAGCAGCAGCCTGGGCACCCAGACCTACA
TCTGTAACGTGAACCACAAGCCCAGCAACACCAAGGTGGACAAGAAGGTGGAGCCCAAGAGCTGTGACAAGACC
CACACCTGCCCCCCCTGCCCTGCCCCCGAGCTGCTGGGAGGCCCCAGCGTGTTCCTGTTCCCCCCCAAGCCTAA
GGACACCCTGATGATCAGCAGAACCCCCGAGGTGACCTGTGTGGTGGTGGATGTGAGCCACGAGGACCCTGAGG
TGAAGTTCAACTGGTACGTGGACGGCGTGGAGGTGCACAATGCCAAGACCAAGCCCAGGGAGGAGCAGTACAAC
AGCACCTACCGGGTGGTGTCCGTGCTGACCGTGCTGCACCAGGATTGGCTGAACGGCAAGGAGTACAAGTGTAA
GGTGTCCAACAAGGCCCTGCCTGCCCCTATCGAGAAAACCATCAGCAAGGCCAAGGGCCAGCCCAGAGAGCCCC
AGGTGTACACCCTGCCCCCTAGCAGAGATGAGCTGACCAAGAACCAGGTGTCCCTGACCTGCCTGGTGAAGGGC
TTCTACCCCAGCGACATCGCCGTGGAGTGGGAGAGCAACGGCCAGCCCGAGAACAACTACAAGACCACCCCCCC
TGTGCTGGACAGCGATGGCAGCTTCTTCCTGTACAGCAAGCTGACCGTGGACAAGAGCAGATGGCAGCAGGGCA
ACGTGTTCAGCTGCTCCGTGATGCACGAGGCCCTGCACAATCACTACACCCAGAAGAGCCTGAGCCTGTCCCCT
GGCAAG SEQ ID NO. 85
GACATCCAGATGACCCAGAGCCCCTCTAGCCTCAGCGCCAGCGTGGGCGACAGGGTGACCATCACCTGCAAGAG
CAGCCAGAGCCTGCTGAACGGCAGCAACCAGAAGAACTACCTGGCCTGGTACCAGCAGAAACCCGGCAAGGCCC
CCAAGCTGCTGGTCTACTTCGCCTCTACCAGGGATTCCGGCGTCCCCAGCAGGTTCAGCGGCAGCGGCAGCGGC
ACCGACTTCACACTGACCATCAGCAGCCTGCAGCCCGAGGACTTCGCCACCTACTACTGCCTGCAGCACTTCGG
CACCCCTCCCACTTTTGGCCAGGGCACCAAGCTGGAGATTAAGCGTACGGTGGCCGCCCCCAGCGTGTTCATCT
TCCCCCCCAGCGATGAGCAGCTGAAGAGCGGCACCGCCAGCGTGGTGTGTCTGCTGAACAACTTCTACCCCCGG
GAGGCCAAGGTGCAGTGGAAGGTGGACAATGCCCTGCAGAGCGGCAACAGCCAGGAGAGCGTGACCGAGCAGGA
CAGCAAGGACTCCACCTACAGCCTGAGCAGCACCCTGACCCTGAGCAAGGCCGACTACGAGAAGCACAAGGTGT
ACGCCTGTGAGGTGACCCACCAGGGCCTGTCCAGCCCCGTGACCAAGAGCTTCAACCGGGGCGAGTGC
SEQ ID NO. 86
CAGGTGCAGCTCCAGGAGAGCGGCCCCGGCCTGGTGAAGCCTAGCGAGACCCTGAGCCTGACCTGCACCGTGAG
CGGCTTCTCCCTGACCGCCTACGGCGTCAACTGGATCAGGCAGCCCCCCGGCAAAGGCCTGGAGTGGATTGGGA
TGATCTGGGACGACGGCAGCACCGACTACAACAGCGCCCTGAAGAGCAGGGTGACCATCAGCGTGGACACCAGC
AAGAACCAGTTCAGCCTGAAGCTGAGCAGCGTGACTGCCGCCGACACCGCCGTCTATTACTGCGCCAGGGAGGG
CGACGTGGCCTTCGATTACTGGGGCCAGGGCACACTAGTGACCGTGTCCAGCGCCAGCACCAAGGGCCCCAGCG
TGTTCCCCCTGGCCCCCAGCAGCAAGAGCACCAGCGGCGGCACAGCCGCCCTGGGCTGCCTGGTGAAGGACTAC
TTCCCCGAACCGGTGACCGTGTCCTGGAACAGCGGAGCCCTGACCAGCGGCGTGCACACCTTCCCCGCCGTGCT
GCAGAGCAGCGGCCTGTACAGCCTGAGCAGCGTGGTGACCGTGCCCAGCAGCAGCCTGGGCACCCAGACCTACA
TCTGTAACGTGAACCACAAGCCCAGCAACACCAAGGTGGACAAGAAGGTGGAGCCCAAGAGCTGTGACAAGACC
CACACCTGCCCCCCCTGCCCTGCCCCCGAGCTGCTGGGAGGCCCCAGCGTGTTCCTGTTCCCCCCCAAGCCTAA
GGACACCCTGATGATCAGCAGAACCCCCGAGGTGACCTGTGTGGTGGTGGATGTGAGCCACGAGGACCCTGAGG
TGAAGTTCAACTGGTACGTGGACGGCGTGGAGGTGCACAATGCCAAGACCAAGCCCAGGGAGGAGCAGTACAAC
AGCACCTACCGGGTGGTGTCCGTGCTGACCGTGCTGCACCAGGATTGGCTGAACGGCAAGGAGTACAAGTGTAA
GGTGTCCAACAAGGCCCTGCCTGCCCCTATCGAGAAAACCATCAGCAAGGCCAAGGGCCAGCCCAGAGAGCCCC
AGGTGTACACCCTGCCCCCTAGCAGAGATGAGCTGACCAAGAACCAGGTGTCCCTGACCTGCCTGGTGAAGGGC
TTCTACCCCAGCGACATCGCCGTGGAGTGGGAGAGCAACGGCCAGCCCGAGAACAACTACAAGACCACCCCCCC
TGTGCTGGACAGCGATGGCAGCTTCTTCCTGTACAGCAAGCTGACCGTGGACAAGAGCAGATGGCAGCAGGGCA
ACGTGTTCAGCTGCTCCGTGATGCACGAGGCCCTGCACAATCACTACACCCAGAAGAGCCTGAGCCTGTCCCCT
GGCAAG SEQ ID NO. 87
GACATCCAGATGACCCAGAGCCCCTCTAGCCTCAGCGCCAGCGTGGGCGACAGGGTGACCATCACCTGCAAGAG
CAGCCAGAGCCTGCTGAACGGCAGCAACCAGAAGAACTACCTGGCCTGGTACCAGCAGAAACCCGGCAAGGCCC
CCAAGCTGCTGGTCTACTTCGCCTCTACCAGGGATTCCGGCGTCCCCAGCAGGTTCAGCGGCAGCGGCAGCGGC
ACCGACTTCACACTGACCATCAGCAGCCTGCAGCCCGAGGACTTCGCCACCTACTACTGCCTGCAGCACTTCGG
CACCCCTCCCACTTTTGGCCAGGGCACCAAGCTGGAGATTAAGCGTACGGTGGCCGCCCCCAGCGTGTTCATCT
TCCCCCCCAGCGATGAGCAGCTGAAGAGCGGCACCGCCAGCGTGGTGTGTCTGCTGAACAACTTCTACCCCCGG
GAGGCCAAGGTGCAGTGGAAGGTGGACAATGCCCTGCAGAGCGGCAACAGCCAGGAGAGCGTGACCGAGCAGGA
CAGCAAGGACTCCACCTACAGCCTGAGCAGCACCCTGACCCTGAGCAAGGCCGACTACGAGAAGCACAAGGTGT
ACGCCTGTGAGGTGACCCACCAGGGCCTGTCCAGCCCCGTGACCAAGAGCTTCAACCGGGGCGAGTGC
SEQ ID NO. 88
CAGGTGCAGCTCCAGGAGAGCGGCCCCGGCCTGGTGAAGCCTAGCGAGACCCTGAGCCTGACCTGCACCGTGAG
CGGCTTCTCCCTGACCGCCTACGGCGTCAACTGGATCAGGCAGCCCCCCGGCAAAGGCCTGGAGTGGATTGGGA
TGATCTGGGACGACGGCAGCACCGACTACGACAGCGCCCTGAAGAGCAGGGTGACCATCAGCGTGGACACCAGC
AAGAACCAGTTCAGCCTGAAGCTGAGCAGCGTGACTGCCGCCGACACCGCCGTCTATTACTGCGCCAGGGAGGG
CGACGTGGCCTTCGATTACTGGGGCCAGGGCACACTAGTGACCGTGTCCAGCGCCAGCACCAAGGGCCCCAGCG
TGTTCCCCCTGGCCCCCAGCAGCAAGAGCACCAGCGGCGGCACAGCCGCCCTGGGCTGCCTGGTGAAGGACTAC
TTCCCCGAACCGGTGACCGTGTCCTGGAACAGCGGAGCCCTGACCAGCGGCGTGCACACCTTCCCCGCCGTGCT
GCAGAGCAGCGGCCTGTACAGCCTGAGCAGCGTGGTGACCGTGCCCAGCAGCAGCCTGGGCACCCAGACCTACA
TCTGTAACGTGAACCACAAGCCCAGCAACACCAAGGTGGACAAGAAGGTGGAGCCCAAGAGCTGTGACAAGACC
CACACCTGCCCCCCCTGCCCTGCCCCCGAGCTGCTGGGAGGCCCCAGCGTGTTCCTGTTCCCCCCCAAGCCTAA
GGACACCCTGATGATCAGCAGAACCCCCGAGGTGACCTGTGTGGTGGTGGATGTGAGCCACGAGGACCCTGAGG
TGAAGTTCAACTGGTACGTGGACGGCGTGGAGGTGCACAATGCCAAGACCAAGCCCAGGGAGGAGCAGTACAAC
AGCACCTACCGGGTGGTGTCCGTGCTGACCGTGCTGCACCAGGATTGGCTGAACGGCAAGGAGTACAAGTGTAA
GGTGTCCAACAAGGCCCTGCCTGCCCCTATCGAGAAAACCATCAGCAAGGCCAAGGGCCAGCCCAGAGAGCCCC
AGGTGTACACCCTGCCCCCTAGCAGAGATGAGCTGACCAAGAACCAGGTGTCCCTGACCTGCCTGGTGAAGGGC
TTCTACCCCAGCGACATCGCCGTGGAGTGGGAGAGCAACGGCCAGCCCGAGAACAACTACAAGACCACCCCCCC
TGTGCTGGACAGCGATGGCAGCTTCTTCCTGTACAGCAAGCTGACCGTGGACAAGAGCAGATGGCAGCAGGGCA
ACGTGTTCAGCTGCTCCGTGATGCACGAGGCCCTGCACAATCACTACACCCAGAAGAGCCTGAGCCTGTCCCCT
GGCAAG SEQ ID NO. 89
GACATCCAGATGACCCAGAGCCCCTCTAGCCTCAGCGCCAGCGTGGGCGACAGGGTGACCATCACCTGCAAGAG
CAGCCAGAGCCTGCTGAACGGCAGCAACCAGAAGAACTACCTGGCCTGGTACCAGCAGAAACCCGGCAAGGCCC
CCAAGCTGCTGGTCTACTTCGCCTCTACCAGGGATTCCGGCGTCCCCAGCAGGTTCAGCGGCAGCGGCAGCGGC
ACCGACTTCACACTGACCATCAGCAGCCTGCAGCCCGAGGACTTCGCCACCTACTACTGCCTGCAGCACTTCGG
CACCCCTCCCACTTTTGGCCAGGGCACCAAGCTGGAGATTAAGCGTACGGTGGCCGCCCCCAGCGTGTTCATCT
TCCCCCCCAGCGATGAGCAGCTGAAGAGCGGCACCGCCAGCGTGGTGTGTCTGCTGAACAACTTCTACCCCCGG
GAGGCCAAGGTGCAGTGGAAGGTGGACAATGCCCTGCAGAGCGGCAACAGCCAGGAGAGCGTGACCGAGCAGGA
CAGCAAGGACTCCACCTACAGCCTGAGCAGCACCCTGACCCTGAGCAAGGCCGACTACGAGAAGCACAAGGTGT
ACGCCTGTGAGGTGACCCACCAGGGCCTGTCCAGCCCCGTGACCAAGAGCTTCAACCGGGGCGAGTGC
SEQ ID NO. 90
CAGGTGCAGCTCGTGCAGAGCGGGGCCGAAGTCAAGAAACCCGGCAGCTCCGTGAAGGTGAGCTGCAAGGCCAG
CGGCTTCTCTCTCACTGCCTACGGCGTGAACTGGGTGAGGCAGGCTCCCGGCCAGGGCCTGGAGTGGATGGGCA
TGATCTGGGACGACGGCAGCACCGACTACAACAGCGCCCTGAAGAGCAGGGTGACCATCACCGCCGACAAGAGC
ACCAGCACCGCCTACATGGAACTGAGCAGCCTGAGGAGCGAGGACACCGCCGTGTACTATTGCGCCAGGGAGGG
CGACGTGGCCTTCGATTACTGGGGCCAGGGCACACTAGTGACCGTGTCCAGCGCCAGCACCAAGGGCCCCAGCG
TGTTCCCCCTGGCCCCCAGCAGCAAGAGCACCAGCGGCGGCACAGCCGCCCTGGGCTGCCTGGTGAAGGACTAC
TTCCCCGAACCGGTGACCGTGTCCTGGAACAGCGGAGCCCTGACCAGCGGCGTGCACACCTTCCCCGCCGTGCT
GCAGAGCAGCGGCCTGTACAGCCTGAGCAGCGTGGTGACCGTGCCCAGCAGCAGCCTGGGCACCCAGACCTACA
TCTGTAACGTGAACCACAAGCCCAGCAACACCAAGGTGGACAAGAAGGTGGAGCCCAAGAGCTGTGACAAGACC
CACACCTGCCCCCCCTGCCCTGCCCCCGAGCTGCTGGGAGGCCCCAGCGTGTTCCTGTTCCCCCCCAAGCCTAA
GGACACCCTGATGATCAGCAGAACCCCCGAGGTGACCTGTGTGGTGGTGGATGTGAGCCACGAGGACCCTGAGG
TGAAGTTCAACTGGTACGTGGACGGCGTGGAGGTGCACAATGCCAAGACCAAGCCCAGGGAGGAGCAGTACAAC
AGCACCTACCGGGTGGTGTCCGTGCTGACCGTGCTGCACCAGGATTGGCTGAACGGCAAGGAGTACAAGTGTAA
GGTGTCCAACAAGGCCCTGCCTGCCCCTATCGAGAAAACCATCAGCAAGGCCAAGGGCCAGCCCAGAGAGCCCC
AGGTGTACACCCTGCCCCCTAGCAGAGATGAGCTGACCAAGAACCAGGTGTCCCTGACCTGCCTGGTGAAGGGC
TTCTACCCCAGCGACATCGCCGTGGAGTGGGAGAGCAACGGCCAGCCCGAGAACAACTACAAGACCACCCCCCC
TGTGCTGGACAGCGATGGCAGCTTCTTCCTGTACAGCAAGCTGACCGTGGACAAGAGCAGATGGCAGCAGGGCA
ACGTGTTCAGCTGCTCCGTGATGCACGAGGCCCTGCACAATCACTACACCCAGAAGAGCCTGAGCCTGTCCCCT
GGCAAG SEQ ID NO. 91
GACATCCAGATGACCCAGAGCCCCTCTAGCCTCAGCGCCAGCGTGGGCGACAGGGTGACCATCACCTGCAAGAG
CAGCCAGAGCCTGCTGAACGGCAGCAACCAGAAGAACTACCTGGCCTGGTACCAGCAGAAACCCGGCAAGGCCC
CCAAGCTGCTGGTCTACTTCGCCTCTACCAGGGATTCCGGCGTCCCCAGCAGGTTCAGCGGCAGCGGCAGCGGC
ACCGACTTCACACTGACCATCAGCAGCCTGCAGCCCGAGGACTTCGCCACCTACTACTGCCTGCAGCACTTCGG
CACCCCTCCCACTTTTGGCCAGGGCACCAAGCTGGAGATTAAGCGTACGGTGGCCGCCCCCAGCGTGTTCATCT
TCCCCCCCAGCGATGAGCAGCTGAAGAGCGGCACCGCCAGCGTGGTGTGTCTGCTGAACAACTTCTACCCCCGG
GAGGCCAAGGTGCAGTGGAAGGTGGACAATGCCCTGCAGAGCGGCAACAGCCAGGAGAGCGTGACCGAGCAGGA
CAGCAAGGACTCCACCTACAGCCTGAGCAGCACCCTGACCCTGAGCAAGGCCGACTACGAGAAGCACAAGGTGT
ACGCCTGTGAGGTGACCCACCAGGGCCTGTCCAGCCCCGTGACCAAGAGCTTCAACCGGGGCGAGTGC
SEQ ID NO. 92
CAGGTGCAGCTCGTGCAGAGCGGGGCCGAAGTCAAGAAACCCGGCAGCTCCGTGAAGGTGAGCTGCAAGGCCAG
CGGCTTCTCTCTCACTGCCTACGGCGTGAACTGGGTGAGGCAGGCTCCCGGCCAGGGCCTGGAGTGGATGGGCA
TGATCTGGGACGACGGCAGCACCGACTACGACAGCGCCCTGAAGAGCAGGGTGACCATCACCGCCGACAAGAGC
ACCAGCACCGCCTACATGGAACTGAGCAGCCTGAGGAGCGAGGACACCGCCGTGTACTATTGCGCCAGGGAGGG
CGACGTGGCCTTCGATTACTGGGGCCAGGGCACACTAGTGACCGTGTCCAGCGCCAGCACCAAGGGCCCCAGCG
TGTTCCCCCTGGCCCCCAGCAGCAAGAGCACCAGCGGCGGCACAGCCGCCCTGGGCTGCCTGGTGAAGGACTAC
TTCCCCGAACCGGTGACCGTGTCCTGGAACAGCGGAGCCCTGACCAGCGGCGTGCACACCTTCCCCGCCGTGCT
GCAGAGCAGCGGCCTGTACAGCCTGAGCAGCGTGGTGACCGTGCCCAGCAGCAGCCTGGGCACCCAGACCTACA
TCTGTAACGTGAACCACAAGCCCAGCAACACCAAGGTGGACAAGAAGGTGGAGCCCAAGAGCTGTGACAAGACC
CACACCTGCCCCCCCTGCCCTGCCCCCGAGCTGCTGGGAGGCCCCAGCGTGTTCCTGTTCCCCCCCAAGCCTAA
GGACACCCTGATGATCAGCAGAACCCCCGAGGTGACCTGTGTGGTGGTGGATGTGAGCCACGAGGACCCTGAGG
TGAAGTTCAACTGGTACGTGGACGGCGTGGAGGTGCACAATGCCAAGACCAAGCCCAGGGAGGAGCAGTACAAC
AGCACCTACCGGGTGGTGTCCGTGCTGACCGTGCTGCACCAGGATTGGCTGAACGGCAAGGAGTACAAGTGTAA
GGTGTCCAACAAGGCCCTGCCTGCCCCTATCGAGAAAACCATCAGCAAGGCCAAGGGCCAGCCCAGAGAGCCCC
AGGTGTACACCCTGCCCCCTAGCAGAGATGAGCTGACCAAGAACCAGGTGTCCCTGACCTGCCTGGTGAAGGGC
TTCTACCCCAGCGACATCGCCGTGGAGTGGGAGAGCAACGGCCAGCCCGAGAACAACTACAAGACCACCCCCCC
TGTGCTGGACAGCGATGGCAGCTTCTTCCTGTACAGCAAGCTGACCGTGGACAAGAGCAGATGGCAGCAGGGCA
ACGTGTTCAGCTGCTCCGTGATGCACGAGGCCCTGCACAATCACTACACCCAGAAGAGCCTGAGCCTGTCCCCT
GGCAAG SEQ ID NO. 93
GACATCCAGATGACCCAGAGCCCCTCTAGCCTCAGCGCCAGCGTGGGCGACAGGGTGACCATCACCTGCAAGAG
CAGCCAGAGCCTGCTGAACGGCAGCAACCAGAAGAACTACCTGGCCTGGTACCAGCAGAAACCCGGCAAGGCCC
CCAAGCTGCTGGTCTACTTCGCCTCTACCAGGGATTCCGGCGTCCCCAGCAGGTTCAGCGGCAGCGGCAGCGGC
ACCGACTTCACACTGACCATCAGCAGCCTGCAGCCCGAGGACTTCGCCACCTACTACTGCCTGCAGCACTTCGG
CACCCCTCCCACTTTTGGCCAGGGCACCAAGCTGGAGATTAAGCGTACGGTGGCCGCCCCCAGCGTGTTCATCT
TCCCCCCCAGCGATGAGCAGCTGAAGAGCGGCACCGCCAGCGTGGTGTGTCTGCTGAACAACTTCTACCCCCGG
GAGGCCAAGGTGCAGTGGAAGGTGGACAATGCCCTGCAGAGCGGCAACAGCCAGGAGAGCGTGACCGAGCAGGA
CAGCAAGGACTCCACCTACAGCCTGAGCAGCACCCTGACCCTGAGCAAGGCCGACTACGAGAAGCACAAGGTGT
ACGCCTGTGAGGTGACCCACCAGGGCCTGTCCAGCCCCGTGACCAAGAGCTTCAACCGGGGCGAGTGC
SEQ ID NO. 94
CAGGTGCAGCTCGTGCAGAGCGGGGCCGAAGTCAAGAAACCCGGCAGCTCCGTGAAGGTGAGCTGCAAGGCCAG
CGGCGGCACCTTCAGCGCCTACGGCGTGAACTGGGTGAGGCAGGCTCCCGGCCAGGGCCTGGAGTGGATGGGCA
TGATCTGGGACGACGGCAGCACCGACTACGACAGCGCCCTGAAGAGCAGGGTGACCATCACCGCCGACAAGAGC
ACCAGCACCGCCTACATGGAACTGAGCAGCCTGAGGAGCGAGGACACCGCCGTGTACTATTGCGCCAGGGAGGG
CGACGTGGCCTTCGATTACTGGGGCCAGGGCACACTAGTGACCGTGTCCAGCGCCAGCACCAAGGGCCCCAGCG
TGTTCCCCCTGGCCCCCAGCAGCAAGAGCACCAGCGGCGGCACAGCCGCCCTGGGCTGCCTGGTGAAGGACTAC
TTCCCCGAACCGGTGACCGTGTCCTGGAACAGCGGAGCCCTGACCAGCGGCGTGCACACCTTCCCCGCCGTGCT
GCAGAGCAGCGGCCTGTACAGCCTGAGCAGCGTGGTGACCGTGCCCAGCAGCAGCCTGGGCACCCAGACCTACA
TCTGTAACGTGAACCACAAGCCCAGCAACACCAAGGTGGACAAGAAGGTGGAGCCCAAGAGCTGTGACAAGACC
CACACCTGCCCCCCCTGCCCTGCCCCCGAGCTGCTGGGAGGCCCCAGCGTGTTCCTGTTCCCCCCCAAGCCTAA
GGACACCCTGATGATCAGCAGAACCCCCGAGGTGACCTGTGTGGTGGTGGATGTGAGCCACGAGGACCCTGAGG
TGAAGTTCAACTGGTACGTGGACGGCGTGGAGGTGCACAATGCCAAGACCAAGCCCAGGGAGGAGCAGTACAAC
AGCACCTACCGGGTGGTGTCCGTGCTGACCGTGCTGCACCAGGATTGGCTGAACGGCAAGGAGTACAAGTGTAA
GGTGTCCAACAAGGCCCTGCCTGCCCCTATCGAGAAAACCATCAGCAAGGCCAAGGGCCAGCCCAGAGAGCCCC
AGGTGTACACCCTGCCCCCTAGCAGAGATGAGCTGACCAAGAACCAGGTGTCCCTGACCTGCCTGGTGAAGGGC
TTCTACCCCAGCGACATCGCCGTGGAGTGGGAGAGCAACGGCCAGCCCGAGAACAACTACAAGACCACCCCCCC
TGTGCTGGACAGCGATGGCAGCTTCTTCCTGTACAGCAAGCTGACCGTGGACAAGAGCAGATGGCAGCAGGGCA
ACGTGTTCAGCTGCTCCGTGATGCACGAGGCCCTGCACAATCACTACACCCAGAAGAGCCTGAGCCTGTCCCCT
GGCAAG SEQ ID NO. 95
GACATCCAGATGACCCAGAGCCCCTCTAGCCTCAGCGCCAGCGTGGGCGACAGGGTGACCATCACCTGCAAGAG
CAGCCAGAGCCTGCTGAACGGCAGCAACCAGAAGAACTACCTGGCCTGGTACCAGCAGAAACCCGGCAAGGCCC
CCAAGCTGCTGGTCTACTTCGCCTCTACCAGGGATTCCGGCGTCCCCAGCAGGTTCAGCGGCAGCGGCAGCGGC
ACCGACTTCACACTGACCATCAGCAGCCTGCAGCCCGAGGACTTCGCCACCTACTACTGCCTGCAGCACTTCGG
CACCCCTCCCACTTTTGGCCAGGGCACCAAGCTGGAGATTAAGCGTACGGTGGCCGCCCCCAGCGTGTTCATCT
TCCCCCCCAGCGATGAGCAGCTGAAGAGCGGCACCGCCAGCGTGGTGTGTCTGCTGAACAACTTCTACCCCCGG
GAGGCCAAGGTGCAGTGGAAGGTGGACAATGCCCTGCAGAGCGGCAACAGCCAGGAGAGCGTGACCGAGCAGGA
CAGCAAGGACTCCACCTACAGCCTGAGCAGCACCCTGACCCTGAGCAAGGCCGACTACGAGAAGCACAAGGTGT
ACGCCTGTGAGGTGACCCACCAGGGCCTGTCCAGCCCCGTGACCAAGAGCTTCAACCGGGGCGAGTGC
SEQ ID NO. 96
CAGGTGCAGCTCCAGGAGAGCGGCCCCGGCCTGGTGAAGCCTAGCGAGACCCTGAGCCTGACCTGCACCGTGAG
CGGCGGCTCCATCAGCGCCTACGGCGTCAACTGGATCAGGCAGCCCCCCGGCAAAGGCCTGGAGTGGATTGGGA
TGATCTGGGACGACGGCAGCACCGACTACGACAGCGCCCTGAAGAGCAGGGTGACCATCAGCGTGGACACCAGC
AAGAACCAGTTCAGCCTGAAGCTGAGCAGCGTGACTGCCGCCGACACCGCCGTCTATTACTGCGCCAGGGAGGG
CGACGTGGCCTTCGATTACTGGGGCCAGGGCACACTAGTGACCGTGTCCAGCGCCAGCACCAAGGGCCCCAGCG
TGTTCCCCCTGGCCCCCAGCAGCAAGAGCACCAGCGGCGGCACAGCCGCCCTGGGCTGCCTGGTGAAGGACTAC
TTCCCCGAACCGGTGACCGTGTCCTGGAACAGCGGAGCCCTGACCAGCGGCGTGCACACCTTCCCCGCCGTGCT
GCAGAGCAGCGGCCTGTACAGCCTGAGCAGCGTGGTGACCGTGCCCAGCAGCAGCCTGGGCACCCAGACCTACA
TCTGTAACGTGAACCACAAGCCCAGCAACACCAAGGTGGACAAGAAGGTGGAGCCCAAGAGCTGTGACAAGACC
CACACCTGCCCCCCCTGCCCTGCCCCCGAGCTGCTGGGAGGCCCCAGCGTGTTCCTGTTCCCCCCCAAGCCTAA
GGACACCCTGATGATCAGCAGAACCCCCGAGGTGACCTGTGTGGTGGTGGATGTGAGCCACGAGGACCCTGAGG
TGAAGTTCAACTGGTACGTGGACGGCGTGGAGGTGCACAATGCCAAGACCAAGCCCAGGGAGGAGCAGTACAAC
AGCACCTACCGGGTGGTGTCCGTGCTGACCGTGCTGCACCAGGATTGGCTGAACGGCAAGGAGTACAAGTGTAA
GGTGTCCAACAAGGCCCTGCCTGCCCCTATCGAGAAAACCATCAGCAAGGCCAAGGGCCAGCCCAGAGAGCCCC
AGGTGTACACCCTGCCCCCTAGCAGAGATGAGCTGACCAAGAACCAGGTGTCCCTGACCTGCCTGGTGAAGGGC
TTCTACCCCAGCGACATCGCCGTGGAGTGGGAGAGCAACGGCCAGCCCGAGAACAACTACAAGACCACCCCCCC
TGTGCTGGACAGCGATGGCAGCTTCTTCCTGTACAGCAAGCTGACCGTGGACAAGAGCAGATGGCAGCAGGGCA
ACGTGTTCAGCTGCTCCGTGATGCACGAGGCCCTGCACAATCACTACACCCAGAAGAGCCTGAGCCTGTCCCCT
GGCAAG SEQ ID NO. 97
GACATCCAGATGACCCAGAGCCCCTCTAGCCTCAGCGCCAGCGTGGGCGACAGGGTGACCATCACCTGCAAGAG
CAGCCAGAGCCTGCTGAACGGCAGCAACCAGAAGAACTACCTGGCCTGGTACCAGCAGAAACCCGGCAAGGCCC
CCAAGCTGCTGGTCTACTTCGCCTCTACCAGGGATTCCGGCGTCCCCAGCAGGTTCAGCGGCAGCGGCAGCGGC
ACCGACTTCACACTGACCATCAGCAGCCTGCAGCCCGAGGACTTCGCCACCTACTACTGCCTGCAGCACTTCGG
CACCCCTCCCACTTTTGGCCAGGGCACCAAGCTGGAGATTAAGCGTACGGTGGCCGCCCCCAGCGTGTTCATCT
TCCCCCCCAGCGATGAGCAGCTGAAGAGCGGCACCGCCAGCGTGGTGTGTCTGCTGAACAACTTCTACCCCCGG
GAGGCCAAGGTGCAGTGGAAGGTGGACAATGCCCTGCAGAGCGGCAACAGCCAGGAGAGCGTGACCGAGCAGGA
CAGCAAGGACTCCACCTACAGCCTGAGCAGCACCCTGACCCTGAGCAAGGCCGACTACGAGAAGCACAAGGTGT
ACGCCTGTGAGGTGACCCACCAGGGCCTGTCCAGCCCCGTGACCAAGAGCTTCAACCGGGGCGAGTGC
SEQ ID NO. 98
CAGGTGCAGCTCGTGCAGAGCGGGGCCGAAGTCAAGAAACCCGGCAGCTCCGTGAAGGTGAGCTGCAAGGCCAG
CGGCGGCACCTTCAGCGCCTACGGCGTGAACTGGGTGAGGCAGGCTCCCGGCCAGGGCCTGGAGTGGATGGGCA
TGATCTGGGACGACGGCAGCACCGACTACAACAGCGCCCTGAAGAGCAGGGTGACCATCACCGCCGACAAGAGC
ACCAGCACCGCCTACATGGAACTGAGCAGCCTGAGGAGCGAGGACACCGCCGTGTACTATTGCGCCAGGGAGGG
CGACGTGGCCTTCGATTACTGGGGCCAGGGCACACTAGTGACCGTGTCCAGCGCCAGCACCAAGGGCCCCAGCG
TGTTCCCCCTGGCCCCCAGCAGCAAGAGCACCAGCGGCGGCACAGCCGCCCTGGGCTGCCTGGTGAAGGACTAC
TTCCCCGAACCGGTGACCGTGTCCTGGAACAGCGGAGCCCTGACCAGCGGCGTGCACACCTTCCCCGCCGTGCT
GCAGAGCAGCGGCCTGTACAGCCTGAGCAGCGTGGTGACCGTGCCCAGCAGCAGCCTGGGCACCCAGACCTACA
TCTGTAACGTGAACCACAAGCCCAGCAACACCAAGGTGGACAAGAAGGTGGAGCCCAAGAGCTGTGACAAGACC
CACACCTGCCCCCCCTGCCCTGCCCCCGAGCTGCTGGGAGGCCCCAGCGTGTTCCTGTTCCCCCCCAAGCCTAA
GGACACCCTGATGATCAGCAGAACCCCCGAGGTGACCTGTGTGGTGGTGGATGTGAGCCACGAGGACCCTGAGG
TGAAGTTCAACTGGTACGTGGACGGCGTGGAGGTGCACAATGCCAAGACCAAGCCCAGGGAGGAGCAGTACAAC
AGCACCTACCGGGTGGTGTCCGTGCTGACCGTGCTGCACCAGGATTGGCTGAACGGCAAGGAGTACAAGTGTAA
GGTGTCCAACAAGGCCCTGCCTGCCCCTATCGAGAAAACCATCAGCAAGGCCAAGGGCCAGCCCAGAGAGCCCC
AGGTGTACACCCTGCCCCCTAGCAGAGATGAGCTGACCAAGAACCAGGTGTCCCTGACCTGCCTGGTGAAGGGC
TTCTACCCCAGCGACATCGCCGTGGAGTGGGAGAGCAACGGCCAGCCCGAGAACAACTACAAGACCACCCCCCC
TGTGCTGGACAGCGATGGCAGCTTCTTCCTGTACAGCAAGCTGACCGTGGACAAGAGCAGATGGCAGCAGGGCA
ACGTGTTCAGCTGCTCCGTGATGCACGAGGCCCTGCACAATCACTACACCCAGAAGAGCCTGAGCCTGTCCCCT
GGCAAG SEQ ID NO. 99
GACATCCAGATGACCCAGAGCCCCTCTAGCCTCAGCGCCAGCGTGGGCGACAGGGTGACCATCACCTGCAAGAG
CAGCCAGAGCCTGCTGAACGGCAGCAACCAGAAGAACTACCTGGCCTGGTACCAGCAGAAACCCGGCAAGGCCC
CCAAGCTGCTGGTCTACTTCGCCTCTACCAGGGATTCCGGCGTCCCCAGCAGGTTCAGCGGCAGCGGCAGCGGC
ACCGACTTCACACTGACCATCAGCAGCCTGCAGCCCGAGGACTTCGCCACCTACTACTGCCTGCAGCACTTCGG
CACCCCTCCCACTTTTGGCCAGGGCACCAAGCTGGAGATTAAGCGTACGGTGGCCGCCCCCAGCGTGTTCATCT
TCCCCCCCAGCGATGAGCAGCTGAAGAGCGGCACCGCCAGCGTGGTGTGTCTGCTGAACAACTTCTACCCCCGG
GAGGCCAAGGTGCAGTGGAAGGTGGACAATGCCCTGCAGAGCGGCAACAGCCAGGAGAGCGTGACCGAGCAGGA
CAGCAAGGACTCCACCTACAGCCTGAGCAGCACCCTGACCCTGAGCAAGGCCGACTACGAGAAGCACAAGGTGT
ACGCCTGTGAGGTGACCCACCAGGGCCTGTCCAGCCCCGTGACCAAGAGCTTCAACCGGGGCGAGTGC
SEQ ID NO. 100
CAGGTGCAGCTCCAGGAGAGCGGCCCCGGCCTGGTGAAGCCTAGCGAGACCCTGAGCCTGACCTGCACCGTGAG
CGGCGGCTCCATCAGCGCCTACGGCGTCAACTGGATCAGGCAGCCCCCCGGCAAAGGCCTGGAGTGGATTGGGA
TGATCTGGGACGACGGCAGCACCGACTACAACAGCGCCCTGAAGAGCAGGGTGACCATCAGCGTGGACACCAGC
AAGAACCAGTTCAGCCTGAAGCTGAGCAGCGTGACTGCCGCCGACACCGCCGTCTATTACTGCGCCAGGGAGGG
CGACGTGGCCTTCGATTACTGGGGCCAGGGCACACTAGTGACCGTGTCCAGCGCCAGCACCAAGGGCCCCAGCG
TGTTCCCCCTGGCCCCCAGCAGCAAGAGCACCAGCGGCGGCACAGCCGCCCTGGGCTGCCTGGTGAAGGACTAC
TTCCCCGAACCGGTGACCGTGTCCTGGAACAGCGGAGCCCTGACCAGCGGCGTGCACACCTTCCCCGCCGTGCT
GCAGAGCAGCGGCCTGTACAGCCTGAGCAGCGTGGTGACCGTGCCCAGCAGCAGCCTGGGCACCCAGACCTACA
TCTGTAACGTGAACCACAAGCCCAGCAACACCAAGGTGGACAAGAAGGTGGAGCCCAAGAGCTGTGACAAGACC
CACACCTGCCCCCCCTGCCCTGCCCCCGAGCTGCTGGGAGGCCCCAGCGTGTTCCTGTTCCCCCCCAAGCCTAA
GGACACCCTGATGATCAGCAGAACCCCCGAGGTGACCTGTGTGGTGGTGGATGTGAGCCACGAGGACCCTGAGG
TGAAGTTCAACTGGTACGTGGACGGCGTGGAGGTGCACAATGCCAAGACCAAGCCCAGGGAGGAGCAGTACAAC
AGCACCTACCGGGTGGTGTCCGTGCTGACCGTGCTGCACCAGGATTGGCTGAACGGCAAGGAGTACAAGTGTAA
GGTGTCCAACAAGGCCCTGCCTGCCCCTATCGAGAAAACCATCAGCAAGGCCAAGGGCCAGCCCAGAGAGCCCC
AGGTGTACACCCTGCCCCCTAGCAGAGATGAGCTGACCAAGAACCAGGTGTCCCTGACCTGCCTGGTGAAGGGC
TTCTACCCCAGCGACATCGCCGTGGAGTGGGAGAGCAACGGCCAGCCCGAGAACAACTACAAGACCACCCCCCC
TGTGCTGGACAGCGATGGCAGCTTCTTCCTGTACAGCAAGCTGACCGTGGACAAGAGCAGATGGCAGCAGGGCA
ACGTGTTCAGCTGCTCCGTGATGCACGAGGCCCTGCACAATCACTACACCCAGAAGAGCCTGAGCCTGTCCCCT
GGCAAG SEQ ID NO. 101
ACGGTGGCCGCCCCCAGCGTGTTCATCTTCCCCCCCAGCGATGAGCAGCTGAAGAGCGGCACCGCCAGCGTGGT
GTGTCTGCTGAACAACTTCTACCCCCGGGAGGCCAAGGTGCAGTGGAAGGTGGACAATGCCCTGCAGAGCGGCA
ACAGCCAGGAGAGCGTGACCGAGCAGGACAGCAAGGACTCCACCTACAGCCTGAGCAGCACCCTGACCCTGAGC
AAGGCCGACTACGAGAAGCACAAGGTGTACGCCTGTGAGGTGACCCACCAGGGCCTGTCCAGCCCCGTGACCAA
GAGCTTCAACCGGGGCGAGTGC SEQ ID NO. 102
GCCAGCACCAAGGGCCCCAGCGTGTTCCCCCTGGCCCCCAGCAGCAAGAGCACCAGCGGCGGCACAGCCGCCCT
GGGCTGCCTGGTGAAGGACTACTTCCCCGAACCGGTGACCGTGTCCTGGAACAGCGGAGCCCTGACCAGCGGCG
TGCACACCTTCCCCGCCGTGCTGCAGAGCAGCGGCCTGTACAGCCTGAGCAGCGTGGTGACCGTGCCCAGCAGC
AGCCTGGGCACCCAGACCTACATCTGTAACGTGAACCACAAGCCCAGCAACACCAAGGTGGACAAGAAGGTGGA
GCCCAAGAGCTGTGACAAGACCCACACCTGCCCCCCCTGCCCTGCCCCCGAGCTGCTGGGAGGCCCCAGCGTGT
TCCTGTTCCCCCCCAAGCCTAAGGACACCCTGATGATCAGCAGAACCCCCGAGGTGACCTGTGTGGTGGTGGAT
GTGAGCCACGAGGACCCTGAGGTGAAGTTCAACTGGTACGTGGACGGCGTGGAGGTGCACAATGCCAAGACCAA
GCCCAGGGAGGAGCAGTACAACAGCACCTACCGGGTGGTGTCCGTGCTGACCGTGCTGCACCAGGATTGGCTGA
ACGGCAAGGAGTACAAGTGTAAGGTGTCCAACAAGGCCCTGCCTGCCCCTATCGAGAAAACCATCAGCAAGGCC
AAGGGCCAGCCCAGAGAGCCCCAGGTGTACACCCTGCCCCCTAGCAGAGATGAGCTGACCAAGAACCAGGTGTC
CCTGACCTGCCTGGTGAAGGGCTTCTACCCCAGCGACATCGCCGTGGAGTGGGAGAGCAACGGCCAGCCCGAGA
ACAACTACAAGACCACCCCCCCTGTGCTGGACAGCGATGGCAGCTTCTTCCTGTACAGCAAGCTGACCGTGGAC
AAGAGCAGATGGCAGCAGGGCAACGTGTTCAGCTGCTCCGTGATGCACGAGGCCCTGCACAATCACTACACCCA
GAAGAGCCTGAGCCTGTCCCCTGGCAAG SEQ ID NO. 103
CAGGTGCAGCTGAAGGAGTCAGGTCCTGGCCTGGTGGCGCCCTCACAGAGCCTGTCCATCACATGCACCGTCTC
AGGGTTCTCATTAACCGCCTATGGTGTAAACTGGGTTCGCCAGCCTCCAGGAAAGGGTCTGGAGTGGCTGGGAA
TGATATGGGATGATGGAAGCACAGACTATAATTCAGCTCTCAAATCCAGACTGAGCATCAGTAAGGACAACTCC
AAGAGCCAAGTTTTCTTAAAAATGAACAGTCTGCAAACTGATGACACAGCCAGGTACTACTGTGCCAGAGAAGG
GGACGTAGCCTTTGACTACTGGGGCCAAGGCACCACTCTCACAGTCTCCTCA SEQ ID NO. 104
GACATTGTGATGACACAGTCTCCCTCCTCCCTGGCTGTGTCAGTAGGACAGAAGGTCACTATGAGCTGCAAGTC
CAGTCAGAGCCTTTTAAATGGTAGCAATCAAAAGAACTACTTGGCCTGGTACCAGCAGAAACCAGGACAGTCTC
CTAAACTTCTGGTATACTTTGCATCCACTAGGGATTCTGGGGTCCCTGATCGCTTCATAGGCAGTGGATCTGGG
ACAGATTTCACTCTTACCATCAGCAGTGTGCAGGCTGAAGACCTGGCAGATTACTTCTGTCTGCAACATTTTGG
CACTCCTCCGACGTTCGGTGGAGGCACCAAACTGGAAATCAAACGG SEQ ID NO. 105
CAGGTGCAGCTGAAGGAGTCAGGTCCTGGCCTGGTGGCGCCCTCACAGAGCCTGTCCATCACATGCACCGTCTC
AGGGTTCTCATTAACCGCCTATGGTGTAAACTGGGTTCGCCAGCCTCCAGGAAAGGGTCTGGAGTGGCTGGGAA
TGATATGGGATGATGGAAGCACAGACTATAATTCAGCTCTCAAATCCAGACTGAGCATCAGTAAGGACAACTCC
AAGAGCCAAGTTTTCTTAAAAATGAACAGTCTGCAAACTGATGACACAGCCAGGTACTACTGTGCCAGAGAAGG
GGACGTAGCCTTTGACTACTGGGGCCAAGGCACCACTCTCACAGTCTCCTCAGCTAGCACCAAGGGCCCATCGG
TCTTCCCCCTGGCACCCTCCTCCAAGAGCACCTCTGGGGGCACAGCGGCCCTGGGCTGCCTGGTCAAGGACTAC
TTCCCCGAACCGGTGACGGTGTCGTGGAACTCAGGCGCCCTGACCAGCGGCGTGCACACCTTCCCGGCTGTCCT
ACAGTCCTCAGGACTCTACTCCCTCAGCAGCGTGGTGACCGTGCCCTCCAGCAGCTTGGGCACCCAGACCTACA
TCTGCAACGTGAATCACAAGCCCAGCAACACCAAGGTGGACAAGAAAGTTGAGCCCAAATCTTGTGACAAAACT
CACACATGCCCACCGTGCCCAGCACCTGAACTCCTGGGGGGACCGTCAGTCTTCCTCTTCCCCCCAAAACCCAA
GGACACCCTCATGATCTCCCGGACCCCTGAGGTCACATGCGTGGTGGTGGACGTGAGCCACGAAGACCCTGAGG
TCAAGTTCAACTGGTACGTGGACGGCGTGGAGGTGCATAATGCCAAGACAAAGCCGCGGGAGGAGCAGTACAAC
AGCACGTACCGTGTGGTCAGCGTCCTCACCGTCCTGCACCAGGACTGGCTGAATGGCAAGGAGTACAAGTGCAA
GGTCTCCAACAAAGCCCTCCCAGCCCCCATCGAGAAAACCATCTCCAAAGCCAAAGGGCAGCCCCGAGAACCAC
AGGTGTACACCCTGCCCCCATCCCGGGATGAGCTGACCAAGAACCAGGTCAGCCTGACCTGCCTGGTCAAAGGC
TTCTATCCCAGCGACATCGCCGTGGAGTGGGAGAGCAATGGGCAGCCGGAGAACAACTACAAGACCACGCCTCC
CGTGCTGGACTCCGACGGCTCCTTCTTCCTCTACAGCAAGCTCACCGTGGACAAGAGCAGGTGGCAGCAGGGGA
ACGTCTTCTCATGCTCCGTGATGCATGAGGCTCTGCACAACCACTACACGCAGAAGAGCCTCTCCCTGTCTCCG
GGTAAA SEQ ID NO. 106
GACATTGTGATGACACAGTCTCCCTCCTCCCTGGCTGTGTCAGTAGGACAGAAGGTCACTATGAGCTGCAAGTC
CAGTCAGAGCCTTTTAAATGGTAGCAATCAAAAGAACTACTTGGCCTGGTACCAGCAGAAACCAGGACAGTCTC
CTAAACTTCTGGTATACTTTGCATCCACTAGGGATTCTGGGGTCCCTGATCGCTTCATAGGCAGTGGATCTGGG
ACAGATTTCACTCTTACCATCAGCAGTGTGCAGGCTGAAGACCTGGCAGATTACTTCTGTCTGCAACATTTTGG
CACTCCTCCGACGTTCGGTGGAGGCACCAAACTGGAAATCAAACGGACCGTGGCTGCACCATCTGTCTTCATCT
TCCCGCCATCTGATGAGCAGTTGAAATCTGGAACTGCCTCTGTTGTGTGCCTGCTGAATAACTTCTATCCCAGA
GAGGCCAAAGTACAGTGGAAGGTGGATAACGCCCTCCAATCGGGTAACTCCCAGGAGAGTGTCACAGAGCAGGA
CAGCAAGGACAGCACCTACAGCCTCAGCAGCACCCTGACGCTGAGCAAAGCAGACTACGAGAAACACAAAGTCT
ACGCCTGCGAAGTCACCCATCAGGGCCTGAGTTCGCCCGTCACAAAGAGCTTCAACAGGGGAGAGTGT
SEQ ID NO. 107
CTCCAGCCAGGGGCTGAGGTCCCGGTGGTGTGGGCCCAGGAGGGGGCTCCTGCCCAGCTCCCCTGCAGCCCCAC
AATCCCCCTCCAGGATCTCAGCCTTCTGCGAAGAGCAGGGGTCACTTGGCAGCATCAGCCAGACAGTGGCCCGC
CCGCTGCCGCCCCCGGCCATCCCCTGGCCCCCGGCCCTCACCCGGCGGCGCCCTCCTCCTGGGGGCCCAGGCCC
CGCCGCTACACGGTGCTGAGCGTGGGTCCCGGAGGCCTGCGCAGCGGGAGGCTGCCCCTGCAGCCCCGCGTCCA
GCTGGATGAGCGCGGCCGGCAGCGCGGGGACTTCTCGCTATGGCTGCGCCCAGCCCGGCGCGCGGACGCCGGCG
AGTACCGCGCCGCGGTGCACCTCAGGGACCGCGCCCTCTCCTGCCGCCTCCGTCTGCGCCTGGGCCAGGCCTCG
ATGACTGCCAGCCCCCCAGGATCTCTCAGAGCCTCCGACTGGGTCATTTTGAACTGCTCCTTCAGCCGCCCTGA
CCGCCCAGCCTCTGTGCATTGGTTCCGGAACCGGGGCCAGGGCCGAGTCCCTGTCCGGGAGTCCCCCCATCACC
ACTTAGCGGAAAGCTTCCTCTTCCTGCCCCAAGTCAGCCCCATGGACTCTGGGCCCTGGGGCTGCATCCTCACC
TACAGAGATGGCTTCAACGTCTCOATCATGTATAACCTCACTGTTCTGGGTCTGGAGCCCCCAACTCCCTTGAC
AGTGTACGCTGGAGCAGGTTCCAGGGTGGGGCTGCCCTGCCGCCTGCCTGCTGGTGTGGGGACCCGGTCTTTCC
TCACTGCCAAGTGGACTCCTCCTGGGGGAGGCCCTGACCTCCTGGTGACTGGAGACAATGGCGACTTTACCCTT
CGACTAGAGGATGTGAGCCAGGCCCAGGCTGGGACCTACACCTGCCATATCCATCTGCAGGAACAGCAGCTCAA
TGCCACTGTCACATTGGCAATCATCACAGTGACTCCCAAATCCTTTGGGTCACCTGGATCCCTGGGGAAGCTGC
TTTGTGAGGTGACTCCAGTATCTGGACAAGAACGCTTTGTGTGGAGCTCTCTGGACACCCCATCCCAGAGGAGT
TTCTCAGGACCTTGGCTGGAGGCACAGGAGGCCCAGCTCCTTTCCCAGCCTTGGCAATGCCAGCTGTACCAGGG
GGAGAGGCTTCTTGGAGCAGCAGTGTACTTCACAGAGCTGTCTAGCCCACACCACCATCATCACCAT
SEQ ID NO. 108
CCCCAGCCAGGGGCTGAGATCTCGGTGGTGTGGGCCCAGGAGGGGGCTCCTGCCCAGCTCCCCTGCAGCCCCAC
AATCCCCCTCCAGGATCTCAGCCTTCTGCGAAGAGCAGGGGTCACTTGGCAGCATCAACCAGACAGTGGCCCGC
CCGCTCCCGCCCCCGGCCACCCCCCGGCCCCCGGCCATCGCCCGGCGGCGCCCTACTCTTGGGGGCCCAGGCCC
CGCCGCTACACAGTGCTGAGCGTGGGTCCTGGAGGCCTGCGCAGCGGGAGGCTGCCCCTGCAGCCCCGCGTCCA
GCTGGATGAGCGCGGCCGGCAGCGCGGGGACTTCTCGCTGTGGCTGCGCCCAGCCCGGCGCGCGGACGCCGGCG
AGTACCGCGCCACGGTGCACCTCAGGGACCGCGCCCTCTCCTGCCGCCTTCGTCTGCGCGTGGGCCAGGCCTCG
ATGACTGCCAGCCCCCCAGGGTCTCTCAGGACCTCTGACTGGGTCATTTTGAACTGCTCCTTCAGCCGCCCTGA
CCGCCCAGCCTCTGTGCATTGGTTCCGGAGCCGTGGCCAGGGCCGAGTCCCTGTCCAGGGGTCCCCCCATCACC
ACTTAGCGGAAAGCTTCCTCTTCCTGCCCCATGTCGGCCCCATGGACTCTGGGCTCTGGGGCTGCATCCTCACC
TACAGAGATGGCTTCAATGTCTCCATCATGTATAACCTCACTGTTCTGGGTCTGGAGCCCGCAACTCCCTTGAC
AGTGTACGCTGGAGCAGGTTCCAGGGTGGAGCTGCCCTGCCGCCTGCCTCCTGCTGTGGGGACCCAGTCTTTCC
TTACTGCCAAGTGGGCTCCTCCTGGGGGAGGCCCTGACCTCCTGGTGGCTGGAGACAATGGCGACTTTACCCTT
CGACTAGAGGATGTAAGCCAGGCCCAGGCTGGGACCTACATCTGCCATATCCGTCTACAGGGACAGCAGCTCAA
TGCCACTGTCACATTGGCAATCATCACAGTGACTCCCAAATCCTTTGGGTCACCTGGCTCCCTGGGGAAGCTGC
TTTGTGAGGTGACTCCAGCATCTGGACAAGAACACTTTGTGTGGAGCCCCCTGAACACCCCATCCCAGAGGAGT
TTCTCAGGACCATGGCTGGAGGCCCAGGAAGCCCAGCTCCTTTCCCAGCCTTGGCAATGCCAGCTGCACCAGGG
GGAGAGGCTTCTTGGAGCAGCAGTATACTTCACAGAACTGTCTAGCCCACACCACCATCATCACCAT
SEQ ID NO. 109
CCCCAGCCAGGGGCTGAGATCTCGGTGGTGTGGGCCCAGGAGGGGGCTCCTGCCCAGCTCCCCTGCAGCCCCAC
AATCCCCCTCCAGGATCTCAGCCTTCTGCGAAGAGCAGGGGTCACTTGGCAGCATCAACCAGACAGTGGCCCGC
CCGCTCCCGCCCCCGGCCACCCCCCGGCCCCCGGCCATCGCCCGGCGGCGCCCTACTCTTGGGGGCCCAGGCCC
CGCCGCTACACAGTGCTGAGCGTGGGTCCTGGAGGCCTGCGCAGCGGGAGGCTGCCCCTGCAGCCCCGCGTCCA
GCTGGATGAGCGCGGCCGGCAGCGCGGGGACTTCTCGCTGTGGCTGCGCCCAGCCCGGCGCGCGGACGCCGGCG
AGTACCGCGCCACGGTGCACCTCAGGGACCGCGCCCTCTCCTGCCGCCTTCGTCTGCGCGTGGGCCAGGCCTCG
ATGACTGCCAGCCCCCCAGGGTCTCTCAGGACCTCTGACTGGGTCATTTTGAACTGCTCCTTCAGCCGCCCTGA
CCGCCCAGCCTCTGTGCATTGGTTCCGGAGCCGTGGCCAGGGCCAAGTCCCTGTCCAGGAGTCCCCCCATCACC
ACTTAGCGGAAAGCTTCCTCTTCCTGCCCCATGTCGGCCCCATGGACTCTGGGCTCTGGGGCTGCATCCTCACC
TACAGAGATGGCTTCAATGTCTCCATCATGTATAACCTCACTGTTCTGGGTCTGGAGCCCACAACTCCCTTGAC
AGTGTACGCTGGAGCAGGTTCCAGGGTGGAGCTGCCCTGCCGCCTGCCTCCTGCTGTGGGGACCCAGTCTTTCC
TTACTGCCAAGTGGGCTCCTCCTGGGGGAGGCCCTGACCTCCTGGTGGTTGGAGACAATGGCAACTTTACCCTT
CGACTAGAGGATGTAAGCCAGGCCCAGGCTGGGACCTACATCTGCCATATCCGTCTACAGGGACAGCAGCTCAA
TGCCACTGTCACATTGGCAATCATCACAGTGACTCCCAAATCCTTTGGGTCACCTGGCTCCCTGGGGAAGCTGC
TTTGTGAGGTGACTCCAGCATCTGGACAAGAACGCTTTGTGTGGAGCCCCCTGAACACCCCATCCCAGAGGAGT
TTCTCAGGACCGTGGCTGGAGGCCCAGGAAGCCCAGCTCCTTTCCCAGCCTTGGCAATGCCAGCTGCACCAGGG
GGAGAGGCTTCTTGGAGCAGCAGTATACTTCACAGAACTGTCTAGCCCACACCACCATCATCACCAT
SEQ ID NO. 110
ATGGGCTGGAGCTGCATCATCCTGTTCCTGGTGGCCACCGCTACCGGAGTGCACAGC SEQ ID
NO. 111
ATGGAATCACAGACCCAGGTCCTCATGTTTCTTCTGCTCTGGGTATCTGGTGCCTGTGCA SEQ ID
NO. 112 ATGCCGCTGC TGCTACTGCT GCCCCTGCTG TGGGCAGGGG CGCTAGCT
Sequence CWU 1
1
112117PRTArtificial SequenceH5L7, CDRL1 (Kabat defined) 1Lys Ser
Ser Gln Ser Leu Leu Asn Pro Ser Asn Gln Lys Asn Tyr Leu1 5 10
15Ala27PRTMurine 2Phe Ala Ser Thr Arg Asp Ser1 539PRTMurine 3Leu
Gln His Phe Gly Thr Pro Pro Thr1 54114PRTArtificial SequenceH5L7,
VL 4Asp Ile Gln Met Thr Gln Ser Pro Ser Ser Leu Ser Ala Ser Val
Gly1 5 10 15Asp Arg Val Thr Ile Thr Cys Lys Ser Ser Gln Ser Leu Leu
Asn Pro 20 25 30Ser Asn Gln Lys Asn Tyr Leu Ala Trp Tyr Gln Gln Lys
Pro Gly Lys 35 40 45Ala Pro Lys Leu Leu Val Tyr Phe Ala Ser Thr Arg
Asp Ser Gly Val 50 55 60Pro Ser Arg Phe Ser Gly Ser Gly Ser Gly Thr
Asp Phe Thr Leu Thr65 70 75 80Ile Ser Ser Leu Gln Pro Glu Asp Phe
Ala Thr Tyr Tyr Cys Leu Gln 85 90 95His Phe Gly Thr Pro Pro Thr Phe
Gly Gln Gly Thr Lys Leu Glu Ile 100 105 110Lys Arg5220PRTArtificial
SequenceH5L7, light chain humanised construct 5Asp Ile Gln Met Thr
Gln Ser Pro Ser Ser Leu Ser Ala Ser Val Gly1 5 10 15Asp Arg Val Thr
Ile Thr Cys Lys Ser Ser Gln Ser Leu Leu Asn Pro 20 25 30Ser Asn Gln
Lys Asn Tyr Leu Ala Trp Tyr Gln Gln Lys Pro Gly Lys 35 40 45Ala Pro
Lys Leu Leu Val Tyr Phe Ala Ser Thr Arg Asp Ser Gly Val 50 55 60Pro
Ser Arg Phe Ser Gly Ser Gly Ser Gly Thr Asp Phe Thr Leu Thr65 70 75
80Ile Ser Ser Leu Gln Pro Glu Asp Phe Ala Thr Tyr Tyr Cys Leu Gln
85 90 95His Phe Gly Thr Pro Pro Thr Phe Gly Gln Gly Thr Lys Leu Glu
Ile 100 105 110Lys Arg Thr Val Ala Ala Pro Ser Val Phe Ile Phe Pro
Pro Ser Asp 115 120 125Glu Gln Leu Lys Ser Gly Thr Ala Ser Val Val
Cys Leu Leu Asn Asn 130 135 140Phe Tyr Pro Arg Glu Ala Lys Val Gln
Trp Lys Val Asp Asn Ala Leu145 150 155 160Gln Ser Gly Asn Ser Gln
Glu Ser Val Thr Glu Gln Asp Ser Lys Asp 165 170 175Ser Thr Tyr Ser
Leu Ser Ser Thr Leu Thr Leu Ser Lys Ala Asp Tyr 180 185 190Glu Lys
His Lys Val Tyr Ala Cys Glu Val Thr His Gln Gly Leu Ser 195 200
205Ser Pro Val Thr Lys Ser Phe Asn Arg Gly Glu Cys 210 215
22065PRTMurine 6Ala Tyr Gly Val Asn1 5716PRTArtificial
SequenceH5L7, CDRH2 (Kabat defined) 7Met Ile Trp Asp Asp Gly Ser
Thr Asp Tyr Asp Ser Ala Leu Lys Ser1 5 10 1588PRTMurine 8Glu Gly
Asp Val Ala Phe Asp Tyr1 59116PRTArtificial SequenceH5L7, VH 9Gln
Val Gln Leu Gln Glu Ser Gly Pro Gly Leu Val Lys Pro Ser Glu1 5 10
15Thr Leu Ser Leu Thr Cys Thr Val Ser Gly Phe Ser Leu Thr Ala Tyr
20 25 30Gly Val Asn Trp Ile Arg Gln Pro Pro Gly Lys Gly Leu Glu Trp
Ile 35 40 45Gly Met Ile Trp Asp Asp Gly Ser Thr Asp Tyr Asp Ser Ala
Leu Lys 50 55 60Ser Arg Val Thr Ile Ser Val Asp Thr Ser Lys Asn Gln
Phe Ser Leu65 70 75 80Lys Leu Ser Ser Val Thr Ala Ala Asp Thr Ala
Val Tyr Tyr Cys Ala 85 90 95Arg Glu Gly Asp Val Ala Phe Asp Tyr Trp
Gly Gln Gly Thr Leu Val 100 105 110Thr Val Ser Ser
11510446PRTArtificial SequenceH5L7, heavy chain humanised construct
10Gln Val Gln Leu Gln Glu Ser Gly Pro Gly Leu Val Lys Pro Ser Glu1
5 10 15Thr Leu Ser Leu Thr Cys Thr Val Ser Gly Phe Ser Leu Thr Ala
Tyr 20 25 30Gly Val Asn Trp Ile Arg Gln Pro Pro Gly Lys Gly Leu Glu
Trp Ile 35 40 45Gly Met Ile Trp Asp Asp Gly Ser Thr Asp Tyr Asp Ser
Ala Leu Lys 50 55 60Ser Arg Val Thr Ile Ser Val Asp Thr Ser Lys Asn
Gln Phe Ser Leu65 70 75 80Lys Leu Ser Ser Val Thr Ala Ala Asp Thr
Ala Val Tyr Tyr Cys Ala 85 90 95Arg Glu Gly Asp Val Ala Phe Asp Tyr
Trp Gly Gln Gly Thr Leu Val 100 105 110Thr Val Ser Ser Ala Ser Thr
Lys Gly Pro Ser Val Phe Pro Leu Ala 115 120 125Pro Ser Ser Lys Ser
Thr Ser Gly Gly Thr Ala Ala Leu Gly Cys Leu 130 135 140Val Lys Asp
Tyr Phe Pro Glu Pro Val Thr Val Ser Trp Asn Ser Gly145 150 155
160Ala Leu Thr Ser Gly Val His Thr Phe Pro Ala Val Leu Gln Ser Ser
165 170 175Gly Leu Tyr Ser Leu Ser Ser Val Val Thr Val Pro Ser Ser
Ser Leu 180 185 190Gly Thr Gln Thr Tyr Ile Cys Asn Val Asn His Lys
Pro Ser Asn Thr 195 200 205Lys Val Asp Lys Lys Val Glu Pro Lys Ser
Cys Asp Lys Thr His Thr 210 215 220Cys Pro Pro Cys Pro Ala Pro Glu
Leu Leu Gly Gly Pro Ser Val Phe225 230 235 240Leu Phe Pro Pro Lys
Pro Lys Asp Thr Leu Met Ile Ser Arg Thr Pro 245 250 255Glu Val Thr
Cys Val Val Val Asp Val Ser His Glu Asp Pro Glu Val 260 265 270Lys
Phe Asn Trp Tyr Val Asp Gly Val Glu Val His Asn Ala Lys Thr 275 280
285Lys Pro Arg Glu Glu Gln Tyr Asn Ser Thr Tyr Arg Val Val Ser Val
290 295 300Leu Thr Val Leu His Gln Asp Trp Leu Asn Gly Lys Glu Tyr
Lys Cys305 310 315 320Lys Val Ser Asn Lys Ala Leu Pro Ala Pro Ile
Glu Lys Thr Ile Ser 325 330 335Lys Ala Lys Gly Gln Pro Arg Glu Pro
Gln Val Tyr Thr Leu Pro Pro 340 345 350Ser Arg Asp Glu Leu Thr Lys
Asn Gln Val Ser Leu Thr Cys Leu Val 355 360 365Lys Gly Phe Tyr Pro
Ser Asp Ile Ala Val Glu Trp Glu Ser Asn Gly 370 375 380Gln Pro Glu
Asn Asn Tyr Lys Thr Thr Pro Pro Val Leu Asp Ser Asp385 390 395
400Gly Ser Phe Phe Leu Tyr Ser Lys Leu Thr Val Asp Lys Ser Arg Trp
405 410 415Gln Gln Gly Asn Val Phe Ser Cys Ser Val Met His Glu Ala
Leu His 420 425 430Asn His Tyr Thr Gln Lys Ser Leu Ser Leu Ser Pro
Gly Lys 435 440 44511220PRTArtificial SequenceH1L7, light chain
humanised construct 11Asp Ile Gln Met Thr Gln Ser Pro Ser Ser Leu
Ser Ala Ser Val Gly1 5 10 15Asp Arg Val Thr Ile Thr Cys Lys Ser Ser
Gln Ser Leu Leu Asn Pro 20 25 30Ser Asn Gln Lys Asn Tyr Leu Ala Trp
Tyr Gln Gln Lys Pro Gly Lys 35 40 45Ala Pro Lys Leu Leu Val Tyr Phe
Ala Ser Thr Arg Asp Ser Gly Val 50 55 60Pro Ser Arg Phe Ser Gly Ser
Gly Ser Gly Thr Asp Phe Thr Leu Thr65 70 75 80Ile Ser Ser Leu Gln
Pro Glu Asp Phe Ala Thr Tyr Tyr Cys Leu Gln 85 90 95His Phe Gly Thr
Pro Pro Thr Phe Gly Gln Gly Thr Lys Leu Glu Ile 100 105 110Lys Arg
Thr Val Ala Ala Pro Ser Val Phe Ile Phe Pro Pro Ser Asp 115 120
125Glu Gln Leu Lys Ser Gly Thr Ala Ser Val Val Cys Leu Leu Asn Asn
130 135 140Phe Tyr Pro Arg Glu Ala Lys Val Gln Trp Lys Val Asp Asn
Ala Leu145 150 155 160Gln Ser Gly Asn Ser Gln Glu Ser Val Thr Glu
Gln Asp Ser Lys Asp 165 170 175Ser Thr Tyr Ser Leu Ser Ser Thr Leu
Thr Leu Ser Lys Ala Asp Tyr 180 185 190Glu Lys His Lys Val Tyr Ala
Cys Glu Val Thr His Gln Gly Leu Ser 195 200 205Ser Pro Val Thr Lys
Ser Phe Asn Arg Gly Glu Cys 210 215 22012446PRTArtificial
SequenceH1L7, heavy chain humanised construct 12Gln Val Gln Leu Gln
Glu Ser Gly Pro Gly Leu Val Lys Pro Ser Glu1 5 10 15Thr Leu Ser Leu
Thr Cys Thr Val Ser Gly Phe Ser Leu Thr Ala Tyr 20 25 30Gly Val Asn
Trp Ile Arg Gln Pro Pro Gly Lys Gly Leu Glu Trp Ile 35 40 45Gly Met
Ile Trp Asp Asp Gly Ser Thr Asp Tyr Asn Ser Ala Leu Lys 50 55 60Ser
Arg Val Thr Ile Ser Val Asp Thr Ser Lys Asn Gln Phe Ser Leu65 70 75
80Lys Leu Ser Ser Val Thr Ala Ala Asp Thr Ala Val Tyr Tyr Cys Ala
85 90 95Arg Glu Gly Asp Val Ala Phe Asp Tyr Trp Gly Gln Gly Thr Leu
Val 100 105 110Thr Val Ser Ser Ala Ser Thr Lys Gly Pro Ser Val Phe
Pro Leu Ala 115 120 125Pro Ser Ser Lys Ser Thr Ser Gly Gly Thr Ala
Ala Leu Gly Cys Leu 130 135 140Val Lys Asp Tyr Phe Pro Glu Pro Val
Thr Val Ser Trp Asn Ser Gly145 150 155 160Ala Leu Thr Ser Gly Val
His Thr Phe Pro Ala Val Leu Gln Ser Ser 165 170 175Gly Leu Tyr Ser
Leu Ser Ser Val Val Thr Val Pro Ser Ser Ser Leu 180 185 190Gly Thr
Gln Thr Tyr Ile Cys Asn Val Asn His Lys Pro Ser Asn Thr 195 200
205Lys Val Asp Lys Lys Val Glu Pro Lys Ser Cys Asp Lys Thr His Thr
210 215 220Cys Pro Pro Cys Pro Ala Pro Glu Leu Leu Gly Gly Pro Ser
Val Phe225 230 235 240Leu Phe Pro Pro Lys Pro Lys Asp Thr Leu Met
Ile Ser Arg Thr Pro 245 250 255Glu Val Thr Cys Val Val Val Asp Val
Ser His Glu Asp Pro Glu Val 260 265 270Lys Phe Asn Trp Tyr Val Asp
Gly Val Glu Val His Asn Ala Lys Thr 275 280 285Lys Pro Arg Glu Glu
Gln Tyr Asn Ser Thr Tyr Arg Val Val Ser Val 290 295 300Leu Thr Val
Leu His Gln Asp Trp Leu Asn Gly Lys Glu Tyr Lys Cys305 310 315
320Lys Val Ser Asn Lys Ala Leu Pro Ala Pro Ile Glu Lys Thr Ile Ser
325 330 335Lys Ala Lys Gly Gln Pro Arg Glu Pro Gln Val Tyr Thr Leu
Pro Pro 340 345 350Ser Arg Asp Glu Leu Thr Lys Asn Gln Val Ser Leu
Thr Cys Leu Val 355 360 365Lys Gly Phe Tyr Pro Ser Asp Ile Ala Val
Glu Trp Glu Ser Asn Gly 370 375 380Gln Pro Glu Asn Asn Tyr Lys Thr
Thr Pro Pro Val Leu Asp Ser Asp385 390 395 400Gly Ser Phe Phe Leu
Tyr Ser Lys Leu Thr Val Asp Lys Ser Arg Trp 405 410 415Gln Gln Gly
Asn Val Phe Ser Cys Ser Val Met His Glu Ala Leu His 420 425 430Asn
His Tyr Thr Gln Lys Ser Leu Ser Leu Ser Pro Gly Lys 435 440
44513220PRTArtificial SequenceJ7L7, light chain humanised construct
13Asp Ile Gln Met Thr Gln Ser Pro Ser Ser Leu Ser Ala Ser Val Gly1
5 10 15Asp Arg Val Thr Ile Thr Cys Lys Ser Ser Gln Ser Leu Leu Asn
Pro 20 25 30Ser Asn Gln Lys Asn Tyr Leu Ala Trp Tyr Gln Gln Lys Pro
Gly Lys 35 40 45Ala Pro Lys Leu Leu Val Tyr Phe Ala Ser Thr Arg Asp
Ser Gly Val 50 55 60Pro Ser Arg Phe Ser Gly Ser Gly Ser Gly Thr Asp
Phe Thr Leu Thr65 70 75 80Ile Ser Ser Leu Gln Pro Glu Asp Phe Ala
Thr Tyr Tyr Cys Leu Gln 85 90 95His Phe Gly Thr Pro Pro Thr Phe Gly
Gln Gly Thr Lys Leu Glu Ile 100 105 110Lys Arg Thr Val Ala Ala Pro
Ser Val Phe Ile Phe Pro Pro Ser Asp 115 120 125Glu Gln Leu Lys Ser
Gly Thr Ala Ser Val Val Cys Leu Leu Asn Asn 130 135 140Phe Tyr Pro
Arg Glu Ala Lys Val Gln Trp Lys Val Asp Asn Ala Leu145 150 155
160Gln Ser Gly Asn Ser Gln Glu Ser Val Thr Glu Gln Asp Ser Lys Asp
165 170 175Ser Thr Tyr Ser Leu Ser Ser Thr Leu Thr Leu Ser Lys Ala
Asp Tyr 180 185 190Glu Lys His Lys Val Tyr Ala Cys Glu Val Thr His
Gln Gly Leu Ser 195 200 205Ser Pro Val Thr Lys Ser Phe Asn Arg Gly
Glu Cys 210 215 22014446PRTArtificial SequenceJ7L7, heavy chain
humanised construct 14Gln Val Gln Leu Val Gln Ser Gly Ala Glu Val
Lys Lys Pro Gly Ser1 5 10 15Ser Val Lys Val Ser Cys Lys Ala Ser Gly
Phe Ser Leu Thr Ala Tyr 20 25 30Gly Val Asn Trp Val Arg Gln Ala Pro
Gly Gln Gly Leu Glu Trp Met 35 40 45Gly Met Ile Trp Asp Asp Gly Ser
Thr Asp Tyr Asn Ser Ala Leu Lys 50 55 60Ser Arg Val Thr Ile Thr Ala
Asp Lys Ser Thr Ser Thr Ala Tyr Met65 70 75 80Glu Leu Ser Ser Leu
Arg Ser Glu Asp Thr Ala Val Tyr Tyr Cys Ala 85 90 95Arg Glu Gly Asp
Val Ala Phe Asp Tyr Trp Gly Gln Gly Thr Leu Val 100 105 110Thr Val
Ser Ser Ala Ser Thr Lys Gly Pro Ser Val Phe Pro Leu Ala 115 120
125Pro Ser Ser Lys Ser Thr Ser Gly Gly Thr Ala Ala Leu Gly Cys Leu
130 135 140Val Lys Asp Tyr Phe Pro Glu Pro Val Thr Val Ser Trp Asn
Ser Gly145 150 155 160Ala Leu Thr Ser Gly Val His Thr Phe Pro Ala
Val Leu Gln Ser Ser 165 170 175Gly Leu Tyr Ser Leu Ser Ser Val Val
Thr Val Pro Ser Ser Ser Leu 180 185 190Gly Thr Gln Thr Tyr Ile Cys
Asn Val Asn His Lys Pro Ser Asn Thr 195 200 205Lys Val Asp Lys Lys
Val Glu Pro Lys Ser Cys Asp Lys Thr His Thr 210 215 220Cys Pro Pro
Cys Pro Ala Pro Glu Leu Leu Gly Gly Pro Ser Val Phe225 230 235
240Leu Phe Pro Pro Lys Pro Lys Asp Thr Leu Met Ile Ser Arg Thr Pro
245 250 255Glu Val Thr Cys Val Val Val Asp Val Ser His Glu Asp Pro
Glu Val 260 265 270Lys Phe Asn Trp Tyr Val Asp Gly Val Glu Val His
Asn Ala Lys Thr 275 280 285Lys Pro Arg Glu Glu Gln Tyr Asn Ser Thr
Tyr Arg Val Val Ser Val 290 295 300Leu Thr Val Leu His Gln Asp Trp
Leu Asn Gly Lys Glu Tyr Lys Cys305 310 315 320Lys Val Ser Asn Lys
Ala Leu Pro Ala Pro Ile Glu Lys Thr Ile Ser 325 330 335Lys Ala Lys
Gly Gln Pro Arg Glu Pro Gln Val Tyr Thr Leu Pro Pro 340 345 350Ser
Arg Asp Glu Leu Thr Lys Asn Gln Val Ser Leu Thr Cys Leu Val 355 360
365Lys Gly Phe Tyr Pro Ser Asp Ile Ala Val Glu Trp Glu Ser Asn Gly
370 375 380Gln Pro Glu Asn Asn Tyr Lys Thr Thr Pro Pro Val Leu Asp
Ser Asp385 390 395 400Gly Ser Phe Phe Leu Tyr Ser Lys Leu Thr Val
Asp Lys Ser Arg Trp 405 410 415Gln Gln Gly Asn Val Phe Ser Cys Ser
Val Met His Glu Ala Leu His 420 425 430Asn His Tyr Thr Gln Lys Ser
Leu Ser Leu Ser Pro Gly Lys 435 440 44515220PRTArtificial
SequenceH4L7, light chain humanised construct 15Asp Ile Gln Met Thr
Gln Ser Pro Ser Ser Leu Ser Ala Ser Val Gly1 5 10 15Asp Arg Val Thr
Ile Thr Cys Lys Ser Ser Gln Ser Leu Leu Asn Pro 20 25 30Ser Asn Gln
Lys Asn Tyr Leu Ala Trp Tyr Gln Gln Lys Pro Gly Lys 35 40 45Ala Pro
Lys Leu Leu Val Tyr Phe Ala Ser Thr Arg Asp Ser Gly Val 50 55 60Pro
Ser Arg Phe Ser Gly Ser Gly Ser Gly Thr Asp Phe Thr Leu Thr65 70 75
80Ile Ser Ser Leu Gln Pro Glu Asp Phe Ala Thr Tyr Tyr Cys Leu
Gln
85 90 95His Phe Gly Thr Pro Pro Thr Phe Gly Gln Gly Thr Lys Leu Glu
Ile 100 105 110Lys Arg Thr Val Ala Ala Pro Ser Val Phe Ile Phe Pro
Pro Ser Asp 115 120 125Glu Gln Leu Lys Ser Gly Thr Ala Ser Val Val
Cys Leu Leu Asn Asn 130 135 140Phe Tyr Pro Arg Glu Ala Lys Val Gln
Trp Lys Val Asp Asn Ala Leu145 150 155 160Gln Ser Gly Asn Ser Gln
Glu Ser Val Thr Glu Gln Asp Ser Lys Asp 165 170 175Ser Thr Tyr Ser
Leu Ser Ser Thr Leu Thr Leu Ser Lys Ala Asp Tyr 180 185 190Glu Lys
His Lys Val Tyr Ala Cys Glu Val Thr His Gln Gly Leu Ser 195 200
205Ser Pro Val Thr Lys Ser Phe Asn Arg Gly Glu Cys 210 215
22016446PRTArtificial SequenceH4L7, heavy chain humanised construct
16Gln Val Gln Leu Gln Glu Ser Gly Pro Gly Leu Val Lys Pro Ser Glu1
5 10 15Thr Leu Ser Leu Thr Cys Thr Val Ser Gly Phe Ser Leu Thr Ala
Tyr 20 25 30Gly Val Asn Trp Ile Arg Gln Pro Pro Gly Lys Gly Leu Glu
Trp Leu 35 40 45Gly Met Ile Trp Asp Asp Gly Ser Thr Asp Tyr Asn Ser
Ala Leu Lys 50 55 60Ser Arg Leu Thr Ile Ser Lys Asp Asn Ser Lys Asn
Gln Val Ser Leu65 70 75 80Lys Leu Ser Ser Val Thr Ala Ala Asp Thr
Ala Val Tyr Tyr Cys Ala 85 90 95Arg Glu Gly Asp Val Ala Phe Asp Tyr
Trp Gly Gln Gly Thr Leu Val 100 105 110Thr Val Ser Ser Ala Ser Thr
Lys Gly Pro Ser Val Phe Pro Leu Ala 115 120 125Pro Ser Ser Lys Ser
Thr Ser Gly Gly Thr Ala Ala Leu Gly Cys Leu 130 135 140Val Lys Asp
Tyr Phe Pro Glu Pro Val Thr Val Ser Trp Asn Ser Gly145 150 155
160Ala Leu Thr Ser Gly Val His Thr Phe Pro Ala Val Leu Gln Ser Ser
165 170 175Gly Leu Tyr Ser Leu Ser Ser Val Val Thr Val Pro Ser Ser
Ser Leu 180 185 190Gly Thr Gln Thr Tyr Ile Cys Asn Val Asn His Lys
Pro Ser Asn Thr 195 200 205Lys Val Asp Lys Lys Val Glu Pro Lys Ser
Cys Asp Lys Thr His Thr 210 215 220Cys Pro Pro Cys Pro Ala Pro Glu
Leu Leu Gly Gly Pro Ser Val Phe225 230 235 240Leu Phe Pro Pro Lys
Pro Lys Asp Thr Leu Met Ile Ser Arg Thr Pro 245 250 255Glu Val Thr
Cys Val Val Val Asp Val Ser His Glu Asp Pro Glu Val 260 265 270Lys
Phe Asn Trp Tyr Val Asp Gly Val Glu Val His Asn Ala Lys Thr 275 280
285Lys Pro Arg Glu Glu Gln Tyr Asn Ser Thr Tyr Arg Val Val Ser Val
290 295 300Leu Thr Val Leu His Gln Asp Trp Leu Asn Gly Lys Glu Tyr
Lys Cys305 310 315 320Lys Val Ser Asn Lys Ala Leu Pro Ala Pro Ile
Glu Lys Thr Ile Ser 325 330 335Lys Ala Lys Gly Gln Pro Arg Glu Pro
Gln Val Tyr Thr Leu Pro Pro 340 345 350Ser Arg Asp Glu Leu Thr Lys
Asn Gln Val Ser Leu Thr Cys Leu Val 355 360 365Lys Gly Phe Tyr Pro
Ser Asp Ile Ala Val Glu Trp Glu Ser Asn Gly 370 375 380Gln Pro Glu
Asn Asn Tyr Lys Thr Thr Pro Pro Val Leu Asp Ser Asp385 390 395
400Gly Ser Phe Phe Leu Tyr Ser Lys Leu Thr Val Asp Lys Ser Arg Trp
405 410 415Gln Gln Gly Asn Val Phe Ser Cys Ser Val Met His Glu Ala
Leu His 420 425 430Asn His Tyr Thr Gln Lys Ser Leu Ser Leu Ser Pro
Gly Lys 435 440 44517220PRTArtificial SequenceJ11L7, light chain
humanised construct 17Asp Ile Gln Met Thr Gln Ser Pro Ser Ser Leu
Ser Ala Ser Val Gly1 5 10 15Asp Arg Val Thr Ile Thr Cys Lys Ser Ser
Gln Ser Leu Leu Asn Pro 20 25 30Ser Asn Gln Lys Asn Tyr Leu Ala Trp
Tyr Gln Gln Lys Pro Gly Lys 35 40 45Ala Pro Lys Leu Leu Val Tyr Phe
Ala Ser Thr Arg Asp Ser Gly Val 50 55 60Pro Ser Arg Phe Ser Gly Ser
Gly Ser Gly Thr Asp Phe Thr Leu Thr65 70 75 80Ile Ser Ser Leu Gln
Pro Glu Asp Phe Ala Thr Tyr Tyr Cys Leu Gln 85 90 95His Phe Gly Thr
Pro Pro Thr Phe Gly Gln Gly Thr Lys Leu Glu Ile 100 105 110Lys Arg
Thr Val Ala Ala Pro Ser Val Phe Ile Phe Pro Pro Ser Asp 115 120
125Glu Gln Leu Lys Ser Gly Thr Ala Ser Val Val Cys Leu Leu Asn Asn
130 135 140Phe Tyr Pro Arg Glu Ala Lys Val Gln Trp Lys Val Asp Asn
Ala Leu145 150 155 160Gln Ser Gly Asn Ser Gln Glu Ser Val Thr Glu
Gln Asp Ser Lys Asp 165 170 175Ser Thr Tyr Ser Leu Ser Ser Thr Leu
Thr Leu Ser Lys Ala Asp Tyr 180 185 190Glu Lys His Lys Val Tyr Ala
Cys Glu Val Thr His Gln Gly Leu Ser 195 200 205Ser Pro Val Thr Lys
Ser Phe Asn Arg Gly Glu Cys 210 215 22018446PRTArtificial
SequenceJ11L7, heavy chain humanised construct 18Gln Val Gln Leu
Val Gln Ser Gly Ala Glu Val Lys Lys Pro Gly Ser1 5 10 15Ser Val Lys
Val Ser Cys Lys Ala Ser Gly Phe Ser Leu Thr Ala Tyr 20 25 30Gly Val
Asn Trp Val Arg Gln Ala Pro Gly Gln Gly Leu Glu Trp Met 35 40 45Gly
Met Ile Trp Asp Asp Gly Ser Thr Asp Tyr Asp Ser Ala Leu Lys 50 55
60Ser Arg Val Thr Ile Thr Ala Asp Lys Ser Thr Ser Thr Ala Tyr Met65
70 75 80Glu Leu Ser Ser Leu Arg Ser Glu Asp Thr Ala Val Tyr Tyr Cys
Ala 85 90 95Arg Glu Gly Asp Val Ala Phe Asp Tyr Trp Gly Gln Gly Thr
Leu Val 100 105 110Thr Val Ser Ser Ala Ser Thr Lys Gly Pro Ser Val
Phe Pro Leu Ala 115 120 125Pro Ser Ser Lys Ser Thr Ser Gly Gly Thr
Ala Ala Leu Gly Cys Leu 130 135 140Val Lys Asp Tyr Phe Pro Glu Pro
Val Thr Val Ser Trp Asn Ser Gly145 150 155 160Ala Leu Thr Ser Gly
Val His Thr Phe Pro Ala Val Leu Gln Ser Ser 165 170 175Gly Leu Tyr
Ser Leu Ser Ser Val Val Thr Val Pro Ser Ser Ser Leu 180 185 190Gly
Thr Gln Thr Tyr Ile Cys Asn Val Asn His Lys Pro Ser Asn Thr 195 200
205Lys Val Asp Lys Lys Val Glu Pro Lys Ser Cys Asp Lys Thr His Thr
210 215 220Cys Pro Pro Cys Pro Ala Pro Glu Leu Leu Gly Gly Pro Ser
Val Phe225 230 235 240Leu Phe Pro Pro Lys Pro Lys Asp Thr Leu Met
Ile Ser Arg Thr Pro 245 250 255Glu Val Thr Cys Val Val Val Asp Val
Ser His Glu Asp Pro Glu Val 260 265 270Lys Phe Asn Trp Tyr Val Asp
Gly Val Glu Val His Asn Ala Lys Thr 275 280 285Lys Pro Arg Glu Glu
Gln Tyr Asn Ser Thr Tyr Arg Val Val Ser Val 290 295 300Leu Thr Val
Leu His Gln Asp Trp Leu Asn Gly Lys Glu Tyr Lys Cys305 310 315
320Lys Val Ser Asn Lys Ala Leu Pro Ala Pro Ile Glu Lys Thr Ile Ser
325 330 335Lys Ala Lys Gly Gln Pro Arg Glu Pro Gln Val Tyr Thr Leu
Pro Pro 340 345 350Ser Arg Asp Glu Leu Thr Lys Asn Gln Val Ser Leu
Thr Cys Leu Val 355 360 365Lys Gly Phe Tyr Pro Ser Asp Ile Ala Val
Glu Trp Glu Ser Asn Gly 370 375 380Gln Pro Glu Asn Asn Tyr Lys Thr
Thr Pro Pro Val Leu Asp Ser Asp385 390 395 400Gly Ser Phe Phe Leu
Tyr Ser Lys Leu Thr Val Asp Lys Ser Arg Trp 405 410 415Gln Gln Gly
Asn Val Phe Ser Cys Ser Val Met His Glu Ala Leu His 420 425 430Asn
His Tyr Thr Gln Lys Ser Leu Ser Leu Ser Pro Gly Lys 435 440
44519220PRTArtificial SequenceH2L7, light chain humanised construct
19Asp Ile Gln Met Thr Gln Ser Pro Ser Ser Leu Ser Ala Ser Val Gly1
5 10 15Asp Arg Val Thr Ile Thr Cys Lys Ser Ser Gln Ser Leu Leu Asn
Pro 20 25 30Ser Asn Gln Lys Asn Tyr Leu Ala Trp Tyr Gln Gln Lys Pro
Gly Lys 35 40 45Ala Pro Lys Leu Leu Val Tyr Phe Ala Ser Thr Arg Asp
Ser Gly Val 50 55 60Pro Ser Arg Phe Ser Gly Ser Gly Ser Gly Thr Asp
Phe Thr Leu Thr65 70 75 80Ile Ser Ser Leu Gln Pro Glu Asp Phe Ala
Thr Tyr Tyr Cys Leu Gln 85 90 95His Phe Gly Thr Pro Pro Thr Phe Gly
Gln Gly Thr Lys Leu Glu Ile 100 105 110Lys Arg Thr Val Ala Ala Pro
Ser Val Phe Ile Phe Pro Pro Ser Asp 115 120 125Glu Gln Leu Lys Ser
Gly Thr Ala Ser Val Val Cys Leu Leu Asn Asn 130 135 140Phe Tyr Pro
Arg Glu Ala Lys Val Gln Trp Lys Val Asp Asn Ala Leu145 150 155
160Gln Ser Gly Asn Ser Gln Glu Ser Val Thr Glu Gln Asp Ser Lys Asp
165 170 175Ser Thr Tyr Ser Leu Ser Ser Thr Leu Thr Leu Ser Lys Ala
Asp Tyr 180 185 190Glu Lys His Lys Val Tyr Ala Cys Glu Val Thr His
Gln Gly Leu Ser 195 200 205Ser Pro Val Thr Lys Ser Phe Asn Arg Gly
Glu Cys 210 215 22020446PRTArtificial SequenceH2L7, heavy chain
humanised construct 20Gln Val Gln Leu Gln Glu Ser Gly Pro Gly Leu
Val Lys Pro Ser Glu1 5 10 15Thr Leu Ser Leu Thr Cys Thr Val Ser Gly
Phe Ser Leu Thr Ala Tyr 20 25 30Gly Val Asn Trp Ile Arg Gln Pro Pro
Gly Lys Gly Leu Glu Trp Ile 35 40 45Gly Met Ile Trp Asp Asp Gly Ser
Thr Asp Tyr Asn Ser Ala Leu Lys 50 55 60Ser Arg Val Thr Ile Ser Lys
Asp Asn Ser Lys Asn Gln Val Ser Leu65 70 75 80Lys Leu Ser Ser Val
Thr Ala Ala Asp Thr Ala Val Tyr Tyr Cys Ala 85 90 95Arg Glu Gly Asp
Val Ala Phe Asp Tyr Trp Gly Gln Gly Thr Leu Val 100 105 110Thr Val
Ser Ser Ala Ser Thr Lys Gly Pro Ser Val Phe Pro Leu Ala 115 120
125Pro Ser Ser Lys Ser Thr Ser Gly Gly Thr Ala Ala Leu Gly Cys Leu
130 135 140Val Lys Asp Tyr Phe Pro Glu Pro Val Thr Val Ser Trp Asn
Ser Gly145 150 155 160Ala Leu Thr Ser Gly Val His Thr Phe Pro Ala
Val Leu Gln Ser Ser 165 170 175Gly Leu Tyr Ser Leu Ser Ser Val Val
Thr Val Pro Ser Ser Ser Leu 180 185 190Gly Thr Gln Thr Tyr Ile Cys
Asn Val Asn His Lys Pro Ser Asn Thr 195 200 205Lys Val Asp Lys Lys
Val Glu Pro Lys Ser Cys Asp Lys Thr His Thr 210 215 220Cys Pro Pro
Cys Pro Ala Pro Glu Leu Leu Gly Gly Pro Ser Val Phe225 230 235
240Leu Phe Pro Pro Lys Pro Lys Asp Thr Leu Met Ile Ser Arg Thr Pro
245 250 255Glu Val Thr Cys Val Val Val Asp Val Ser His Glu Asp Pro
Glu Val 260 265 270Lys Phe Asn Trp Tyr Val Asp Gly Val Glu Val His
Asn Ala Lys Thr 275 280 285Lys Pro Arg Glu Glu Gln Tyr Asn Ser Thr
Tyr Arg Val Val Ser Val 290 295 300Leu Thr Val Leu His Gln Asp Trp
Leu Asn Gly Lys Glu Tyr Lys Cys305 310 315 320Lys Val Ser Asn Lys
Ala Leu Pro Ala Pro Ile Glu Lys Thr Ile Ser 325 330 335Lys Ala Lys
Gly Gln Pro Arg Glu Pro Gln Val Tyr Thr Leu Pro Pro 340 345 350Ser
Arg Asp Glu Leu Thr Lys Asn Gln Val Ser Leu Thr Cys Leu Val 355 360
365Lys Gly Phe Tyr Pro Ser Asp Ile Ala Val Glu Trp Glu Ser Asn Gly
370 375 380Gln Pro Glu Asn Asn Tyr Lys Thr Thr Pro Pro Val Leu Asp
Ser Asp385 390 395 400Gly Ser Phe Phe Leu Tyr Ser Lys Leu Thr Val
Asp Lys Ser Arg Trp 405 410 415Gln Gln Gly Asn Val Phe Ser Cys Ser
Val Met His Glu Ala Leu His 420 425 430Asn His Tyr Thr Gln Lys Ser
Leu Ser Leu Ser Pro Gly Lys 435 440 44521220PRTArtificial
SequenceJ13L7, light chain humanised construct 21Asp Ile Gln Met
Thr Gln Ser Pro Ser Ser Leu Ser Ala Ser Val Gly1 5 10 15Asp Arg Val
Thr Ile Thr Cys Lys Ser Ser Gln Ser Leu Leu Asn Pro 20 25 30Ser Asn
Gln Lys Asn Tyr Leu Ala Trp Tyr Gln Gln Lys Pro Gly Lys 35 40 45Ala
Pro Lys Leu Leu Val Tyr Phe Ala Ser Thr Arg Asp Ser Gly Val 50 55
60Pro Ser Arg Phe Ser Gly Ser Gly Ser Gly Thr Asp Phe Thr Leu Thr65
70 75 80Ile Ser Ser Leu Gln Pro Glu Asp Phe Ala Thr Tyr Tyr Cys Leu
Gln 85 90 95His Phe Gly Thr Pro Pro Thr Phe Gly Gln Gly Thr Lys Leu
Glu Ile 100 105 110Lys Arg Thr Val Ala Ala Pro Ser Val Phe Ile Phe
Pro Pro Ser Asp 115 120 125Glu Gln Leu Lys Ser Gly Thr Ala Ser Val
Val Cys Leu Leu Asn Asn 130 135 140Phe Tyr Pro Arg Glu Ala Lys Val
Gln Trp Lys Val Asp Asn Ala Leu145 150 155 160Gln Ser Gly Asn Ser
Gln Glu Ser Val Thr Glu Gln Asp Ser Lys Asp 165 170 175Ser Thr Tyr
Ser Leu Ser Ser Thr Leu Thr Leu Ser Lys Ala Asp Tyr 180 185 190Glu
Lys His Lys Val Tyr Ala Cys Glu Val Thr His Gln Gly Leu Ser 195 200
205Ser Pro Val Thr Lys Ser Phe Asn Arg Gly Glu Cys 210 215
22022446PRTArtificial SequenceJ13L7, heavy chain humanised
construct 22Gln Val Gln Leu Val Gln Ser Gly Ala Glu Val Lys Lys Pro
Gly Ser1 5 10 15Ser Val Lys Val Ser Cys Lys Ala Ser Gly Gly Thr Phe
Ser Ala Tyr 20 25 30Gly Val Asn Trp Val Arg Gln Ala Pro Gly Gln Gly
Leu Glu Trp Met 35 40 45Gly Met Ile Trp Asp Asp Gly Ser Thr Asp Tyr
Asp Ser Ala Leu Lys 50 55 60Ser Arg Val Thr Ile Thr Ala Asp Lys Ser
Thr Ser Thr Ala Tyr Met65 70 75 80Glu Leu Ser Ser Leu Arg Ser Glu
Asp Thr Ala Val Tyr Tyr Cys Ala 85 90 95Arg Glu Gly Asp Val Ala Phe
Asp Tyr Trp Gly Gln Gly Thr Leu Val 100 105 110Thr Val Ser Ser Ala
Ser Thr Lys Gly Pro Ser Val Phe Pro Leu Ala 115 120 125Pro Ser Ser
Lys Ser Thr Ser Gly Gly Thr Ala Ala Leu Gly Cys Leu 130 135 140Val
Lys Asp Tyr Phe Pro Glu Pro Val Thr Val Ser Trp Asn Ser Gly145 150
155 160Ala Leu Thr Ser Gly Val His Thr Phe Pro Ala Val Leu Gln Ser
Ser 165 170 175Gly Leu Tyr Ser Leu Ser Ser Val Val Thr Val Pro Ser
Ser Ser Leu 180 185 190Gly Thr Gln Thr Tyr Ile Cys Asn Val Asn His
Lys Pro Ser Asn Thr 195 200 205Lys Val Asp Lys Lys Val Glu Pro Lys
Ser Cys Asp Lys Thr His Thr 210 215 220Cys Pro Pro Cys Pro Ala Pro
Glu Leu Leu Gly Gly Pro Ser Val Phe225 230 235 240Leu Phe Pro Pro
Lys Pro Lys Asp Thr Leu Met Ile Ser Arg Thr Pro 245 250 255Glu Val
Thr Cys Val Val Val Asp Val Ser His Glu Asp Pro Glu Val 260 265
270Lys Phe Asn Trp Tyr
Val Asp Gly Val Glu Val His Asn Ala Lys Thr 275 280 285Lys Pro Arg
Glu Glu Gln Tyr Asn Ser Thr Tyr Arg Val Val Ser Val 290 295 300Leu
Thr Val Leu His Gln Asp Trp Leu Asn Gly Lys Glu Tyr Lys Cys305 310
315 320Lys Val Ser Asn Lys Ala Leu Pro Ala Pro Ile Glu Lys Thr Ile
Ser 325 330 335Lys Ala Lys Gly Gln Pro Arg Glu Pro Gln Val Tyr Thr
Leu Pro Pro 340 345 350Ser Arg Asp Glu Leu Thr Lys Asn Gln Val Ser
Leu Thr Cys Leu Val 355 360 365Lys Gly Phe Tyr Pro Ser Asp Ile Ala
Val Glu Trp Glu Ser Asn Gly 370 375 380Gln Pro Glu Asn Asn Tyr Lys
Thr Thr Pro Pro Val Leu Asp Ser Asp385 390 395 400Gly Ser Phe Phe
Leu Tyr Ser Lys Leu Thr Val Asp Lys Ser Arg Trp 405 410 415Gln Gln
Gly Asn Val Phe Ser Cys Ser Val Met His Glu Ala Leu His 420 425
430Asn His Tyr Thr Gln Lys Ser Leu Ser Leu Ser Pro Gly Lys 435 440
44523220PRTArtificial SequenceH7L7, light chain humanised construct
23Asp Ile Gln Met Thr Gln Ser Pro Ser Ser Leu Ser Ala Ser Val Gly1
5 10 15Asp Arg Val Thr Ile Thr Cys Lys Ser Ser Gln Ser Leu Leu Asn
Pro 20 25 30Ser Asn Gln Lys Asn Tyr Leu Ala Trp Tyr Gln Gln Lys Pro
Gly Lys 35 40 45Ala Pro Lys Leu Leu Val Tyr Phe Ala Ser Thr Arg Asp
Ser Gly Val 50 55 60Pro Ser Arg Phe Ser Gly Ser Gly Ser Gly Thr Asp
Phe Thr Leu Thr65 70 75 80Ile Ser Ser Leu Gln Pro Glu Asp Phe Ala
Thr Tyr Tyr Cys Leu Gln 85 90 95His Phe Gly Thr Pro Pro Thr Phe Gly
Gln Gly Thr Lys Leu Glu Ile 100 105 110Lys Arg Thr Val Ala Ala Pro
Ser Val Phe Ile Phe Pro Pro Ser Asp 115 120 125Glu Gln Leu Lys Ser
Gly Thr Ala Ser Val Val Cys Leu Leu Asn Asn 130 135 140Phe Tyr Pro
Arg Glu Ala Lys Val Gln Trp Lys Val Asp Asn Ala Leu145 150 155
160Gln Ser Gly Asn Ser Gln Glu Ser Val Thr Glu Gln Asp Ser Lys Asp
165 170 175Ser Thr Tyr Ser Leu Ser Ser Thr Leu Thr Leu Ser Lys Ala
Asp Tyr 180 185 190Glu Lys His Lys Val Tyr Ala Cys Glu Val Thr His
Gln Gly Leu Ser 195 200 205Ser Pro Val Thr Lys Ser Phe Asn Arg Gly
Glu Cys 210 215 22024446PRTArtificial SequenceH7L7, heavy chain
humanised construct 24Gln Val Gln Leu Gln Glu Ser Gly Pro Gly Leu
Val Lys Pro Ser Glu1 5 10 15Thr Leu Ser Leu Thr Cys Thr Val Ser Gly
Gly Ser Ile Ser Ala Tyr 20 25 30Gly Val Asn Trp Ile Arg Gln Pro Pro
Gly Lys Gly Leu Glu Trp Ile 35 40 45Gly Met Ile Trp Asp Asp Gly Ser
Thr Asp Tyr Asp Ser Ala Leu Lys 50 55 60Ser Arg Val Thr Ile Ser Val
Asp Thr Ser Lys Asn Gln Phe Ser Leu65 70 75 80Lys Leu Ser Ser Val
Thr Ala Ala Asp Thr Ala Val Tyr Tyr Cys Ala 85 90 95Arg Glu Gly Asp
Val Ala Phe Asp Tyr Trp Gly Gln Gly Thr Leu Val 100 105 110Thr Val
Ser Ser Ala Ser Thr Lys Gly Pro Ser Val Phe Pro Leu Ala 115 120
125Pro Ser Ser Lys Ser Thr Ser Gly Gly Thr Ala Ala Leu Gly Cys Leu
130 135 140Val Lys Asp Tyr Phe Pro Glu Pro Val Thr Val Ser Trp Asn
Ser Gly145 150 155 160Ala Leu Thr Ser Gly Val His Thr Phe Pro Ala
Val Leu Gln Ser Ser 165 170 175Gly Leu Tyr Ser Leu Ser Ser Val Val
Thr Val Pro Ser Ser Ser Leu 180 185 190Gly Thr Gln Thr Tyr Ile Cys
Asn Val Asn His Lys Pro Ser Asn Thr 195 200 205Lys Val Asp Lys Lys
Val Glu Pro Lys Ser Cys Asp Lys Thr His Thr 210 215 220Cys Pro Pro
Cys Pro Ala Pro Glu Leu Leu Gly Gly Pro Ser Val Phe225 230 235
240Leu Phe Pro Pro Lys Pro Lys Asp Thr Leu Met Ile Ser Arg Thr Pro
245 250 255Glu Val Thr Cys Val Val Val Asp Val Ser His Glu Asp Pro
Glu Val 260 265 270Lys Phe Asn Trp Tyr Val Asp Gly Val Glu Val His
Asn Ala Lys Thr 275 280 285Lys Pro Arg Glu Glu Gln Tyr Asn Ser Thr
Tyr Arg Val Val Ser Val 290 295 300Leu Thr Val Leu His Gln Asp Trp
Leu Asn Gly Lys Glu Tyr Lys Cys305 310 315 320Lys Val Ser Asn Lys
Ala Leu Pro Ala Pro Ile Glu Lys Thr Ile Ser 325 330 335Lys Ala Lys
Gly Gln Pro Arg Glu Pro Gln Val Tyr Thr Leu Pro Pro 340 345 350Ser
Arg Asp Glu Leu Thr Lys Asn Gln Val Ser Leu Thr Cys Leu Val 355 360
365Lys Gly Phe Tyr Pro Ser Asp Ile Ala Val Glu Trp Glu Ser Asn Gly
370 375 380Gln Pro Glu Asn Asn Tyr Lys Thr Thr Pro Pro Val Leu Asp
Ser Asp385 390 395 400Gly Ser Phe Phe Leu Tyr Ser Lys Leu Thr Val
Asp Lys Ser Arg Trp 405 410 415Gln Gln Gly Asn Val Phe Ser Cys Ser
Val Met His Glu Ala Leu His 420 425 430Asn His Tyr Thr Gln Lys Ser
Leu Ser Leu Ser Pro Gly Lys 435 440 44525220PRTArtificial
SequenceJ0L7, light chain humanised construct 25Asp Ile Gln Met Thr
Gln Ser Pro Ser Ser Leu Ser Ala Ser Val Gly1 5 10 15Asp Arg Val Thr
Ile Thr Cys Lys Ser Ser Gln Ser Leu Leu Asn Pro 20 25 30Ser Asn Gln
Lys Asn Tyr Leu Ala Trp Tyr Gln Gln Lys Pro Gly Lys 35 40 45Ala Pro
Lys Leu Leu Val Tyr Phe Ala Ser Thr Arg Asp Ser Gly Val 50 55 60Pro
Ser Arg Phe Ser Gly Ser Gly Ser Gly Thr Asp Phe Thr Leu Thr65 70 75
80Ile Ser Ser Leu Gln Pro Glu Asp Phe Ala Thr Tyr Tyr Cys Leu Gln
85 90 95His Phe Gly Thr Pro Pro Thr Phe Gly Gln Gly Thr Lys Leu Glu
Ile 100 105 110Lys Arg Thr Val Ala Ala Pro Ser Val Phe Ile Phe Pro
Pro Ser Asp 115 120 125Glu Gln Leu Lys Ser Gly Thr Ala Ser Val Val
Cys Leu Leu Asn Asn 130 135 140Phe Tyr Pro Arg Glu Ala Lys Val Gln
Trp Lys Val Asp Asn Ala Leu145 150 155 160Gln Ser Gly Asn Ser Gln
Glu Ser Val Thr Glu Gln Asp Ser Lys Asp 165 170 175Ser Thr Tyr Ser
Leu Ser Ser Thr Leu Thr Leu Ser Lys Ala Asp Tyr 180 185 190Glu Lys
His Lys Val Tyr Ala Cys Glu Val Thr His Gln Gly Leu Ser 195 200
205Ser Pro Val Thr Lys Ser Phe Asn Arg Gly Glu Cys 210 215
22026446PRTArtificial SequenceJ0L7, heavy chain humanised construct
26Gln Val Gln Leu Val Gln Ser Gly Ala Glu Val Lys Lys Pro Gly Ser1
5 10 15Ser Val Lys Val Ser Cys Lys Ala Ser Gly Gly Thr Phe Ser Ala
Tyr 20 25 30Gly Val Asn Trp Val Arg Gln Ala Pro Gly Gln Gly Leu Glu
Trp Met 35 40 45Gly Met Ile Trp Asp Asp Gly Ser Thr Asp Tyr Asn Ser
Ala Leu Lys 50 55 60Ser Arg Val Thr Ile Thr Ala Asp Lys Ser Thr Ser
Thr Ala Tyr Met65 70 75 80Glu Leu Ser Ser Leu Arg Ser Glu Asp Thr
Ala Val Tyr Tyr Cys Ala 85 90 95Arg Glu Gly Asp Val Ala Phe Asp Tyr
Trp Gly Gln Gly Thr Leu Val 100 105 110Thr Val Ser Ser Ala Ser Thr
Lys Gly Pro Ser Val Phe Pro Leu Ala 115 120 125Pro Ser Ser Lys Ser
Thr Ser Gly Gly Thr Ala Ala Leu Gly Cys Leu 130 135 140Val Lys Asp
Tyr Phe Pro Glu Pro Val Thr Val Ser Trp Asn Ser Gly145 150 155
160Ala Leu Thr Ser Gly Val His Thr Phe Pro Ala Val Leu Gln Ser Ser
165 170 175Gly Leu Tyr Ser Leu Ser Ser Val Val Thr Val Pro Ser Ser
Ser Leu 180 185 190Gly Thr Gln Thr Tyr Ile Cys Asn Val Asn His Lys
Pro Ser Asn Thr 195 200 205Lys Val Asp Lys Lys Val Glu Pro Lys Ser
Cys Asp Lys Thr His Thr 210 215 220Cys Pro Pro Cys Pro Ala Pro Glu
Leu Leu Gly Gly Pro Ser Val Phe225 230 235 240Leu Phe Pro Pro Lys
Pro Lys Asp Thr Leu Met Ile Ser Arg Thr Pro 245 250 255Glu Val Thr
Cys Val Val Val Asp Val Ser His Glu Asp Pro Glu Val 260 265 270Lys
Phe Asn Trp Tyr Val Asp Gly Val Glu Val His Asn Ala Lys Thr 275 280
285Lys Pro Arg Glu Glu Gln Tyr Asn Ser Thr Tyr Arg Val Val Ser Val
290 295 300Leu Thr Val Leu His Gln Asp Trp Leu Asn Gly Lys Glu Tyr
Lys Cys305 310 315 320Lys Val Ser Asn Lys Ala Leu Pro Ala Pro Ile
Glu Lys Thr Ile Ser 325 330 335Lys Ala Lys Gly Gln Pro Arg Glu Pro
Gln Val Tyr Thr Leu Pro Pro 340 345 350Ser Arg Asp Glu Leu Thr Lys
Asn Gln Val Ser Leu Thr Cys Leu Val 355 360 365Lys Gly Phe Tyr Pro
Ser Asp Ile Ala Val Glu Trp Glu Ser Asn Gly 370 375 380Gln Pro Glu
Asn Asn Tyr Lys Thr Thr Pro Pro Val Leu Asp Ser Asp385 390 395
400Gly Ser Phe Phe Leu Tyr Ser Lys Leu Thr Val Asp Lys Ser Arg Trp
405 410 415Gln Gln Gly Asn Val Phe Ser Cys Ser Val Met His Glu Ala
Leu His 420 425 430Asn His Tyr Thr Gln Lys Ser Leu Ser Leu Ser Pro
Gly Lys 435 440 44527220PRTArtificial SequenceH0L7, light chain
humanised construct 27Asp Ile Gln Met Thr Gln Ser Pro Ser Ser Leu
Ser Ala Ser Val Gly1 5 10 15Asp Arg Val Thr Ile Thr Cys Lys Ser Ser
Gln Ser Leu Leu Asn Pro 20 25 30Ser Asn Gln Lys Asn Tyr Leu Ala Trp
Tyr Gln Gln Lys Pro Gly Lys 35 40 45Ala Pro Lys Leu Leu Val Tyr Phe
Ala Ser Thr Arg Asp Ser Gly Val 50 55 60Pro Ser Arg Phe Ser Gly Ser
Gly Ser Gly Thr Asp Phe Thr Leu Thr65 70 75 80Ile Ser Ser Leu Gln
Pro Glu Asp Phe Ala Thr Tyr Tyr Cys Leu Gln 85 90 95His Phe Gly Thr
Pro Pro Thr Phe Gly Gln Gly Thr Lys Leu Glu Ile 100 105 110Lys Arg
Thr Val Ala Ala Pro Ser Val Phe Ile Phe Pro Pro Ser Asp 115 120
125Glu Gln Leu Lys Ser Gly Thr Ala Ser Val Val Cys Leu Leu Asn Asn
130 135 140Phe Tyr Pro Arg Glu Ala Lys Val Gln Trp Lys Val Asp Asn
Ala Leu145 150 155 160Gln Ser Gly Asn Ser Gln Glu Ser Val Thr Glu
Gln Asp Ser Lys Asp 165 170 175Ser Thr Tyr Ser Leu Ser Ser Thr Leu
Thr Leu Ser Lys Ala Asp Tyr 180 185 190Glu Lys His Lys Val Tyr Ala
Cys Glu Val Thr His Gln Gly Leu Ser 195 200 205Ser Pro Val Thr Lys
Ser Phe Asn Arg Gly Glu Cys 210 215 22028446PRTArtificial
SequenceH0L7, heavy chain humanised construct 28Gln Val Gln Leu Gln
Glu Ser Gly Pro Gly Leu Val Lys Pro Ser Glu1 5 10 15Thr Leu Ser Leu
Thr Cys Thr Val Ser Gly Gly Ser Ile Ser Ala Tyr 20 25 30Gly Val Asn
Trp Ile Arg Gln Pro Pro Gly Lys Gly Leu Glu Trp Ile 35 40 45Gly Met
Ile Trp Asp Asp Gly Ser Thr Asp Tyr Asn Ser Ala Leu Lys 50 55 60Ser
Arg Val Thr Ile Ser Val Asp Thr Ser Lys Asn Gln Phe Ser Leu65 70 75
80Lys Leu Ser Ser Val Thr Ala Ala Asp Thr Ala Val Tyr Tyr Cys Ala
85 90 95Arg Glu Gly Asp Val Ala Phe Asp Tyr Trp Gly Gln Gly Thr Leu
Val 100 105 110Thr Val Ser Ser Ala Ser Thr Lys Gly Pro Ser Val Phe
Pro Leu Ala 115 120 125Pro Ser Ser Lys Ser Thr Ser Gly Gly Thr Ala
Ala Leu Gly Cys Leu 130 135 140Val Lys Asp Tyr Phe Pro Glu Pro Val
Thr Val Ser Trp Asn Ser Gly145 150 155 160Ala Leu Thr Ser Gly Val
His Thr Phe Pro Ala Val Leu Gln Ser Ser 165 170 175Gly Leu Tyr Ser
Leu Ser Ser Val Val Thr Val Pro Ser Ser Ser Leu 180 185 190Gly Thr
Gln Thr Tyr Ile Cys Asn Val Asn His Lys Pro Ser Asn Thr 195 200
205Lys Val Asp Lys Lys Val Glu Pro Lys Ser Cys Asp Lys Thr His Thr
210 215 220Cys Pro Pro Cys Pro Ala Pro Glu Leu Leu Gly Gly Pro Ser
Val Phe225 230 235 240Leu Phe Pro Pro Lys Pro Lys Asp Thr Leu Met
Ile Ser Arg Thr Pro 245 250 255Glu Val Thr Cys Val Val Val Asp Val
Ser His Glu Asp Pro Glu Val 260 265 270Lys Phe Asn Trp Tyr Val Asp
Gly Val Glu Val His Asn Ala Lys Thr 275 280 285Lys Pro Arg Glu Glu
Gln Tyr Asn Ser Thr Tyr Arg Val Val Ser Val 290 295 300Leu Thr Val
Leu His Gln Asp Trp Leu Asn Gly Lys Glu Tyr Lys Cys305 310 315
320Lys Val Ser Asn Lys Ala Leu Pro Ala Pro Ile Glu Lys Thr Ile Ser
325 330 335Lys Ala Lys Gly Gln Pro Arg Glu Pro Gln Val Tyr Thr Leu
Pro Pro 340 345 350Ser Arg Asp Glu Leu Thr Lys Asn Gln Val Ser Leu
Thr Cys Leu Val 355 360 365Lys Gly Phe Tyr Pro Ser Asp Ile Ala Val
Glu Trp Glu Ser Asn Gly 370 375 380Gln Pro Glu Asn Asn Tyr Lys Thr
Thr Pro Pro Val Leu Asp Ser Asp385 390 395 400Gly Ser Phe Phe Leu
Tyr Ser Lys Leu Thr Val Asp Lys Ser Arg Trp 405 410 415Gln Gln Gly
Asn Val Phe Ser Cys Ser Val Met His Glu Ala Leu His 420 425 430Asn
His Tyr Thr Gln Lys Ser Leu Ser Leu Ser Pro Gly Lys 435 440
44529220PRTArtificial SequenceH1L1, light chain humanised construct
29Asp Ile Gln Met Thr Gln Ser Pro Ser Ser Leu Ser Ala Ser Val Gly1
5 10 15Asp Arg Val Thr Ile Thr Cys Lys Ser Ser Gln Ser Leu Leu Asn
Gly 20 25 30Ser Asn Gln Lys Asn Tyr Leu Ala Trp Tyr Gln Gln Lys Pro
Gly Lys 35 40 45Ala Pro Lys Leu Leu Val Tyr Phe Ala Ser Thr Arg Asp
Ser Gly Val 50 55 60Pro Ser Arg Phe Ser Gly Ser Gly Ser Gly Thr Asp
Phe Thr Leu Thr65 70 75 80Ile Ser Ser Leu Gln Pro Glu Asp Phe Ala
Thr Tyr Tyr Cys Leu Gln 85 90 95His Phe Gly Thr Pro Pro Thr Phe Gly
Gln Gly Thr Lys Leu Glu Ile 100 105 110Lys Arg Thr Val Ala Ala Pro
Ser Val Phe Ile Phe Pro Pro Ser Asp 115 120 125Glu Gln Leu Lys Ser
Gly Thr Ala Ser Val Val Cys Leu Leu Asn Asn 130 135 140Phe Tyr Pro
Arg Glu Ala Lys Val Gln Trp Lys Val Asp Asn Ala Leu145 150 155
160Gln Ser Gly Asn Ser Gln Glu Ser Val Thr Glu Gln Asp Ser Lys Asp
165 170 175Ser Thr Tyr Ser Leu Ser Ser Thr Leu Thr Leu Ser Lys Ala
Asp Tyr 180 185 190Glu Lys His Lys Val Tyr Ala Cys Glu Val Thr His
Gln Gly Leu Ser 195 200 205Ser Pro Val Thr Lys Ser Phe Asn Arg Gly
Glu Cys 210 215 22030446PRTArtificial SequenceH1L1, heavy chain
humanised construct 30Gln
Val Gln Leu Gln Glu Ser Gly Pro Gly Leu Val Lys Pro Ser Glu1 5 10
15Thr Leu Ser Leu Thr Cys Thr Val Ser Gly Phe Ser Leu Thr Ala Tyr
20 25 30Gly Val Asn Trp Ile Arg Gln Pro Pro Gly Lys Gly Leu Glu Trp
Ile 35 40 45Gly Met Ile Trp Asp Asp Gly Ser Thr Asp Tyr Asn Ser Ala
Leu Lys 50 55 60Ser Arg Val Thr Ile Ser Val Asp Thr Ser Lys Asn Gln
Phe Ser Leu65 70 75 80Lys Leu Ser Ser Val Thr Ala Ala Asp Thr Ala
Val Tyr Tyr Cys Ala 85 90 95Arg Glu Gly Asp Val Ala Phe Asp Tyr Trp
Gly Gln Gly Thr Leu Val 100 105 110Thr Val Ser Ser Ala Ser Thr Lys
Gly Pro Ser Val Phe Pro Leu Ala 115 120 125Pro Ser Ser Lys Ser Thr
Ser Gly Gly Thr Ala Ala Leu Gly Cys Leu 130 135 140Val Lys Asp Tyr
Phe Pro Glu Pro Val Thr Val Ser Trp Asn Ser Gly145 150 155 160Ala
Leu Thr Ser Gly Val His Thr Phe Pro Ala Val Leu Gln Ser Ser 165 170
175Gly Leu Tyr Ser Leu Ser Ser Val Val Thr Val Pro Ser Ser Ser Leu
180 185 190Gly Thr Gln Thr Tyr Ile Cys Asn Val Asn His Lys Pro Ser
Asn Thr 195 200 205Lys Val Asp Lys Lys Val Glu Pro Lys Ser Cys Asp
Lys Thr His Thr 210 215 220Cys Pro Pro Cys Pro Ala Pro Glu Leu Leu
Gly Gly Pro Ser Val Phe225 230 235 240Leu Phe Pro Pro Lys Pro Lys
Asp Thr Leu Met Ile Ser Arg Thr Pro 245 250 255Glu Val Thr Cys Val
Val Val Asp Val Ser His Glu Asp Pro Glu Val 260 265 270Lys Phe Asn
Trp Tyr Val Asp Gly Val Glu Val His Asn Ala Lys Thr 275 280 285Lys
Pro Arg Glu Glu Gln Tyr Asn Ser Thr Tyr Arg Val Val Ser Val 290 295
300Leu Thr Val Leu His Gln Asp Trp Leu Asn Gly Lys Glu Tyr Lys
Cys305 310 315 320Lys Val Ser Asn Lys Ala Leu Pro Ala Pro Ile Glu
Lys Thr Ile Ser 325 330 335Lys Ala Lys Gly Gln Pro Arg Glu Pro Gln
Val Tyr Thr Leu Pro Pro 340 345 350Ser Arg Asp Glu Leu Thr Lys Asn
Gln Val Ser Leu Thr Cys Leu Val 355 360 365Lys Gly Phe Tyr Pro Ser
Asp Ile Ala Val Glu Trp Glu Ser Asn Gly 370 375 380Gln Pro Glu Asn
Asn Tyr Lys Thr Thr Pro Pro Val Leu Asp Ser Asp385 390 395 400Gly
Ser Phe Phe Leu Tyr Ser Lys Leu Thr Val Asp Lys Ser Arg Trp 405 410
415Gln Gln Gly Asn Val Phe Ser Cys Ser Val Met His Glu Ala Leu His
420 425 430Asn His Tyr Thr Gln Lys Ser Leu Ser Leu Ser Pro Gly Lys
435 440 44531220PRTArtificial SequenceH5L1, light chain humanised
construct 31Asp Ile Gln Met Thr Gln Ser Pro Ser Ser Leu Ser Ala Ser
Val Gly1 5 10 15Asp Arg Val Thr Ile Thr Cys Lys Ser Ser Gln Ser Leu
Leu Asn Gly 20 25 30Ser Asn Gln Lys Asn Tyr Leu Ala Trp Tyr Gln Gln
Lys Pro Gly Lys 35 40 45Ala Pro Lys Leu Leu Val Tyr Phe Ala Ser Thr
Arg Asp Ser Gly Val 50 55 60Pro Ser Arg Phe Ser Gly Ser Gly Ser Gly
Thr Asp Phe Thr Leu Thr65 70 75 80Ile Ser Ser Leu Gln Pro Glu Asp
Phe Ala Thr Tyr Tyr Cys Leu Gln 85 90 95His Phe Gly Thr Pro Pro Thr
Phe Gly Gln Gly Thr Lys Leu Glu Ile 100 105 110Lys Arg Thr Val Ala
Ala Pro Ser Val Phe Ile Phe Pro Pro Ser Asp 115 120 125Glu Gln Leu
Lys Ser Gly Thr Ala Ser Val Val Cys Leu Leu Asn Asn 130 135 140Phe
Tyr Pro Arg Glu Ala Lys Val Gln Trp Lys Val Asp Asn Ala Leu145 150
155 160Gln Ser Gly Asn Ser Gln Glu Ser Val Thr Glu Gln Asp Ser Lys
Asp 165 170 175Ser Thr Tyr Ser Leu Ser Ser Thr Leu Thr Leu Ser Lys
Ala Asp Tyr 180 185 190Glu Lys His Lys Val Tyr Ala Cys Glu Val Thr
His Gln Gly Leu Ser 195 200 205Ser Pro Val Thr Lys Ser Phe Asn Arg
Gly Glu Cys 210 215 22032446PRTArtificial SequenceH5L1, heavy chain
humanised construct 32Gln Val Gln Leu Gln Glu Ser Gly Pro Gly Leu
Val Lys Pro Ser Glu1 5 10 15Thr Leu Ser Leu Thr Cys Thr Val Ser Gly
Phe Ser Leu Thr Ala Tyr 20 25 30Gly Val Asn Trp Ile Arg Gln Pro Pro
Gly Lys Gly Leu Glu Trp Ile 35 40 45Gly Met Ile Trp Asp Asp Gly Ser
Thr Asp Tyr Asp Ser Ala Leu Lys 50 55 60Ser Arg Val Thr Ile Ser Val
Asp Thr Ser Lys Asn Gln Phe Ser Leu65 70 75 80Lys Leu Ser Ser Val
Thr Ala Ala Asp Thr Ala Val Tyr Tyr Cys Ala 85 90 95Arg Glu Gly Asp
Val Ala Phe Asp Tyr Trp Gly Gln Gly Thr Leu Val 100 105 110Thr Val
Ser Ser Ala Ser Thr Lys Gly Pro Ser Val Phe Pro Leu Ala 115 120
125Pro Ser Ser Lys Ser Thr Ser Gly Gly Thr Ala Ala Leu Gly Cys Leu
130 135 140Val Lys Asp Tyr Phe Pro Glu Pro Val Thr Val Ser Trp Asn
Ser Gly145 150 155 160Ala Leu Thr Ser Gly Val His Thr Phe Pro Ala
Val Leu Gln Ser Ser 165 170 175Gly Leu Tyr Ser Leu Ser Ser Val Val
Thr Val Pro Ser Ser Ser Leu 180 185 190Gly Thr Gln Thr Tyr Ile Cys
Asn Val Asn His Lys Pro Ser Asn Thr 195 200 205Lys Val Asp Lys Lys
Val Glu Pro Lys Ser Cys Asp Lys Thr His Thr 210 215 220Cys Pro Pro
Cys Pro Ala Pro Glu Leu Leu Gly Gly Pro Ser Val Phe225 230 235
240Leu Phe Pro Pro Lys Pro Lys Asp Thr Leu Met Ile Ser Arg Thr Pro
245 250 255Glu Val Thr Cys Val Val Val Asp Val Ser His Glu Asp Pro
Glu Val 260 265 270Lys Phe Asn Trp Tyr Val Asp Gly Val Glu Val His
Asn Ala Lys Thr 275 280 285Lys Pro Arg Glu Glu Gln Tyr Asn Ser Thr
Tyr Arg Val Val Ser Val 290 295 300Leu Thr Val Leu His Gln Asp Trp
Leu Asn Gly Lys Glu Tyr Lys Cys305 310 315 320Lys Val Ser Asn Lys
Ala Leu Pro Ala Pro Ile Glu Lys Thr Ile Ser 325 330 335Lys Ala Lys
Gly Gln Pro Arg Glu Pro Gln Val Tyr Thr Leu Pro Pro 340 345 350Ser
Arg Asp Glu Leu Thr Lys Asn Gln Val Ser Leu Thr Cys Leu Val 355 360
365Lys Gly Phe Tyr Pro Ser Asp Ile Ala Val Glu Trp Glu Ser Asn Gly
370 375 380Gln Pro Glu Asn Asn Tyr Lys Thr Thr Pro Pro Val Leu Asp
Ser Asp385 390 395 400Gly Ser Phe Phe Leu Tyr Ser Lys Leu Thr Val
Asp Lys Ser Arg Trp 405 410 415Gln Gln Gly Asn Val Phe Ser Cys Ser
Val Met His Glu Ala Leu His 420 425 430Asn His Tyr Thr Gln Lys Ser
Leu Ser Leu Ser Pro Gly Lys 435 440 44533220PRTArtificial
SequenceJ7L1, light chain humanised construct 33Asp Ile Gln Met Thr
Gln Ser Pro Ser Ser Leu Ser Ala Ser Val Gly1 5 10 15Asp Arg Val Thr
Ile Thr Cys Lys Ser Ser Gln Ser Leu Leu Asn Gly 20 25 30Ser Asn Gln
Lys Asn Tyr Leu Ala Trp Tyr Gln Gln Lys Pro Gly Lys 35 40 45Ala Pro
Lys Leu Leu Val Tyr Phe Ala Ser Thr Arg Asp Ser Gly Val 50 55 60Pro
Ser Arg Phe Ser Gly Ser Gly Ser Gly Thr Asp Phe Thr Leu Thr65 70 75
80Ile Ser Ser Leu Gln Pro Glu Asp Phe Ala Thr Tyr Tyr Cys Leu Gln
85 90 95His Phe Gly Thr Pro Pro Thr Phe Gly Gln Gly Thr Lys Leu Glu
Ile 100 105 110Lys Arg Thr Val Ala Ala Pro Ser Val Phe Ile Phe Pro
Pro Ser Asp 115 120 125Glu Gln Leu Lys Ser Gly Thr Ala Ser Val Val
Cys Leu Leu Asn Asn 130 135 140Phe Tyr Pro Arg Glu Ala Lys Val Gln
Trp Lys Val Asp Asn Ala Leu145 150 155 160Gln Ser Gly Asn Ser Gln
Glu Ser Val Thr Glu Gln Asp Ser Lys Asp 165 170 175Ser Thr Tyr Ser
Leu Ser Ser Thr Leu Thr Leu Ser Lys Ala Asp Tyr 180 185 190Glu Lys
His Lys Val Tyr Ala Cys Glu Val Thr His Gln Gly Leu Ser 195 200
205Ser Pro Val Thr Lys Ser Phe Asn Arg Gly Glu Cys 210 215
22034446PRTArtificial SequenceJ7L1, heavy chain humanised construct
34Gln Val Gln Leu Val Gln Ser Gly Ala Glu Val Lys Lys Pro Gly Ser1
5 10 15Ser Val Lys Val Ser Cys Lys Ala Ser Gly Phe Ser Leu Thr Ala
Tyr 20 25 30Gly Val Asn Trp Val Arg Gln Ala Pro Gly Gln Gly Leu Glu
Trp Met 35 40 45Gly Met Ile Trp Asp Asp Gly Ser Thr Asp Tyr Asn Ser
Ala Leu Lys 50 55 60Ser Arg Val Thr Ile Thr Ala Asp Lys Ser Thr Ser
Thr Ala Tyr Met65 70 75 80Glu Leu Ser Ser Leu Arg Ser Glu Asp Thr
Ala Val Tyr Tyr Cys Ala 85 90 95Arg Glu Gly Asp Val Ala Phe Asp Tyr
Trp Gly Gln Gly Thr Leu Val 100 105 110Thr Val Ser Ser Ala Ser Thr
Lys Gly Pro Ser Val Phe Pro Leu Ala 115 120 125Pro Ser Ser Lys Ser
Thr Ser Gly Gly Thr Ala Ala Leu Gly Cys Leu 130 135 140Val Lys Asp
Tyr Phe Pro Glu Pro Val Thr Val Ser Trp Asn Ser Gly145 150 155
160Ala Leu Thr Ser Gly Val His Thr Phe Pro Ala Val Leu Gln Ser Ser
165 170 175Gly Leu Tyr Ser Leu Ser Ser Val Val Thr Val Pro Ser Ser
Ser Leu 180 185 190Gly Thr Gln Thr Tyr Ile Cys Asn Val Asn His Lys
Pro Ser Asn Thr 195 200 205Lys Val Asp Lys Lys Val Glu Pro Lys Ser
Cys Asp Lys Thr His Thr 210 215 220Cys Pro Pro Cys Pro Ala Pro Glu
Leu Leu Gly Gly Pro Ser Val Phe225 230 235 240Leu Phe Pro Pro Lys
Pro Lys Asp Thr Leu Met Ile Ser Arg Thr Pro 245 250 255Glu Val Thr
Cys Val Val Val Asp Val Ser His Glu Asp Pro Glu Val 260 265 270Lys
Phe Asn Trp Tyr Val Asp Gly Val Glu Val His Asn Ala Lys Thr 275 280
285Lys Pro Arg Glu Glu Gln Tyr Asn Ser Thr Tyr Arg Val Val Ser Val
290 295 300Leu Thr Val Leu His Gln Asp Trp Leu Asn Gly Lys Glu Tyr
Lys Cys305 310 315 320Lys Val Ser Asn Lys Ala Leu Pro Ala Pro Ile
Glu Lys Thr Ile Ser 325 330 335Lys Ala Lys Gly Gln Pro Arg Glu Pro
Gln Val Tyr Thr Leu Pro Pro 340 345 350Ser Arg Asp Glu Leu Thr Lys
Asn Gln Val Ser Leu Thr Cys Leu Val 355 360 365Lys Gly Phe Tyr Pro
Ser Asp Ile Ala Val Glu Trp Glu Ser Asn Gly 370 375 380Gln Pro Glu
Asn Asn Tyr Lys Thr Thr Pro Pro Val Leu Asp Ser Asp385 390 395
400Gly Ser Phe Phe Leu Tyr Ser Lys Leu Thr Val Asp Lys Ser Arg Trp
405 410 415Gln Gln Gly Asn Val Phe Ser Cys Ser Val Met His Glu Ala
Leu His 420 425 430Asn His Tyr Thr Gln Lys Ser Leu Ser Leu Ser Pro
Gly Lys 435 440 44535220PRTArtificial SequenceJ11L1, light chain
humanised construct 35Asp Ile Gln Met Thr Gln Ser Pro Ser Ser Leu
Ser Ala Ser Val Gly1 5 10 15Asp Arg Val Thr Ile Thr Cys Lys Ser Ser
Gln Ser Leu Leu Asn Gly 20 25 30Ser Asn Gln Lys Asn Tyr Leu Ala Trp
Tyr Gln Gln Lys Pro Gly Lys 35 40 45Ala Pro Lys Leu Leu Val Tyr Phe
Ala Ser Thr Arg Asp Ser Gly Val 50 55 60Pro Ser Arg Phe Ser Gly Ser
Gly Ser Gly Thr Asp Phe Thr Leu Thr65 70 75 80Ile Ser Ser Leu Gln
Pro Glu Asp Phe Ala Thr Tyr Tyr Cys Leu Gln 85 90 95His Phe Gly Thr
Pro Pro Thr Phe Gly Gln Gly Thr Lys Leu Glu Ile 100 105 110Lys Arg
Thr Val Ala Ala Pro Ser Val Phe Ile Phe Pro Pro Ser Asp 115 120
125Glu Gln Leu Lys Ser Gly Thr Ala Ser Val Val Cys Leu Leu Asn Asn
130 135 140Phe Tyr Pro Arg Glu Ala Lys Val Gln Trp Lys Val Asp Asn
Ala Leu145 150 155 160Gln Ser Gly Asn Ser Gln Glu Ser Val Thr Glu
Gln Asp Ser Lys Asp 165 170 175Ser Thr Tyr Ser Leu Ser Ser Thr Leu
Thr Leu Ser Lys Ala Asp Tyr 180 185 190Glu Lys His Lys Val Tyr Ala
Cys Glu Val Thr His Gln Gly Leu Ser 195 200 205Ser Pro Val Thr Lys
Ser Phe Asn Arg Gly Glu Cys 210 215 22036446PRTArtificial
SequenceJ11L1, heavy chain humanised construct 36Gln Val Gln Leu
Val Gln Ser Gly Ala Glu Val Lys Lys Pro Gly Ser1 5 10 15Ser Val Lys
Val Ser Cys Lys Ala Ser Gly Phe Ser Leu Thr Ala Tyr 20 25 30Gly Val
Asn Trp Val Arg Gln Ala Pro Gly Gln Gly Leu Glu Trp Met 35 40 45Gly
Met Ile Trp Asp Asp Gly Ser Thr Asp Tyr Asp Ser Ala Leu Lys 50 55
60Ser Arg Val Thr Ile Thr Ala Asp Lys Ser Thr Ser Thr Ala Tyr Met65
70 75 80Glu Leu Ser Ser Leu Arg Ser Glu Asp Thr Ala Val Tyr Tyr Cys
Ala 85 90 95Arg Glu Gly Asp Val Ala Phe Asp Tyr Trp Gly Gln Gly Thr
Leu Val 100 105 110Thr Val Ser Ser Ala Ser Thr Lys Gly Pro Ser Val
Phe Pro Leu Ala 115 120 125Pro Ser Ser Lys Ser Thr Ser Gly Gly Thr
Ala Ala Leu Gly Cys Leu 130 135 140Val Lys Asp Tyr Phe Pro Glu Pro
Val Thr Val Ser Trp Asn Ser Gly145 150 155 160Ala Leu Thr Ser Gly
Val His Thr Phe Pro Ala Val Leu Gln Ser Ser 165 170 175Gly Leu Tyr
Ser Leu Ser Ser Val Val Thr Val Pro Ser Ser Ser Leu 180 185 190Gly
Thr Gln Thr Tyr Ile Cys Asn Val Asn His Lys Pro Ser Asn Thr 195 200
205Lys Val Asp Lys Lys Val Glu Pro Lys Ser Cys Asp Lys Thr His Thr
210 215 220Cys Pro Pro Cys Pro Ala Pro Glu Leu Leu Gly Gly Pro Ser
Val Phe225 230 235 240Leu Phe Pro Pro Lys Pro Lys Asp Thr Leu Met
Ile Ser Arg Thr Pro 245 250 255Glu Val Thr Cys Val Val Val Asp Val
Ser His Glu Asp Pro Glu Val 260 265 270Lys Phe Asn Trp Tyr Val Asp
Gly Val Glu Val His Asn Ala Lys Thr 275 280 285Lys Pro Arg Glu Glu
Gln Tyr Asn Ser Thr Tyr Arg Val Val Ser Val 290 295 300Leu Thr Val
Leu His Gln Asp Trp Leu Asn Gly Lys Glu Tyr Lys Cys305 310 315
320Lys Val Ser Asn Lys Ala Leu Pro Ala Pro Ile Glu Lys Thr Ile Ser
325 330 335Lys Ala Lys Gly Gln Pro Arg Glu Pro Gln Val Tyr Thr Leu
Pro Pro 340 345 350Ser Arg Asp Glu Leu Thr Lys Asn Gln Val Ser Leu
Thr Cys Leu Val 355 360 365Lys Gly Phe Tyr Pro Ser Asp Ile Ala Val
Glu Trp Glu Ser Asn Gly 370 375 380Gln Pro Glu Asn Asn Tyr Lys Thr
Thr Pro Pro Val Leu Asp Ser Asp385 390 395 400Gly Ser Phe Phe Leu
Tyr Ser Lys Leu Thr Val Asp Lys Ser Arg Trp 405 410
415Gln Gln Gly Asn Val Phe Ser Cys Ser Val Met His Glu Ala Leu His
420 425 430Asn His Tyr Thr Gln Lys Ser Leu Ser Leu Ser Pro Gly Lys
435 440 44537220PRTArtificial SequenceJ13L1, light chain humanised
construct 37Asp Ile Gln Met Thr Gln Ser Pro Ser Ser Leu Ser Ala Ser
Val Gly1 5 10 15Asp Arg Val Thr Ile Thr Cys Lys Ser Ser Gln Ser Leu
Leu Asn Gly 20 25 30Ser Asn Gln Lys Asn Tyr Leu Ala Trp Tyr Gln Gln
Lys Pro Gly Lys 35 40 45Ala Pro Lys Leu Leu Val Tyr Phe Ala Ser Thr
Arg Asp Ser Gly Val 50 55 60Pro Ser Arg Phe Ser Gly Ser Gly Ser Gly
Thr Asp Phe Thr Leu Thr65 70 75 80Ile Ser Ser Leu Gln Pro Glu Asp
Phe Ala Thr Tyr Tyr Cys Leu Gln 85 90 95His Phe Gly Thr Pro Pro Thr
Phe Gly Gln Gly Thr Lys Leu Glu Ile 100 105 110Lys Arg Thr Val Ala
Ala Pro Ser Val Phe Ile Phe Pro Pro Ser Asp 115 120 125Glu Gln Leu
Lys Ser Gly Thr Ala Ser Val Val Cys Leu Leu Asn Asn 130 135 140Phe
Tyr Pro Arg Glu Ala Lys Val Gln Trp Lys Val Asp Asn Ala Leu145 150
155 160Gln Ser Gly Asn Ser Gln Glu Ser Val Thr Glu Gln Asp Ser Lys
Asp 165 170 175Ser Thr Tyr Ser Leu Ser Ser Thr Leu Thr Leu Ser Lys
Ala Asp Tyr 180 185 190Glu Lys His Lys Val Tyr Ala Cys Glu Val Thr
His Gln Gly Leu Ser 195 200 205Ser Pro Val Thr Lys Ser Phe Asn Arg
Gly Glu Cys 210 215 22038446PRTArtificial SequenceJ13L1, heavy
chain humanised construct 38Gln Val Gln Leu Val Gln Ser Gly Ala Glu
Val Lys Lys Pro Gly Ser1 5 10 15Ser Val Lys Val Ser Cys Lys Ala Ser
Gly Gly Thr Phe Ser Ala Tyr 20 25 30Gly Val Asn Trp Val Arg Gln Ala
Pro Gly Gln Gly Leu Glu Trp Met 35 40 45Gly Met Ile Trp Asp Asp Gly
Ser Thr Asp Tyr Asp Ser Ala Leu Lys 50 55 60Ser Arg Val Thr Ile Thr
Ala Asp Lys Ser Thr Ser Thr Ala Tyr Met65 70 75 80Glu Leu Ser Ser
Leu Arg Ser Glu Asp Thr Ala Val Tyr Tyr Cys Ala 85 90 95Arg Glu Gly
Asp Val Ala Phe Asp Tyr Trp Gly Gln Gly Thr Leu Val 100 105 110Thr
Val Ser Ser Ala Ser Thr Lys Gly Pro Ser Val Phe Pro Leu Ala 115 120
125Pro Ser Ser Lys Ser Thr Ser Gly Gly Thr Ala Ala Leu Gly Cys Leu
130 135 140Val Lys Asp Tyr Phe Pro Glu Pro Val Thr Val Ser Trp Asn
Ser Gly145 150 155 160Ala Leu Thr Ser Gly Val His Thr Phe Pro Ala
Val Leu Gln Ser Ser 165 170 175Gly Leu Tyr Ser Leu Ser Ser Val Val
Thr Val Pro Ser Ser Ser Leu 180 185 190Gly Thr Gln Thr Tyr Ile Cys
Asn Val Asn His Lys Pro Ser Asn Thr 195 200 205Lys Val Asp Lys Lys
Val Glu Pro Lys Ser Cys Asp Lys Thr His Thr 210 215 220Cys Pro Pro
Cys Pro Ala Pro Glu Leu Leu Gly Gly Pro Ser Val Phe225 230 235
240Leu Phe Pro Pro Lys Pro Lys Asp Thr Leu Met Ile Ser Arg Thr Pro
245 250 255Glu Val Thr Cys Val Val Val Asp Val Ser His Glu Asp Pro
Glu Val 260 265 270Lys Phe Asn Trp Tyr Val Asp Gly Val Glu Val His
Asn Ala Lys Thr 275 280 285Lys Pro Arg Glu Glu Gln Tyr Asn Ser Thr
Tyr Arg Val Val Ser Val 290 295 300Leu Thr Val Leu His Gln Asp Trp
Leu Asn Gly Lys Glu Tyr Lys Cys305 310 315 320Lys Val Ser Asn Lys
Ala Leu Pro Ala Pro Ile Glu Lys Thr Ile Ser 325 330 335Lys Ala Lys
Gly Gln Pro Arg Glu Pro Gln Val Tyr Thr Leu Pro Pro 340 345 350Ser
Arg Asp Glu Leu Thr Lys Asn Gln Val Ser Leu Thr Cys Leu Val 355 360
365Lys Gly Phe Tyr Pro Ser Asp Ile Ala Val Glu Trp Glu Ser Asn Gly
370 375 380Gln Pro Glu Asn Asn Tyr Lys Thr Thr Pro Pro Val Leu Asp
Ser Asp385 390 395 400Gly Ser Phe Phe Leu Tyr Ser Lys Leu Thr Val
Asp Lys Ser Arg Trp 405 410 415Gln Gln Gly Asn Val Phe Ser Cys Ser
Val Met His Glu Ala Leu His 420 425 430Asn His Tyr Thr Gln Lys Ser
Leu Ser Leu Ser Pro Gly Lys 435 440 44539220PRTArtificial
SequenceH7L1, light chain humanised construct 39Asp Ile Gln Met Thr
Gln Ser Pro Ser Ser Leu Ser Ala Ser Val Gly1 5 10 15Asp Arg Val Thr
Ile Thr Cys Lys Ser Ser Gln Ser Leu Leu Asn Gly 20 25 30Ser Asn Gln
Lys Asn Tyr Leu Ala Trp Tyr Gln Gln Lys Pro Gly Lys 35 40 45Ala Pro
Lys Leu Leu Val Tyr Phe Ala Ser Thr Arg Asp Ser Gly Val 50 55 60Pro
Ser Arg Phe Ser Gly Ser Gly Ser Gly Thr Asp Phe Thr Leu Thr65 70 75
80Ile Ser Ser Leu Gln Pro Glu Asp Phe Ala Thr Tyr Tyr Cys Leu Gln
85 90 95His Phe Gly Thr Pro Pro Thr Phe Gly Gln Gly Thr Lys Leu Glu
Ile 100 105 110Lys Arg Thr Val Ala Ala Pro Ser Val Phe Ile Phe Pro
Pro Ser Asp 115 120 125Glu Gln Leu Lys Ser Gly Thr Ala Ser Val Val
Cys Leu Leu Asn Asn 130 135 140Phe Tyr Pro Arg Glu Ala Lys Val Gln
Trp Lys Val Asp Asn Ala Leu145 150 155 160Gln Ser Gly Asn Ser Gln
Glu Ser Val Thr Glu Gln Asp Ser Lys Asp 165 170 175Ser Thr Tyr Ser
Leu Ser Ser Thr Leu Thr Leu Ser Lys Ala Asp Tyr 180 185 190Glu Lys
His Lys Val Tyr Ala Cys Glu Val Thr His Gln Gly Leu Ser 195 200
205Ser Pro Val Thr Lys Ser Phe Asn Arg Gly Glu Cys 210 215
22040446PRTArtificial SequenceH7L1, heavy chain humanised construct
40Gln Val Gln Leu Gln Glu Ser Gly Pro Gly Leu Val Lys Pro Ser Glu1
5 10 15Thr Leu Ser Leu Thr Cys Thr Val Ser Gly Gly Ser Ile Ser Ala
Tyr 20 25 30Gly Val Asn Trp Ile Arg Gln Pro Pro Gly Lys Gly Leu Glu
Trp Ile 35 40 45Gly Met Ile Trp Asp Asp Gly Ser Thr Asp Tyr Asp Ser
Ala Leu Lys 50 55 60Ser Arg Val Thr Ile Ser Val Asp Thr Ser Lys Asn
Gln Phe Ser Leu65 70 75 80Lys Leu Ser Ser Val Thr Ala Ala Asp Thr
Ala Val Tyr Tyr Cys Ala 85 90 95Arg Glu Gly Asp Val Ala Phe Asp Tyr
Trp Gly Gln Gly Thr Leu Val 100 105 110Thr Val Ser Ser Ala Ser Thr
Lys Gly Pro Ser Val Phe Pro Leu Ala 115 120 125Pro Ser Ser Lys Ser
Thr Ser Gly Gly Thr Ala Ala Leu Gly Cys Leu 130 135 140Val Lys Asp
Tyr Phe Pro Glu Pro Val Thr Val Ser Trp Asn Ser Gly145 150 155
160Ala Leu Thr Ser Gly Val His Thr Phe Pro Ala Val Leu Gln Ser Ser
165 170 175Gly Leu Tyr Ser Leu Ser Ser Val Val Thr Val Pro Ser Ser
Ser Leu 180 185 190Gly Thr Gln Thr Tyr Ile Cys Asn Val Asn His Lys
Pro Ser Asn Thr 195 200 205Lys Val Asp Lys Lys Val Glu Pro Lys Ser
Cys Asp Lys Thr His Thr 210 215 220Cys Pro Pro Cys Pro Ala Pro Glu
Leu Leu Gly Gly Pro Ser Val Phe225 230 235 240Leu Phe Pro Pro Lys
Pro Lys Asp Thr Leu Met Ile Ser Arg Thr Pro 245 250 255Glu Val Thr
Cys Val Val Val Asp Val Ser His Glu Asp Pro Glu Val 260 265 270Lys
Phe Asn Trp Tyr Val Asp Gly Val Glu Val His Asn Ala Lys Thr 275 280
285Lys Pro Arg Glu Glu Gln Tyr Asn Ser Thr Tyr Arg Val Val Ser Val
290 295 300Leu Thr Val Leu His Gln Asp Trp Leu Asn Gly Lys Glu Tyr
Lys Cys305 310 315 320Lys Val Ser Asn Lys Ala Leu Pro Ala Pro Ile
Glu Lys Thr Ile Ser 325 330 335Lys Ala Lys Gly Gln Pro Arg Glu Pro
Gln Val Tyr Thr Leu Pro Pro 340 345 350Ser Arg Asp Glu Leu Thr Lys
Asn Gln Val Ser Leu Thr Cys Leu Val 355 360 365Lys Gly Phe Tyr Pro
Ser Asp Ile Ala Val Glu Trp Glu Ser Asn Gly 370 375 380Gln Pro Glu
Asn Asn Tyr Lys Thr Thr Pro Pro Val Leu Asp Ser Asp385 390 395
400Gly Ser Phe Phe Leu Tyr Ser Lys Leu Thr Val Asp Lys Ser Arg Trp
405 410 415Gln Gln Gly Asn Val Phe Ser Cys Ser Val Met His Glu Ala
Leu His 420 425 430Asn His Tyr Thr Gln Lys Ser Leu Ser Leu Ser Pro
Gly Lys 435 440 44541220PRTArtificial SequenceJ0L1, light chain
humanised construct 41Asp Ile Gln Met Thr Gln Ser Pro Ser Ser Leu
Ser Ala Ser Val Gly1 5 10 15Asp Arg Val Thr Ile Thr Cys Lys Ser Ser
Gln Ser Leu Leu Asn Gly 20 25 30Ser Asn Gln Lys Asn Tyr Leu Ala Trp
Tyr Gln Gln Lys Pro Gly Lys 35 40 45Ala Pro Lys Leu Leu Val Tyr Phe
Ala Ser Thr Arg Asp Ser Gly Val 50 55 60Pro Ser Arg Phe Ser Gly Ser
Gly Ser Gly Thr Asp Phe Thr Leu Thr65 70 75 80Ile Ser Ser Leu Gln
Pro Glu Asp Phe Ala Thr Tyr Tyr Cys Leu Gln 85 90 95His Phe Gly Thr
Pro Pro Thr Phe Gly Gln Gly Thr Lys Leu Glu Ile 100 105 110Lys Arg
Thr Val Ala Ala Pro Ser Val Phe Ile Phe Pro Pro Ser Asp 115 120
125Glu Gln Leu Lys Ser Gly Thr Ala Ser Val Val Cys Leu Leu Asn Asn
130 135 140Phe Tyr Pro Arg Glu Ala Lys Val Gln Trp Lys Val Asp Asn
Ala Leu145 150 155 160Gln Ser Gly Asn Ser Gln Glu Ser Val Thr Glu
Gln Asp Ser Lys Asp 165 170 175Ser Thr Tyr Ser Leu Ser Ser Thr Leu
Thr Leu Ser Lys Ala Asp Tyr 180 185 190Glu Lys His Lys Val Tyr Ala
Cys Glu Val Thr His Gln Gly Leu Ser 195 200 205Ser Pro Val Thr Lys
Ser Phe Asn Arg Gly Glu Cys 210 215 22042446PRTArtificial
SequenceJ0L1, heavy chain humanised construct 42Gln Val Gln Leu Val
Gln Ser Gly Ala Glu Val Lys Lys Pro Gly Ser1 5 10 15Ser Val Lys Val
Ser Cys Lys Ala Ser Gly Gly Thr Phe Ser Ala Tyr 20 25 30Gly Val Asn
Trp Val Arg Gln Ala Pro Gly Gln Gly Leu Glu Trp Met 35 40 45Gly Met
Ile Trp Asp Asp Gly Ser Thr Asp Tyr Asn Ser Ala Leu Lys 50 55 60Ser
Arg Val Thr Ile Thr Ala Asp Lys Ser Thr Ser Thr Ala Tyr Met65 70 75
80Glu Leu Ser Ser Leu Arg Ser Glu Asp Thr Ala Val Tyr Tyr Cys Ala
85 90 95Arg Glu Gly Asp Val Ala Phe Asp Tyr Trp Gly Gln Gly Thr Leu
Val 100 105 110Thr Val Ser Ser Ala Ser Thr Lys Gly Pro Ser Val Phe
Pro Leu Ala 115 120 125Pro Ser Ser Lys Ser Thr Ser Gly Gly Thr Ala
Ala Leu Gly Cys Leu 130 135 140Val Lys Asp Tyr Phe Pro Glu Pro Val
Thr Val Ser Trp Asn Ser Gly145 150 155 160Ala Leu Thr Ser Gly Val
His Thr Phe Pro Ala Val Leu Gln Ser Ser 165 170 175Gly Leu Tyr Ser
Leu Ser Ser Val Val Thr Val Pro Ser Ser Ser Leu 180 185 190Gly Thr
Gln Thr Tyr Ile Cys Asn Val Asn His Lys Pro Ser Asn Thr 195 200
205Lys Val Asp Lys Lys Val Glu Pro Lys Ser Cys Asp Lys Thr His Thr
210 215 220Cys Pro Pro Cys Pro Ala Pro Glu Leu Leu Gly Gly Pro Ser
Val Phe225 230 235 240Leu Phe Pro Pro Lys Pro Lys Asp Thr Leu Met
Ile Ser Arg Thr Pro 245 250 255Glu Val Thr Cys Val Val Val Asp Val
Ser His Glu Asp Pro Glu Val 260 265 270Lys Phe Asn Trp Tyr Val Asp
Gly Val Glu Val His Asn Ala Lys Thr 275 280 285Lys Pro Arg Glu Glu
Gln Tyr Asn Ser Thr Tyr Arg Val Val Ser Val 290 295 300Leu Thr Val
Leu His Gln Asp Trp Leu Asn Gly Lys Glu Tyr Lys Cys305 310 315
320Lys Val Ser Asn Lys Ala Leu Pro Ala Pro Ile Glu Lys Thr Ile Ser
325 330 335Lys Ala Lys Gly Gln Pro Arg Glu Pro Gln Val Tyr Thr Leu
Pro Pro 340 345 350Ser Arg Asp Glu Leu Thr Lys Asn Gln Val Ser Leu
Thr Cys Leu Val 355 360 365Lys Gly Phe Tyr Pro Ser Asp Ile Ala Val
Glu Trp Glu Ser Asn Gly 370 375 380Gln Pro Glu Asn Asn Tyr Lys Thr
Thr Pro Pro Val Leu Asp Ser Asp385 390 395 400Gly Ser Phe Phe Leu
Tyr Ser Lys Leu Thr Val Asp Lys Ser Arg Trp 405 410 415Gln Gln Gly
Asn Val Phe Ser Cys Ser Val Met His Glu Ala Leu His 420 425 430Asn
His Tyr Thr Gln Lys Ser Leu Ser Leu Ser Pro Gly Lys 435 440
44543220PRTArtificial SequenceH0L1, light chain humanised construct
43Asp Ile Gln Met Thr Gln Ser Pro Ser Ser Leu Ser Ala Ser Val Gly1
5 10 15Asp Arg Val Thr Ile Thr Cys Lys Ser Ser Gln Ser Leu Leu Asn
Gly 20 25 30Ser Asn Gln Lys Asn Tyr Leu Ala Trp Tyr Gln Gln Lys Pro
Gly Lys 35 40 45Ala Pro Lys Leu Leu Val Tyr Phe Ala Ser Thr Arg Asp
Ser Gly Val 50 55 60Pro Ser Arg Phe Ser Gly Ser Gly Ser Gly Thr Asp
Phe Thr Leu Thr65 70 75 80Ile Ser Ser Leu Gln Pro Glu Asp Phe Ala
Thr Tyr Tyr Cys Leu Gln 85 90 95His Phe Gly Thr Pro Pro Thr Phe Gly
Gln Gly Thr Lys Leu Glu Ile 100 105 110Lys Arg Thr Val Ala Ala Pro
Ser Val Phe Ile Phe Pro Pro Ser Asp 115 120 125Glu Gln Leu Lys Ser
Gly Thr Ala Ser Val Val Cys Leu Leu Asn Asn 130 135 140Phe Tyr Pro
Arg Glu Ala Lys Val Gln Trp Lys Val Asp Asn Ala Leu145 150 155
160Gln Ser Gly Asn Ser Gln Glu Ser Val Thr Glu Gln Asp Ser Lys Asp
165 170 175Ser Thr Tyr Ser Leu Ser Ser Thr Leu Thr Leu Ser Lys Ala
Asp Tyr 180 185 190Glu Lys His Lys Val Tyr Ala Cys Glu Val Thr His
Gln Gly Leu Ser 195 200 205Ser Pro Val Thr Lys Ser Phe Asn Arg Gly
Glu Cys 210 215 22044446PRTArtificial SequenceH0L1, heavy chain
humanised construct 44Gln Val Gln Leu Gln Glu Ser Gly Pro Gly Leu
Val Lys Pro Ser Glu1 5 10 15Thr Leu Ser Leu Thr Cys Thr Val Ser Gly
Gly Ser Ile Ser Ala Tyr 20 25 30Gly Val Asn Trp Ile Arg Gln Pro Pro
Gly Lys Gly Leu Glu Trp Ile 35 40 45Gly Met Ile Trp Asp Asp Gly Ser
Thr Asp Tyr Asn Ser Ala Leu Lys 50 55 60Ser Arg Val Thr Ile Ser Val
Asp Thr Ser Lys Asn Gln Phe Ser Leu65 70 75 80Lys Leu Ser Ser Val
Thr Ala Ala Asp Thr Ala Val Tyr Tyr Cys Ala 85 90 95Arg Glu Gly Asp
Val Ala Phe Asp Tyr Trp Gly Gln Gly Thr Leu Val 100 105 110Thr Val
Ser Ser Ala Ser Thr Lys Gly Pro Ser Val Phe Pro Leu Ala 115 120
125Pro Ser Ser Lys Ser Thr Ser Gly Gly Thr Ala Ala Leu Gly Cys Leu
130 135 140Val Lys Asp
Tyr Phe Pro Glu Pro Val Thr Val Ser Trp Asn Ser Gly145 150 155
160Ala Leu Thr Ser Gly Val His Thr Phe Pro Ala Val Leu Gln Ser Ser
165 170 175Gly Leu Tyr Ser Leu Ser Ser Val Val Thr Val Pro Ser Ser
Ser Leu 180 185 190Gly Thr Gln Thr Tyr Ile Cys Asn Val Asn His Lys
Pro Ser Asn Thr 195 200 205Lys Val Asp Lys Lys Val Glu Pro Lys Ser
Cys Asp Lys Thr His Thr 210 215 220Cys Pro Pro Cys Pro Ala Pro Glu
Leu Leu Gly Gly Pro Ser Val Phe225 230 235 240Leu Phe Pro Pro Lys
Pro Lys Asp Thr Leu Met Ile Ser Arg Thr Pro 245 250 255Glu Val Thr
Cys Val Val Val Asp Val Ser His Glu Asp Pro Glu Val 260 265 270Lys
Phe Asn Trp Tyr Val Asp Gly Val Glu Val His Asn Ala Lys Thr 275 280
285Lys Pro Arg Glu Glu Gln Tyr Asn Ser Thr Tyr Arg Val Val Ser Val
290 295 300Leu Thr Val Leu His Gln Asp Trp Leu Asn Gly Lys Glu Tyr
Lys Cys305 310 315 320Lys Val Ser Asn Lys Ala Leu Pro Ala Pro Ile
Glu Lys Thr Ile Ser 325 330 335Lys Ala Lys Gly Gln Pro Arg Glu Pro
Gln Val Tyr Thr Leu Pro Pro 340 345 350Ser Arg Asp Glu Leu Thr Lys
Asn Gln Val Ser Leu Thr Cys Leu Val 355 360 365Lys Gly Phe Tyr Pro
Ser Asp Ile Ala Val Glu Trp Glu Ser Asn Gly 370 375 380Gln Pro Glu
Asn Asn Tyr Lys Thr Thr Pro Pro Val Leu Asp Ser Asp385 390 395
400Gly Ser Phe Phe Leu Tyr Ser Lys Leu Thr Val Asp Lys Ser Arg Trp
405 410 415Gln Gln Gly Asn Val Phe Ser Cys Ser Val Met His Glu Ala
Leu His 420 425 430Asn His Tyr Thr Gln Lys Ser Leu Ser Leu Ser Pro
Gly Lys 435 440 44545106PRTHomo Sapien 45Thr Val Ala Ala Pro Ser
Val Phe Ile Phe Pro Pro Ser Asp Glu Gln1 5 10 15Leu Lys Ser Gly Thr
Ala Ser Val Val Cys Leu Leu Asn Asn Phe Tyr 20 25 30Pro Arg Glu Ala
Lys Val Gln Trp Lys Val Asp Asn Ala Leu Gln Ser 35 40 45Gly Asn Ser
Gln Glu Ser Val Thr Glu Gln Asp Ser Lys Asp Ser Thr 50 55 60Tyr Ser
Leu Ser Ser Thr Leu Thr Leu Ser Lys Ala Asp Tyr Glu Lys65 70 75
80His Lys Val Tyr Ala Cys Glu Val Thr His Gln Gly Leu Ser Ser Pro
85 90 95Val Thr Lys Ser Phe Asn Arg Gly Glu Cys 100 10546330PRTHomo
Sapien 46Ala Ser Thr Lys Gly Pro Ser Val Phe Pro Leu Ala Pro Ser
Ser Lys1 5 10 15Ser Thr Ser Gly Gly Thr Ala Ala Leu Gly Cys Leu Val
Lys Asp Tyr 20 25 30Phe Pro Glu Pro Val Thr Val Ser Trp Asn Ser Gly
Ala Leu Thr Ser 35 40 45Gly Val His Thr Phe Pro Ala Val Leu Gln Ser
Ser Gly Leu Tyr Ser 50 55 60Leu Ser Ser Val Val Thr Val Pro Ser Ser
Ser Leu Gly Thr Gln Thr65 70 75 80Tyr Ile Cys Asn Val Asn His Lys
Pro Ser Asn Thr Lys Val Asp Lys 85 90 95Lys Val Glu Pro Lys Ser Cys
Asp Lys Thr His Thr Cys Pro Pro Cys 100 105 110Pro Ala Pro Glu Leu
Leu Gly Gly Pro Ser Val Phe Leu Phe Pro Pro 115 120 125Lys Pro Lys
Asp Thr Leu Met Ile Ser Arg Thr Pro Glu Val Thr Cys 130 135 140Val
Val Val Asp Val Ser His Glu Asp Pro Glu Val Lys Phe Asn Trp145 150
155 160Tyr Val Asp Gly Val Glu Val His Asn Ala Lys Thr Lys Pro Arg
Glu 165 170 175Glu Gln Tyr Asn Ser Thr Tyr Arg Val Val Ser Val Leu
Thr Val Leu 180 185 190His Gln Asp Trp Leu Asn Gly Lys Glu Tyr Lys
Cys Lys Val Ser Asn 195 200 205Lys Ala Leu Pro Ala Pro Ile Glu Lys
Thr Ile Ser Lys Ala Lys Gly 210 215 220Gln Pro Arg Glu Pro Gln Val
Tyr Thr Leu Pro Pro Ser Arg Asp Glu225 230 235 240Leu Thr Lys Asn
Gln Val Ser Leu Thr Cys Leu Val Lys Gly Phe Tyr 245 250 255Pro Ser
Asp Ile Ala Val Glu Trp Glu Ser Asn Gly Gln Pro Glu Asn 260 265
270Asn Tyr Lys Thr Thr Pro Pro Val Leu Asp Ser Asp Gly Ser Phe Phe
275 280 285Leu Tyr Ser Lys Leu Thr Val Asp Lys Ser Arg Trp Gln Gln
Gly Asn 290 295 300Val Phe Ser Cys Ser Val Met His Glu Ala Leu His
Asn His Tyr Thr305 310 315 320Gln Lys Ser Leu Ser Leu Ser Pro Gly
Lys 325 33047116PRTMurine 47Gln Val Gln Leu Lys Glu Ser Gly Pro Gly
Leu Val Ala Pro Ser Gln1 5 10 15Ser Leu Ser Ile Thr Cys Thr Val Ser
Gly Phe Ser Leu Thr Ala Tyr 20 25 30Gly Val Asn Trp Val Arg Gln Pro
Pro Gly Lys Gly Leu Glu Trp Leu 35 40 45Gly Met Ile Trp Asp Asp Gly
Ser Thr Asp Tyr Asn Ser Ala Leu Lys 50 55 60Ser Arg Leu Ser Ile Ser
Lys Asp Asn Ser Lys Ser Gln Val Phe Leu65 70 75 80Lys Met Asn Ser
Leu Gln Thr Asp Asp Thr Ala Arg Tyr Tyr Cys Ala 85 90 95Arg Glu Gly
Asp Val Ala Phe Asp Tyr Trp Gly Gln Gly Thr Thr Leu 100 105 110Thr
Val Ser Ser 11548114PRTMurine 48Asp Ile Val Met Thr Gln Ser Pro Ser
Ser Leu Ala Val Ser Val Gly1 5 10 15Gln Lys Val Thr Met Ser Cys Lys
Ser Ser Gln Ser Leu Leu Asn Gly 20 25 30Ser Asn Gln Lys Asn Tyr Leu
Ala Trp Tyr Gln Gln Lys Pro Gly Gln 35 40 45Ser Pro Lys Leu Leu Val
Tyr Phe Ala Ser Thr Arg Asp Ser Gly Val 50 55 60Pro Asp Arg Phe Ile
Gly Ser Gly Ser Gly Thr Asp Phe Thr Leu Thr65 70 75 80Ile Ser Ser
Val Gln Ala Glu Asp Leu Ala Asp Tyr Phe Cys Leu Gln 85 90 95His Phe
Gly Thr Pro Pro Thr Phe Gly Gly Gly Thr Lys Leu Glu Ile 100 105
110Lys Arg49446PRTArtificial SequenceIMP731, heavy chain sequence
49Gln Val Gln Leu Lys Glu Ser Gly Pro Gly Leu Val Ala Pro Ser Gln1
5 10 15Ser Leu Ser Ile Thr Cys Thr Val Ser Gly Phe Ser Leu Thr Ala
Tyr 20 25 30Gly Val Asn Trp Val Arg Gln Pro Pro Gly Lys Gly Leu Glu
Trp Leu 35 40 45Gly Met Ile Trp Asp Asp Gly Ser Thr Asp Tyr Asn Ser
Ala Leu Lys 50 55 60Ser Arg Leu Ser Ile Ser Lys Asp Asn Ser Lys Ser
Gln Val Phe Leu65 70 75 80Lys Met Asn Ser Leu Gln Thr Asp Asp Thr
Ala Arg Tyr Tyr Cys Ala 85 90 95Arg Glu Gly Asp Val Ala Phe Asp Tyr
Trp Gly Gln Gly Thr Thr Leu 100 105 110Thr Val Ser Ser Ala Ser Thr
Lys Gly Pro Ser Val Phe Pro Leu Ala 115 120 125Pro Ser Ser Lys Ser
Thr Ser Gly Gly Thr Ala Ala Leu Gly Cys Leu 130 135 140Val Lys Asp
Tyr Phe Pro Glu Pro Val Thr Val Ser Trp Asn Ser Gly145 150 155
160Ala Leu Thr Ser Gly Val His Thr Phe Pro Ala Val Leu Gln Ser Ser
165 170 175Gly Leu Tyr Ser Leu Ser Ser Val Val Thr Val Pro Ser Ser
Ser Leu 180 185 190Gly Thr Gln Thr Tyr Ile Cys Asn Val Asn His Lys
Pro Ser Asn Thr 195 200 205Lys Val Asp Lys Lys Val Glu Pro Lys Ser
Cys Asp Lys Thr His Thr 210 215 220Cys Pro Pro Cys Pro Ala Pro Glu
Leu Leu Gly Gly Pro Ser Val Phe225 230 235 240Leu Phe Pro Pro Lys
Pro Lys Asp Thr Leu Met Ile Ser Arg Thr Pro 245 250 255Glu Val Thr
Cys Val Val Val Asp Val Ser His Glu Asp Pro Glu Val 260 265 270Lys
Phe Asn Trp Tyr Val Asp Gly Val Glu Val His Asn Ala Lys Thr 275 280
285Lys Pro Arg Glu Glu Gln Tyr Asn Ser Thr Tyr Arg Val Val Ser Val
290 295 300Leu Thr Val Leu His Gln Asp Trp Leu Asn Gly Lys Glu Tyr
Lys Cys305 310 315 320Lys Val Ser Asn Lys Ala Leu Pro Ala Pro Ile
Glu Lys Thr Ile Ser 325 330 335Lys Ala Lys Gly Gln Pro Arg Glu Pro
Gln Val Tyr Thr Leu Pro Pro 340 345 350Ser Arg Asp Glu Leu Thr Lys
Asn Gln Val Ser Leu Thr Cys Leu Val 355 360 365Lys Gly Phe Tyr Pro
Ser Asp Ile Ala Val Glu Trp Glu Ser Asn Gly 370 375 380Gln Pro Glu
Asn Asn Tyr Lys Thr Thr Pro Pro Val Leu Asp Ser Asp385 390 395
400Gly Ser Phe Phe Leu Tyr Ser Lys Leu Thr Val Asp Lys Ser Arg Trp
405 410 415Gln Gln Gly Asn Val Phe Ser Cys Ser Val Met His Glu Ala
Leu His 420 425 430Asn His Tyr Thr Gln Lys Ser Leu Ser Leu Ser Pro
Gly Lys 435 440 44550220PRTArtificial SequenceIMP731, light chain
sequence 50Asp Ile Val Met Thr Gln Ser Pro Ser Ser Leu Ala Val Ser
Val Gly1 5 10 15Gln Lys Val Thr Met Ser Cys Lys Ser Ser Gln Ser Leu
Leu Asn Gly 20 25 30Ser Asn Gln Lys Asn Tyr Leu Ala Trp Tyr Gln Gln
Lys Pro Gly Gln 35 40 45Ser Pro Lys Leu Leu Val Tyr Phe Ala Ser Thr
Arg Asp Ser Gly Val 50 55 60Pro Asp Arg Phe Ile Gly Ser Gly Ser Gly
Thr Asp Phe Thr Leu Thr65 70 75 80Ile Ser Ser Val Gln Ala Glu Asp
Leu Ala Asp Tyr Phe Cys Leu Gln 85 90 95His Phe Gly Thr Pro Pro Thr
Phe Gly Gly Gly Thr Lys Leu Glu Ile 100 105 110Lys Arg Thr Val Ala
Ala Pro Ser Val Phe Ile Phe Pro Pro Ser Asp 115 120 125Glu Gln Leu
Lys Ser Gly Thr Ala Ser Val Val Cys Leu Leu Asn Asn 130 135 140Phe
Tyr Pro Arg Glu Ala Lys Val Gln Trp Lys Val Asp Asn Ala Leu145 150
155 160Gln Ser Gly Asn Ser Gln Glu Ser Val Thr Glu Gln Asp Ser Lys
Asp 165 170 175Ser Thr Tyr Ser Leu Ser Ser Thr Leu Thr Leu Ser Lys
Ala Asp Tyr 180 185 190Glu Lys His Lys Val Tyr Ala Cys Glu Val Thr
His Gln Gly Leu Ser 195 200 205Ser Pro Val Thr Lys Ser Phe Asn Arg
Gly Glu Cys 210 215 22051417PRTArtificial SequenceRecombinant human
LAG-3-ECD-His6 51Leu Gln Pro Gly Ala Glu Val Pro Val Val Trp Ala
Gln Glu Gly Ala1 5 10 15Pro Ala Gln Leu Pro Cys Ser Pro Thr Ile Pro
Leu Gln Asp Leu Ser 20 25 30Leu Leu Arg Arg Ala Gly Val Thr Trp Gln
His Gln Pro Asp Ser Gly 35 40 45Pro Pro Ala Ala Ala Pro Gly His Pro
Leu Ala Pro Gly Pro His Pro 50 55 60Ala Ala Pro Ser Ser Trp Gly Pro
Arg Pro Arg Arg Tyr Thr Val Leu65 70 75 80Ser Val Gly Pro Gly Gly
Leu Arg Ser Gly Arg Leu Pro Leu Gln Pro 85 90 95Arg Val Gln Leu Asp
Glu Arg Gly Arg Gln Arg Gly Asp Phe Ser Leu 100 105 110Trp Leu Arg
Pro Ala Arg Arg Ala Asp Ala Gly Glu Tyr Arg Ala Ala 115 120 125Val
His Leu Arg Asp Arg Ala Leu Ser Cys Arg Leu Arg Leu Arg Leu 130 135
140Gly Gln Ala Ser Met Thr Ala Ser Pro Pro Gly Ser Leu Arg Ala
Ser145 150 155 160Asp Trp Val Ile Leu Asn Cys Ser Phe Ser Arg Pro
Asp Arg Pro Ala 165 170 175Ser Val His Trp Phe Arg Asn Arg Gly Gln
Gly Arg Val Pro Val Arg 180 185 190Glu Ser Pro His His His Leu Ala
Glu Ser Phe Leu Phe Leu Pro Gln 195 200 205Val Ser Pro Met Asp Ser
Gly Pro Trp Gly Cys Ile Leu Thr Tyr Arg 210 215 220Asp Gly Phe Asn
Val Ser Ile Met Tyr Asn Leu Thr Val Leu Gly Leu225 230 235 240Glu
Pro Pro Thr Pro Leu Thr Val Tyr Ala Gly Ala Gly Ser Arg Val 245 250
255Gly Leu Pro Cys Arg Leu Pro Ala Gly Val Gly Thr Arg Ser Phe Leu
260 265 270Thr Ala Lys Trp Thr Pro Pro Gly Gly Gly Pro Asp Leu Leu
Val Thr 275 280 285Gly Asp Asn Gly Asp Phe Thr Leu Arg Leu Glu Asp
Val Ser Gln Ala 290 295 300Gln Ala Gly Thr Tyr Thr Cys His Ile His
Leu Gln Glu Gln Gln Leu305 310 315 320Asn Ala Thr Val Thr Leu Ala
Ile Ile Thr Val Thr Pro Lys Ser Phe 325 330 335Gly Ser Pro Gly Ser
Leu Gly Lys Leu Leu Cys Glu Val Thr Pro Val 340 345 350Ser Gly Gln
Glu Arg Phe Val Trp Ser Ser Leu Asp Thr Pro Ser Gln 355 360 365Arg
Ser Phe Ser Gly Pro Trp Leu Glu Ala Gln Glu Ala Gln Leu Leu 370 375
380Ser Gln Pro Trp Gln Cys Gln Leu Tyr Gln Gly Glu Arg Leu Leu
Gly385 390 395 400Ala Ala Val Tyr Phe Thr Glu Leu Ser Ser Pro His
His His His His 405 410 415His52417PRTArtificial
SequenceRecombinant cynomolgus macaque LAG-3 ECD-His6 52Pro Gln Pro
Gly Ala Glu Ile Ser Val Val Trp Ala Gln Glu Gly Ala1 5 10 15Pro Ala
Gln Leu Pro Cys Ser Pro Thr Ile Pro Leu Gln Asp Leu Ser 20 25 30Leu
Leu Arg Arg Ala Gly Val Thr Trp Gln His Gln Pro Asp Ser Gly 35 40
45Pro Pro Ala Pro Ala Pro Gly His Pro Pro Ala Pro Gly His Arg Pro
50 55 60Ala Ala Pro Tyr Ser Trp Gly Pro Arg Pro Arg Arg Tyr Thr Val
Leu65 70 75 80Ser Val Gly Pro Gly Gly Leu Arg Ser Gly Arg Leu Pro
Leu Gln Pro 85 90 95Arg Val Gln Leu Asp Glu Arg Gly Arg Gln Arg Gly
Asp Phe Ser Leu 100 105 110Trp Leu Arg Pro Ala Arg Arg Ala Asp Ala
Gly Glu Tyr Arg Ala Thr 115 120 125Val His Leu Arg Asp Arg Ala Leu
Ser Cys Arg Leu Arg Leu Arg Val 130 135 140Gly Gln Ala Ser Met Thr
Ala Ser Pro Pro Gly Ser Leu Arg Thr Ser145 150 155 160Asp Trp Val
Ile Leu Asn Cys Ser Phe Ser Arg Pro Asp Arg Pro Ala 165 170 175Ser
Val His Trp Phe Arg Ser Arg Gly Gln Gly Arg Val Pro Val Gln 180 185
190Gly Ser Pro His His His Leu Ala Glu Ser Phe Leu Phe Leu Pro His
195 200 205Val Gly Pro Met Asp Ser Gly Leu Trp Gly Cys Ile Leu Thr
Tyr Arg 210 215 220Asp Gly Phe Asn Val Ser Ile Met Tyr Asn Leu Thr
Val Leu Gly Leu225 230 235 240Glu Pro Ala Thr Pro Leu Thr Val Tyr
Ala Gly Ala Gly Ser Arg Val 245 250 255Glu Leu Pro Cys Arg Leu Pro
Pro Ala Val Gly Thr Gln Ser Phe Leu 260 265 270Thr Ala Lys Trp Ala
Pro Pro Gly Gly Gly Pro Asp Leu Leu Val Ala 275 280 285Gly Asp Asn
Gly Asp Phe Thr Leu Arg Leu Glu Asp Val Ser Gln Ala 290 295 300Gln
Ala Gly Thr Tyr Ile Cys His Ile Arg Leu Gln Gly Gln Gln Leu305 310
315 320Asn Ala Thr Val Thr Leu Ala Ile Ile Thr Val Thr Pro Lys Ser
Phe 325 330 335Gly Ser Pro Gly Ser Leu Gly Lys Leu Leu Cys Glu Val
Thr Pro Ala 340 345 350Ser Gly Gln Glu His Phe Val Trp Ser Pro Leu
Asn Thr Pro Ser Gln 355 360 365Arg Ser Phe Ser Gly Pro Trp Leu
Glu
Ala Gln Glu Ala Gln Leu Leu 370 375 380Ser Gln Pro Trp Gln Cys Gln
Leu His Gln Gly Glu Arg Leu Leu Gly385 390 395 400Ala Ala Val Tyr
Phe Thr Glu Leu Ser Ser Pro His His His His His 405 410
415His53417PRTArtificial SequenceRecombinant baboon LAG-3 ECD-His6
53Pro Gln Pro Gly Ala Glu Ile Ser Val Val Trp Ala Gln Glu Gly Ala1
5 10 15Pro Ala Gln Leu Pro Cys Ser Pro Thr Ile Pro Leu Gln Asp Leu
Ser 20 25 30Leu Leu Arg Arg Ala Gly Val Thr Trp Gln His Gln Pro Asp
Ser Gly 35 40 45Pro Pro Ala Pro Ala Pro Gly His Pro Pro Ala Pro Gly
His Arg Pro 50 55 60Ala Ala Pro Tyr Ser Trp Gly Pro Arg Pro Arg Arg
Tyr Thr Val Leu65 70 75 80Ser Val Gly Pro Gly Gly Leu Arg Ser Gly
Arg Leu Pro Leu Gln Pro 85 90 95Arg Val Gln Leu Asp Glu Arg Gly Arg
Gln Arg Gly Asp Phe Ser Leu 100 105 110Trp Leu Arg Pro Ala Arg Arg
Ala Asp Ala Gly Glu Tyr Arg Ala Thr 115 120 125Val His Leu Arg Asp
Arg Ala Leu Ser Cys Arg Leu Arg Leu Arg Val 130 135 140Gly Gln Ala
Ser Met Thr Ala Ser Pro Pro Gly Ser Leu Arg Thr Ser145 150 155
160Asp Trp Val Ile Leu Asn Cys Ser Phe Ser Arg Pro Asp Arg Pro Ala
165 170 175Ser Val His Trp Phe Arg Ser Arg Gly Gln Gly Gln Val Pro
Val Gln 180 185 190Glu Ser Pro His His His Leu Ala Glu Ser Phe Leu
Phe Leu Pro His 195 200 205Val Gly Pro Met Asp Ser Gly Leu Trp Gly
Cys Ile Leu Thr Tyr Arg 210 215 220Asp Gly Phe Asn Val Ser Ile Met
Tyr Asn Leu Thr Val Leu Gly Leu225 230 235 240Glu Pro Thr Thr Pro
Leu Thr Val Tyr Ala Gly Ala Gly Ser Arg Val 245 250 255Glu Leu Pro
Cys Arg Leu Pro Pro Ala Val Gly Thr Gln Ser Phe Leu 260 265 270Thr
Ala Lys Trp Ala Pro Pro Gly Gly Gly Pro Asp Leu Leu Val Val 275 280
285Gly Asp Asn Gly Asn Phe Thr Leu Arg Leu Glu Asp Val Ser Gln Ala
290 295 300Gln Ala Gly Thr Tyr Ile Cys His Ile Arg Leu Gln Gly Gln
Gln Leu305 310 315 320Asn Ala Thr Val Thr Leu Ala Ile Ile Thr Val
Thr Pro Lys Ser Phe 325 330 335Gly Ser Pro Gly Ser Leu Gly Lys Leu
Leu Cys Glu Val Thr Pro Ala 340 345 350Ser Gly Gln Glu Arg Phe Val
Trp Ser Pro Leu Asn Thr Pro Ser Gln 355 360 365Arg Ser Phe Ser Gly
Pro Trp Leu Glu Ala Gln Glu Ala Gln Leu Leu 370 375 380Ser Gln Pro
Trp Gln Cys Gln Leu His Gln Gly Glu Arg Leu Leu Gly385 390 395
400Ala Ala Val Tyr Phe Thr Glu Leu Ser Ser Pro His His His His His
405 410 415His5419PRTMurine 54Met Gly Trp Ser Cys Ile Ile Leu Phe
Leu Val Ala Thr Ala Thr Gly1 5 10 15Val His Ser5520PRTMurine 55Met
Glu Ser Gln Thr Gln Val Leu Met Phe Leu Leu Leu Trp Val Ser1 5 10
15Gly Ala Cys Ala 205616PRTHomo Sapien 56Met Pro Leu Leu Leu Leu
Leu Pro Leu Leu Trp Ala Gly Ala Leu Ala1 5 10 155751DNAArtificial
SequenceH5L7, CDRL1 (Kabat defined) 57aagagcagcc agagcctgct
gaaccccagc aaccagaaga actacctggc c 515821DNAMurine 58ttcgcctcta
ccagggattc c 215927DNAMurine 59ctgcagcact tcggcacccc tcccact
2760342DNAArtificial SequenceH5L7, VL 60gacatccaga tgacccagag
cccctctagc ctcagcgcca gcgtgggcga cagggtgacc 60atcacctgca agagcagcca
gagcctgctg aaccccagca accagaagaa ctacctggcc 120tggtaccagc
agaaacccgg caaggccccc aagctgctgg tctacttcgc ctctaccagg
180gattccggcg tccccagcag gttcagcggc agcggcagcg gcaccgactt
cacactgacc 240atcagcagcc tgcagcccga ggacttcgcc acctactact
gcctgcagca cttcggcacc 300cctcccactt ttggccaggg caccaagctg
gagattaagc gt 34261660DNAArtificial SequenceH5L7, light chain
humanised construct 61gacatccaga tgacccagag cccctctagc ctcagcgcca
gcgtgggcga cagggtgacc 60atcacctgca agagcagcca gagcctgctg aaccccagca
accagaagaa ctacctggcc 120tggtaccagc agaaacccgg caaggccccc
aagctgctgg tctacttcgc ctctaccagg 180gattccggcg tccccagcag
gttcagcggc agcggcagcg gcaccgactt cacactgacc 240atcagcagcc
tgcagcccga ggacttcgcc acctactact gcctgcagca cttcggcacc
300cctcccactt ttggccaggg caccaagctg gagattaagc gtacggtggc
cgcccccagc 360gtgttcatct tcccccccag cgatgagcag ctgaagagcg
gcaccgccag cgtggtgtgt 420ctgctgaaca acttctaccc ccgggaggcc
aaggtgcagt ggaaggtgga caatgccctg 480cagagcggca acagccagga
gagcgtgacc gagcaggaca gcaaggactc cacctacagc 540ctgagcagca
ccctgaccct gagcaaggcc gactacgaga agcacaaggt gtacgcctgt
600gaggtgaccc accagggcct gtccagcccc gtgaccaaga gcttcaaccg
gggcgagtgc 6606215DNAMurine 62gcctacggcg tcaac 156348DNAArtificial
SequenceH5L7, CDRH2 (Kabat defined) 63atgatctggg acgacggcag
caccgactac gacagcgccc tgaagagc 486424DNAMurine 64gagggcgacg
tggccttcga ttac 2465348DNAArtificial SequenceH5L7, VH 65caggtgcagc
tccaggagag cggccccggc ctggtgaagc ctagcgagac cctgagcctg 60acctgcaccg
tgagcggctt ctccctgacc gcctacggcg tcaactggat caggcagccc
120cccggcaaag gcctggagtg gattgggatg atctgggacg acggcagcac
cgactacgac 180agcgccctga agagcagggt gaccatcagc gtggacacca
gcaagaacca gttcagcctg 240aagctgagca gcgtgactgc cgccgacacc
gccgtctatt actgcgccag ggagggcgac 300gtggccttcg attactgggg
ccagggcaca ctagtgaccg tgtccagc 348661338DNAArtificial SequenceH5L7,
heavy chain humanised construct 66caggtgcagc tccaggagag cggccccggc
ctggtgaagc ctagcgagac cctgagcctg 60acctgcaccg tgagcggctt ctccctgacc
gcctacggcg tcaactggat caggcagccc 120cccggcaaag gcctggagtg
gattgggatg atctgggacg acggcagcac cgactacgac 180agcgccctga
agagcagggt gaccatcagc gtggacacca gcaagaacca gttcagcctg
240aagctgagca gcgtgactgc cgccgacacc gccgtctatt actgcgccag
ggagggcgac 300gtggccttcg attactgggg ccagggcaca ctagtgaccg
tgtccagcgc cagcaccaag 360ggccccagcg tgttccccct ggcccccagc
agcaagagca ccagcggcgg cacagccgcc 420ctgggctgcc tggtgaagga
ctacttcccc gaaccggtga ccgtgtcctg gaacagcgga 480gccctgacca
gcggcgtgca caccttcccc gccgtgctgc agagcagcgg cctgtacagc
540ctgagcagcg tggtgaccgt gcccagcagc agcctgggca cccagaccta
catctgtaac 600gtgaaccaca agcccagcaa caccaaggtg gacaagaagg
tggagcccaa gagctgtgac 660aagacccaca cctgcccccc ctgccctgcc
cccgagctgc tgggaggccc cagcgtgttc 720ctgttccccc ccaagcctaa
ggacaccctg atgatcagca gaacccccga ggtgacctgt 780gtggtggtgg
atgtgagcca cgaggaccct gaggtgaagt tcaactggta cgtggacggc
840gtggaggtgc acaatgccaa gaccaagccc agggaggagc agtacaacag
cacctaccgg 900gtggtgtccg tgctgaccgt gctgcaccag gattggctga
acggcaagga gtacaagtgt 960aaggtgtcca acaaggccct gcctgcccct
atcgagaaaa ccatcagcaa ggccaagggc 1020cagcccagag agccccaggt
gtacaccctg ccccctagca gagatgagct gaccaagaac 1080caggtgtccc
tgacctgcct ggtgaagggc ttctacccca gcgacatcgc cgtggagtgg
1140gagagcaacg gccagcccga gaacaactac aagaccaccc cccctgtgct
ggacagcgat 1200ggcagcttct tcctgtacag caagctgacc gtggacaaga
gcagatggca gcagggcaac 1260gtgttcagct gctccgtgat gcacgaggcc
ctgcacaatc actacaccca gaagagcctg 1320agcctgtccc ctggcaag
133867660DNAArtificial SequenceH1L7, light chain humanised
construct 67gacatccaga tgacccagag cccctctagc ctcagcgcca gcgtgggcga
cagggtgacc 60atcacctgca agagcagcca gagcctgctg aaccccagca accagaagaa
ctacctggcc 120tggtaccagc agaaacccgg caaggccccc aagctgctgg
tctacttcgc ctctaccagg 180gattccggcg tccccagcag gttcagcggc
agcggcagcg gcaccgactt cacactgacc 240atcagcagcc tgcagcccga
ggacttcgcc acctactact gcctgcagca cttcggcacc 300cctcccactt
ttggccaggg caccaagctg gagattaagc gtacggtggc cgcccccagc
360gtgttcatct tcccccccag cgatgagcag ctgaagagcg gcaccgccag
cgtggtgtgt 420ctgctgaaca acttctaccc ccgggaggcc aaggtgcagt
ggaaggtgga caatgccctg 480cagagcggca acagccagga gagcgtgacc
gagcaggaca gcaaggactc cacctacagc 540ctgagcagca ccctgaccct
gagcaaggcc gactacgaga agcacaaggt gtacgcctgt 600gaggtgaccc
accagggcct gtccagcccc gtgaccaaga gcttcaaccg gggcgagtgc
660681338DNAArtificial SequenceH1L7, heavy chain humanised
construct 68caggtgcagc tccaggagag cggccccggc ctggtgaagc ctagcgagac
cctgagcctg 60acctgcaccg tgagcggctt ctccctgacc gcctacggcg tcaactggat
caggcagccc 120cccggcaaag gcctggagtg gattgggatg atctgggacg
acggcagcac cgactacaac 180agcgccctga agagcagggt gaccatcagc
gtggacacca gcaagaacca gttcagcctg 240aagctgagca gcgtgactgc
cgccgacacc gccgtctatt actgcgccag ggagggcgac 300gtggccttcg
attactgggg ccagggcaca ctagtgaccg tgtccagcgc cagcaccaag
360ggccccagcg tgttccccct ggcccccagc agcaagagca ccagcggcgg
cacagccgcc 420ctgggctgcc tggtgaagga ctacttcccc gaaccggtga
ccgtgtcctg gaacagcgga 480gccctgacca gcggcgtgca caccttcccc
gccgtgctgc agagcagcgg cctgtacagc 540ctgagcagcg tggtgaccgt
gcccagcagc agcctgggca cccagaccta catctgtaac 600gtgaaccaca
agcccagcaa caccaaggtg gacaagaagg tggagcccaa gagctgtgac
660aagacccaca cctgcccccc ctgccctgcc cccgagctgc tgggaggccc
cagcgtgttc 720ctgttccccc ccaagcctaa ggacaccctg atgatcagca
gaacccccga ggtgacctgt 780gtggtggtgg atgtgagcca cgaggaccct
gaggtgaagt tcaactggta cgtggacggc 840gtggaggtgc acaatgccaa
gaccaagccc agggaggagc agtacaacag cacctaccgg 900gtggtgtccg
tgctgaccgt gctgcaccag gattggctga acggcaagga gtacaagtgt
960aaggtgtcca acaaggccct gcctgcccct atcgagaaaa ccatcagcaa
ggccaagggc 1020cagcccagag agccccaggt gtacaccctg ccccctagca
gagatgagct gaccaagaac 1080caggtgtccc tgacctgcct ggtgaagggc
ttctacccca gcgacatcgc cgtggagtgg 1140gagagcaacg gccagcccga
gaacaactac aagaccaccc cccctgtgct ggacagcgat 1200ggcagcttct
tcctgtacag caagctgacc gtggacaaga gcagatggca gcagggcaac
1260gtgttcagct gctccgtgat gcacgaggcc ctgcacaatc actacaccca
gaagagcctg 1320agcctgtccc ctggcaag 133869660DNAArtificial
SequenceJ7L7, light chain humanised construct 69gacatccaga
tgacccagag cccctctagc ctcagcgcca gcgtgggcga cagggtgacc 60atcacctgca
agagcagcca gagcctgctg aaccccagca accagaagaa ctacctggcc
120tggtaccagc agaaacccgg caaggccccc aagctgctgg tctacttcgc
ctctaccagg 180gattccggcg tccccagcag gttcagcggc agcggcagcg
gcaccgactt cacactgacc 240atcagcagcc tgcagcccga ggacttcgcc
acctactact gcctgcagca cttcggcacc 300cctcccactt ttggccaggg
caccaagctg gagattaagc gtacggtggc cgcccccagc 360gtgttcatct
tcccccccag cgatgagcag ctgaagagcg gcaccgccag cgtggtgtgt
420ctgctgaaca acttctaccc ccgggaggcc aaggtgcagt ggaaggtgga
caatgccctg 480cagagcggca acagccagga gagcgtgacc gagcaggaca
gcaaggactc cacctacagc 540ctgagcagca ccctgaccct gagcaaggcc
gactacgaga agcacaaggt gtacgcctgt 600gaggtgaccc accagggcct
gtccagcccc gtgaccaaga gcttcaaccg gggcgagtgc 660701338DNAArtificial
SequenceJ7L7, heavy chain humanised construct 70caggtgcagc
tcgtgcagag cggggccgaa gtcaagaaac ccggcagctc cgtgaaggtg 60agctgcaagg
ccagcggctt ctctctcact gcctacggcg tgaactgggt gaggcaggct
120cccggccagg gcctggagtg gatgggcatg atctgggacg acggcagcac
cgactacaac 180agcgccctga agagcagggt gaccatcacc gccgacaaga
gcaccagcac cgcctacatg 240gaactgagca gcctgaggag cgaggacacc
gccgtgtact attgcgccag ggagggcgac 300gtggccttcg attactgggg
ccagggcaca ctagtgaccg tgtccagcgc cagcaccaag 360ggccccagcg
tgttccccct ggcccccagc agcaagagca ccagcggcgg cacagccgcc
420ctgggctgcc tggtgaagga ctacttcccc gaaccggtga ccgtgtcctg
gaacagcgga 480gccctgacca gcggcgtgca caccttcccc gccgtgctgc
agagcagcgg cctgtacagc 540ctgagcagcg tggtgaccgt gcccagcagc
agcctgggca cccagaccta catctgtaac 600gtgaaccaca agcccagcaa
caccaaggtg gacaagaagg tggagcccaa gagctgtgac 660aagacccaca
cctgcccccc ctgccctgcc cccgagctgc tgggaggccc cagcgtgttc
720ctgttccccc ccaagcctaa ggacaccctg atgatcagca gaacccccga
ggtgacctgt 780gtggtggtgg atgtgagcca cgaggaccct gaggtgaagt
tcaactggta cgtggacggc 840gtggaggtgc acaatgccaa gaccaagccc
agggaggagc agtacaacag cacctaccgg 900gtggtgtccg tgctgaccgt
gctgcaccag gattggctga acggcaagga gtacaagtgt 960aaggtgtcca
acaaggccct gcctgcccct atcgagaaaa ccatcagcaa ggccaagggc
1020cagcccagag agccccaggt gtacaccctg ccccctagca gagatgagct
gaccaagaac 1080caggtgtccc tgacctgcct ggtgaagggc ttctacccca
gcgacatcgc cgtggagtgg 1140gagagcaacg gccagcccga gaacaactac
aagaccaccc cccctgtgct ggacagcgat 1200ggcagcttct tcctgtacag
caagctgacc gtggacaaga gcagatggca gcagggcaac 1260gtgttcagct
gctccgtgat gcacgaggcc ctgcacaatc actacaccca gaagagcctg
1320agcctgtccc ctggcaag 133871660DNAArtificial SequenceH4L7, light
chain humanised construct 71gacatccaga tgacccagag cccctctagc
ctcagcgcca gcgtgggcga cagggtgacc 60atcacctgca agagcagcca gagcctgctg
aaccccagca accagaagaa ctacctggcc 120tggtaccagc agaaacccgg
caaggccccc aagctgctgg tctacttcgc ctctaccagg 180gattccggcg
tccccagcag gttcagcggc agcggcagcg gcaccgactt cacactgacc
240atcagcagcc tgcagcccga ggacttcgcc acctactact gcctgcagca
cttcggcacc 300cctcccactt ttggccaggg caccaagctg gagattaagc
gtacggtggc cgcccccagc 360gtgttcatct tcccccccag cgatgagcag
ctgaagagcg gcaccgccag cgtggtgtgt 420ctgctgaaca acttctaccc
ccgggaggcc aaggtgcagt ggaaggtgga caatgccctg 480cagagcggca
acagccagga gagcgtgacc gagcaggaca gcaaggactc cacctacagc
540ctgagcagca ccctgaccct gagcaaggcc gactacgaga agcacaaggt
gtacgcctgt 600gaggtgaccc accagggcct gtccagcccc gtgaccaaga
gcttcaaccg gggcgagtgc 660721338DNAArtificial SequenceH4L7, heavy
chain humanised construct 72caggtgcagc tccaggagag cggccccggc
ctggtgaagc ctagcgagac cctgagcctg 60acctgcaccg tgagcggctt ctccctgacc
gcctacggcg tcaactggat caggcagccc 120cccggcaaag gcctggagtg
gctggggatg atctgggacg acggcagcac cgactacaac 180agcgccctga
agagcaggct gaccatcagc aaggacaaca gcaagaacca ggtgagcctg
240aagctgagca gcgtgactgc cgccgacacc gccgtctatt actgcgccag
ggagggcgac 300gtggccttcg attactgggg ccagggcaca ctagtgaccg
tgtccagcgc cagcaccaag 360ggccccagcg tgttccccct ggcccccagc
agcaagagca ccagcggcgg cacagccgcc 420ctgggctgcc tggtgaagga
ctacttcccc gaaccggtga ccgtgtcctg gaacagcgga 480gccctgacca
gcggcgtgca caccttcccc gccgtgctgc agagcagcgg cctgtacagc
540ctgagcagcg tggtgaccgt gcccagcagc agcctgggca cccagaccta
catctgtaac 600gtgaaccaca agcccagcaa caccaaggtg gacaagaagg
tggagcccaa gagctgtgac 660aagacccaca cctgcccccc ctgccctgcc
cccgagctgc tgggaggccc cagcgtgttc 720ctgttccccc ccaagcctaa
ggacaccctg atgatcagca gaacccccga ggtgacctgt 780gtggtggtgg
atgtgagcca cgaggaccct gaggtgaagt tcaactggta cgtggacggc
840gtggaggtgc acaatgccaa gaccaagccc agggaggagc agtacaacag
cacctaccgg 900gtggtgtccg tgctgaccgt gctgcaccag gattggctga
acggcaagga gtacaagtgt 960aaggtgtcca acaaggccct gcctgcccct
atcgagaaaa ccatcagcaa ggccaagggc 1020cagcccagag agccccaggt
gtacaccctg ccccctagca gagatgagct gaccaagaac 1080caggtgtccc
tgacctgcct ggtgaagggc ttctacccca gcgacatcgc cgtggagtgg
1140gagagcaacg gccagcccga gaacaactac aagaccaccc cccctgtgct
ggacagcgat 1200ggcagcttct tcctgtacag caagctgacc gtggacaaga
gcagatggca gcagggcaac 1260gtgttcagct gctccgtgat gcacgaggcc
ctgcacaatc actacaccca gaagagcctg 1320agcctgtccc ctggcaag
133873660DNAArtificial SequenceJ11L7, light chain humanised
construct 73gacatccaga tgacccagag cccctctagc ctcagcgcca gcgtgggcga
cagggtgacc 60atcacctgca agagcagcca gagcctgctg aaccccagca accagaagaa
ctacctggcc 120tggtaccagc agaaacccgg caaggccccc aagctgctgg
tctacttcgc ctctaccagg 180gattccggcg tccccagcag gttcagcggc
agcggcagcg gcaccgactt cacactgacc 240atcagcagcc tgcagcccga
ggacttcgcc acctactact gcctgcagca cttcggcacc 300cctcccactt
ttggccaggg caccaagctg gagattaagc gtacggtggc cgcccccagc
360gtgttcatct tcccccccag cgatgagcag ctgaagagcg gcaccgccag
cgtggtgtgt 420ctgctgaaca acttctaccc ccgggaggcc aaggtgcagt
ggaaggtgga caatgccctg 480cagagcggca acagccagga gagcgtgacc
gagcaggaca gcaaggactc cacctacagc 540ctgagcagca ccctgaccct
gagcaaggcc gactacgaga agcacaaggt gtacgcctgt 600gaggtgaccc
accagggcct gtccagcccc gtgaccaaga gcttcaaccg gggcgagtgc
660741338DNAArtificial SequenceJ11L7, heavy chain humanised
construct 74caggtgcagc tcgtgcagag cggggccgaa gtcaagaaac ccggcagctc
cgtgaaggtg 60agctgcaagg ccagcggctt ctctctcact gcctacggcg tgaactgggt
gaggcaggct 120cccggccagg gcctggagtg gatgggcatg atctgggacg
acggcagcac cgactacgac 180agcgccctga agagcagggt gaccatcacc
gccgacaaga gcaccagcac cgcctacatg 240gaactgagca gcctgaggag
cgaggacacc gccgtgtact attgcgccag ggagggcgac 300gtggccttcg
attactgggg ccagggcaca ctagtgaccg tgtccagcgc cagcaccaag
360ggccccagcg tgttccccct ggcccccagc agcaagagca ccagcggcgg
cacagccgcc 420ctgggctgcc tggtgaagga ctacttcccc gaaccggtga
ccgtgtcctg gaacagcgga 480gccctgacca gcggcgtgca caccttcccc
gccgtgctgc agagcagcgg cctgtacagc 540ctgagcagcg tggtgaccgt
gcccagcagc agcctgggca cccagaccta catctgtaac 600gtgaaccaca
agcccagcaa caccaaggtg gacaagaagg tggagcccaa gagctgtgac
660aagacccaca cctgcccccc ctgccctgcc cccgagctgc tgggaggccc
cagcgtgttc 720ctgttccccc ccaagcctaa ggacaccctg atgatcagca
gaacccccga ggtgacctgt 780gtggtggtgg atgtgagcca cgaggaccct
gaggtgaagt tcaactggta cgtggacggc 840gtggaggtgc acaatgccaa
gaccaagccc agggaggagc agtacaacag cacctaccgg 900gtggtgtccg
tgctgaccgt gctgcaccag gattggctga acggcaagga gtacaagtgt
960aaggtgtcca acaaggccct gcctgcccct atcgagaaaa ccatcagcaa
ggccaagggc 1020cagcccagag agccccaggt gtacaccctg ccccctagca
gagatgagct gaccaagaac
1080caggtgtccc tgacctgcct ggtgaagggc ttctacccca gcgacatcgc
cgtggagtgg 1140gagagcaacg gccagcccga gaacaactac aagaccaccc
cccctgtgct ggacagcgat 1200ggcagcttct tcctgtacag caagctgacc
gtggacaaga gcagatggca gcagggcaac 1260gtgttcagct gctccgtgat
gcacgaggcc ctgcacaatc actacaccca gaagagcctg 1320agcctgtccc ctggcaag
133875660DNAArtificial SequenceH2L7, light chain humanised
construct 75gacatccaga tgacccagag cccctctagc ctcagcgcca gcgtgggcga
cagggtgacc 60atcacctgca agagcagcca gagcctgctg aaccccagca accagaagaa
ctacctggcc 120tggtaccagc agaaacccgg caaggccccc aagctgctgg
tctacttcgc ctctaccagg 180gattccggcg tccccagcag gttcagcggc
agcggcagcg gcaccgactt cacactgacc 240atcagcagcc tgcagcccga
ggacttcgcc acctactact gcctgcagca cttcggcacc 300cctcccactt
ttggccaggg caccaagctg gagattaagc gtacggtggc cgcccccagc
360gtgttcatct tcccccccag cgatgagcag ctgaagagcg gcaccgccag
cgtggtgtgt 420ctgctgaaca acttctaccc ccgggaggcc aaggtgcagt
ggaaggtgga caatgccctg 480cagagcggca acagccagga gagcgtgacc
gagcaggaca gcaaggactc cacctacagc 540ctgagcagca ccctgaccct
gagcaaggcc gactacgaga agcacaaggt gtacgcctgt 600gaggtgaccc
accagggcct gtccagcccc gtgaccaaga gcttcaaccg gggcgagtgc
660761338DNAArtificial SequenceH2L7, heavy chain humanised
construct 76caggtgcagc tccaggagag cggccccggc ctggtgaagc ctagcgagac
cctgagcctg 60acctgcaccg tgagcggctt ctccctgacc gcctacggcg tcaactggat
caggcagccc 120cccggcaaag gcctggagtg gattgggatg atctgggacg
acggcagcac cgactacaac 180agcgccctga agagcagggt gaccatcagc
aaggacaaca gcaagaacca ggtgagcctg 240aagctgagca gcgtgactgc
cgccgacacc gccgtctatt actgcgccag ggagggcgac 300gtggccttcg
attactgggg ccagggcaca ctagtgaccg tgtccagcgc cagcaccaag
360ggccccagcg tgttccccct ggcccccagc agcaagagca ccagcggcgg
cacagccgcc 420ctgggctgcc tggtgaagga ctacttcccc gaaccggtga
ccgtgtcctg gaacagcgga 480gccctgacca gcggcgtgca caccttcccc
gccgtgctgc agagcagcgg cctgtacagc 540ctgagcagcg tggtgaccgt
gcccagcagc agcctgggca cccagaccta catctgtaac 600gtgaaccaca
agcccagcaa caccaaggtg gacaagaagg tggagcccaa gagctgtgac
660aagacccaca cctgcccccc ctgccctgcc cccgagctgc tgggaggccc
cagcgtgttc 720ctgttccccc ccaagcctaa ggacaccctg atgatcagca
gaacccccga ggtgacctgt 780gtggtggtgg atgtgagcca cgaggaccct
gaggtgaagt tcaactggta cgtggacggc 840gtggaggtgc acaatgccaa
gaccaagccc agggaggagc agtacaacag cacctaccgg 900gtggtgtccg
tgctgaccgt gctgcaccag gattggctga acggcaagga gtacaagtgt
960aaggtgtcca acaaggccct gcctgcccct atcgagaaaa ccatcagcaa
ggccaagggc 1020cagcccagag agccccaggt gtacaccctg ccccctagca
gagatgagct gaccaagaac 1080caggtgtccc tgacctgcct ggtgaagggc
ttctacccca gcgacatcgc cgtggagtgg 1140gagagcaacg gccagcccga
gaacaactac aagaccaccc cccctgtgct ggacagcgat 1200ggcagcttct
tcctgtacag caagctgacc gtggacaaga gcagatggca gcagggcaac
1260gtgttcagct gctccgtgat gcacgaggcc ctgcacaatc actacaccca
gaagagcctg 1320agcctgtccc ctggcaag 133877660DNAArtificial
SequenceJ13L7, light chain humanised construct 77gacatccaga
tgacccagag cccctctagc ctcagcgcca gcgtgggcga cagggtgacc 60atcacctgca
agagcagcca gagcctgctg aaccccagca accagaagaa ctacctggcc
120tggtaccagc agaaacccgg caaggccccc aagctgctgg tctacttcgc
ctctaccagg 180gattccggcg tccccagcag gttcagcggc agcggcagcg
gcaccgactt cacactgacc 240atcagcagcc tgcagcccga ggacttcgcc
acctactact gcctgcagca cttcggcacc 300cctcccactt ttggccaggg
caccaagctg gagattaagc gtacggtggc cgcccccagc 360gtgttcatct
tcccccccag cgatgagcag ctgaagagcg gcaccgccag cgtggtgtgt
420ctgctgaaca acttctaccc ccgggaggcc aaggtgcagt ggaaggtgga
caatgccctg 480cagagcggca acagccagga gagcgtgacc gagcaggaca
gcaaggactc cacctacagc 540ctgagcagca ccctgaccct gagcaaggcc
gactacgaga agcacaaggt gtacgcctgt 600gaggtgaccc accagggcct
gtccagcccc gtgaccaaga gcttcaaccg gggcgagtgc 660781338DNAArtificial
SequenceJ13L7, heavy chain humanised construct 78caggtgcagc
tcgtgcagag cggggccgaa gtcaagaaac ccggcagctc cgtgaaggtg 60agctgcaagg
ccagcggcgg caccttcagc gcctacggcg tgaactgggt gaggcaggct
120cccggccagg gcctggagtg gatgggcatg atctgggacg acggcagcac
cgactacgac 180agcgccctga agagcagggt gaccatcacc gccgacaaga
gcaccagcac cgcctacatg 240gaactgagca gcctgaggag cgaggacacc
gccgtgtact attgcgccag ggagggcgac 300gtggccttcg attactgggg
ccagggcaca ctagtgaccg tgtccagcgc cagcaccaag 360ggccccagcg
tgttccccct ggcccccagc agcaagagca ccagcggcgg cacagccgcc
420ctgggctgcc tggtgaagga ctacttcccc gaaccggtga ccgtgtcctg
gaacagcgga 480gccctgacca gcggcgtgca caccttcccc gccgtgctgc
agagcagcgg cctgtacagc 540ctgagcagcg tggtgaccgt gcccagcagc
agcctgggca cccagaccta catctgtaac 600gtgaaccaca agcccagcaa
caccaaggtg gacaagaagg tggagcccaa gagctgtgac 660aagacccaca
cctgcccccc ctgccctgcc cccgagctgc tgggaggccc cagcgtgttc
720ctgttccccc ccaagcctaa ggacaccctg atgatcagca gaacccccga
ggtgacctgt 780gtggtggtgg atgtgagcca cgaggaccct gaggtgaagt
tcaactggta cgtggacggc 840gtggaggtgc acaatgccaa gaccaagccc
agggaggagc agtacaacag cacctaccgg 900gtggtgtccg tgctgaccgt
gctgcaccag gattggctga acggcaagga gtacaagtgt 960aaggtgtcca
acaaggccct gcctgcccct atcgagaaaa ccatcagcaa ggccaagggc
1020cagcccagag agccccaggt gtacaccctg ccccctagca gagatgagct
gaccaagaac 1080caggtgtccc tgacctgcct ggtgaagggc ttctacccca
gcgacatcgc cgtggagtgg 1140gagagcaacg gccagcccga gaacaactac
aagaccaccc cccctgtgct ggacagcgat 1200ggcagcttct tcctgtacag
caagctgacc gtggacaaga gcagatggca gcagggcaac 1260gtgttcagct
gctccgtgat gcacgaggcc ctgcacaatc actacaccca gaagagcctg
1320agcctgtccc ctggcaag 133879660DNAArtificial SequenceH7L7, light
chain humanised construct 79gacatccaga tgacccagag cccctctagc
ctcagcgcca gcgtgggcga cagggtgacc 60atcacctgca agagcagcca gagcctgctg
aaccccagca accagaagaa ctacctggcc 120tggtaccagc agaaacccgg
caaggccccc aagctgctgg tctacttcgc ctctaccagg 180gattccggcg
tccccagcag gttcagcggc agcggcagcg gcaccgactt cacactgacc
240atcagcagcc tgcagcccga ggacttcgcc acctactact gcctgcagca
cttcggcacc 300cctcccactt ttggccaggg caccaagctg gagattaagc
gtacggtggc cgcccccagc 360gtgttcatct tcccccccag cgatgagcag
ctgaagagcg gcaccgccag cgtggtgtgt 420ctgctgaaca acttctaccc
ccgggaggcc aaggtgcagt ggaaggtgga caatgccctg 480cagagcggca
acagccagga gagcgtgacc gagcaggaca gcaaggactc cacctacagc
540ctgagcagca ccctgaccct gagcaaggcc gactacgaga agcacaaggt
gtacgcctgt 600gaggtgaccc accagggcct gtccagcccc gtgaccaaga
gcttcaaccg gggcgagtgc 660801338DNAArtificial SequenceH7L7, heavy
chain humanised construct 80caggtgcagc tccaggagag cggccccggc
ctggtgaagc ctagcgagac cctgagcctg 60acctgcaccg tgagcggcgg ctccatcagc
gcctacggcg tcaactggat caggcagccc 120cccggcaaag gcctggagtg
gattgggatg atctgggacg acggcagcac cgactacgac 180agcgccctga
agagcagggt gaccatcagc gtggacacca gcaagaacca gttcagcctg
240aagctgagca gcgtgactgc cgccgacacc gccgtctatt actgcgccag
ggagggcgac 300gtggccttcg attactgggg ccagggcaca ctagtgaccg
tgtccagcgc cagcaccaag 360ggccccagcg tgttccccct ggcccccagc
agcaagagca ccagcggcgg cacagccgcc 420ctgggctgcc tggtgaagga
ctacttcccc gaaccggtga ccgtgtcctg gaacagcgga 480gccctgacca
gcggcgtgca caccttcccc gccgtgctgc agagcagcgg cctgtacagc
540ctgagcagcg tggtgaccgt gcccagcagc agcctgggca cccagaccta
catctgtaac 600gtgaaccaca agcccagcaa caccaaggtg gacaagaagg
tggagcccaa gagctgtgac 660aagacccaca cctgcccccc ctgccctgcc
cccgagctgc tgggaggccc cagcgtgttc 720ctgttccccc ccaagcctaa
ggacaccctg atgatcagca gaacccccga ggtgacctgt 780gtggtggtgg
atgtgagcca cgaggaccct gaggtgaagt tcaactggta cgtggacggc
840gtggaggtgc acaatgccaa gaccaagccc agggaggagc agtacaacag
cacctaccgg 900gtggtgtccg tgctgaccgt gctgcaccag gattggctga
acggcaagga gtacaagtgt 960aaggtgtcca acaaggccct gcctgcccct
atcgagaaaa ccatcagcaa ggccaagggc 1020cagcccagag agccccaggt
gtacaccctg ccccctagca gagatgagct gaccaagaac 1080caggtgtccc
tgacctgcct ggtgaagggc ttctacccca gcgacatcgc cgtggagtgg
1140gagagcaacg gccagcccga gaacaactac aagaccaccc cccctgtgct
ggacagcgat 1200ggcagcttct tcctgtacag caagctgacc gtggacaaga
gcagatggca gcagggcaac 1260gtgttcagct gctccgtgat gcacgaggcc
ctgcacaatc actacaccca gaagagcctg 1320agcctgtccc ctggcaag
133881660DNAArtificial SequenceJ0L7, light chain humanised
construct 81gacatccaga tgacccagag cccctctagc ctcagcgcca gcgtgggcga
cagggtgacc 60atcacctgca agagcagcca gagcctgctg aaccccagca accagaagaa
ctacctggcc 120tggtaccagc agaaacccgg caaggccccc aagctgctgg
tctacttcgc ctctaccagg 180gattccggcg tccccagcag gttcagcggc
agcggcagcg gcaccgactt cacactgacc 240atcagcagcc tgcagcccga
ggacttcgcc acctactact gcctgcagca cttcggcacc 300cctcccactt
ttggccaggg caccaagctg gagattaagc gtacggtggc cgcccccagc
360gtgttcatct tcccccccag cgatgagcag ctgaagagcg gcaccgccag
cgtggtgtgt 420ctgctgaaca acttctaccc ccgggaggcc aaggtgcagt
ggaaggtgga caatgccctg 480cagagcggca acagccagga gagcgtgacc
gagcaggaca gcaaggactc cacctacagc 540ctgagcagca ccctgaccct
gagcaaggcc gactacgaga agcacaaggt gtacgcctgt 600gaggtgaccc
accagggcct gtccagcccc gtgaccaaga gcttcaaccg gggcgagtgc
660821338DNAArtificial SequenceJ0L7, heavy chain humanised
construct 82caggtgcagc tcgtgcagag cggggccgaa gtcaagaaac ccggcagctc
cgtgaaggtg 60agctgcaagg ccagcggcgg caccttcagc gcctacggcg tgaactgggt
gaggcaggct 120cccggccagg gcctggagtg gatgggcatg atctgggacg
acggcagcac cgactacaac 180agcgccctga agagcagggt gaccatcacc
gccgacaaga gcaccagcac cgcctacatg 240gaactgagca gcctgaggag
cgaggacacc gccgtgtact attgcgccag ggagggcgac 300gtggccttcg
attactgggg ccagggcaca ctagtgaccg tgtccagcgc cagcaccaag
360ggccccagcg tgttccccct ggcccccagc agcaagagca ccagcggcgg
cacagccgcc 420ctgggctgcc tggtgaagga ctacttcccc gaaccggtga
ccgtgtcctg gaacagcgga 480gccctgacca gcggcgtgca caccttcccc
gccgtgctgc agagcagcgg cctgtacagc 540ctgagcagcg tggtgaccgt
gcccagcagc agcctgggca cccagaccta catctgtaac 600gtgaaccaca
agcccagcaa caccaaggtg gacaagaagg tggagcccaa gagctgtgac
660aagacccaca cctgcccccc ctgccctgcc cccgagctgc tgggaggccc
cagcgtgttc 720ctgttccccc ccaagcctaa ggacaccctg atgatcagca
gaacccccga ggtgacctgt 780gtggtggtgg atgtgagcca cgaggaccct
gaggtgaagt tcaactggta cgtggacggc 840gtggaggtgc acaatgccaa
gaccaagccc agggaggagc agtacaacag cacctaccgg 900gtggtgtccg
tgctgaccgt gctgcaccag gattggctga acggcaagga gtacaagtgt
960aaggtgtcca acaaggccct gcctgcccct atcgagaaaa ccatcagcaa
ggccaagggc 1020cagcccagag agccccaggt gtacaccctg ccccctagca
gagatgagct gaccaagaac 1080caggtgtccc tgacctgcct ggtgaagggc
ttctacccca gcgacatcgc cgtggagtgg 1140gagagcaacg gccagcccga
gaacaactac aagaccaccc cccctgtgct ggacagcgat 1200ggcagcttct
tcctgtacag caagctgacc gtggacaaga gcagatggca gcagggcaac
1260gtgttcagct gctccgtgat gcacgaggcc ctgcacaatc actacaccca
gaagagcctg 1320agcctgtccc ctggcaag 133883660DNAArtificial
SequenceH0L7, light chain humanised construct 83gacatccaga
tgacccagag cccctctagc ctcagcgcca gcgtgggcga cagggtgacc 60atcacctgca
agagcagcca gagcctgctg aaccccagca accagaagaa ctacctggcc
120tggtaccagc agaaacccgg caaggccccc aagctgctgg tctacttcgc
ctctaccagg 180gattccggcg tccccagcag gttcagcggc agcggcagcg
gcaccgactt cacactgacc 240atcagcagcc tgcagcccga ggacttcgcc
acctactact gcctgcagca cttcggcacc 300cctcccactt ttggccaggg
caccaagctg gagattaagc gtacggtggc cgcccccagc 360gtgttcatct
tcccccccag cgatgagcag ctgaagagcg gcaccgccag cgtggtgtgt
420ctgctgaaca acttctaccc ccgggaggcc aaggtgcagt ggaaggtgga
caatgccctg 480cagagcggca acagccagga gagcgtgacc gagcaggaca
gcaaggactc cacctacagc 540ctgagcagca ccctgaccct gagcaaggcc
gactacgaga agcacaaggt gtacgcctgt 600gaggtgaccc accagggcct
gtccagcccc gtgaccaaga gcttcaaccg gggcgagtgc 660841338DNAArtificial
SequenceH0L7, heavy chain humanised construct 84caggtgcagc
tccaggagag cggccccggc ctggtgaagc ctagcgagac cctgagcctg 60acctgcaccg
tgagcggcgg ctccatcagc gcctacggcg tcaactggat caggcagccc
120cccggcaaag gcctggagtg gattgggatg atctgggacg acggcagcac
cgactacaac 180agcgccctga agagcagggt gaccatcagc gtggacacca
gcaagaacca gttcagcctg 240aagctgagca gcgtgactgc cgccgacacc
gccgtctatt actgcgccag ggagggcgac 300gtggccttcg attactgggg
ccagggcaca ctagtgaccg tgtccagcgc cagcaccaag 360ggccccagcg
tgttccccct ggcccccagc agcaagagca ccagcggcgg cacagccgcc
420ctgggctgcc tggtgaagga ctacttcccc gaaccggtga ccgtgtcctg
gaacagcgga 480gccctgacca gcggcgtgca caccttcccc gccgtgctgc
agagcagcgg cctgtacagc 540ctgagcagcg tggtgaccgt gcccagcagc
agcctgggca cccagaccta catctgtaac 600gtgaaccaca agcccagcaa
caccaaggtg gacaagaagg tggagcccaa gagctgtgac 660aagacccaca
cctgcccccc ctgccctgcc cccgagctgc tgggaggccc cagcgtgttc
720ctgttccccc ccaagcctaa ggacaccctg atgatcagca gaacccccga
ggtgacctgt 780gtggtggtgg atgtgagcca cgaggaccct gaggtgaagt
tcaactggta cgtggacggc 840gtggaggtgc acaatgccaa gaccaagccc
agggaggagc agtacaacag cacctaccgg 900gtggtgtccg tgctgaccgt
gctgcaccag gattggctga acggcaagga gtacaagtgt 960aaggtgtcca
acaaggccct gcctgcccct atcgagaaaa ccatcagcaa ggccaagggc
1020cagcccagag agccccaggt gtacaccctg ccccctagca gagatgagct
gaccaagaac 1080caggtgtccc tgacctgcct ggtgaagggc ttctacccca
gcgacatcgc cgtggagtgg 1140gagagcaacg gccagcccga gaacaactac
aagaccaccc cccctgtgct ggacagcgat 1200ggcagcttct tcctgtacag
caagctgacc gtggacaaga gcagatggca gcagggcaac 1260gtgttcagct
gctccgtgat gcacgaggcc ctgcacaatc actacaccca gaagagcctg
1320agcctgtccc ctggcaag 133885660DNAArtificial SequenceH1L1, light
chain humanised construct 85gacatccaga tgacccagag cccctctagc
ctcagcgcca gcgtgggcga cagggtgacc 60atcacctgca agagcagcca gagcctgctg
aacggcagca accagaagaa ctacctggcc 120tggtaccagc agaaacccgg
caaggccccc aagctgctgg tctacttcgc ctctaccagg 180gattccggcg
tccccagcag gttcagcggc agcggcagcg gcaccgactt cacactgacc
240atcagcagcc tgcagcccga ggacttcgcc acctactact gcctgcagca
cttcggcacc 300cctcccactt ttggccaggg caccaagctg gagattaagc
gtacggtggc cgcccccagc 360gtgttcatct tcccccccag cgatgagcag
ctgaagagcg gcaccgccag cgtggtgtgt 420ctgctgaaca acttctaccc
ccgggaggcc aaggtgcagt ggaaggtgga caatgccctg 480cagagcggca
acagccagga gagcgtgacc gagcaggaca gcaaggactc cacctacagc
540ctgagcagca ccctgaccct gagcaaggcc gactacgaga agcacaaggt
gtacgcctgt 600gaggtgaccc accagggcct gtccagcccc gtgaccaaga
gcttcaaccg gggcgagtgc 660861338DNAArtificial SequenceH1L1, heavy
chain humanised construct 86caggtgcagc tccaggagag cggccccggc
ctggtgaagc ctagcgagac cctgagcctg 60acctgcaccg tgagcggctt ctccctgacc
gcctacggcg tcaactggat caggcagccc 120cccggcaaag gcctggagtg
gattgggatg atctgggacg acggcagcac cgactacaac 180agcgccctga
agagcagggt gaccatcagc gtggacacca gcaagaacca gttcagcctg
240aagctgagca gcgtgactgc cgccgacacc gccgtctatt actgcgccag
ggagggcgac 300gtggccttcg attactgggg ccagggcaca ctagtgaccg
tgtccagcgc cagcaccaag 360ggccccagcg tgttccccct ggcccccagc
agcaagagca ccagcggcgg cacagccgcc 420ctgggctgcc tggtgaagga
ctacttcccc gaaccggtga ccgtgtcctg gaacagcgga 480gccctgacca
gcggcgtgca caccttcccc gccgtgctgc agagcagcgg cctgtacagc
540ctgagcagcg tggtgaccgt gcccagcagc agcctgggca cccagaccta
catctgtaac 600gtgaaccaca agcccagcaa caccaaggtg gacaagaagg
tggagcccaa gagctgtgac 660aagacccaca cctgcccccc ctgccctgcc
cccgagctgc tgggaggccc cagcgtgttc 720ctgttccccc ccaagcctaa
ggacaccctg atgatcagca gaacccccga ggtgacctgt 780gtggtggtgg
atgtgagcca cgaggaccct gaggtgaagt tcaactggta cgtggacggc
840gtggaggtgc acaatgccaa gaccaagccc agggaggagc agtacaacag
cacctaccgg 900gtggtgtccg tgctgaccgt gctgcaccag gattggctga
acggcaagga gtacaagtgt 960aaggtgtcca acaaggccct gcctgcccct
atcgagaaaa ccatcagcaa ggccaagggc 1020cagcccagag agccccaggt
gtacaccctg ccccctagca gagatgagct gaccaagaac 1080caggtgtccc
tgacctgcct ggtgaagggc ttctacccca gcgacatcgc cgtggagtgg
1140gagagcaacg gccagcccga gaacaactac aagaccaccc cccctgtgct
ggacagcgat 1200ggcagcttct tcctgtacag caagctgacc gtggacaaga
gcagatggca gcagggcaac 1260gtgttcagct gctccgtgat gcacgaggcc
ctgcacaatc actacaccca gaagagcctg 1320agcctgtccc ctggcaag
133887660DNAArtificial SequenceH5L1, light chain humanised
construct 87gacatccaga tgacccagag cccctctagc ctcagcgcca gcgtgggcga
cagggtgacc 60atcacctgca agagcagcca gagcctgctg aacggcagca accagaagaa
ctacctggcc 120tggtaccagc agaaacccgg caaggccccc aagctgctgg
tctacttcgc ctctaccagg 180gattccggcg tccccagcag gttcagcggc
agcggcagcg gcaccgactt cacactgacc 240atcagcagcc tgcagcccga
ggacttcgcc acctactact gcctgcagca cttcggcacc 300cctcccactt
ttggccaggg caccaagctg gagattaagc gtacggtggc cgcccccagc
360gtgttcatct tcccccccag cgatgagcag ctgaagagcg gcaccgccag
cgtggtgtgt 420ctgctgaaca acttctaccc ccgggaggcc aaggtgcagt
ggaaggtgga caatgccctg 480cagagcggca acagccagga gagcgtgacc
gagcaggaca gcaaggactc cacctacagc 540ctgagcagca ccctgaccct
gagcaaggcc gactacgaga agcacaaggt gtacgcctgt 600gaggtgaccc
accagggcct gtccagcccc gtgaccaaga gcttcaaccg gggcgagtgc
660881338DNAArtificial SequenceH5L1, heavy chain humanised
construct 88caggtgcagc tccaggagag cggccccggc ctggtgaagc ctagcgagac
cctgagcctg 60acctgcaccg tgagcggctt ctccctgacc gcctacggcg tcaactggat
caggcagccc 120cccggcaaag gcctggagtg gattgggatg atctgggacg
acggcagcac cgactacgac 180agcgccctga agagcagggt gaccatcagc
gtggacacca gcaagaacca gttcagcctg 240aagctgagca gcgtgactgc
cgccgacacc gccgtctatt actgcgccag ggagggcgac 300gtggccttcg
attactgggg ccagggcaca ctagtgaccg tgtccagcgc cagcaccaag
360ggccccagcg tgttccccct ggcccccagc agcaagagca ccagcggcgg
cacagccgcc 420ctgggctgcc tggtgaagga ctacttcccc gaaccggtga
ccgtgtcctg gaacagcgga 480gccctgacca gcggcgtgca caccttcccc
gccgtgctgc agagcagcgg cctgtacagc 540ctgagcagcg tggtgaccgt
gcccagcagc agcctgggca cccagaccta catctgtaac 600gtgaaccaca
agcccagcaa caccaaggtg gacaagaagg tggagcccaa gagctgtgac
660aagacccaca cctgcccccc ctgccctgcc cccgagctgc tgggaggccc
cagcgtgttc 720ctgttccccc ccaagcctaa ggacaccctg atgatcagca
gaacccccga ggtgacctgt 780gtggtggtgg atgtgagcca cgaggaccct
gaggtgaagt tcaactggta cgtggacggc 840gtggaggtgc acaatgccaa
gaccaagccc agggaggagc agtacaacag cacctaccgg 900gtggtgtccg
tgctgaccgt gctgcaccag gattggctga acggcaagga gtacaagtgt
960aaggtgtcca acaaggccct gcctgcccct atcgagaaaa ccatcagcaa
ggccaagggc
1020cagcccagag agccccaggt gtacaccctg ccccctagca gagatgagct
gaccaagaac 1080caggtgtccc tgacctgcct ggtgaagggc ttctacccca
gcgacatcgc cgtggagtgg 1140gagagcaacg gccagcccga gaacaactac
aagaccaccc cccctgtgct ggacagcgat 1200ggcagcttct tcctgtacag
caagctgacc gtggacaaga gcagatggca gcagggcaac 1260gtgttcagct
gctccgtgat gcacgaggcc ctgcacaatc actacaccca gaagagcctg
1320agcctgtccc ctggcaag 133889660DNAArtificial SequenceJ7L1, light
chain humanised construct 89gacatccaga tgacccagag cccctctagc
ctcagcgcca gcgtgggcga cagggtgacc 60atcacctgca agagcagcca gagcctgctg
aacggcagca accagaagaa ctacctggcc 120tggtaccagc agaaacccgg
caaggccccc aagctgctgg tctacttcgc ctctaccagg 180gattccggcg
tccccagcag gttcagcggc agcggcagcg gcaccgactt cacactgacc
240atcagcagcc tgcagcccga ggacttcgcc acctactact gcctgcagca
cttcggcacc 300cctcccactt ttggccaggg caccaagctg gagattaagc
gtacggtggc cgcccccagc 360gtgttcatct tcccccccag cgatgagcag
ctgaagagcg gcaccgccag cgtggtgtgt 420ctgctgaaca acttctaccc
ccgggaggcc aaggtgcagt ggaaggtgga caatgccctg 480cagagcggca
acagccagga gagcgtgacc gagcaggaca gcaaggactc cacctacagc
540ctgagcagca ccctgaccct gagcaaggcc gactacgaga agcacaaggt
gtacgcctgt 600gaggtgaccc accagggcct gtccagcccc gtgaccaaga
gcttcaaccg gggcgagtgc 660901338DNAArtificial SequenceJ7L1, heavy
chain humanised construct 90caggtgcagc tcgtgcagag cggggccgaa
gtcaagaaac ccggcagctc cgtgaaggtg 60agctgcaagg ccagcggctt ctctctcact
gcctacggcg tgaactgggt gaggcaggct 120cccggccagg gcctggagtg
gatgggcatg atctgggacg acggcagcac cgactacaac 180agcgccctga
agagcagggt gaccatcacc gccgacaaga gcaccagcac cgcctacatg
240gaactgagca gcctgaggag cgaggacacc gccgtgtact attgcgccag
ggagggcgac 300gtggccttcg attactgggg ccagggcaca ctagtgaccg
tgtccagcgc cagcaccaag 360ggccccagcg tgttccccct ggcccccagc
agcaagagca ccagcggcgg cacagccgcc 420ctgggctgcc tggtgaagga
ctacttcccc gaaccggtga ccgtgtcctg gaacagcgga 480gccctgacca
gcggcgtgca caccttcccc gccgtgctgc agagcagcgg cctgtacagc
540ctgagcagcg tggtgaccgt gcccagcagc agcctgggca cccagaccta
catctgtaac 600gtgaaccaca agcccagcaa caccaaggtg gacaagaagg
tggagcccaa gagctgtgac 660aagacccaca cctgcccccc ctgccctgcc
cccgagctgc tgggaggccc cagcgtgttc 720ctgttccccc ccaagcctaa
ggacaccctg atgatcagca gaacccccga ggtgacctgt 780gtggtggtgg
atgtgagcca cgaggaccct gaggtgaagt tcaactggta cgtggacggc
840gtggaggtgc acaatgccaa gaccaagccc agggaggagc agtacaacag
cacctaccgg 900gtggtgtccg tgctgaccgt gctgcaccag gattggctga
acggcaagga gtacaagtgt 960aaggtgtcca acaaggccct gcctgcccct
atcgagaaaa ccatcagcaa ggccaagggc 1020cagcccagag agccccaggt
gtacaccctg ccccctagca gagatgagct gaccaagaac 1080caggtgtccc
tgacctgcct ggtgaagggc ttctacccca gcgacatcgc cgtggagtgg
1140gagagcaacg gccagcccga gaacaactac aagaccaccc cccctgtgct
ggacagcgat 1200ggcagcttct tcctgtacag caagctgacc gtggacaaga
gcagatggca gcagggcaac 1260gtgttcagct gctccgtgat gcacgaggcc
ctgcacaatc actacaccca gaagagcctg 1320agcctgtccc ctggcaag
133891660DNAArtificial SequenceJ11L1, light chain humanised
construct 91gacatccaga tgacccagag cccctctagc ctcagcgcca gcgtgggcga
cagggtgacc 60atcacctgca agagcagcca gagcctgctg aacggcagca accagaagaa
ctacctggcc 120tggtaccagc agaaacccgg caaggccccc aagctgctgg
tctacttcgc ctctaccagg 180gattccggcg tccccagcag gttcagcggc
agcggcagcg gcaccgactt cacactgacc 240atcagcagcc tgcagcccga
ggacttcgcc acctactact gcctgcagca cttcggcacc 300cctcccactt
ttggccaggg caccaagctg gagattaagc gtacggtggc cgcccccagc
360gtgttcatct tcccccccag cgatgagcag ctgaagagcg gcaccgccag
cgtggtgtgt 420ctgctgaaca acttctaccc ccgggaggcc aaggtgcagt
ggaaggtgga caatgccctg 480cagagcggca acagccagga gagcgtgacc
gagcaggaca gcaaggactc cacctacagc 540ctgagcagca ccctgaccct
gagcaaggcc gactacgaga agcacaaggt gtacgcctgt 600gaggtgaccc
accagggcct gtccagcccc gtgaccaaga gcttcaaccg gggcgagtgc
660921338DNAArtificial SequenceJ11L1, heavy chain humanised
construct 92caggtgcagc tcgtgcagag cggggccgaa gtcaagaaac ccggcagctc
cgtgaaggtg 60agctgcaagg ccagcggctt ctctctcact gcctacggcg tgaactgggt
gaggcaggct 120cccggccagg gcctggagtg gatgggcatg atctgggacg
acggcagcac cgactacgac 180agcgccctga agagcagggt gaccatcacc
gccgacaaga gcaccagcac cgcctacatg 240gaactgagca gcctgaggag
cgaggacacc gccgtgtact attgcgccag ggagggcgac 300gtggccttcg
attactgggg ccagggcaca ctagtgaccg tgtccagcgc cagcaccaag
360ggccccagcg tgttccccct ggcccccagc agcaagagca ccagcggcgg
cacagccgcc 420ctgggctgcc tggtgaagga ctacttcccc gaaccggtga
ccgtgtcctg gaacagcgga 480gccctgacca gcggcgtgca caccttcccc
gccgtgctgc agagcagcgg cctgtacagc 540ctgagcagcg tggtgaccgt
gcccagcagc agcctgggca cccagaccta catctgtaac 600gtgaaccaca
agcccagcaa caccaaggtg gacaagaagg tggagcccaa gagctgtgac
660aagacccaca cctgcccccc ctgccctgcc cccgagctgc tgggaggccc
cagcgtgttc 720ctgttccccc ccaagcctaa ggacaccctg atgatcagca
gaacccccga ggtgacctgt 780gtggtggtgg atgtgagcca cgaggaccct
gaggtgaagt tcaactggta cgtggacggc 840gtggaggtgc acaatgccaa
gaccaagccc agggaggagc agtacaacag cacctaccgg 900gtggtgtccg
tgctgaccgt gctgcaccag gattggctga acggcaagga gtacaagtgt
960aaggtgtcca acaaggccct gcctgcccct atcgagaaaa ccatcagcaa
ggccaagggc 1020cagcccagag agccccaggt gtacaccctg ccccctagca
gagatgagct gaccaagaac 1080caggtgtccc tgacctgcct ggtgaagggc
ttctacccca gcgacatcgc cgtggagtgg 1140gagagcaacg gccagcccga
gaacaactac aagaccaccc cccctgtgct ggacagcgat 1200ggcagcttct
tcctgtacag caagctgacc gtggacaaga gcagatggca gcagggcaac
1260gtgttcagct gctccgtgat gcacgaggcc ctgcacaatc actacaccca
gaagagcctg 1320agcctgtccc ctggcaag 133893660DNAArtificial
SequenceJ13L1, light chain humanised construct 93gacatccaga
tgacccagag cccctctagc ctcagcgcca gcgtgggcga cagggtgacc 60atcacctgca
agagcagcca gagcctgctg aacggcagca accagaagaa ctacctggcc
120tggtaccagc agaaacccgg caaggccccc aagctgctgg tctacttcgc
ctctaccagg 180gattccggcg tccccagcag gttcagcggc agcggcagcg
gcaccgactt cacactgacc 240atcagcagcc tgcagcccga ggacttcgcc
acctactact gcctgcagca cttcggcacc 300cctcccactt ttggccaggg
caccaagctg gagattaagc gtacggtggc cgcccccagc 360gtgttcatct
tcccccccag cgatgagcag ctgaagagcg gcaccgccag cgtggtgtgt
420ctgctgaaca acttctaccc ccgggaggcc aaggtgcagt ggaaggtgga
caatgccctg 480cagagcggca acagccagga gagcgtgacc gagcaggaca
gcaaggactc cacctacagc 540ctgagcagca ccctgaccct gagcaaggcc
gactacgaga agcacaaggt gtacgcctgt 600gaggtgaccc accagggcct
gtccagcccc gtgaccaaga gcttcaaccg gggcgagtgc 660941338DNAArtificial
SequenceJ13L1, heavy chain humanised construct 94caggtgcagc
tcgtgcagag cggggccgaa gtcaagaaac ccggcagctc cgtgaaggtg 60agctgcaagg
ccagcggcgg caccttcagc gcctacggcg tgaactgggt gaggcaggct
120cccggccagg gcctggagtg gatgggcatg atctgggacg acggcagcac
cgactacgac 180agcgccctga agagcagggt gaccatcacc gccgacaaga
gcaccagcac cgcctacatg 240gaactgagca gcctgaggag cgaggacacc
gccgtgtact attgcgccag ggagggcgac 300gtggccttcg attactgggg
ccagggcaca ctagtgaccg tgtccagcgc cagcaccaag 360ggccccagcg
tgttccccct ggcccccagc agcaagagca ccagcggcgg cacagccgcc
420ctgggctgcc tggtgaagga ctacttcccc gaaccggtga ccgtgtcctg
gaacagcgga 480gccctgacca gcggcgtgca caccttcccc gccgtgctgc
agagcagcgg cctgtacagc 540ctgagcagcg tggtgaccgt gcccagcagc
agcctgggca cccagaccta catctgtaac 600gtgaaccaca agcccagcaa
caccaaggtg gacaagaagg tggagcccaa gagctgtgac 660aagacccaca
cctgcccccc ctgccctgcc cccgagctgc tgggaggccc cagcgtgttc
720ctgttccccc ccaagcctaa ggacaccctg atgatcagca gaacccccga
ggtgacctgt 780gtggtggtgg atgtgagcca cgaggaccct gaggtgaagt
tcaactggta cgtggacggc 840gtggaggtgc acaatgccaa gaccaagccc
agggaggagc agtacaacag cacctaccgg 900gtggtgtccg tgctgaccgt
gctgcaccag gattggctga acggcaagga gtacaagtgt 960aaggtgtcca
acaaggccct gcctgcccct atcgagaaaa ccatcagcaa ggccaagggc
1020cagcccagag agccccaggt gtacaccctg ccccctagca gagatgagct
gaccaagaac 1080caggtgtccc tgacctgcct ggtgaagggc ttctacccca
gcgacatcgc cgtggagtgg 1140gagagcaacg gccagcccga gaacaactac
aagaccaccc cccctgtgct ggacagcgat 1200ggcagcttct tcctgtacag
caagctgacc gtggacaaga gcagatggca gcagggcaac 1260gtgttcagct
gctccgtgat gcacgaggcc ctgcacaatc actacaccca gaagagcctg
1320agcctgtccc ctggcaag 133895660DNAArtificial SequenceH7L1, light
chain humanised construct 95gacatccaga tgacccagag cccctctagc
ctcagcgcca gcgtgggcga cagggtgacc 60atcacctgca agagcagcca gagcctgctg
aacggcagca accagaagaa ctacctggcc 120tggtaccagc agaaacccgg
caaggccccc aagctgctgg tctacttcgc ctctaccagg 180gattccggcg
tccccagcag gttcagcggc agcggcagcg gcaccgactt cacactgacc
240atcagcagcc tgcagcccga ggacttcgcc acctactact gcctgcagca
cttcggcacc 300cctcccactt ttggccaggg caccaagctg gagattaagc
gtacggtggc cgcccccagc 360gtgttcatct tcccccccag cgatgagcag
ctgaagagcg gcaccgccag cgtggtgtgt 420ctgctgaaca acttctaccc
ccgggaggcc aaggtgcagt ggaaggtgga caatgccctg 480cagagcggca
acagccagga gagcgtgacc gagcaggaca gcaaggactc cacctacagc
540ctgagcagca ccctgaccct gagcaaggcc gactacgaga agcacaaggt
gtacgcctgt 600gaggtgaccc accagggcct gtccagcccc gtgaccaaga
gcttcaaccg gggcgagtgc 660961338DNAArtificial SequenceH7L1, heavy
chain humanised construct 96caggtgcagc tccaggagag cggccccggc
ctggtgaagc ctagcgagac cctgagcctg 60acctgcaccg tgagcggcgg ctccatcagc
gcctacggcg tcaactggat caggcagccc 120cccggcaaag gcctggagtg
gattgggatg atctgggacg acggcagcac cgactacgac 180agcgccctga
agagcagggt gaccatcagc gtggacacca gcaagaacca gttcagcctg
240aagctgagca gcgtgactgc cgccgacacc gccgtctatt actgcgccag
ggagggcgac 300gtggccttcg attactgggg ccagggcaca ctagtgaccg
tgtccagcgc cagcaccaag 360ggccccagcg tgttccccct ggcccccagc
agcaagagca ccagcggcgg cacagccgcc 420ctgggctgcc tggtgaagga
ctacttcccc gaaccggtga ccgtgtcctg gaacagcgga 480gccctgacca
gcggcgtgca caccttcccc gccgtgctgc agagcagcgg cctgtacagc
540ctgagcagcg tggtgaccgt gcccagcagc agcctgggca cccagaccta
catctgtaac 600gtgaaccaca agcccagcaa caccaaggtg gacaagaagg
tggagcccaa gagctgtgac 660aagacccaca cctgcccccc ctgccctgcc
cccgagctgc tgggaggccc cagcgtgttc 720ctgttccccc ccaagcctaa
ggacaccctg atgatcagca gaacccccga ggtgacctgt 780gtggtggtgg
atgtgagcca cgaggaccct gaggtgaagt tcaactggta cgtggacggc
840gtggaggtgc acaatgccaa gaccaagccc agggaggagc agtacaacag
cacctaccgg 900gtggtgtccg tgctgaccgt gctgcaccag gattggctga
acggcaagga gtacaagtgt 960aaggtgtcca acaaggccct gcctgcccct
atcgagaaaa ccatcagcaa ggccaagggc 1020cagcccagag agccccaggt
gtacaccctg ccccctagca gagatgagct gaccaagaac 1080caggtgtccc
tgacctgcct ggtgaagggc ttctacccca gcgacatcgc cgtggagtgg
1140gagagcaacg gccagcccga gaacaactac aagaccaccc cccctgtgct
ggacagcgat 1200ggcagcttct tcctgtacag caagctgacc gtggacaaga
gcagatggca gcagggcaac 1260gtgttcagct gctccgtgat gcacgaggcc
ctgcacaatc actacaccca gaagagcctg 1320agcctgtccc ctggcaag
133897660DNAArtificial SequenceJ0L1, light chain humanised
construct 97gacatccaga tgacccagag cccctctagc ctcagcgcca gcgtgggcga
cagggtgacc 60atcacctgca agagcagcca gagcctgctg aacggcagca accagaagaa
ctacctggcc 120tggtaccagc agaaacccgg caaggccccc aagctgctgg
tctacttcgc ctctaccagg 180gattccggcg tccccagcag gttcagcggc
agcggcagcg gcaccgactt cacactgacc 240atcagcagcc tgcagcccga
ggacttcgcc acctactact gcctgcagca cttcggcacc 300cctcccactt
ttggccaggg caccaagctg gagattaagc gtacggtggc cgcccccagc
360gtgttcatct tcccccccag cgatgagcag ctgaagagcg gcaccgccag
cgtggtgtgt 420ctgctgaaca acttctaccc ccgggaggcc aaggtgcagt
ggaaggtgga caatgccctg 480cagagcggca acagccagga gagcgtgacc
gagcaggaca gcaaggactc cacctacagc 540ctgagcagca ccctgaccct
gagcaaggcc gactacgaga agcacaaggt gtacgcctgt 600gaggtgaccc
accagggcct gtccagcccc gtgaccaaga gcttcaaccg gggcgagtgc
660981338DNAArtificial SequenceJ0L1, heavy chain humanised
construct 98caggtgcagc tcgtgcagag cggggccgaa gtcaagaaac ccggcagctc
cgtgaaggtg 60agctgcaagg ccagcggcgg caccttcagc gcctacggcg tgaactgggt
gaggcaggct 120cccggccagg gcctggagtg gatgggcatg atctgggacg
acggcagcac cgactacaac 180agcgccctga agagcagggt gaccatcacc
gccgacaaga gcaccagcac cgcctacatg 240gaactgagca gcctgaggag
cgaggacacc gccgtgtact attgcgccag ggagggcgac 300gtggccttcg
attactgggg ccagggcaca ctagtgaccg tgtccagcgc cagcaccaag
360ggccccagcg tgttccccct ggcccccagc agcaagagca ccagcggcgg
cacagccgcc 420ctgggctgcc tggtgaagga ctacttcccc gaaccggtga
ccgtgtcctg gaacagcgga 480gccctgacca gcggcgtgca caccttcccc
gccgtgctgc agagcagcgg cctgtacagc 540ctgagcagcg tggtgaccgt
gcccagcagc agcctgggca cccagaccta catctgtaac 600gtgaaccaca
agcccagcaa caccaaggtg gacaagaagg tggagcccaa gagctgtgac
660aagacccaca cctgcccccc ctgccctgcc cccgagctgc tgggaggccc
cagcgtgttc 720ctgttccccc ccaagcctaa ggacaccctg atgatcagca
gaacccccga ggtgacctgt 780gtggtggtgg atgtgagcca cgaggaccct
gaggtgaagt tcaactggta cgtggacggc 840gtggaggtgc acaatgccaa
gaccaagccc agggaggagc agtacaacag cacctaccgg 900gtggtgtccg
tgctgaccgt gctgcaccag gattggctga acggcaagga gtacaagtgt
960aaggtgtcca acaaggccct gcctgcccct atcgagaaaa ccatcagcaa
ggccaagggc 1020cagcccagag agccccaggt gtacaccctg ccccctagca
gagatgagct gaccaagaac 1080caggtgtccc tgacctgcct ggtgaagggc
ttctacccca gcgacatcgc cgtggagtgg 1140gagagcaacg gccagcccga
gaacaactac aagaccaccc cccctgtgct ggacagcgat 1200ggcagcttct
tcctgtacag caagctgacc gtggacaaga gcagatggca gcagggcaac
1260gtgttcagct gctccgtgat gcacgaggcc ctgcacaatc actacaccca
gaagagcctg 1320agcctgtccc ctggcaag 133899660DNAArtificial
SequenceH0L1, light chain humanised construct 99gacatccaga
tgacccagag cccctctagc ctcagcgcca gcgtgggcga cagggtgacc 60atcacctgca
agagcagcca gagcctgctg aacggcagca accagaagaa ctacctggcc
120tggtaccagc agaaacccgg caaggccccc aagctgctgg tctacttcgc
ctctaccagg 180gattccggcg tccccagcag gttcagcggc agcggcagcg
gcaccgactt cacactgacc 240atcagcagcc tgcagcccga ggacttcgcc
acctactact gcctgcagca cttcggcacc 300cctcccactt ttggccaggg
caccaagctg gagattaagc gtacggtggc cgcccccagc 360gtgttcatct
tcccccccag cgatgagcag ctgaagagcg gcaccgccag cgtggtgtgt
420ctgctgaaca acttctaccc ccgggaggcc aaggtgcagt ggaaggtgga
caatgccctg 480cagagcggca acagccagga gagcgtgacc gagcaggaca
gcaaggactc cacctacagc 540ctgagcagca ccctgaccct gagcaaggcc
gactacgaga agcacaaggt gtacgcctgt 600gaggtgaccc accagggcct
gtccagcccc gtgaccaaga gcttcaaccg gggcgagtgc 6601001338DNAArtificial
SequenceH0L1, heavy chain humanised construct 100caggtgcagc
tccaggagag cggccccggc ctggtgaagc ctagcgagac cctgagcctg 60acctgcaccg
tgagcggcgg ctccatcagc gcctacggcg tcaactggat caggcagccc
120cccggcaaag gcctggagtg gattgggatg atctgggacg acggcagcac
cgactacaac 180agcgccctga agagcagggt gaccatcagc gtggacacca
gcaagaacca gttcagcctg 240aagctgagca gcgtgactgc cgccgacacc
gccgtctatt actgcgccag ggagggcgac 300gtggccttcg attactgggg
ccagggcaca ctagtgaccg tgtccagcgc cagcaccaag 360ggccccagcg
tgttccccct ggcccccagc agcaagagca ccagcggcgg cacagccgcc
420ctgggctgcc tggtgaagga ctacttcccc gaaccggtga ccgtgtcctg
gaacagcgga 480gccctgacca gcggcgtgca caccttcccc gccgtgctgc
agagcagcgg cctgtacagc 540ctgagcagcg tggtgaccgt gcccagcagc
agcctgggca cccagaccta catctgtaac 600gtgaaccaca agcccagcaa
caccaaggtg gacaagaagg tggagcccaa gagctgtgac 660aagacccaca
cctgcccccc ctgccctgcc cccgagctgc tgggaggccc cagcgtgttc
720ctgttccccc ccaagcctaa ggacaccctg atgatcagca gaacccccga
ggtgacctgt 780gtggtggtgg atgtgagcca cgaggaccct gaggtgaagt
tcaactggta cgtggacggc 840gtggaggtgc acaatgccaa gaccaagccc
agggaggagc agtacaacag cacctaccgg 900gtggtgtccg tgctgaccgt
gctgcaccag gattggctga acggcaagga gtacaagtgt 960aaggtgtcca
acaaggccct gcctgcccct atcgagaaaa ccatcagcaa ggccaagggc
1020cagcccagag agccccaggt gtacaccctg ccccctagca gagatgagct
gaccaagaac 1080caggtgtccc tgacctgcct ggtgaagggc ttctacccca
gcgacatcgc cgtggagtgg 1140gagagcaacg gccagcccga gaacaactac
aagaccaccc cccctgtgct ggacagcgat 1200ggcagcttct tcctgtacag
caagctgacc gtggacaaga gcagatggca gcagggcaac 1260gtgttcagct
gctccgtgat gcacgaggcc ctgcacaatc actacaccca gaagagcctg
1320agcctgtccc ctggcaag 1338101318DNAHomo Sapien 101acggtggccg
cccccagcgt gttcatcttc ccccccagcg atgagcagct gaagagcggc 60accgccagcg
tggtgtgtct gctgaacaac ttctaccccc gggaggccaa ggtgcagtgg
120aaggtggaca atgccctgca gagcggcaac agccaggaga gcgtgaccga
gcaggacagc 180aaggactcca cctacagcct gagcagcacc ctgaccctga
gcaaggccga ctacgagaag 240cacaaggtgt acgcctgtga ggtgacccac
cagggcctgt ccagccccgt gaccaagagc 300ttcaaccggg gcgagtgc
318102990DNAHomo Sapien 102gccagcacca agggccccag cgtgttcccc
ctggccccca gcagcaagag caccagcggc 60ggcacagccg ccctgggctg cctggtgaag
gactacttcc ccgaaccggt gaccgtgtcc 120tggaacagcg gagccctgac
cagcggcgtg cacaccttcc ccgccgtgct gcagagcagc 180ggcctgtaca
gcctgagcag cgtggtgacc gtgcccagca gcagcctggg cacccagacc
240tacatctgta acgtgaacca caagcccagc aacaccaagg tggacaagaa
ggtggagccc 300aagagctgtg acaagaccca cacctgcccc ccctgccctg
cccccgagct gctgggaggc 360cccagcgtgt tcctgttccc ccccaagcct
aaggacaccc tgatgatcag cagaaccccc 420gaggtgacct gtgtggtggt
ggatgtgagc cacgaggacc ctgaggtgaa gttcaactgg 480tacgtggacg
gcgtggaggt gcacaatgcc aagaccaagc ccagggagga gcagtacaac
540agcacctacc gggtggtgtc cgtgctgacc gtgctgcacc aggattggct
gaacggcaag 600gagtacaagt gtaaggtgtc caacaaggcc ctgcctgccc
ctatcgagaa aaccatcagc 660aaggccaagg gccagcccag agagccccag
gtgtacaccc tgccccctag cagagatgag 720ctgaccaaga accaggtgtc
cctgacctgc ctggtgaagg gcttctaccc cagcgacatc 780gccgtggagt
gggagagcaa cggccagccc gagaacaact acaagaccac cccccctgtg
840ctggacagcg atggcagctt cttcctgtac agcaagctga ccgtggacaa
gagcagatgg 900cagcagggca acgtgttcag ctgctccgtg atgcacgagg
ccctgcacaa tcactacacc 960cagaagagcc tgagcctgtc ccctggcaag
990103348DNAMurine 103caggtgcagc tgaaggagtc aggtcctggc ctggtggcgc
cctcacagag cctgtccatc 60acatgcaccg tctcagggtt ctcattaacc gcctatggtg
taaactgggt tcgccagcct 120ccaggaaagg gtctggagtg gctgggaatg
atatgggatg atggaagcac agactataat 180tcagctctca aatccagact
gagcatcagt aaggacaact ccaagagcca agttttctta 240aaaatgaaca
gtctgcaaac tgatgacaca gccaggtact actgtgccag agaaggggac
300gtagcctttg actactgggg ccaaggcacc actctcacag tctcctca
348104342DNAMurine 104gacattgtga tgacacagtc tccctcctcc ctggctgtgt
cagtaggaca gaaggtcact 60atgagctgca agtccagtca gagcctttta aatggtagca
atcaaaagaa ctacttggcc 120tggtaccagc agaaaccagg acagtctcct
aaacttctgg tatactttgc atccactagg 180gattctgggg tccctgatcg
cttcataggc agtggatctg ggacagattt cactcttacc 240atcagcagtg
tgcaggctga agacctggca gattacttct gtctgcaaca ttttggcact
300cctccgacgt tcggtggagg caccaaactg gaaatcaaac gg
3421051338DNAArtificial SequenceIMP731, heavy chain sequence
105caggtgcagc tgaaggagtc aggtcctggc ctggtggcgc cctcacagag
cctgtccatc 60acatgcaccg tctcagggtt ctcattaacc gcctatggtg taaactgggt
tcgccagcct 120ccaggaaagg gtctggagtg gctgggaatg atatgggatg
atggaagcac agactataat 180tcagctctca aatccagact gagcatcagt
aaggacaact ccaagagcca agttttctta 240aaaatgaaca gtctgcaaac
tgatgacaca gccaggtact actgtgccag agaaggggac 300gtagcctttg
actactgggg ccaaggcacc actctcacag tctcctcagc tagcaccaag
360ggcccatcgg tcttccccct ggcaccctcc tccaagagca cctctggggg
cacagcggcc 420ctgggctgcc tggtcaagga ctacttcccc gaaccggtga
cggtgtcgtg gaactcaggc 480gccctgacca gcggcgtgca caccttcccg
gctgtcctac agtcctcagg actctactcc 540ctcagcagcg tggtgaccgt
gccctccagc agcttgggca cccagaccta catctgcaac 600gtgaatcaca
agcccagcaa caccaaggtg gacaagaaag ttgagcccaa atcttgtgac
660aaaactcaca catgcccacc gtgcccagca cctgaactcc tggggggacc
gtcagtcttc 720ctcttccccc caaaacccaa ggacaccctc atgatctccc
ggacccctga ggtcacatgc 780gtggtggtgg acgtgagcca cgaagaccct
gaggtcaagt tcaactggta cgtggacggc 840gtggaggtgc ataatgccaa
gacaaagccg cgggaggagc agtacaacag cacgtaccgt 900gtggtcagcg
tcctcaccgt cctgcaccag gactggctga atggcaagga gtacaagtgc
960aaggtctcca acaaagccct cccagccccc atcgagaaaa ccatctccaa
agccaaaggg 1020cagccccgag aaccacaggt gtacaccctg cccccatccc
gggatgagct gaccaagaac 1080caggtcagcc tgacctgcct ggtcaaaggc
ttctatccca gcgacatcgc cgtggagtgg 1140gagagcaatg ggcagccgga
gaacaactac aagaccacgc ctcccgtgct ggactccgac 1200ggctccttct
tcctctacag caagctcacc gtggacaaga gcaggtggca gcaggggaac
1260gtcttctcat gctccgtgat gcatgaggct ctgcacaacc actacacgca
gaagagcctc 1320tccctgtctc cgggtaaa 1338106660DNAArtificial
SequenceIMP731, light chain sequence 106gacattgtga tgacacagtc
tccctcctcc ctggctgtgt cagtaggaca gaaggtcact 60atgagctgca agtccagtca
gagcctttta aatggtagca atcaaaagaa ctacttggcc 120tggtaccagc
agaaaccagg acagtctcct aaacttctgg tatactttgc atccactagg
180gattctgggg tccctgatcg cttcataggc agtggatctg ggacagattt
cactcttacc 240atcagcagtg tgcaggctga agacctggca gattacttct
gtctgcaaca ttttggcact 300cctccgacgt tcggtggagg caccaaactg
gaaatcaaac ggaccgtggc tgcaccatct 360gtcttcatct tcccgccatc
tgatgagcag ttgaaatctg gaactgcctc tgttgtgtgc 420ctgctgaata
acttctatcc cagagaggcc aaagtacagt ggaaggtgga taacgccctc
480caatcgggta actcccagga gagtgtcaca gagcaggaca gcaaggacag
cacctacagc 540ctcagcagca ccctgacgct gagcaaagca gactacgaga
aacacaaagt ctacgcctgc 600gaagtcaccc atcagggcct gagttcgccc
gtcacaaaga gcttcaacag gggagagtgt 6601071251DNAArtificial
SequenceRecombinant human LAG-3-ECD-His6 107ctccagccag gggctgaggt
cccggtggtg tgggcccagg agggggctcc tgcccagctc 60ccctgcagcc ccacaatccc
cctccaggat ctcagccttc tgcgaagagc aggggtcact 120tggcagcatc
agccagacag tggcccgccc gctgccgccc ccggccatcc cctggccccc
180ggccctcacc cggcggcgcc ctcctcctgg gggcccaggc cccgccgcta
cacggtgctg 240agcgtgggtc ccggaggcct gcgcagcggg aggctgcccc
tgcagccccg cgtccagctg 300gatgagcgcg gccggcagcg cggggacttc
tcgctatggc tgcgcccagc ccggcgcgcg 360gacgccggcg agtaccgcgc
cgcggtgcac ctcagggacc gcgccctctc ctgccgcctc 420cgtctgcgcc
tgggccaggc ctcgatgact gccagccccc caggatctct cagagcctcc
480gactgggtca ttttgaactg ctccttcagc cgccctgacc gcccagcctc
tgtgcattgg 540ttccggaacc ggggccaggg ccgagtccct gtccgggagt
ccccccatca ccacttagcg 600gaaagcttcc tcttcctgcc ccaagtcagc
cccatggact ctgggccctg gggctgcatc 660ctcacctaca gagatggctt
caacgtctcc atcatgtata acctcactgt tctgggtctg 720gagcccccaa
ctcccttgac agtgtacgct ggagcaggtt ccagggtggg gctgccctgc
780cgcctgcctg ctggtgtggg gacccggtct ttcctcactg ccaagtggac
tcctcctggg 840ggaggccctg acctcctggt gactggagac aatggcgact
ttacccttcg actagaggat 900gtgagccagg cccaggctgg gacctacacc
tgccatatcc atctgcagga acagcagctc 960aatgccactg tcacattggc
aatcatcaca gtgactccca aatcctttgg gtcacctgga 1020tccctgggga
agctgctttg tgaggtgact ccagtatctg gacaagaacg ctttgtgtgg
1080agctctctgg acaccccatc ccagaggagt ttctcaggac cttggctgga
ggcacaggag 1140gcccagctcc tttcccagcc ttggcaatgc cagctgtacc
agggggagag gcttcttgga 1200gcagcagtgt acttcacaga gctgtctagc
ccacaccacc atcatcacca t 12511081251DNAArtificial
SequenceRecombinant cynomolgus macaque LAG-3 ECD-His6 108ccccagccag
gggctgagat ctcggtggtg tgggcccagg agggggctcc tgcccagctc 60ccctgcagcc
ccacaatccc cctccaggat ctcagccttc tgcgaagagc aggggtcact
120tggcagcatc aaccagacag tggcccgccc gctcccgccc ccggccaccc
cccggccccc 180ggccatcgcc cggcggcgcc ctactcttgg gggcccaggc
cccgccgcta cacagtgctg 240agcgtgggtc ctggaggcct gcgcagcggg
aggctgcccc tgcagccccg cgtccagctg 300gatgagcgcg gccggcagcg
cggggacttc tcgctgtggc tgcgcccagc ccggcgcgcg 360gacgccggcg
agtaccgcgc cacggtgcac ctcagggacc gcgccctctc ctgccgcctt
420cgtctgcgcg tgggccaggc ctcgatgact gccagccccc cagggtctct
caggacctct 480gactgggtca ttttgaactg ctccttcagc cgccctgacc
gcccagcctc tgtgcattgg 540ttccggagcc gtggccaggg ccgagtccct
gtccaggggt ccccccatca ccacttagcg 600gaaagcttcc tcttcctgcc
ccatgtcggc cccatggact ctgggctctg gggctgcatc 660ctcacctaca
gagatggctt caatgtctcc atcatgtata acctcactgt tctgggtctg
720gagcccgcaa ctcccttgac agtgtacgct ggagcaggtt ccagggtgga
gctgccctgc 780cgcctgcctc ctgctgtggg gacccagtct ttccttactg
ccaagtgggc tcctcctggg 840ggaggccctg acctcctggt ggctggagac
aatggcgact ttacccttcg actagaggat 900gtaagccagg cccaggctgg
gacctacatc tgccatatcc gtctacaggg acagcagctc 960aatgccactg
tcacattggc aatcatcaca gtgactccca aatcctttgg gtcacctggc
1020tccctgggga agctgctttg tgaggtgact ccagcatctg gacaagaaca
ctttgtgtgg 1080agccccctga acaccccatc ccagaggagt ttctcaggac
catggctgga ggcccaggaa 1140gcccagctcc tttcccagcc ttggcaatgc
cagctgcacc agggggagag gcttcttgga 1200gcagcagtat acttcacaga
actgtctagc ccacaccacc atcatcacca t 12511091251DNAArtificial
SequenceRecombinant baboon LAG-3 ECD-His6 109ccccagccag gggctgagat
ctcggtggtg tgggcccagg agggggctcc tgcccagctc 60ccctgcagcc ccacaatccc
cctccaggat ctcagccttc tgcgaagagc aggggtcact 120tggcagcatc
aaccagacag tggcccgccc gctcccgccc ccggccaccc cccggccccc
180ggccatcgcc cggcggcgcc ctactcttgg gggcccaggc cccgccgcta
cacagtgctg 240agcgtgggtc ctggaggcct gcgcagcggg aggctgcccc
tgcagccccg cgtccagctg 300gatgagcgcg gccggcagcg cggggacttc
tcgctgtggc tgcgcccagc ccggcgcgcg 360gacgccggcg agtaccgcgc
cacggtgcac ctcagggacc gcgccctctc ctgccgcctt 420cgtctgcgcg
tgggccaggc ctcgatgact gccagccccc cagggtctct caggacctct
480gactgggtca ttttgaactg ctccttcagc cgccctgacc gcccagcctc
tgtgcattgg 540ttccggagcc gtggccaggg ccaagtccct gtccaggagt
ccccccatca ccacttagcg 600gaaagcttcc tcttcctgcc ccatgtcggc
cccatggact ctgggctctg gggctgcatc 660ctcacctaca gagatggctt
caatgtctcc atcatgtata acctcactgt tctgggtctg 720gagcccacaa
ctcccttgac agtgtacgct ggagcaggtt ccagggtgga gctgccctgc
780cgcctgcctc ctgctgtggg gacccagtct ttccttactg ccaagtgggc
tcctcctggg 840ggaggccctg acctcctggt ggttggagac aatggcaact
ttacccttcg actagaggat 900gtaagccagg cccaggctgg gacctacatc
tgccatatcc gtctacaggg acagcagctc 960aatgccactg tcacattggc
aatcatcaca gtgactccca aatcctttgg gtcacctggc 1020tccctgggga
agctgctttg tgaggtgact ccagcatctg gacaagaacg ctttgtgtgg
1080agccccctga acaccccatc ccagaggagt ttctcaggac cgtggctgga
ggcccaggaa 1140gcccagctcc tttcccagcc ttggcaatgc cagctgcacc
agggggagag gcttcttgga 1200gcagcagtat acttcacaga actgtctagc
ccacaccacc atcatcacca t 125111057DNAMurine 110atgggctgga gctgcatcat
cctgttcctg gtggccaccg ctaccggagt gcacagc 5711160DNAMurine
111atggaatcac agacccaggt cctcatgttt cttctgctct gggtatctgg
tgcctgtgca 6011248DNAHomo Sapien 112atgccgctgc tgctactgct
gcccctgctg tgggcagggg cgctagct 48
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