U.S. patent application number 14/864677 was filed with the patent office on 2017-06-29 for antigen binding proteins that bind pd-l1.
This patent application is currently assigned to Sorrento Therapeutics, Inc.. The applicant listed for this patent is Sorrento Therapeutics, Inc.. Invention is credited to Randy Gastwirt, John Dixon Gray, Gunnar F. Kaufmann, Barbara A. Swanson, Heyue Zhou.
Application Number | 20170182161 14/864677 |
Document ID | / |
Family ID | 49670536 |
Filed Date | 2017-06-29 |
United States Patent
Application |
20170182161 |
Kind Code |
A1 |
Zhou; Heyue ; et
al. |
June 29, 2017 |
Antigen Binding Proteins that Bind PD-L1
Abstract
There is disclosed compositions and methods relating to or
derived from anti-PD-L1 antibodies. More specifically, there is
disclosed fully human antibodies that bind PD-L1, PD-L1-binding
fragments and derivatives of such antibodies, and PD-L1-binding
polypeptides comprising such fragments. Further still, there is
disclosed nucleic acids encoding such antibodies, antibody
fragments and derivatives and polypeptides, cells comprising such
polynucleotides, methods of making such antibodies, antibody
fragments and derivatives and polypeptides, and methods of using
such antibodies, antibody fragments and derivatives and
polypeptides, including methods of treating or diagnosing subjects
having PD-L1 related disorders or conditions, including various
inflammatory disorders and various cancers.
Inventors: |
Zhou; Heyue; (San Diego,
CA) ; Gastwirt; Randy; (San Diego, CA) ;
Swanson; Barbara A.; (Encinitas, CA) ; Gray; John
Dixon; (San Diego, CA) ; Kaufmann; Gunnar F.;
(San Diego, CA) |
|
Applicant: |
Name |
City |
State |
Country |
Type |
Sorrento Therapeutics, Inc. |
San Diego |
CA |
US |
|
|
Assignee: |
Sorrento Therapeutics, Inc.
San Diego
CA
|
Family ID: |
49670536 |
Appl. No.: |
14/864677 |
Filed: |
September 24, 2015 |
Related U.S. Patent Documents
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Application
Number |
Filing Date |
Patent Number |
|
|
13907685 |
May 31, 2013 |
9175082 |
|
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14864677 |
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61654022 |
May 31, 2012 |
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61739982 |
Dec 20, 2012 |
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Current U.S.
Class: |
1/1 |
Current CPC
Class: |
A61P 35/00 20180101;
C07K 16/28 20130101; A61K 2121/00 20130101; C07K 2317/622 20130101;
C07K 2317/55 20130101; C07K 2317/21 20130101; C07K 2317/76
20130101; C07K 16/2818 20130101; C07K 16/2827 20130101; C07K
2317/92 20130101; C07K 2317/73 20130101; A61K 2039/505 20130101;
A61K 39/39541 20130101 |
International
Class: |
A61K 39/395 20060101
A61K039/395; C07K 16/28 20060101 C07K016/28 |
Claims
1. A fully human antibody of an IgG class that binds to a PD-L1
epitope, that has a heavy chain variable domain sequence that is at
least 95% identical to the amino acid sequences selected from the
group consisting of SEQ ID NO. 1, SEQ ID NO. 3, SEQ ID NO. 5, SEQ
ID NO. 7, SEQ ID NO. 9, SEQ ID NO. 11, SEQ ID NO. 13, SEQ ID NO.
15, SEQ ID NO. 17, SEQ ID NO. 19, SEQ ID NO. 21, SEQ ID NO. 23, SEQ
ID NO. 25, SEQ ID NO. 27, SEQ ID NO. 29, SEQ ID NO. 31, SEQ ID NO.
33, SEQ ID NO. 37, SEQ ID NO. 39, SEQ ID NO. 41, SEQ ID NO. 43, SEQ
ID NO. 45, SEQ ID NO. 47, SEQ ID NO. 49, SEQ ID NO. 53, SEQ ID NO.
55, SEQ ID NO. 57, SEQ ID NO. 59, SEQ ID NO. 61, SEQ ID NO. 63, SEQ
ID NO. 65, SEQ ID NO. 67, SEQ ID NO. 69, SEQ ID NO. 71, SEQ ID NO.
73, SEQ ID NO. 75, SEQ ID NO. 77, SEQ ID NO. 79, SEQ ID NO. 81, SEQ
ID NO. 83, SEQ ID NO. 85, SEQ ID NO. 87, SEQ ID NO. 89, SEQ ID NO.
91, SEQ ID NO. 93, SEQ ID NO. 95, SEQ ID NO. 97, SEQ ID NO. 99, SEQ
ID NO. 101, SEQ ID NO. 103, SEQ ID NO. 105, SEQ ID NO. 107, SEQ ID
NO. 109, SEQ ID NO. 111, SEQ ID NO. 113, SEQ ID NO. 115, SEQ ID NO.
117, SEQ ID NO. 119, SEQ ID NO. 121, SEQ ID NO. 123, SEQ ID NO.
125, SEQ ID NO. 127, SEQ ID NO. 129, SEQ ID NO. 131, SEQ ID NO.
133, SEQ ID NO. 135, SEQ ID NO. 139, SEQ ID NO. 141, SEQ ID NO.
143, SEQ ID NO. 145, SEQ ID NO. 147, SEQ ID NO. 149, SEQ ID NO.
151, SEQ ID NO. 153, SEQ ID NO. 167, SEQ ID NO. 169, SEQ ID NO.
171, SEQ ID NO. 173, SEQ ID NO. 175, SEQ ID NO. 177, SEQ ID NO.
181, SEQ ID NO. 187, SEQ ID NO. 189, SEQ ID NO. 191, SEQ ID NO.
193, SEQ ID NO. 195, SEQ ID NO. 197, SEQ ID NO. 199, SEQ ID NO.
201, SEQ ID NO. 203, SEQ ID NO. 205, SEQ ID NO. 207, SEQ ID NO.
209, SEQ ID NO. 211, SEQ ID NO. 213, SEQ ID NO. 215, SEQ ID NO.
217, SEQ ID NO. 219, SEQ ID NO. 221, SEQ ID NO. 223, SEQ ID NO.
225, SEQ ID NO. 227, SEQ ID NO. 229, SEQ ID NO. 231, SEQ ID NO.
233, SEQ ID NO. 235, SEQ ID NO. 237, SEQ ID NO. 239, SEQ ID NO.
241, and combinations thereof, and that has a light chain variable
domain sequence that is at least 95% identical to the amino acid
sequences selected from the group consisting of SEQ ID NO. 2, SEQ
ID NO. 4, SEQ ID NO. 6, SEQ ID NO. 8, SEQ ID NO. 10, SEQ ID NO. 12,
SEQ ID NO. 14, SEQ ID NO. 16, SEQ ID NO. 18, SEQ ID NO. 20, SEQ ID
NO. 22, SEQ ID NO. 24, SEQ ID NO. 26, SEQ ID NO. 28, SEQ ID NO. 30,
SEQ ID NO. 32, SEQ ID NO. 34, SEQ ID NO. 38, SEQ ID NO. 40, SEQ ID
NO. 42, SEQ ID NO. 44, SEQ ID NO. 46, SEQ ID NO. 48, SEQ ID NO. 50,
SEQ ID NO. 54, SEQ ID NO. 56, SEQ ID NO. 58, SEQ ID NO. 60, SEQ ID
NO. 62, SEQ ID NO. 64, SEQ ID NO. 66, SEQ ID NO. 68, SEQ ID NO. 70,
SEQ ID NO. 72, SEQ ID NO. 74, SEQ ID NO. 76, SEQ ID NO. 78, SEQ ID
NO. 80, SEQ ID NO. 82, SEQ ID NO. 84, SEQ ID NO. 86, SEQ ID NO. 88,
SEQ ID NO. 90, SEQ ID NO. 92, SEQ ID NO. 94, SEQ ID NO. 96, SEQ ID
NO. 98, SEQ ID NO. 100, SEQ ID NO. 102, SEQ ID NO. 104, SEQ ID NO.
106, SEQ ID NO. 108, SEQ ID NO. 110, SEQ ID NO. 112, SEQ ID NO.
114, SEQ ID NO. 116, SEQ ID NO. 118, SEQ ID NO. 120, SEQ ID NO.
122, SEQ ID NO. 124, SEQ ID NO. 126, SEQ ID NO. 128, SEQ ID NO.
130, SEQ ID NO. 132, SEQ ID NO. 134, SEQ ID NO. 136, SEQ ID NO.
140, SEQ ID NO. 142, SEQ ID NO. 144, SEQ ID NO. 146, SEQ ID NO.
148, SEQ ID NO. 150, SEQ ID NO. 152, SEQ ID NO. 154, SEQ ID NO.
168, SEQ ID NO. 170, SEQ ID NO. 172, SEQ ID NO. 174, SEQ ID NO.
176, SEQ ID NO. 178, SEQ ID NO. 182, SEQ ID NO. 188, SEQ ID NO.
190, SEQ ID NO. 192, SEQ ID NO. 194, SEQ ID NO. 196, SEQ ID NO.
198, SEQ ID NO. 200, SEQ ID NO. 202, SEQ ID NO. 204, SEQ ID NO.
206, SEQ ID NO. 208, SEQ ID NO. 210, SEQ ID NO. 212, SEQ ID NO.
222, SEQ ID NO. 224, SEQ ID NO. 226, SEQ ID NO. 228, SEQ ID NO.
230, SEQ ID NO. 232, SEQ ID NO. 234, SEQ ID NO. 236, SEQ ID NO.
238, SEQ ID NO. 240, SEQ ID NO. 242, and combinations thereof.
2. The fully human antibody of claim 1, wherein the antibody has a
heavy chain/light chain variable domain sequence selected from the
group consisting of SEQ ID NO. 1/SEQ ID NO. 2 (called E6 herein),
SEQ ID NO. 3/SEQ ID NO. 4 (called E7 herein), SEQ ID NO. 5/SEQ ID
NO. 6 (called E9 herein), SEQ ID NO. 7/SEQ ID NO. 8 (called E11
herein), SEQ ID NO. 9/SEQ ID NO. 10 (called F1 herein), SEQ ID NO.
11/SEQ ID NO. 12 (called F4 herein), SEQ ID NO. 13/SEQ ID NO. 14
(called F7 herein), SEQ ID NO. 15/SEQ ID NO. 16 (called F8 herein),
SEQ ID NO. 17/SEQ ID NO. 18 (called F11 herein), SEQ ID NO. 19/SEQ
ID NO. 20 (called G4 herein), SEQ ID NO. 21/SEQ ID NO. 22 (called
G9 herein), SEQ ID NO. 23/SEQ ID NO. 24 (called G11 herein), SEQ ID
NO. 25/SEQ ID NO. 26 (called G12 herein), SEQ ID NO. 27/SEQ ID NO.
28 (called H1 herein), SEQ ID NO. 29/SEQ ID NO. 30 (called H3
herein), SEQ ID NO. 31/SEQ ID NO. 32 (called H4 herein), SEQ ID NO.
33/SEQ ID NO. 34 (called H5 herein), SEQ ID NO. 37/SEQ ID NO. 38
(called H10 herein), SEQ ID NO. 39/SEQ ID NO. 40 (called H12
herein), SEQ ID NO. 41/SEQ ID NO. 42 (called PDL-D2 herein), SEQ ID
NO. 43/SEQ ID NO. 44 (called PDL-D11 herein), SEQ ID NO. 45/SEQ ID
NO. 46 (called PDL-H1 herein), SEQ ID NO. 47/SEQ ID NO. 48 (called
RB4 herein), SEQ ID NO. 49/SEQ ID NO. 50 (called RB11 herein), SEQ
ID NO. 53/SEQ ID NO. 54 (called RF5 herein), SEQ ID NO. 55/SEQ ID
NO. 56 (called RG9 herein), SEQ ID NO. 57/SEQ ID NO. 58 (called RD1
herein), SEQ ID NO. 59/SEQ ID NO. 60 (called RF11 herein), SEQ ID
NO. 61/SEQ ID NO. 62 (called RH11 herein), SEQ ID NO. 63/SEQ ID NO.
64 (called RD9 herein), SEQ ID NO. 65/SEQ ID NO. 66 (called RE10
herein), SEQ ID NO. 67/SEQ ID NO. 68 (called RA3 herein), SEQ ID
NO. 69/SEQ ID NO. 70 (called RG1 herein), SEQ ID NO. 71/SEQ ID NO.
72 (called RB1 herein), SEQ ID NO. 73/SEQ ID NO. 74 (called RG7
herein), SEQ ID NO. 75/SEQ ID NO. 76 (called RA6 herein), SEQ ID
NO. 77/SEQ ID NO. 78 (called RA8 herein), SEQ ID NO. 79/SEQ ID NO.
80 (called RA9 herein), SEQ ID NO. 81/SEQ ID NO. 82 (called RB5
herein), SEQ ID NO. 83/SEQ ID NO. 84 (called RB8 herein), SEQ ID
NO. 85/SEQ ID NO. 86 (called RC8 herein), SEQ ID NO. 87/SEQ ID NO.
88 (called RC10 herein), SEQ ID NO. 89/SEQ ID NO. 90 (called RD2
herein), SEQ ID NO. 91/SEQ ID NO. 92 (called RE8 herein), SEQ ID
NO. 93/SEQ ID NO. 94 (called RE9 herein), SEQ ID NO. 95/SEQ ID NO.
96 (called RG12 herein), SEQ ID NO. 97/SEQ ID NO. 98 (called RSA1
herein), SEQ ID NO. 99/SEQ ID NO. 100 (called R2A7 herein), SEQ ID
NO. 101/SEQ ID NO. 102 (called R2B12 herein), SEQ ID NO. 103/SEQ ID
NO. 104 (called R2C9 herein), SEQ ID NO. 105/SEQ ID NO. 106 (called
R2D5 herein), SEQ ID NO. 107/SEQ ID NO. 108 (called R2D7 herein),
SEQ ID NO. 109/SEQ ID NO. 110 (called R2F4 herein), SEQ ID NO.
111/SEQ ID NO. 112 (called R2A10 herein), SEQ ID NO. 113/SEQ ID NO.
114 (called R2E2 herein), SEQ ID NO. 115/SEQ ID NO. 116 (called
R3B8 herein), SEQ ID NO. 117/SEQ ID NO. 118 (called R3C3 herein),
SEQ ID NO. 119/SEQ ID NO. 120 (called R3E9 herein), SEQ ID NO.
121/SEQ ID NO. 122 (called R3E10 herein), SEQ ID NO. 123/SEQ ID NO.
124 (called R3F7 herein), SEQ ID NO. 125/SEQ ID NO. 126 (called
R3F10 herein), SEQ ID NO. 127/SEQ ID NO. 128 (called R4B10 herein),
SEQ ID NO. 129/SEQ ID NO. 130 (called R4H1 herein), SEQ ID NO.
131/SEQ ID NO. 132 (called R4A11 herein), SEQ ID NO. 133/SEQ ID NO.
134 (called R3D2 herein), SEQ ID NO. 135/SEQ ID NO. 136 (called
R5B8 herein), SEQ ID NO. 139/SEQ ID NO. 140 (called SH1B7B(K)
herein), SEQ ID NO. 141/SEQ ID NO. 142 (called SH1C1 herein), SEQ
ID NO. 143/SEQ ID NO. 144 (called SH1C8 herein), SEQ ID NO. 145/SEQ
ID NO. 146 (called SH1E10 herein), SEQ ID NO. 147/SEQ ID NO. 148
(called SH1E2 herein), SEQ ID NO. 149/SEQ ID NO. 150 (called SH1A9
herein), SEQ ID NO. 151/SEQ ID NO. 152 (called SH1B11 herein), SEQ
ID NO. 153/SEQ ID NO. 154 (called SH1E4 herein), SEQ ID NO. SEQ ID
NO. 167/SEQ ID NO. 168 (called SH1A11 herein), SEQ ID NO. 169/SEQ
ID NO. 170 (called SH1C2 herein), SEQ ID NO. 171/SEQ ID NO. 172
(called SH1G8 herein), SEQ ID NO. 173/SEQ ID NO. 174 (called SH1H2
herein), SEQ ID NO. 175/SEQ ID NO. 176 (called SH1B10 herein), SEQ
ID NO. 177/SEQ ID NO. 178 (called SH1B7A(L) herein), SEQ ID NO.
181/SEQ ID NO. 182 (called SH1C11 herein), SEQ ID NO. 187/SEQ ID
NO. 188 (called R6B2 herein), SEQ ID NO. 189/SEQ ID NO. 190 (called
R6B7 herein), SEQ ID NO. 191/SEQ ID NO. 192 (called R6B11 herein),
SEQ ID NO. 193/SEQ ID NO. 194 (called R6D1 herein), SEQ ID NO.
195/SEQ ID NO. 196 (called R6C8 herein), SEQ ID NO. 197/SEQ ID NO.
198 (called R9G8 herein), SEQ ID NO. 199/SEQ ID NO. 200 (called
R7D1 herein), SEQ ID NO. 201/SEQ ID NO. 202 (called R7D2 herein),
SEQ ID NO. 203/SEQ ID NO. 204 (called R7E7 herein), SEQ ID NO.
205/SEQ ID NO. 206 (called R7F2 herein), SEQ ID NO. 207/SEQ ID NO.
208 (called R7F7 herein), SEQ ID NO. 209/SEQ ID NO. 210 (called
R9H2 herein), SEQ ID NO. 211/SEQ ID NO. 212 (called R9H6 herein),
SEQ ID NO. 221/SEQ ID NO. 222 (called H19C herein), SEQ ID NO.
223/SEQ ID NO. 224 (called H110D herein), SEQ ID NO. 225/SEQ ID NO.
226 (called H11F herein), SEQ ID NO. 227/SEQ ID NO. 228 (called
H1C1 herein), SEQ ID NO. 229/SEQ ID NO. 230 (called GPG1A2 herein),
SEQ ID NO. 231/SEQ ID NO. 232 (called GPGG8 herein), SEQ ID NO.
233/SEQ ID NO. 234 (called GPGG10 herein), SEQ ID NO. 235/SEQ ID
NO. 236 (called GPGH7 herein), SEQ ID NO. 237/SEQ ID NO. 238
(called GPGH10 herein), SEQ ID NO. 239/SEQ ID NO. 240 (called
GPGH11 herein), SEQ ID NO. 241/SEQ ID NO. 242 (called GPGH10P
herein), and combinations thereof.
3. A Fab fully human antibody fragment, having a variable domain
region from a heavy chain and a variable domain region from a light
chain, wherein the heavy chain variable domain sequence that is at
least 95% identical to the amino acid sequences selected from the
group consisting of SEQ ID NO. 1, SEQ ID NO. 3, SEQ ID NO. 5, SEQ
ID NO. 7, SEQ ID NO. 9, SEQ ID NO. 11, SEQ ID NO. 13, SEQ ID NO.
15, SEQ ID NO. 17, SEQ ID NO. 19, SEQ ID NO. 21, SEQ ID NO. 23, SEQ
ID NO. 25, SEQ ID NO. 27, SEQ ID NO. 29, SEQ ID NO. 31, SEQ ID NO.
33, SEQ ID NO. 37, SEQ ID NO. 39, SEQ ID NO. 41, SEQ ID NO. 43, SEQ
ID NO. 45, SEQ ID NO. 47, SEQ ID NO. 49, SEQ ID NO. 51, SEQ ID NO.
53, SEQ ID NO. 55, SEQ ID NO. 57, SEQ ID NO. 59, SEQ ID NO. 61, SEQ
ID NO. 63, SEQ ID NO. 65, SEQ ID NO. 67, SEQ ID NO. 69, SEQ ID NO.
71, SEQ ID NO. 73, SEQ ID NO. 75, SEQ ID NO. 77, SEQ ID NO. 79, SEQ
ID NO. 81, SEQ ID NO. 83, SEQ ID NO. 85, SEQ ID NO. 87, SEQ ID NO.
89, SEQ ID NO. 91, SEQ ID NO. 93, SEQ ID NO. 95, SEQ ID NO. 97, SEQ
ID NO. 99, SEQ ID NO. 101, SEQ ID NO. 103, SEQ ID NO. 105, SEQ ID
NO. 107, SEQ ID NO. 109, SEQ ID NO. 111, SEQ ID NO. 113, SEQ ID NO.
115, SEQ ID NO. 117, SEQ ID NO. 119, SEQ ID NO. 121, SEQ ID NO.
123, SEQ ID NO. 125, SEQ ID NO. 127, SEQ ID NO. 129, SEQ ID NO.
131, SEQ ID NO. 133, SEQ ID NO. 135, SEQ ID NO. 137, SEQ ID NO.
139, SEQ ID NO. 141, SEQ ID NO. 143, SEQ ID NO. 145, SEQ ID NO.
147, SEQ ID NO. 149, SEQ ID NO. 151, SEQ ID NO. 153, SEQ ID NO.
167, SEQ ID NO. 169, SEQ ID NO. 171, SEQ ID NO. 173, SEQ ID NO.
175, SEQ ID NO. 177, SEQ ID NO. 181, SEQ ID NO. 187, SEQ ID NO.
189, SEQ ID NO. 191, SEQ ID NO. 193, SEQ ID NO. 195, SEQ ID NO.
197, SEQ ID NO. 199, SEQ ID NO. 201, SEQ ID NO. 203, SEQ ID NO.
205, SEQ ID NO. 207, SEQ ID NO. 209, SEQ ID NO. 211, SEQ ID NO.
213, SEQ ID NO. 215, SEQ ID NO. 217, SEQ ID NO. 219, SEQ ID NO.
221, SEQ ID NO. 223, SEQ ID NO. 225, SEQ ID NO. 227, SEQ ID NO.
229, SEQ ID NO. 231, SEQ ID NO. 233, SEQ ID NO. 235, SEQ ID NO.
237, SEQ ID NO. 239, SEQ ID NO. 241, and combinations thereof, and
that has a light chain variable domain sequence that is at least
95% identical to the amino acid sequences selected from the group
consisting of SEQ ID NO. 2, SEQ ID NO. 4, SEQ ID NO. 6, SEQ ID NO.
8, SEQ ID NO. 10, SEQ ID NO. 12, SEQ ID NO. 14, SEQ ID NO. 16, SEQ
ID NO. 18, SEQ ID NO. 20, SEQ ID NO. 22, SEQ ID NO. 24, SEQ ID NO.
26, SEQ ID NO. 28, SEQ ID NO. 30, SEQ ID NO. 32, SEQ ID NO. 34, SEQ
ID NO. 38, SEQ ID NO. 40, SEQ ID NO. 42, SEQ ID NO. 44, SEQ ID NO.
46, SEQ ID NO. 48, SEQ ID NO. 50, SEQ ID NO. 54, SEQ ID NO. 56, SEQ
ID NO. 58, SEQ ID NO. 60, SEQ ID NO. 62, SEQ ID NO. 64, SEQ ID NO.
66, SEQ ID NO. 68, SEQ ID NO. 70, SEQ ID NO. 72, SEQ ID NO. 74, SEQ
ID NO. 76, SEQ ID NO. 78, SEQ ID NO. 80, SEQ ID NO. 82, SEQ ID NO.
84, SEQ ID NO. 86, SEQ ID NO. 88, SEQ ID NO. 90, SEQ ID NO. 92, SEQ
ID NO. 94, SEQ ID NO. 96, SEQ ID NO. 98, SEQ ID NO. 100, SEQ ID NO.
102, SEQ ID NO. 104, SEQ ID NO. 106, SEQ ID NO. 108, SEQ ID NO.
110, SEQ ID NO. 112, SEQ ID NO. 114, SEQ ID NO. 116, SEQ ID NO.
118, SEQ ID NO. 120, SEQ ID NO. 122, SEQ ID NO. 124, SEQ ID NO.
126, SEQ ID NO. 128, SEQ ID NO. 130, SEQ ID NO. 132, SEQ ID NO.
134, SEQ ID NO. 136, SEQ ID NO. 140, SEQ ID NO. 142, SEQ ID NO.
144, SEQ ID NO. 146, SEQ ID NO. 148, SEQ ID NO. 150, SEQ ID NO.
152, SEQ ID NO. 154, SEQ ID NO. 168, SEQ ID NO. 170, SEQ ID NO.
172, SEQ ID NO. 174, SEQ ID NO. 176, SEQ ID NO. 178, SEQ ID NO.
182, SEQ ID NO. 188, SEQ ID NO. 190, SEQ ID NO. 192, SEQ ID NO.
194, SEQ ID NO. 196, SEQ ID NO. 198, SEQ ID NO. 200, SEQ ID NO.
202, SEQ ID NO. 204, SEQ ID NO. 206, SEQ ID NO. 208, SEQ ID NO.
210, SEQ ID NO. 212, SEQ ID NO. 222, SEQ ID NO. 224, SEQ ID NO.
226, SEQ ID NO. 228, SEQ ID NO. 230, SEQ ID NO. 232, SEQ ID NO.
234, SEQ ID NO. 236, SEQ ID NO. 238, SEQ ID NO. 240, SEQ ID NO.
242, and combinations thereof.
4. The fully human antibody Fab fragment of claim 3, wherein the
antibody has a heavy chain/light chain variable domain sequence
selected from the group consisting of SEQ ID NO. 1/SEQ ID NO. 2,
SEQ ID NO. 3/SEQ ID NO. 4, SEQ ID NO. 5/SEQ ID NO. 6, SEQ ID NO.
7/SEQ ID NO. 8, SEQ ID NO. 9/SEQ ID NO. 10, SEQ ID NO. 11/SEQ ID
NO. 12, SEQ ID NO. 13/SEQ ID NO. 14, SEQ ID NO. 15/SEQ ID NO. 16,
SEQ ID NO. 17/SEQ ID NO. 18, SEQ ID NO. 19/SEQ ID NO. 20, SEQ ID
NO. 21/SEQ ID NO. 22, SEQ ID NO. 23/SEQ ID NO. 24, SEQ ID NO.
25/SEQ ID NO. 26, SEQ ID NO. 27/SEQ ID NO. 28, SEQ ID NO. 29/SEQ ID
NO. 30, SEQ ID NO. 31/SEQ ID NO. 32, SEQ ID NO. 33/SEQ ID NO. 34,
SEQ ID NO. 37/SEQ ID NO. 38, SEQ ID NO. 39/SEQ ID NO. 40, SEQ ID
NO. 41/SEQ ID NO. 42, SEQ ID NO. 43/SEQ ID NO. 44, SEQ ID NO.
45/SEQ ID NO. 46, SEQ ID NO. 47/SEQ ID NO. 48, SEQ ID NO. 49/SEQ ID
NO. 50, SEQ ID NO. 53/SEQ ID NO. 54, SEQ ID NO. 55/SEQ ID NO. 56,
SEQ ID NO. 57/SEQ ID NO. 58, SEQ ID NO. 59/SEQ ID NO. 60, SEQ ID
NO. 61/SEQ ID NO. 62, SEQ ID NO. 63/SEQ ID NO. 64, SEQ ID NO.
65/SEQ ID NO. 66, SEQ ID NO. 67/SEQ ID NO. 68, SEQ ID NO. 69/SEQ ID
NO. 70, SEQ ID NO. 71/SEQ ID NO. 72, SEQ ID NO. 73/SEQ ID NO. 74,
SEQ ID NO. 75/SEQ ID NO. 76, SEQ ID NO. 77/SEQ ID NO. 78, SEQ ID
NO. 79/SEQ ID NO. 80, SEQ ID NO. 81/SEQ ID NO. 82, SEQ ID NO.
83/SEQ ID NO. 84, SEQ ID NO. 85/SEQ ID NO. 86, SEQ ID NO. 87/SEQ ID
NO. 88, SEQ ID NO. 89/SEQ ID NO. 90, SEQ ID NO. 91/SEQ ID NO. 92,
SEQ ID NO. 93/SEQ ID NO. 94, SEQ ID NO. 95/SEQ ID NO. 96, SEQ ID
NO. 97/SEQ ID NO. 98, SEQ ID NO. 99/SEQ ID NO. 100, SEQ ID NO.
101/SEQ ID NO. 102, SEQ ID NO. 103/SEQ ID NO. 104, SEQ ID NO.
105/SEQ ID NO. 106, SEQ ID NO. 107/SEQ ID NO. 108, SEQ ID NO.
109/SEQ ID NO. 110, SEQ ID NO. 111/SEQ ID NO. 112, SEQ ID NO.
113/SEQ ID NO. 114, SEQ ID NO. 115/SEQ ID NO. 116, SEQ ID NO.
117/SEQ ID NO. 118, SEQ ID NO. 119/SEQ ID NO. 120, SEQ ID NO.
121/SEQ ID NO. 122, SEQ ID NO. 123/SEQ ID NO. 124, SEQ ID NO.
125/SEQ ID NO. 126, SEQ ID NO. 127/SEQ ID NO. 128, SEQ ID NO.
129/SEQ ID NO. 130, SEQ ID NO. 131/SEQ ID NO. 132, SEQ ID NO.
133/SEQ ID NO. 134, SEQ ID NO. 135/SEQ ID NO. 136, SEQ ID NO.
139/SEQ ID NO. 140, SEQ ID NO. 141/SEQ ID NO. 142, SEQ ID NO.
143/SEQ ID NO. 144, SEQ ID NO. 145/SEQ ID NO. 146, SEQ ID NO.
147/SEQ ID NO. 148, SEQ ID NO. 149/SEQ ID NO. 150, SEQ ID NO.
151/SEQ ID NO. 152, SEQ ID NO. 153/SEQ ID NO. 154, SEQ ID NO.
167/SEQ ID NO. 168, SEQ ID NO. 169/SEQ ID NO. 170, SEQ ID NO.
171/SEQ ID NO. 172, SEQ ID NO. 173/SEQ ID NO. 174, SEQ ID NO.
175/SEQ ID NO. 176, SEQ ID NO. 177/SEQ ID NO. 178, SEQ ID NO.
179/SEQ ID NO. 180, SEQ ID NO. 181/SEQ ID NO. 182, SEQ ID NO.
187/SEQ ID NO. 188, SEQ ID NO. 189/SEQ ID NO. 190, SEQ ID NO.
191/SEQ ID NO. 192, SEQ ID NO. 193/SEQ ID NO. 194, SEQ ID NO.
195/SEQ ID NO. 196, SEQ ID NO. 197/SEQ ID NO. 198, SEQ ID NO.
199/SEQ ID NO. 200, SEQ ID NO. 201/SEQ ID NO. 202, SEQ ID NO.
203/SEQ ID NO. 204, SEQ ID NO. 205/SEQ ID NO. 206, SEQ ID NO.
207/SEQ ID NO. 208, SEQ ID NO. 209/SEQ ID NO. 210, SEQ ID NO.
211/SEQ ID NO. 212, SEQ ID NO. 221/SEQ ID NO. 222, SEQ ID NO.
223/SEQ ID NO. 224, SEQ ID NO. 225/SEQ ID NO. 226, SEQ ID NO.
227/SEQ ID NO. 228, SEQ ID NO. 229/SEQ ID NO. 230, SEQ ID NO.
231/SEQ ID NO. 232, SEQ ID NO. 233/SEQ ID NO. 234, SEQ ID NO.
235/SEQ ID NO. 236, SEQ ID NO. 237/SEQ ID NO. 238, SEQ ID NO.
239/SEQ ID NO. 240, SEQ ID NO. 241/SEQ ID NO. 242, and combinations
thereof.
5. A single chain human antibody, having a variable domain region
from a heavy chain and a variable domain region from a light chain
and a peptide linker connection the heavy chain and light chain
variable domain regions, wherein the heavy chain variable domain
sequence that is at least 95% identical to the amino acid sequences
selected from the group consisting of SEQ ID NO. 1, SEQ ID NO. 3,
SEQ ID NO. 5, SEQ ID NO. 7, SEQ ID NO. 9, SEQ ID NO. 11, SEQ ID NO.
13, SEQ ID NO. 15, SEQ ID NO. 17, SEQ ID NO. 19, SEQ ID NO. 21, SEQ
ID NO. 23, SEQ ID NO. 25, SEQ ID NO. 27, SEQ ID NO. 29, SEQ ID NO.
31, SEQ ID NO. 33, SEQ ID NO. 37, SEQ ID NO. 39, SEQ ID NO. 41, SEQ
ID NO. 43, SEQ ID NO. 45, SEQ ID NO. 47, SEQ ID NO. 49, SEQ ID NO.
53, SEQ ID NO. 55, SEQ ID NO. 57, SEQ ID NO. 59, SEQ ID NO. 61, SEQ
ID NO. 63, SEQ ID NO. 65, SEQ ID NO. 67, SEQ ID NO. 69, SEQ ID NO.
71, SEQ ID NO. 73, SEQ ID NO. 75, SEQ ID NO. 77, SEQ ID NO. 79, SEQ
ID NO. 81, SEQ ID NO. 83, SEQ ID NO. 85, SEQ ID NO. 87, SEQ ID NO.
89, SEQ ID NO. 91, SEQ ID NO. 93, SEQ ID NO. 95, SEQ ID NO. 97, SEQ
ID NO. 99, SEQ ID NO. 101, SEQ ID NO. 103, SEQ ID NO. 105, SEQ ID
NO. 107, SEQ ID NO. 109, SEQ ID NO. 111, SEQ ID NO. 113, SEQ ID NO.
115, SEQ ID NO. 117, SEQ ID NO. 119, SEQ ID NO. 121, SEQ ID NO.
123, SEQ ID NO. 125, SEQ ID NO. 127, SEQ ID NO. 129, SEQ ID NO.
131, SEQ ID NO. 133, SEQ ID NO. 135, SEQ ID NO. 139, SEQ ID NO.
141, SEQ ID NO. 143, SEQ ID NO. 145, SEQ ID NO. 147, SEQ ID NO.
149, SEQ ID NO. 151, SEQ ID NO. 153, SEQ ID NO. 167, SEQ ID NO.
169, SEQ ID NO. 171, SEQ ID NO. 173, SEQ ID NO. 175, SEQ ID NO.
177, SEQ ID NO. 181, SEQ ID NO. 187, SEQ ID NO. 189, SEQ ID NO.
191, SEQ ID NO. 193, SEQ ID NO. 195, SEQ ID NO. 197, SEQ ID NO.
199, SEQ ID NO. 201, SEQ ID NO. 203, SEQ ID NO. 205, SEQ ID NO.
207, SEQ ID NO. 209, SEQ ID NO. 211, SEQ ID NO. 213, SEQ ID NO.
215, SEQ ID NO. 217, SEQ ID NO. 219, SEQ ID NO. 221, SEQ ID NO.
223, SEQ ID NO. 225, SEQ ID NO. 227, SEQ ID NO. 229, SEQ ID NO.
231, SEQ ID NO. 233, SEQ ID NO. 235, SEQ ID NO. 237, SEQ ID NO.
239, SEQ ID NO. 241, and combinations thereof, and that has a light
chain variable domain sequence that is at least 95% identical to
the amino acid sequences selected from the group consisting of SEQ
ID NO. 2, SEQ ID NO. 4, SEQ ID NO. 6, SEQ ID NO. 8, SEQ ID NO. 10,
SEQ ID NO. 12, SEQ ID NO. 14, SEQ ID NO. 16, SEQ ID NO. 18, SEQ ID
NO. 20, SEQ ID NO. 22, SEQ ID NO. 24, SEQ ID NO. 26, SEQ ID NO. 28,
SEQ ID NO. 30, SEQ ID NO. 32, SEQ ID NO. 34, SEQ ID NO. 38, SEQ ID
NO. 40, SEQ ID NO. 42, SEQ ID NO. 44, SEQ ID NO. 46, SEQ ID NO. 48,
SEQ ID NO. 50, SEQ ID NO. 54, SEQ ID NO. 56, SEQ ID NO. 58, SEQ ID
NO. 60, SEQ ID NO. 62, SEQ ID NO. 64, SEQ ID NO. 66, SEQ ID NO. 68,
SEQ ID NO. 70, SEQ ID NO. 72, SEQ ID NO. 74, SEQ ID NO. 76, SEQ ID
NO. 78, SEQ ID NO. 80, SEQ ID NO. 82, SEQ ID NO. 84, SEQ ID NO. 86,
SEQ ID NO. 88, SEQ ID NO. 90, SEQ ID NO. 92, SEQ ID NO. 94, SEQ ID
NO. 96, SEQ ID NO. 98, SEQ ID NO. 100, SEQ ID NO. 102, SEQ ID NO.
104, SEQ ID NO. 106, SEQ ID NO. 108, SEQ ID NO. 110, SEQ ID NO.
112, SEQ ID NO. 114, SEQ ID NO. 116, SEQ ID NO. 118, SEQ ID NO.
120, SEQ ID NO. 122, SEQ ID NO. 124, SEQ ID NO. 126, SEQ ID NO.
128, SEQ ID NO. 130, SEQ ID NO. 132, SEQ ID NO. 134, SEQ ID NO.
136, SEQ ID NO. 140, SEQ ID NO. 142, SEQ ID NO. 144, SEQ ID NO.
146, SEQ ID NO. 148, SEQ ID NO. 150, SEQ ID NO. 152, SEQ ID NO.
154, SEQ ID NO. 168, SEQ ID NO. 170, SEQ ID NO. 172, SEQ ID NO.
174, SEQ ID NO. 176, SEQ ID NO. 178, SEQ ID NO. 182, SEQ ID NO.
188, SEQ ID NO. 190, SEQ ID NO. 192, SEQ ID NO. 194, SEQ ID NO.
196, SEQ ID NO. 198, SEQ ID NO. 200, SEQ ID NO. 202, SEQ ID NO.
204, SEQ ID NO. 206, SEQ ID NO. 208, SEQ ID NO. 210, SEQ ID NO.
212, SEQ ID NO. 222, SEQ ID NO. 224, SEQ ID NO. 226, SEQ ID NO.
228, SEQ ID NO. 230, SEQ ID NO. 232, SEQ ID NO. 234, SEQ ID NO.
236, SEQ ID NO. 238, SEQ ID NO. 240, SEQ ID NO. 242, and
combinations thereof.
6. The fully human single chain antibody of claim 5, wherein the
single chain fully human antibody has a heavy chain/light chain
variable domain sequence selected from the group consisting of SEQ
ID NO. 1/SEQ ID NO. 2, SEQ ID NO. 3/SEQ ID NO. 4, SEQ ID NO. 5/SEQ
ID NO. 6, SEQ ID NO. 7/SEQ ID NO. 8, SEQ ID NO. 9/SEQ ID NO. 10,
SEQ ID NO. 11/SEQ ID NO. 12, SEQ ID NO. 13/SEQ ID NO. 14, SEQ ID
NO. 15/SEQ ID NO. 16, SEQ ID NO. 17/SEQ ID NO. 18, SEQ ID NO.
19/SEQ ID NO. 20, SEQ ID NO. 21/SEQ ID NO. 22, SEQ ID NO. 23/SEQ ID
NO. 24, SEQ ID NO. 25/SEQ ID NO. 26, SEQ ID NO. 27/SEQ ID NO. 28,
SEQ ID NO. 29/SEQ ID NO. 30, SEQ ID NO. 31/SEQ ID NO. 32, SEQ ID
NO. 33/SEQ ID NO. 34, SEQ ID NO. 37/SEQ ID NO. 38, SEQ ID NO.
39/SEQ ID NO. 40, SEQ ID NO. 41/SEQ ID NO. 42, SEQ ID NO. 43/SEQ ID
NO. 44, SEQ ID NO. 45/SEQ ID NO. 46, SEQ ID NO. 47/SEQ ID NO. 48,
SEQ ID NO. 49/SEQ ID NO. 50, SEQ ID NO. 53/SEQ ID NO. 54, SEQ ID
NO. 55/SEQ ID NO. 56, SEQ ID NO. 57/SEQ ID NO. 58, SEQ ID NO.
59/SEQ ID NO. 60, SEQ ID NO. 61/SEQ ID NO. 62, SEQ ID NO. 63/SEQ ID
NO. 64, SEQ ID NO. 65/SEQ ID NO. 66, SEQ ID NO. 67/SEQ ID NO. 68,
SEQ ID NO. 69/SEQ ID NO. 70, SEQ ID NO. 71/SEQ ID NO. 72, SEQ ID
NO. 73/SEQ ID NO. 74, SEQ ID NO. 75/SEQ ID NO. 76, SEQ ID NO.
77/SEQ ID NO. 78, SEQ ID NO. 79/SEQ ID NO. 80, SEQ ID NO. 81/SEQ ID
NO. 82, SEQ ID NO. 83/SEQ ID NO. 84, SEQ ID NO. 85/SEQ ID NO. 86,
SEQ ID NO. 87/SEQ ID NO. 88, SEQ ID NO. 89/SEQ ID NO. 90, SEQ ID
NO. 91/SEQ ID NO. 92, SEQ ID NO. 93/SEQ ID NO. 94, SEQ ID NO.
95/SEQ ID NO. 96, SEQ ID NO. 97/SEQ ID NO. 98, SEQ ID NO. 99/SEQ ID
NO. 100, SEQ ID NO. 101/SEQ ID NO. 102, SEQ ID NO. 103/SEQ ID NO.
104, SEQ ID NO. 105/SEQ ID NO. 106, SEQ ID NO. 107/SEQ ID NO. 108,
SEQ ID NO. 109/SEQ ID NO. 110, SEQ ID NO. 111/SEQ ID NO. 112, SEQ
ID NO. 113/SEQ ID NO. 114, SEQ ID NO. 115/SEQ ID NO. 116, SEQ ID
NO. 117/SEQ ID NO. 118, SEQ ID NO. 119/SEQ ID NO. 120, SEQ ID NO.
121/SEQ ID NO. 122, SEQ ID NO. 123/SEQ ID NO. 124, SEQ ID NO.
125/SEQ ID NO. 126, SEQ ID NO. 127/SEQ ID NO. 128, SEQ ID NO.
129/SEQ ID NO. 130, SEQ ID NO. 131/SEQ ID NO. 132, SEQ ID NO.
133/SEQ ID NO. 134, SEQ ID NO. 135/SEQ ID NO. 136, SEQ ID NO.
139/SEQ ID NO. 140, SEQ ID NO. 141/SEQ ID NO. 142, SEQ ID NO.
143/SEQ ID NO. 144, SEQ ID NO. 145/SEQ ID NO. 146, SEQ ID NO.
147/SEQ ID NO. 148, SEQ ID NO. 149/SEQ ID NO. 150, SEQ ID NO.
151/SEQ ID NO. 152, SEQ ID NO. 153/SEQ ID NO. 154, SEQ ID NO.
167/SEQ ID NO. 168, SEQ ID NO. 169/SEQ ID NO. 170, SEQ ID NO.
171/SEQ ID NO. 172, SEQ ID NO. 173/SEQ ID NO. 174, SEQ ID NO.
175/SEQ ID NO. 176, SEQ ID NO. 177/SEQ ID NO. 178, SEQ ID NO.
179/SEQ ID NO. 180, SEQ ID NO. 181/SEQ ID NO. 182, SEQ ID NO.
187/SEQ ID NO. 188, SEQ ID NO. 189/SEQ ID NO. 190, SEQ ID NO.
191/SEQ ID NO. 192, SEQ ID NO. 193/SEQ ID NO. 194, SEQ ID NO.
195/SEQ ID NO. 196, SEQ ID NO. 197/SEQ ID NO. 198, SEQ ID NO.
199/SEQ ID NO. 200, SEQ ID NO. 201/SEQ ID NO. 202, SEQ ID NO.
203/SEQ ID NO. 204, SEQ ID NO. 205/SEQ ID NO. 206, SEQ ID NO.
207/SEQ ID NO. 208, SEQ ID NO. 209/SEQ ID NO. 210, SEQ ID NO.
211/SEQ ID NO. 212, SEQ ID NO. 221/SEQ ID NO. 222, SEQ ID NO.
223/SEQ ID NO. 224, SEQ ID NO. 225/SEQ ID NO. 226, SEQ ID NO.
227/SEQ ID NO. 228, SEQ ID NO. 229/SEQ ID NO. 230, SEQ ID NO.
231/SEQ ID NO. 232, SEQ ID NO. 233/SEQ ID NO. 234, SEQ ID NO.
235/SEQ ID NO. 236, SEQ ID NO. 237/SEQ ID NO. 238, SEQ ID NO.
239/SEQ ID NO. 240, SEQ ID NO. 241/SEQ ID NO. 242, and combinations
thereof.
7. The fully human single chain antibody of claim 5, wherein the
fully human single chain antibody has both a heavy chain variable
domain region and a light chain variable domain region, wherein the
single chain fully human antibody has a heavy chain/light chain
variable domain sequence selected from the group consisting of SEQ
ID NO. 1/SEQ ID NO. 2, SEQ ID NO. 3/SEQ ID NO. 4, SEQ ID NO. 5/SEQ
ID NO. 6, SEQ ID NO. 7/SEQ ID NO. 8, SEQ ID NO. 9/SEQ ID NO. 10,
SEQ ID NO. 11/SEQ ID NO. 12, SEQ ID NO. 13/SEQ ID NO. 14, SEQ ID
NO. 15/SEQ ID NO. 16, SEQ ID NO. 17/SEQ ID NO. 18, SEQ ID NO.
19/SEQ ID NO. 20, SEQ ID NO. 21/SEQ ID NO. 22, SEQ ID NO. 23/SEQ ID
NO. 24, SEQ ID NO. 25/SEQ ID NO. 26, SEQ ID NO. 27/SEQ ID NO. 28,
SEQ ID NO. 29/SEQ ID NO. 30, SEQ ID NO. 31/SEQ ID NO. 32, SEQ ID
NO. 33/SEQ ID NO. 34, SEQ ID NO. 37/SEQ ID NO. 38, SEQ ID NO.
39/SEQ ID NO. 40, SEQ ID NO. 41/SEQ ID NO. 42, SEQ ID NO. 43/SEQ ID
NO. 44, SEQ ID NO. 45/SEQ ID NO. 46, SEQ ID NO. 47/SEQ ID NO. 48,
SEQ ID NO. 49/SEQ ID NO. 50, SEQ ID NO. 53/SEQ ID NO. 54, SEQ ID
NO. 55/SEQ ID NO. 56, SEQ ID NO. 57/SEQ ID NO. 58, SEQ ID NO.
59/SEQ ID NO. 60, SEQ ID NO. 61/SEQ ID NO. 62, SEQ ID NO. 63/SEQ ID
NO. 64, SEQ ID NO. 65/SEQ ID NO. 66, SEQ ID NO. 67/SEQ ID NO. 68,
SEQ ID NO. 69/SEQ ID NO. 70, SEQ ID NO. 71/SEQ ID NO. 72, SEQ ID
NO. 73/SEQ ID NO. 74, SEQ ID NO. 75/SEQ ID NO. 76, SEQ ID NO.
77/SEQ ID NO. 78, SEQ ID NO. 79/SEQ ID NO. 80, SEQ ID NO. 81/SEQ ID
NO. 82, SEQ ID NO. 83/SEQ ID NO. 84, SEQ ID NO. 85/SEQ ID NO. 86,
SEQ ID NO. 87/SEQ ID NO. 88, SEQ ID NO. 89/SEQ ID NO. 90, SEQ ID
NO. 91/SEQ ID NO. 92, SEQ ID NO. 93/SEQ ID NO. 94, SEQ ID NO.
95/SEQ ID NO. 96, SEQ ID NO. 97/SEQ ID NO. 98, SEQ ID NO. 99/SEQ ID
NO. 100, SEQ ID NO. 101/SEQ ID NO. 102, SEQ ID NO. 103/SEQ ID NO.
104, SEQ ID NO. 105/SEQ ID NO. 106, SEQ ID NO. 107/SEQ ID NO. 108,
SEQ ID NO. 109/SEQ ID NO. 110, SEQ ID NO. 111/SEQ ID NO. 112, SEQ
ID NO. 113/SEQ ID NO. 114, SEQ ID NO. 115/SEQ ID NO. 116, SEQ ID
NO. 117/SEQ ID NO. 118, SEQ ID NO. 119/SEQ ID NO. 120, SEQ ID NO.
121/SEQ ID NO. 122, SEQ ID NO. 123/SEQ ID NO. 124, SEQ ID NO.
125/SEQ ID NO. 126, SEQ ID NO. 127/SEQ ID NO. 128, SEQ ID NO.
129/SEQ ID NO. 130, SEQ ID NO. 131/SEQ ID NO. 132, SEQ ID NO.
133/SEQ ID NO. 134, SEQ ID NO. 135/SEQ ID NO. 136, SEQ ID NO.
139/SEQ ID NO. 140, SEQ ID NO. 141/SEQ ID NO. 142, SEQ ID NO.
143/SEQ ID NO. 144, SEQ ID NO. 145/SEQ ID NO. 146, SEQ ID NO.
147/SEQ ID NO. 148, SEQ ID NO. 149/SEQ ID NO. 150, SEQ ID NO.
151/SEQ ID NO. 152, SEQ ID NO. 153/SEQ ID NO. 154, SEQ ID NO.
167/SEQ ID NO. 168, SEQ ID NO. 169/SEQ ID NO. 170, SEQ ID NO.
171/SEQ ID NO. 172, SEQ ID NO. 173/SEQ ID NO. 174, SEQ ID NO.
175/SEQ ID NO. 176, SEQ ID NO. 177/SEQ ID NO. 178, SEQ ID NO.
179/SEQ ID NO. 180, SEQ ID NO. 181/SEQ ID NO. 182, SEQ ID NO.
187/SEQ ID NO. 188, SEQ ID NO. 189/SEQ ID NO. 190, SEQ ID NO.
191/SEQ ID NO. 192, SEQ ID NO. 193/SEQ ID NO. 194, SEQ ID NO.
195/SEQ ID NO. 196, SEQ ID NO. 197/SEQ ID NO. 198, SEQ ID NO.
199/SEQ ID NO. 200, SEQ ID NO. 201/SEQ ID NO. 202, SEQ ID NO.
203/SEQ ID NO. 204, SEQ ID NO. 205/SEQ ID NO. 206, SEQ ID NO.
207/SEQ ID NO. 208, SEQ ID NO. 209/SEQ ID NO. 210, SEQ ID NO.
211/SEQ ID NO. 212, SEQ ID NO. 221/SEQ ID NO. 222, SEQ ID NO.
223/SEQ ID NO. 224, SEQ ID NO. 225/SEQ ID NO. 226, SEQ ID NO.
227/SEQ ID NO. 228, SEQ ID NO. 229/SEQ ID NO. 230, SEQ ID NO.
231/SEQ ID NO. 232, SEQ ID NO. 233/SEQ ID NO. 234, SEQ ID NO.
235/SEQ ID NO. 236, SEQ ID NO. 237/SEQ ID NO. 238, SEQ ID NO.
239/SEQ ID NO. 240, SEQ ID NO. 241/SEQ ID NO. 242, and combinations
thereof.
8. A method for treating a broad spectrum of mammalian cancers or
treating inflammatory diseases or autoimmune diseases, comprising
administering an effective amount of an anti-PD-L1 polypeptide,
wherein the anti-PD-L1 polypeptide is selected from the group
consisting of a fully human antibody of an IgG class that binds to
a PD-L1 epitope, a Fab fully human antibody fragment, having a
variable domain region from a heavy chain and a variable domain
region from a light chain, a single chain human antibody, having a
variable domain region from a heavy chain and a variable domain
region from a light chain and a peptide linker connection the heavy
chain and light chain variable domain regions, and combinations
thereof; wherein the fully human antibody has a heavy chain
variable domain sequence that is at least 95% identical to the
amino acid sequences selected from the group consisting of SEQ ID
NO. 1, SEQ ID NO. 3, SEQ ID NO. 5, SEQ ID NO. 7, SEQ ID NO. 9, SEQ
ID NO. 11, SEQ ID NO. 13, SEQ ID NO. 15, SEQ ID NO. 17, SEQ ID NO.
19, SEQ ID NO. 21, SEQ ID NO. 23, SEQ ID NO. 25, SEQ ID NO. 27, SEQ
ID NO. 29, SEQ ID NO. 31, SEQ ID NO. 33, SEQ ID NO. 37, SEQ ID NO.
39, SEQ ID NO. 41, SEQ ID NO. 43, SEQ ID NO. 45, SEQ ID NO. 47, SEQ
ID NO. 49, SEQ ID NO. 53, SEQ ID NO. 55, SEQ ID NO. 57, SEQ ID NO.
59, SEQ ID NO. 61, SEQ ID NO. 63, SEQ ID NO. 65, SEQ ID NO. 67, SEQ
ID NO. 69, SEQ ID NO. 71, SEQ ID NO. 73, SEQ ID NO. 75, SEQ ID NO.
77, SEQ ID NO. 79, SEQ ID NO. 81, SEQ ID NO. 83, SEQ ID NO. 85, SEQ
ID NO. 87, SEQ ID NO. 89, SEQ ID NO. 91, SEQ ID NO. 93, SEQ ID NO.
95, SEQ ID NO. 97, SEQ ID NO. 99, SEQ ID NO. 101, SEQ ID NO. 103,
SEQ ID NO. 105, SEQ ID NO. 107, SEQ ID NO. 109, SEQ ID NO. 111, SEQ
ID NO. 113, SEQ ID NO. 115, SEQ ID NO. 117, SEQ ID NO. 119, SEQ ID
NO. 121, SEQ ID NO. 123, SEQ ID NO. 125, SEQ ID NO. 127, SEQ ID NO.
129, SEQ ID NO. 131, SEQ ID NO. 133, SEQ ID NO. 135, SEQ ID NO.
139, SEQ ID NO. 141, SEQ ID NO. 143, SEQ ID NO. 145, SEQ ID NO.
147, SEQ ID NO. 149, SEQ ID NO. 151, SEQ ID NO. 153, SEQ ID NO.
167, SEQ ID NO. 169, SEQ ID NO. 171, SEQ ID NO. 173, SEQ ID NO.
175, SEQ ID NO. 177, SEQ ID NO. 181, SEQ ID NO. 187, SEQ ID NO.
189, SEQ ID NO. 191, SEQ ID NO. 193, SEQ ID NO. 195, SEQ ID NO.
197, SEQ ID NO. 199, SEQ ID NO. 201, SEQ ID NO. 203, SEQ ID NO.
205, SEQ ID NO. 207, SEQ ID NO. 209, SEQ ID NO. 211, SEQ ID NO.
213, SEQ ID NO. 215, SEQ ID NO. 217, SEQ ID NO. 219, SEQ ID NO.
221, SEQ ID NO. 223, SEQ ID NO. 225, SEQ ID NO. 227, SEQ ID NO.
229, SEQ ID NO. 231, SEQ ID NO. 233, SEQ ID NO. 235, SEQ ID NO.
237, SEQ ID NO. 239, SEQ ID NO. 241, and combinations thereof, and
that has a light chain variable domain sequence that is at least
95% identical to the amino acid sequences selected from the group
consisting of SEQ ID NO. 2, SEQ ID NO. 4, SEQ ID NO. 6, SEQ ID NO.
8, SEQ ID NO. 10, SEQ ID NO. 12, SEQ ID NO. 14, SEQ ID NO. 16, SEQ
ID NO. 18, SEQ ID NO. 20, SEQ ID NO. 22, SEQ ID NO. 24, SEQ ID NO.
26, SEQ ID NO. 28, SEQ ID NO. 30, SEQ ID NO. 32, SEQ ID NO. 34, SEQ
ID NO. 38, SEQ ID NO. 40, SEQ ID NO. 42, SEQ ID NO. 44, SEQ ID NO.
46, SEQ ID NO. 48, SEQ ID NO. 50, SEQ ID NO. 54, SEQ ID NO. 56, SEQ
ID NO. 58, SEQ ID NO. 60, SEQ ID NO. 62, SEQ ID NO. 64, SEQ ID NO.
66, SEQ ID NO. 68, SEQ ID NO. 70, SEQ ID NO. 72, SEQ ID NO. 74, SEQ
ID NO. 76, SEQ ID NO. 78, SEQ ID NO. 80, SEQ ID NO. 82, SEQ ID NO.
84, SEQ ID NO. 86, SEQ ID NO. 88, SEQ ID NO. 90, SEQ ID NO. 92, SEQ
ID NO. 94, SEQ ID NO. 96, SEQ ID NO. 98, SEQ ID NO. 100, SEQ ID NO.
102, SEQ ID NO. 104, SEQ ID NO. 106, SEQ ID NO. 108, SEQ ID NO.
110, SEQ ID NO. 112, SEQ ID NO. 114, SEQ ID NO. 116, SEQ ID NO.
118, SEQ ID NO. 120, SEQ ID NO. 122, SEQ ID NO. 124, SEQ ID NO.
126, SEQ ID NO. 128, SEQ ID NO. 130, SEQ ID NO. 132, SEQ ID NO.
134, SEQ ID NO. 136, SEQ ID NO. 140, SEQ ID NO. 142, SEQ ID NO.
144, SEQ ID NO. 146, SEQ ID NO. 148, SEQ ID NO. 150, SEQ ID NO.
152, SEQ ID NO. 154, SEQ ID NO. 168, SEQ ID NO. 170, SEQ ID NO.
172, SEQ ID NO. 174, SEQ ID NO. 176, SEQ ID NO. 178, SEQ ID NO.
182, SEQ ID NO. 188, SEQ ID NO. 190, SEQ ID NO. 192, SEQ ID NO.
194, SEQ ID NO. 196, SEQ ID NO. 198, SEQ ID NO. 200, SEQ ID NO.
202, SEQ ID NO. 204, SEQ ID NO. 206, SEQ ID NO. 208, SEQ ID NO.
210, SEQ ID NO. 212, SEQ ID NO. 222, SEQ ID NO. 224, SEQ ID NO.
226, SEQ ID NO. 228, SEQ ID NO. 230, SEQ ID NO. 232, SEQ ID NO.
234, SEQ ID NO. 236, SEQ ID NO. 238, SEQ ID NO. 240, SEQ ID NO.
242, and combinations thereof; wherein the Fab fully human antibody
fragment has the heavy chain variable domain sequence that is at
least 95% identical to the amino acid sequences selected from the
group consisting of SEQ ID NO. 1, SEQ ID NO. 3, SEQ ID NO. 5, SEQ
ID NO. 7, SEQ ID NO. 9, SEQ ID NO. 11, SEQ ID NO. 13, SEQ ID NO.
15, SEQ ID NO. 17, SEQ ID NO. 19, SEQ ID NO. 21, SEQ ID NO. 23, SEQ
ID NO. 25, SEQ ID NO. 27, SEQ ID NO. 29, SEQ ID NO. 31, SEQ ID NO.
33, SEQ ID NO. 37, SEQ ID NO. 39, SEQ ID NO. 41, SEQ ID NO. 43, SEQ
ID NO. 45, SEQ ID NO. 47, SEQ ID NO. 49, SEQ ID NO. 53, SEQ ID NO.
55, SEQ ID NO. 57, SEQ ID NO. 59, SEQ ID NO. 61, SEQ ID NO. 63, SEQ
ID NO. 65, SEQ ID NO. 67, SEQ ID NO. 69, SEQ ID NO. 71, SEQ ID NO.
73, SEQ ID NO. 75, SEQ ID NO. 77, SEQ ID NO. 79, SEQ ID NO. 81, SEQ
ID NO. 83, SEQ ID NO. 85, SEQ ID NO. 87, SEQ ID NO. 89, SEQ ID NO.
91, SEQ ID NO. 93, SEQ ID NO. 95, SEQ ID NO. 97, SEQ ID NO. 99, SEQ
ID NO. 101, SEQ ID NO. 103, SEQ ID NO. 105, SEQ ID NO. 107, SEQ ID
NO. 109, SEQ ID NO. 111, SEQ ID NO. 113, SEQ ID NO. 115, SEQ ID NO.
117, SEQ ID NO. 119, SEQ ID NO. 121, SEQ ID NO. 123, SEQ ID NO.
125, SEQ ID NO. 127, SEQ ID NO. 129, SEQ ID NO. 131, SEQ ID NO.
133, SEQ ID NO. 135, SEQ ID NO. 139, SEQ ID NO. 141, SEQ ID NO.
143, SEQ ID NO. 145, SEQ ID NO. 147, SEQ ID NO. 149, SEQ ID NO.
151, SEQ ID NO. 153, SEQ ID NO. 167, SEQ ID NO. 169, SEQ ID NO.
171, SEQ ID NO. 173, SEQ ID NO. 175, SEQ ID NO. 177, SEQ ID NO.
181, SEQ ID NO. 187, SEQ ID NO. 189, SEQ ID NO. 191, SEQ ID NO.
193, SEQ ID NO. 195, SEQ ID NO. 197, SEQ ID NO. 199, SEQ ID NO.
201, SEQ ID NO. 203, SEQ ID NO. 205, SEQ ID NO. 207, SEQ ID NO.
209, SEQ ID NO. 211, SEQ ID NO. 213, SEQ ID NO. 215, SEQ ID NO.
217, SEQ ID NO. 219, SEQ ID NO. 221, SEQ ID NO. 223, SEQ ID NO.
225, SEQ ID NO. 227, SEQ ID NO. 229, SEQ ID NO. 231, SEQ ID NO.
233, SEQ ID NO. 235, SEQ ID NO. 237, SEQ ID NO. 239, SEQ ID NO.
241, and combinations thereof, and that has the light chain
variable domain sequence that is at least 95% identical to the
amino acid sequences selected from the group consisting of SEQ ID
NO. 2, SEQ ID NO. 4, SEQ ID NO. 6, SEQ ID NO. 8, SEQ ID NO. 10, SEQ
ID NO. 12, SEQ ID NO. 14, SEQ ID NO. 16, SEQ ID NO. 18, SEQ ID NO.
20, SEQ ID NO. 22, SEQ ID NO. 24, SEQ ID NO. 26, SEQ ID NO. 28, SEQ
ID NO. 30, SEQ ID NO. 32, SEQ ID NO. 34, SEQ ID NO. 38, SEQ ID NO.
40, SEQ ID NO. 42, SEQ ID NO. 44, SEQ ID NO. 46, SEQ ID NO. 48, SEQ
ID NO. 50, SEQ ID NO. 54, SEQ ID NO. 56, SEQ ID NO. 58, SEQ ID NO.
60, SEQ ID NO. 62, SEQ ID NO. 64, SEQ ID NO. 66, SEQ ID NO. 68, SEQ
ID NO. 70, SEQ ID NO. 72, SEQ ID NO. 74, SEQ ID NO. 76, SEQ ID NO.
78, SEQ ID NO. 80, SEQ ID NO. 82, SEQ ID NO. 84, SEQ ID NO. 86, SEQ
ID NO. 88, SEQ ID NO. 90, SEQ ID NO. 92, SEQ ID NO. 94, SEQ ID NO.
96, SEQ ID NO. 98, SEQ ID NO. 100, SEQ ID NO. 102, SEQ ID NO. 104,
SEQ ID NO. 106, SEQ ID NO. 108, SEQ ID NO. 110, SEQ ID NO. 112, SEQ
ID NO. 114, SEQ ID NO. 116, SEQ ID NO. 118, SEQ ID NO. 120, SEQ ID
NO. 122, SEQ ID NO. 124, SEQ ID NO. 126, SEQ ID NO. 128, SEQ ID NO.
130, SEQ ID NO. 132, SEQ ID NO. 134, SEQ ID NO. 136, SEQ ID NO.
140, SEQ ID NO. 142, SEQ ID NO. 144, SEQ ID NO. 146, SEQ ID NO.
148, SEQ ID NO. 150, SEQ ID NO. 152, SEQ ID NO. 154, SEQ ID NO.
168, SEQ ID NO. 170, SEQ ID NO. 172, SEQ ID NO. 174, SEQ ID NO.
176, SEQ ID NO. 178, SEQ ID NO. 182, SEQ ID NO. 188, SEQ ID NO.
190, SEQ ID NO. 192, SEQ ID NO. 194, SEQ ID NO. 196, SEQ ID NO.
198, SEQ ID NO. 200, SEQ ID NO. 202, SEQ ID NO. 204, SEQ ID NO.
206, SEQ ID NO. 208, SEQ ID NO. 210, SEQ ID NO. 212, SEQ ID NO.
222, SEQ ID NO. 224, SEQ ID NO. 226, SEQ ID NO. 228, SEQ ID NO.
230, SEQ ID NO. 232, SEQ ID NO. 234, SEQ ID NO. 236, SEQ ID NO.
238, SEQ ID NO. 240, SEQ ID NO. 242, and combinations thereof; and
wherein the single chain human antibody has the heavy chain
variable domain sequence that is at least 95% identical to the
amino acid sequences selected from the group consisting of SEQ ID
NO. 1, SEQ ID NO. 3, SEQ ID NO. 5, SEQ ID NO. 7, SEQ ID NO. 9, SEQ
ID NO. 11, SEQ ID NO. 13, SEQ ID NO. 15, SEQ ID NO. 17, SEQ ID NO.
19, SEQ ID NO. 21, SEQ ID NO. 23, SEQ ID NO. 25, SEQ ID NO. 27, SEQ
ID NO. 29, SEQ ID NO. 31, SEQ ID NO. 33, SEQ ID NO. 37, SEQ ID NO.
39, SEQ ID NO. 41, SEQ ID NO. 43, SEQ ID NO. 45, SEQ ID NO. 47, SEQ
ID NO. 49, SEQ ID NO. 53, SEQ ID NO. 55, SEQ ID NO. 57, SEQ ID NO.
59, SEQ ID NO. 61, SEQ ID NO. 63, SEQ ID NO. 65, SEQ ID NO. 67, SEQ
ID NO. 69, SEQ ID NO. 71, SEQ ID NO. 73, SEQ ID NO. 75, SEQ ID NO.
77, SEQ ID NO. 79, SEQ ID NO. 81, SEQ ID NO. 83, SEQ ID NO. 85, SEQ
ID NO. 87, SEQ ID NO. 89, SEQ ID NO. 91, SEQ ID NO. 93, SEQ ID NO.
95, SEQ ID NO. 97, SEQ ID NO. 99, SEQ ID NO. 101, SEQ ID NO. 103,
SEQ ID NO. 105, SEQ ID NO. 107, SEQ ID NO. 109, SEQ ID NO. 111, SEQ
ID NO. 113, SEQ ID NO. 115, SEQ ID NO. 117, SEQ ID NO. 119, SEQ ID
NO. 121, SEQ ID NO. 123, SEQ ID NO. 125, SEQ ID NO. 127, SEQ ID NO.
129, SEQ ID NO. 131, SEQ ID NO. 133, SEQ ID NO. 135, SEQ ID NO.
139, SEQ ID NO. 141, SEQ ID NO. 143, SEQ ID NO. 145, SEQ ID NO.
147, SEQ ID NO. 149, SEQ ID NO. 151, SEQ ID NO. 153, SEQ ID NO.
167, SEQ ID NO. 169, SEQ ID NO. 171, SEQ ID NO. 173, SEQ ID NO.
175, SEQ ID NO. 177, SEQ ID NO. 181, SEQ ID NO. 187, SEQ ID NO.
189, SEQ ID NO. 191, SEQ ID NO. 193, SEQ ID NO. 195, SEQ ID NO.
197, SEQ ID NO. 199, SEQ ID NO. 201, SEQ ID NO. 203, SEQ ID NO.
205, SEQ ID NO. 207, SEQ ID NO. 209, SEQ ID NO. 211, SEQ ID NO.
213, SEQ ID NO. 215, SEQ ID NO. 217, SEQ ID NO. 219, SEQ ID NO.
221, SEQ ID NO. 223, SEQ ID NO. 225, SEQ ID NO. 227, SEQ ID NO.
229, SEQ ID NO. 231, SEQ ID NO. 233, SEQ ID NO. 235, SEQ ID NO.
237, SEQ ID NO. 239, SEQ ID NO. 241, and combinations thereof, and
that has the light chain variable domain sequence that is at least
95% identical to the amino acid sequences selected from the group
consisting of SEQ ID NO. 2, SEQ ID NO. 4, SEQ ID NO. 6, SEQ ID NO.
8, SEQ ID NO. 10, SEQ ID NO. 12, SEQ ID NO. 14, SEQ ID NO. 16, SEQ
ID NO. 18, SEQ ID NO. 20, SEQ ID NO. 22, SEQ ID NO. 24, SEQ ID NO.
26, SEQ ID NO. 28, SEQ ID NO. 30, SEQ ID NO. 32, SEQ ID NO. 34, SEQ
ID NO. 38, SEQ ID NO. 40, SEQ ID NO. 42, SEQ ID NO. 44, SEQ ID NO.
46, SEQ ID NO. 48, SEQ ID NO. 50, SEQ ID NO. 54, SEQ ID NO. 56, SEQ
ID NO. 58, SEQ ID NO. 60, SEQ ID NO. 62, SEQ ID NO. 64, SEQ ID NO.
66, SEQ ID NO. 68, SEQ ID NO. 70, SEQ ID NO. 72, SEQ ID NO. 74, SEQ
ID NO. 76, SEQ ID NO. 78, SEQ ID NO. 80, SEQ ID NO. 82, SEQ ID NO.
84, SEQ ID NO. 86, SEQ ID NO. 88, SEQ ID NO. 90, SEQ ID NO. 92, SEQ
ID NO. 94, SEQ ID NO. 96, SEQ ID NO. 98, SEQ ID NO. 100, SEQ ID NO.
102, SEQ ID NO. 104, SEQ ID NO. 106, SEQ ID NO. 108, SEQ ID NO.
110, SEQ ID NO. 112, SEQ ID NO. 114, SEQ ID NO. 116, SEQ ID NO.
118, SEQ ID NO. 120, SEQ ID NO. 122, SEQ ID NO. 124, SEQ ID NO.
126, SEQ ID NO. 128, SEQ ID NO. 130, SEQ ID NO. 132, SEQ ID NO.
134, SEQ ID NO. 136, SEQ ID NO. 140, SEQ ID NO. 142, SEQ ID NO.
144, SEQ ID NO. 146, SEQ ID NO. 148, SEQ ID NO. 150, SEQ ID NO.
152, SEQ ID NO. 154, SEQ ID NO. 168, SEQ ID NO. 170, SEQ ID NO.
172, SEQ ID NO. 174, SEQ ID NO. 176, SEQ ID NO. 178, SEQ ID NO.
182, SEQ ID NO. 188, SEQ ID NO. 190, SEQ ID NO. 192, SEQ ID NO.
194, SEQ ID NO. 196, SEQ ID NO. 198, SEQ ID NO. 200, SEQ ID NO.
202, SEQ ID NO. 204, SEQ ID NO. 206, SEQ ID NO. 208, SEQ ID NO.
210, SEQ ID NO. 212, SEQ ID NO. 222, SEQ ID NO. 224, SEQ ID NO.
226, SEQ ID NO. 228, SEQ ID NO. 230, SEQ ID NO. 232, SEQ ID NO.
234, SEQ ID NO. 236, SEQ ID NO. 238, SEQ ID NO. 240, SEQ ID NO.
242, and combinations thereof.
9. The method for treating a broad spectrum of mammalian cancers of
claim 8, wherein the fully human antibody has a heavy chain/light
chain variable domain sequence selected from the group consisting
of SEQ ID NO. 1/SEQ ID NO. 2, SEQ ID NO. 3/SEQ ID NO. 4, SEQ ID NO.
5/SEQ ID NO. 6, SEQ ID NO. 7/SEQ ID NO. 8, SEQ ID NO. 9/SEQ ID NO.
10, SEQ ID NO. 11/SEQ ID NO. 12, SEQ ID NO. 13/SEQ ID NO. 14, SEQ
ID NO. 15/SEQ ID NO. 16, SEQ ID NO. 17/SEQ ID NO. 18, SEQ ID NO.
19/SEQ ID NO. 20, SEQ ID NO. 21/SEQ ID NO. 22, SEQ ID NO. 23/SEQ ID
NO. 24, SEQ ID NO. 25/SEQ ID NO. 26, SEQ ID NO. 27/SEQ ID NO. 28,
SEQ ID NO. 29/SEQ ID NO. 30, SEQ ID NO. 31/SEQ ID NO. 32, SEQ ID
NO. 33/SEQ ID NO. 34, SEQ ID NO. 37/SEQ ID NO. 38, SEQ ID NO.
39/SEQ ID NO. 40, SEQ ID NO. 41/SEQ ID NO. 42, SEQ ID NO. 43/SEQ ID
NO. 44, SEQ ID NO. 45/SEQ ID NO. 46, SEQ ID NO. 47/SEQ ID NO. 48,
SEQ ID NO. 49/SEQ ID NO. 50, SEQ ID NO. 53/SEQ ID NO. 54, SEQ ID
NO. 55/SEQ ID NO. 56, SEQ ID NO. 57/SEQ ID NO. 58, SEQ ID NO.
59/SEQ ID NO. 60, SEQ ID NO. 61/SEQ ID NO. 62, SEQ ID NO. 63/SEQ ID
NO. 64, SEQ ID NO. 65/SEQ ID NO. 66, SEQ ID NO. 67/SEQ ID NO. 68,
SEQ ID NO. 69/SEQ ID NO. 70, SEQ ID NO. 71/SEQ ID NO. 72, SEQ ID
NO. 73/SEQ ID NO. 74, SEQ ID NO. 75/SEQ ID NO. 76, SEQ ID NO.
77/SEQ ID NO. 78, SEQ ID NO. 79/SEQ ID NO. 80, SEQ ID NO. 81/SEQ ID
NO. 82, SEQ ID NO. 83/SEQ ID NO. 84, SEQ ID NO. 85/SEQ ID NO. 86,
SEQ ID NO. 87/SEQ ID NO. 88, SEQ ID NO. 89/SEQ ID NO. 90, SEQ ID
NO. 91/SEQ ID NO. 92, SEQ ID NO. 93/SEQ ID NO. 94, SEQ ID NO.
95/SEQ ID NO. 96, SEQ ID NO. 97/SEQ ID NO. 98, SEQ ID NO. 99/SEQ ID
NO. 100, SEQ ID NO. 101/SEQ ID NO. 102, SEQ ID NO. 103/SEQ ID NO.
104, SEQ ID NO. 105/SEQ ID NO. 106, SEQ ID NO. 107/SEQ ID NO. 108,
SEQ ID NO. 109/SEQ ID NO. 110, SEQ ID NO. 111/SEQ ID NO. 112, SEQ
ID NO. 113/SEQ ID NO. 114, SEQ ID NO. 115/SEQ ID NO. 116, SEQ ID
NO. 117/SEQ ID NO. 118, SEQ ID NO. 119/SEQ ID NO. 120, SEQ ID NO.
121/SEQ ID NO. 122, SEQ ID NO. 123/SEQ ID NO. 124, SEQ ID NO.
125/SEQ ID NO. 126, SEQ ID NO. 127/SEQ ID NO. 128, SEQ ID NO.
129/SEQ ID NO. 130, SEQ ID NO. 131/SEQ ID NO. 132, SEQ ID NO.
133/SEQ ID NO. 134, SEQ ID NO. 135/SEQ ID NO. 136, SEQ ID NO.
139/SEQ ID NO. 140, SEQ ID NO. 141/SEQ ID NO. 142, SEQ ID NO.
143/SEQ ID NO. 144, SEQ ID NO. 145/SEQ ID NO. 146, SEQ ID NO.
147/SEQ ID NO. 148, SEQ ID NO. 149/SEQ ID NO. 150, SEQ ID NO.
151/SEQ ID NO. 152, SEQ ID NO. 153/SEQ ID NO. 154, SEQ ID NO.
167/SEQ ID NO. 168, SEQ ID NO. 169/SEQ ID NO. 170, SEQ ID NO.
171/SEQ ID NO. 172, SEQ ID NO. 173/SEQ ID NO. 174, SEQ ID NO.
175/SEQ ID NO. 176, SEQ ID NO. 177/SEQ ID NO. 178, SEQ ID NO.
179/SEQ ID NO. 180, SEQ ID NO. 181/SEQ ID NO. 182, SEQ ID NO.
187/SEQ ID NO. 188, SEQ ID NO. 189/SEQ ID NO. 190, SEQ ID NO.
191/SEQ ID NO. 192, SEQ ID NO. 193/SEQ ID NO. 194, SEQ ID NO.
195/SEQ ID NO. 196, SEQ ID NO. 197/SEQ ID NO. 198, SEQ ID NO.
199/SEQ ID NO. 200, SEQ ID NO. 201/SEQ ID NO. 202, SEQ ID NO.
203/SEQ ID NO. 204, SEQ ID NO. 205/SEQ ID NO. 206, SEQ ID NO.
207/SEQ ID NO. 208, SEQ ID NO. 209/SEQ ID NO. 210, SEQ ID NO.
211/SEQ ID NO. 212, SEQ ID NO. 221/SEQ ID NO. 222, SEQ ID NO.
223/SEQ ID NO. 224, SEQ ID NO. 225/SEQ ID NO. 226, SEQ ID NO.
227/SEQ ID NO. 228, SEQ ID NO. 229/SEQ ID NO. 230, SEQ ID NO.
231/SEQ ID NO. 232, SEQ ID NO. 233/SEQ ID NO. 234, SEQ ID NO.
235/SEQ ID NO. 236, SEQ ID NO. 237/SEQ ID NO. 238, SEQ ID NO.
239/SEQ ID NO. 240, SEQ ID NO. 241/SEQ ID NO. 242, and combinations
thereof.
10. The method for treating a broad spectrum of mammalian cancers
of claim 8, wherein the fully human antibody Fab fragment has both
a heavy chain variable domain region and a light chain variable
domain region wherein the antibody has a heavy chain/light chain
variable domain sequence selected from the group consisting of SEQ
ID NO. 1/SEQ ID NO. 2, SEQ ID NO. 3/SEQ ID NO. 4, SEQ ID NO. 5/SEQ
ID NO. 6, SEQ ID NO. 7/SEQ ID NO. 8, SEQ ID NO. 9/SEQ ID NO. 10,
SEQ ID NO. 11/SEQ ID NO. 12, SEQ ID NO. 13/SEQ ID NO. 14, SEQ ID
NO. 15/SEQ ID NO. 16, SEQ ID NO. 17/SEQ ID NO. 18, SEQ ID NO.
19/SEQ ID NO. 20, SEQ ID NO. 21/SEQ ID NO. 22, SEQ ID NO. 23/SEQ ID
NO. 24, SEQ ID NO. 25/SEQ ID NO. 26, SEQ ID NO. 27/SEQ ID NO. 28,
SEQ ID NO. 29/SEQ ID NO. 30, SEQ ID NO. 31/SEQ ID NO. 32, SEQ ID
NO. 33/SEQ ID NO. 34, SEQ ID NO. 37/SEQ ID NO. 38, SEQ ID NO.
39/SEQ ID NO. 40, SEQ ID NO. 41/SEQ ID NO. 42, SEQ ID NO. 43/SEQ ID
NO. 44, SEQ ID NO. 45/SEQ ID NO. 46, SEQ ID NO. 47/SEQ ID NO. 48,
SEQ ID NO. 49/SEQ ID NO. 50, SEQ ID NO. 53/SEQ ID NO. 54, SEQ ID
NO. 55/SEQ ID NO. 56, SEQ ID NO. 57/SEQ ID NO. 58, SEQ ID NO.
59/SEQ ID NO. 60, SEQ ID NO. 61/SEQ ID NO. 62, SEQ ID NO. 63/SEQ ID
NO. 64, SEQ ID NO. 65/SEQ ID NO. 66, SEQ ID NO. 67/SEQ ID NO. 68,
SEQ ID NO. 69/SEQ ID NO. 70, SEQ ID NO. 71/SEQ ID NO. 72, SEQ ID
NO. 73/SEQ ID NO. 74, SEQ ID NO. 75/SEQ ID NO. 76, SEQ ID NO.
77/SEQ ID NO. 78, SEQ ID NO. 79/SEQ ID NO. 80, SEQ ID NO. 81/SEQ ID
NO. 82, SEQ ID NO. 83/SEQ ID NO. 84, SEQ ID NO. 85/SEQ ID NO. 86,
SEQ ID NO. 87/SEQ ID NO. 88, SEQ ID NO. 89/SEQ ID NO. 90, SEQ ID
NO. 91/SEQ ID NO. 92, SEQ ID NO. 93/SEQ ID NO. 94, SEQ ID NO.
95/SEQ ID NO. 96, SEQ ID NO. 97/SEQ ID NO. 98, SEQ ID NO. 99/SEQ ID
NO. 100, SEQ ID NO. 101/SEQ ID NO. 102, SEQ ID NO. 103/SEQ ID NO.
104, SEQ ID NO. 105/SEQ ID NO. 106, SEQ ID NO. 107/SEQ ID NO. 108,
SEQ ID NO. 109/SEQ ID NO. 110, SEQ ID NO. 111/SEQ ID NO. 112, SEQ
ID NO. 113/SEQ ID NO. 114, SEQ ID NO. 115/SEQ ID NO. 116, SEQ ID
NO. 117/SEQ ID NO. 118, SEQ ID NO. 119/SEQ ID NO. 120, SEQ ID NO.
121/SEQ ID NO. 122, SEQ ID NO. 123/SEQ ID NO. 124, SEQ ID NO.
125/SEQ ID NO. 126, SEQ ID NO. 127/SEQ ID NO. 128, SEQ ID NO.
129/SEQ ID NO. 130, SEQ ID NO. 131/SEQ ID NO. 132, SEQ ID NO.
133/SEQ ID NO. 134, SEQ ID NO. 135/SEQ ID NO. 136, SEQ ID NO.
139/SEQ ID NO. 140, SEQ ID NO. 141/SEQ ID NO. 142, SEQ ID NO.
143/SEQ ID NO. 144, SEQ ID NO. 145/SEQ ID NO. 146, SEQ ID NO.
147/SEQ ID NO. 148, SEQ ID NO. 149/SEQ ID NO. 150, SEQ ID NO.
151/SEQ ID NO. 152, SEQ ID NO. 153/SEQ ID NO. 154, SEQ ID NO.
167/SEQ ID NO. 168, SEQ ID NO. 169/SEQ ID NO. 170, SEQ ID NO.
171/SEQ ID NO. 172, SEQ ID NO. 173/SEQ ID NO. 174, SEQ ID NO.
175/SEQ ID NO. 176, SEQ ID NO. 177/SEQ ID NO. 178, SEQ ID NO.
179/SEQ ID NO. 180, SEQ ID NO. 181/SEQ ID NO. 182, SEQ ID NO.
187/SEQ ID NO. 188, SEQ ID NO. 189/SEQ ID NO. 190, SEQ ID NO.
191/SEQ ID NO. 192, SEQ ID NO. 193/SEQ ID NO. 194, SEQ ID NO.
195/SEQ ID NO. 196, SEQ ID NO. 197/SEQ ID NO. 198, SEQ ID NO.
199/SEQ ID NO. 200, SEQ ID NO. 201/SEQ ID NO. 202, SEQ ID NO.
203/SEQ ID NO. 204, SEQ ID NO. 205/SEQ ID NO. 206, SEQ ID NO.
207/SEQ ID NO. 208, SEQ ID NO. 209/SEQ ID NO. 210, SEQ ID NO.
211/SEQ ID NO. 212, SEQ ID NO. 221/SEQ ID NO. 222, SEQ ID NO.
223/SEQ ID NO. 224, SEQ ID NO. 225/SEQ ID NO. 226, SEQ ID NO.
227/SEQ ID NO. 228, SEQ ID NO. 229/SEQ ID NO. 230, SEQ ID NO.
231/SEQ ID NO. 232, SEQ ID NO. 233/SEQ ID NO. 234, SEQ ID NO.
235/SEQ ID NO. 236, SEQ ID NO. 237/SEQ ID NO. 238, SEQ ID NO.
239/SEQ ID NO. 240, SEQ ID NO. 241/SEQ ID NO. 242, and combinations
thereof.
11. The method for treating a broad spectrum of mammalian cancers
of claim 8, wherein the fully human single chain antibody has both
a heavy chain variable domain region and a light chain variable
domain region, wherein the single chain fully human antibody has a
heavy chain/light chain variable domain sequence selected from the
group consisting of SEQ ID NO. 1/SEQ ID NO. 2, SEQ ID NO. 3/SEQ ID
NO. 4, SEQ ID NO. 5/SEQ ID NO. 6, SEQ ID NO. 7/SEQ ID NO. 8, SEQ ID
NO. 9/SEQ ID NO. 10, SEQ ID NO. 11/SEQ ID NO. 12, SEQ ID NO. 13/SEQ
ID NO. 14, SEQ ID NO. 15/SEQ ID NO. 16, SEQ ID NO. 17/SEQ ID NO.
18, SEQ ID NO. 19/SEQ ID NO. 20, SEQ ID NO. 21/SEQ ID NO. 22, SEQ
ID NO. 23/SEQ ID NO. 24, SEQ ID NO. 25/SEQ ID NO. 26, SEQ ID NO.
27/SEQ ID NO. 28, SEQ ID NO. 29/SEQ ID NO. 30, SEQ ID NO. 31/SEQ ID
NO. 32, SEQ ID NO. 33/SEQ ID NO. 34, SEQ ID NO. 37/SEQ ID NO. 38,
SEQ ID NO. 39/SEQ ID NO. 40, SEQ ID NO. 41/SEQ ID NO. 42, SEQ ID
NO. 43/SEQ ID NO. 44, SEQ ID NO. 45/SEQ ID NO. 46, SEQ ID NO.
47/SEQ ID NO. 48, SEQ ID NO. 49/SEQ ID NO. 50, SEQ ID NO. 53/SEQ ID
NO. 54, SEQ ID NO. 55/SEQ ID NO. 56, SEQ ID NO. 57/SEQ ID NO. 58,
SEQ ID NO. 59/SEQ ID NO. 60, SEQ ID NO. 61/SEQ ID NO. 62, SEQ ID
NO. 63/SEQ ID NO. 64, SEQ ID NO. 65/SEQ ID NO. 66, SEQ ID NO.
67/SEQ ID NO. 68, SEQ ID NO. 69/SEQ ID NO. 70, SEQ ID NO. 71/SEQ ID
NO. 72, SEQ ID NO. 73/SEQ ID NO. 74, SEQ ID NO. 75/SEQ ID NO. 76,
SEQ ID NO. 77/SEQ ID NO. 78, SEQ ID NO. 79/SEQ ID NO. 80, SEQ ID
NO. 81/SEQ ID NO. 82, SEQ ID NO. 83/SEQ ID NO. 84, SEQ ID NO.
85/SEQ ID NO. 86, SEQ ID NO. 87/SEQ ID NO. 88, SEQ ID NO. 89/SEQ ID
NO. 90, SEQ ID NO. 91/SEQ ID NO. 92, SEQ ID NO. 93/SEQ ID NO. 94,
SEQ ID NO. 95/SEQ ID NO. 96, SEQ ID NO. 97/SEQ ID NO. 98, SEQ ID
NO. 99/SEQ ID NO. 100, SEQ ID NO. 101/SEQ ID NO. 102, SEQ ID NO.
103/SEQ ID NO. 104, SEQ ID NO. 105/SEQ ID NO. 106, SEQ ID NO.
107/SEQ ID NO. 108, SEQ ID NO. 109/SEQ ID NO. 110, SEQ ID NO.
111/SEQ ID NO. 112, SEQ ID NO. 113/SEQ ID NO. 114, SEQ ID NO.
115/SEQ ID NO. 116, SEQ ID NO. 117/SEQ ID NO. 118, SEQ ID NO.
119/SEQ ID NO. 120, SEQ ID NO. 121/SEQ ID NO. 122, SEQ ID NO.
123/SEQ ID NO. 124, SEQ ID NO. 125/SEQ ID NO. 126, SEQ ID NO.
127/SEQ ID NO. 128, SEQ ID NO. 129/SEQ ID NO. 130, SEQ ID NO.
131/SEQ ID NO. 132, SEQ ID NO. 133/SEQ ID NO. 134, SEQ ID NO.
135/SEQ ID NO. 136, SEQ ID NO. 139/SEQ ID NO. 140, SEQ ID NO.
141/SEQ ID NO. 142, SEQ ID NO. 143/SEQ ID NO. 144, SEQ ID NO.
145/SEQ ID NO. 146, SEQ ID NO. 147/SEQ ID NO. 148, SEQ ID NO.
149/SEQ ID NO. 150, SEQ ID NO. 151/SEQ ID NO. 152, SEQ ID NO.
153/SEQ ID NO. 154, SEQ ID NO. 167/SEQ ID NO. 168, SEQ ID NO.
169/SEQ ID NO. 170, SEQ ID NO. 171/SEQ ID NO. 172, SEQ ID NO.
173/SEQ ID NO. 174, SEQ ID NO. 175/SEQ ID NO. 176, SEQ ID NO.
177/SEQ ID NO. 178, SEQ ID NO. 179/SEQ ID NO. 180, SEQ ID NO.
181/SEQ ID NO. 182, SEQ ID NO. 187/SEQ ID NO. 188, SEQ ID NO.
189/SEQ ID NO. 190, SEQ ID NO. 191/SEQ ID NO. 192, SEQ ID NO.
193/SEQ ID NO. 194, SEQ ID NO. 195/SEQ ID NO. 196, SEQ ID NO.
197/SEQ ID NO. 198, SEQ ID NO. 199/SEQ ID NO. 200, SEQ ID NO.
201/SEQ ID NO. 202, SEQ ID NO. 203/SEQ ID NO. 204, SEQ ID NO.
205/SEQ ID NO. 206, SEQ ID NO. 207/SEQ ID NO. 208, SEQ ID NO.
209/SEQ ID NO. 210, SEQ ID NO. 211/SEQ ID NO. 212, SEQ ID NO.
221/SEQ ID NO. 222, SEQ ID NO. 223/SEQ ID NO. 224, SEQ ID NO.
225/SEQ ID NO. 226, SEQ ID NO. 227/SEQ ID NO. 228, SEQ ID NO.
229/SEQ ID NO. 230, SEQ ID NO. 231/SEQ ID NO. 232, SEQ ID NO.
233/SEQ ID NO. 234, SEQ ID NO. 235/SEQ ID NO. 236, SEQ ID NO.
237/SEQ ID NO. 238, SEQ ID NO. 239/SEQ ID NO. 240, SEQ ID NO.
241/SEQ ID NO. 242, and combinations thereof.
12. The method for treating a broad spectrum of mammalian cancers
or inflammatory diseases or autoimmune diseases of claim 8, wherein
the broad spectrum of mammalian cancers to be treated is selected
from the group consisting of ovarian, colon, breast, lung cancers,
myelomas, neuroblastic-derived CNS tumors, monocytic leukemias,
B-cell derived leukemias, T-cell derived leukemias, B-cell derived
lymphomas, T-cell derived lymphomas, mast cell derived tumors, and
combinations thereof.
13. The method for treating a broad spectrum of mammalian cancers
or inflammatory diseases or autoimmune diseases of claim 8, wherein
the broad the autoimmune disease or inflammatory disease is
selected from the group consisting of intestinal mucosal
inflammation, wasting disease associated with colitis, multiple
sclerosis, systemic lupus erythematosus, viral infections,
rheumatoid arthritis, osteoarthritis, psoriasis, Cohn's disease,
and inflammatory bowel disease.
Description
CROSS REFERENCE TO RELATED APPLICATIONS
[0001] This patent application claims priority to U.S. provisional
patent applications 61/654,022 filed 31 May 2012 and 61/739,982
filed 20 Dec. 2012.
TECHNICAL FIELD
[0002] The present disclosure provides compositions and methods
relating to or derived from anti-PD-L1 antibodies. More
specifically, the present disclosure provides human antibodies that
bind PD-L1, PD-L1-binding fragments and derivatives of such
antibodies, and PD-L1-binding polypeptides comprising such
fragments. Further still, the present disclosure provides nucleic
acids encoding such antibodies, antibody fragments and derivatives
and polypeptides, cells comprising such polynucleotides, methods of
making such antibodies, antibody fragments and derivatives and
polypeptides, and methods of using such antibodies, antibody
fragments and derivatives and polypeptides, including methods of
treating or diagnosing subjects having PD-L1 related disorders or
conditions, including various inflammatory disorders and various
cancers.
BACKGROUND
[0003] Programmed death ligand 1 (PD-L1) is a 40 kDa type 1
transmembrane protein. PD-L1 (human PD-L1 cDNA is composed of the
base sequence shown by EMBL/GenBank Acc. No. NM_001267706 and mouse
PD-L1 cDNA is composed of the base sequence shown by NM_021893)
that is a ligand of PD-1 is expressed in so-called
antigen-presenting cells such as activated monocytes and dendritic
cells. These cells present interaction molecules that induce a
variety of immuno-inductive signals to T lymphocytes, and PD-L1 is
one of these molecules that induce the inhibitory signal by
ligating PD-1. It has been revealed that PD-L1 ligation suppressed
the activation (cellular proliferation and induction of various
cytokine productions) of PD-1 expressing T lymphocytes. PD-L1
expression has been confirmed in not only immunocompetent cells but
also a certain kind of tumor cell lines (cell lines derived from
monocytic leukemia, cell lines derived from mast cells, cell lines
derived from hepatic carcinomas, cell lines derived from
neuroblasts, and cell lines derived from breast carcinomas) (Nature
Immunology (2001), vol. 2, issue 3, p. 261-267.).
[0004] Programmed death 1 (PD-1) is a member of the CD28 family of
receptors, which includes CD28, CTLA-4, ICOS, PD-L1, and BTLA. The
initial member of the family, CD28, was discovered by functional
effect on augmenting T cell proliferation following the addition of
monoclonal antibodies (Hutloff et al. (1999) Nature 397:263-266;
Hansen et al. (1980) Immunogenics 10:247-260). Two cell surface
glycoprotein ligands for PD-1 have been identified, PD-L1 and
PDL-2, and have been shown to down-regulate T cell activation and
cytokine secretion occur upon binding to PD-1 (Freeman et al.
(2000) J. Exp. Med. 192:1027-34; Latchman et al. (2001) Nat.
Immunol. 2:261-8; Carter et al. (2002) Eur. J. Immunol. 32:634-43;
Ohigashi et al. (2005) Clin. Cancer Res. 11:2947-53). Both PD-L1
(B7-H1) and PD-L2 (B7-DC) are B7 homologs that bind to PD-1.
Expression of PD-L1 on the cell surface has also been shown to be
upregulated through IFN-.gamma. stimulation.
[0005] PD-L1 expression has been found in several murine and human
cancers, including human lung, ovarian and colon carcinoma and
various myelomas (Iwai et al. (2002) Proc. Natl. Acad. Sci. USA
99:12293-7; Ohigashi et al. (2005) Clin. Cancer Res. 11:2947-53).
PD-L1 has been suggested to play a role in tumor immunity by
increasing apoptosis of antigen-specific T-cell clones (Dong et al.
(2002) Nat. Med. 8:793-800). It has also been suggested that PD-L1
might be involved in intestinal mucosal inflammation and inhibition
of PD-L1 suppresses wasting disease associated with colitis (Kanai
et al. (2003) J. Immunol. 171:4156-63).
SUMMARY
[0006] The present disclosure provides a fully human antibody of an
IgG class that binds to a PD-L1 epitope with a binding affinity of
at least 10.sup.-6M, which has a heavy chain variable domain
sequence that is at least 95% identical to the amino acid sequences
selected from the group consisting of SEQ ID NO. 1, SEQ ID NO. 3,
SEQ ID NO. 5, SEQ ID NO. 7, SEQ ID NO. 9, SEQ ID NO. 11, SEQ ID NO.
13, SEQ ID NO. 15, SEQ ID NO. 17, SEQ ID NO. 19, SEQ ID NO. 21, SEQ
ID NO. 23, SEQ ID NO. 25, SEQ ID NO. 27, SEQ ID NO. 29, SEQ ID NO.
31, SEQ ID NO. 33, SEQ ID NO. 35, SEQ ID NO. 37, SEQ ID NO. 39, SEQ
ID NO. 41, SEQ ID NO. 43, SEQ ID NO. 45, SEQ ID NO. 47, SEQ ID NO.
49, SEQ ID NO. 51, SEQ ID NO. 53, SEQ ID NO. 55, SEQ ID NO. 57, SEQ
ID NO. 59, SEQ ID NO. 61, SEQ ID NO. 63, SEQ ID NO. 65, SEQ ID NO.
67, SEQ ID NO. 69, SEQ ID NO. 71, SEQ ID NO. 73, SEQ ID NO. 75, SEQ
ID NO. 77, SEQ ID NO. 79, SEQ ID NO. 81, SEQ ID NO. 83, SEQ ID NO.
85, SEQ ID NO. 87, SEQ ID NO. 89, SEQ ID NO. 91, SEQ ID NO. 93, SEQ
ID NO. 95, SEQ ID NO. 97, SEQ ID NO. 99, SEQ ID NO. 101, SEQ ID NO.
103, SEQ ID NO. 105, SEQ ID NO. 107, SEQ ID NO. 109, SEQ ID NO.
111, SEQ ID NO. 113, SEQ ID NO. 115, SEQ ID NO. 117, SEQ ID NO.
119, SEQ ID NO. 121, SEQ ID NO. 123, SEQ ID NO. 125, SEQ ID NO.
127, SEQ ID NO. 129, SEQ ID NO. 131, SEQ ID NO. 133, SEQ ID NO.
135, SEQ ID NO. 137, SEQ ID NO. 139, SEQ ID NO. 141, SEQ ID NO.
143, SEQ ID NO. 145, SEQ ID NO. 147, SEQ ID NO. 149, SEQ ID NO.
151, SEQ ID NO. 153, SEQ ID NO. 155, SEQ ID NO. 157, SEQ ID NO.
159, SEQ ID NO. 161, SEQ ID NO. 163, SEQ ID NO. 165, SEQ ID NO.
167, SEQ ID NO. 169, SEQ ID NO. 171, SEQ ID NO. 173, SEQ ID NO.
175, SEQ ID NO. 177, SEQ ID NO. 179, SEQ ID NO. 181, SEQ ID NO.
183, SEQ ID NO. 185, SEQ ID NO. 187, SEQ ID NO. 189, SEQ ID NO.
191, SEQ ID NO. 193, SEQ ID NO. 195, SEQ ID NO. 197, SEQ ID NO.
199, SEQ ID NO. 201, SEQ ID NO. 203, SEQ ID NO. 205, SEQ ID NO.
207, SEQ ID NO. 209, SEQ ID NO. 211, SEQ ID NO. 213, SEQ ID NO.
215, SEQ ID NO. 217, SEQ ID NO. 219, SEQ ID NO. 221, SEQ ID NO.
223, SEQ ID NO. 225, SEQ ID NO. 227, SEQ ID NO. 229, SEQ ID NO.
231, SEQ ID NO. 233, SEQ ID NO. 235, SEQ ID NO. 237, SEQ ID NO.
239, SEQ ID NO. 241, and combinations thereof, and that has a light
chain variable domain sequence that is at least 95% identical to
the amino acid sequences selected from the group consisting of SEQ
ID NO. 2, SEQ ID NO. 4, SEQ ID NO. 6, SEQ ID NO. 8, SEQ ID NO. 10,
SEQ ID NO. 12, SEQ ID NO. 14, SEQ ID NO. 16, SEQ ID NO. 18, SEQ ID
NO. 20, SEQ ID NO. 22, SEQ ID NO. 24, SEQ ID NO. 26, SEQ ID NO. 28,
SEQ ID NO. 30, SEQ ID NO. 32, SEQ ID NO. 34, SEQ ID NO. 36, SEQ ID
NO. 38, SEQ ID NO. 40, SEQ ID NO. 42, SEQ ID NO. 44, SEQ ID NO. 46,
SEQ ID NO. 48, SEQ ID NO. 50, SEQ ID NO. 52, SEQ ID NO. 54, SEQ ID
NO. 56, SEQ ID NO. 58, SEQ ID NO. 60, SEQ ID NO. 62, SEQ ID NO. 64,
SEQ ID NO. 66, SEQ ID NO. 68, SEQ ID NO. 70, SEQ ID NO. 72, SEQ ID
NO. 74, SEQ ID NO. 76, SEQ ID NO. 78, SEQ ID NO. 80, SEQ ID NO. 82,
SEQ ID NO. 84, SEQ ID NO. 86, SEQ ID NO. 88, SEQ ID NO. 90, SEQ ID
NO. 92, SEQ ID NO. 94, SEQ ID NO. 96, SEQ ID NO. 98, SEQ ID NO.
100, SEQ ID NO. 102, SEQ ID NO. 104, SEQ ID NO. 106, SEQ ID NO.
108, SEQ ID NO. 110, SEQ ID NO. 112, SEQ ID NO. 114, SEQ ID NO.
116, SEQ ID NO. 118, SEQ ID NO. 120, SEQ ID NO. 122, SEQ ID NO.
124, SEQ ID NO. 126, SEQ ID NO. 128, SEQ ID NO. 130, SEQ ID NO.
132, SEQ ID NO. 134, SEQ ID NO. 136, SEQ ID NO. 138, SEQ ID NO.
140, SEQ ID NO. 142, SEQ ID NO. 144, SEQ ID NO. 146, SEQ ID NO.
148, SEQ ID NO. 150, SEQ ID NO. 152, SEQ ID NO. 154, SEQ ID NO.
156, SEQ ID NO. 158, SEQ ID NO. 160, SEQ ID NO. 162, SEQ ID NO.
164, SEQ ID NO. 166, SEQ ID NO. 168, SEQ ID NO. 170, SEQ ID NO.
172, SEQ ID NO. 174, SEQ ID NO. 176, SEQ ID NO. 178, SEQ ID NO.
180, SEQ ID NO. 182, SEQ ID NO. 184, SEQ ID NO. 186, SEQ ID NO.
188, SEQ ID NO. 190, SEQ ID NO. 192, SEQ ID NO. 194, SEQ ID NO.
196, SEQ ID NO. 198, SEQ ID NO. 200, SEQ ID NO. 202, SEQ ID NO.
204, SEQ ID NO. 206, SEQ ID NO. 208, SEQ ID NO. 210, SEQ ID NO.
212, SEQ ID NO. 214, SEQ ID NO. 216, SEQ ID NO. 218, SEQ ID NO.
220, SEQ ID NO. 222, SEQ ID NO. 224, SEQ ID NO. 226, SEQ ID NO.
228, SEQ ID NO. 230, SEQ ID NO. 232, SEQ ID NO. 234, SEQ ID NO.
236, SEQ ID NO. 238, SEQ ID NO. 240, SEQ ID NO. 242, and
combinations thereof. Preferably, the fully human antibody has both
a heavy chain and a light chain wherein the antibody has a heavy
chain/light chain variable domain sequence selected from the group
consisting of SEQ ID NO. 1/SEQ ID NO. 2 (called E6 herein), SEQ ID
NO. 3/SEQ ID NO. 4 (called E7 herein), SEQ ID NO. 5/SEQ ID NO. 6
(called E9 herein), SEQ ID NO. 7/SEQ ID NO. 8 (called E11 herein),
SEQ ID NO. 9/SEQ ID NO. 10 (called F1 herein), SEQ ID NO. 11/SEQ ID
NO. 12 (called F4 herein), SEQ ID NO. 13/SEQ ID NO. 14 (called F7
herein), SEQ ID NO. 15/SEQ ID NO. 16 (called F8 herein), SEQ ID NO.
17/SEQ ID NO. 18 (called F11 herein), SEQ ID NO. 19/SEQ ID NO. 20
(called G4 herein), SEQ ID NO. 21/SEQ ID NO. 22 (called G9 herein),
SEQ ID NO. 23/SEQ ID NO. 24 (called G11 herein), SEQ ID NO. 25/SEQ
ID NO. 26 (called G12 herein), SEQ ID NO. 27/SEQ ID NO. 28 (called
H1 herein), SEQ ID NO. 29/SEQ ID NO. 30 (called H3 herein), SEQ ID
NO. 31/SEQ ID NO. 32 (called H4 herein), SEQ ID NO. 33/SEQ ID NO.
34 (called H5 herein), SEQ ID NO. 35/SEQ ID NO. 36 (called H6
herein), SEQ ID NO. 37/SEQ ID NO. 38 (called H10 herein), SEQ ID
NO. 39/SEQ ID NO. 40 (called H12 herein), SEQ ID NO. 41/SEQ ID NO.
42 (called PDL-D2 herein), SEQ ID NO. 43/SEQ ID NO. 44 (called
PDL-D11 herein), SEQ ID NO. 45/SEQ ID NO. 46 (called PDL-H1
herein), SEQ ID NO. 47/SEQ ID NO. 48 (called RB4 herein), SEQ ID
NO. 49/SEQ ID NO. 50 (called RB11 herein), SEQ ID NO. 51/SEQ ID NO.
52 (called RC5 herein), SEQ ID NO. 53/SEQ ID NO. 54 (called RF5
herein), SEQ ID NO. 55/SEQ ID NO. 56 (called RG9 herein), SEQ ID
NO. 57/SEQ ID NO. 58 (called RD1 herein), SEQ ID NO. 59/SEQ ID NO.
60 (called RF11 herein), SEQ ID NO. 61/SEQ ID NO. 62 (called RH11
herein), SEQ ID NO. 63/SEQ ID NO. 64 (called RD9 herein), SEQ ID
NO. 65/SEQ ID NO. 66 (called RE10 herein), SEQ ID NO. 67/SEQ ID NO.
68 (called RA3 herein), SEQ ID NO. 69/SEQ ID NO. 70 (called RG1
herein), SEQ ID NO. 71/SEQ ID NO. 72 (called RB1 herein), SEQ ID
NO. 73/SEQ ID NO. 74 (called RG7 herein), SEQ ID NO. 75/SEQ ID NO.
76 (called RA6 herein), SEQ ID NO. 77/SEQ ID NO. 78 (called RA8
herein), SEQ ID NO. 79/SEQ ID NO. 80 (called RA9 herein), SEQ ID
NO. 81/SEQ ID NO. 82 (called RB5 herein), SEQ ID NO. 83/SEQ ID NO.
84 (called RB8 herein), SEQ ID NO. 85/SEQ ID NO. 86 (called RC8
herein), SEQ ID NO. 87/SEQ ID NO. 88 (called RC10 herein), SEQ ID
NO. 89/SEQ ID NO. 90 (called RD2 herein), SEQ ID NO. 91/SEQ ID NO.
92 (called RE8 herein), SEQ ID NO. 93/SEQ ID NO. 94 (called RE9
herein), SEQ ID NO. 95/SEQ ID NO. 96 (called RG12 herein), SEQ ID
NO. 97/SEQ ID NO. 98 (called RSA1 herein), SEQ ID NO. 99/SEQ ID NO.
100 (called R2A7 herein), SEQ ID NO. 101/SEQ ID NO. 102 (called
R2B12 herein), SEQ ID NO. 103/SEQ ID NO. 104 (called R2C9 herein),
SEQ ID NO. 105/SEQ ID NO. 106 (called R2D5 herein), SEQ ID NO.
107/SEQ ID NO. 108 (called R2D7 herein), SEQ ID NO. 109/SEQ ID NO.
110 (called R2F4 herein), SEQ ID NO. 111/SEQ ID NO. 112 (called
R2A10 herein), SEQ ID NO. 113/SEQ ID NO. 114 (called R2E2 herein),
SEQ ID NO. 115/SEQ ID NO. 116 (called R3B8 herein), SEQ ID NO.
117/SEQ ID NO. 118 (called R3C3 herein), SEQ ID NO. 119/SEQ ID NO.
120 (called R3E9 herein), SEQ ID NO. 121/SEQ ID NO. 122 (called
R3E10 herein), SEQ ID NO. 123/SEQ ID NO. 124 (called R3F7 herein),
SEQ ID NO. 125/SEQ ID NO. 126 (called R3F10 herein), SEQ ID NO.
127/SEQ ID NO. 128 (called R4B10 herein), SEQ ID NO. 129/SEQ ID NO.
130 (called R4H1 herein), SEQ ID NO. 131/SEQ ID NO. 132 (called
R4A11 herein), SEQ ID NO. 133/SEQ ID NO. 134 (called R3D2 herein),
SEQ ID NO. 135/SEQ ID NO. 136 (called R5B8 herein), SEQ ID NO.
137/SEQ ID NO. 138 (called SH1A1Q herein), SEQ ID NO. 139/SEQ ID
NO. 140 (called SH1B7B(K) herein), SEQ ID NO. 141/SEQ ID NO. 142
(called SH1C1 herein), SEQ ID NO. 143/SEQ ID NO. 144 (called SH1C8
herein), SEQ ID NO. 145/SEQ ID NO. 146 (called SH1E10 herein), SEQ
ID NO. 147/SEQ ID NO. 148 (called SH1E2 herein), SEQ ID NO. 149/SEQ
ID NO. 150 (called SH1A9 herein), SEQ ID NO. 151/SEQ ID NO. 152
(called SH1B11 herein), SEQ ID NO. 153/SEQ ID NO. 154 (called SH1E4
herein), SEQ ID NO. 155/SEQ ID NO. 156 (called SH1B3 herein), SEQ
ID NO. 157/SEQ ID NO. 158 (called SH1D1 herein), SEQ ID NO. 159/SEQ
ID NO. 160 (called SH1D2 herein), SEQ ID NO. 161/SEQ ID NO. 162
(called SH1D12 herein), SEQ ID NO. 163/SEQ ID NO. 164 (called SH1E1
herein), SEQ ID NO. 165/SEQ ID NO. 166 (called SH1G9 herein), SEQ
ID NO. 167/SEQ ID NO. 168 (called SH1A11 herein), SEQ ID NO.
169/SEQ ID NO. 170 (called SH1C2 herein), SEQ ID NO. 171/SEQ ID NO.
172 (called SH1G8 herein), SEQ ID NO. 173/SEQ ID NO. 174 (called
SH1H2 herein), SEQ ID NO. 175/SEQ ID NO. 176 (called SH1B10
herein), SEQ ID NO. 177/SEQ ID NO. 178 (called SH1B7A(L) herein),
SEQ ID NO. 179/SEQ ID NO. 180 (called SH1E6 herein), SEQ ID NO.
181/SEQ ID NO. 182 (called SH1C11 herein), SEQ ID NO. 183/SEQ ID
NO. 184 (called SH1A2 herein), SEQ ID NO. 185/SEQ ID NO. 186
(called SH1B1 herein), SEQ ID NO. 187/SEQ ID NO. 188 (called R6B2
herein), SEQ ID NO. 189/SEQ ID NO. 190 (called R6B7 herein), SEQ ID
NO. 191/SEQ ID NO. 192 (called R6B11 herein), SEQ ID NO. 193/SEQ ID
NO. 194 (called R6D1 herein), SEQ ID NO. 195/SEQ ID NO. 196 (called
R6C8 herein), SEQ ID NO. 197/SEQ ID NO. 198 (called R9G8 herein),
SEQ ID NO. 199/SEQ ID NO. 200 (called R7D1 herein), SEQ ID NO.
201/SEQ ID NO. 202 (called R7D2 herein), SEQ ID NO. 203/SEQ ID NO.
204 (called R7E7 herein), SEQ ID NO. 205/SEQ ID NO. 206 (called
R7F2 herein), SEQ ID NO. 207/SEQ ID NO. 208 (called R7F7 herein),
SEQ ID NO. 209/SEQ ID NO. 210 (called R9H2 herein), SEQ ID NO.
211/SEQ ID NO. 212 (called R9H6 herein), SEQ ID NO. 213/SEQ ID NO.
214 (called H6B1L herein), SEQ ID NO. 215/SEQ ID NO. 216 (called
H6A1 herein), SEQ ID NO. 217/SEQ ID NO. 218 (called H6B1 herein),
SEQ ID NO. 219/SEQ ID NO. 220 (called H6B2 herein), SEQ ID NO.
221/SEQ ID NO. 222 (called H19C herein), SEQ ID NO. 223/SEQ ID NO.
224 (called H110D herein), SEQ ID NO. 225/SEQ ID NO. 226 (called
H11F herein), SEQ ID NO. 227/SEQ ID NO. 228 (called H1C1 herein),
SEQ ID NO. 229/SEQ ID NO. 230 (called GPG1A2 herein), SEQ ID NO.
231/SEQ ID NO. 232 (called GPGG8 herein), SEQ ID NO. 233/SEQ ID NO.
234 (called GPGG10 herein), SEQ ID NO. 235/SEQ ID NO. 236 (called
GPGH7 herein), SEQ ID NO. 237/SEQ ID NO. 238 (called GPGH10
herein), SEQ ID NO. 239/SEQ ID NO. 240 (called GPGH11 herein), SEQ
ID NO. 241/SEQ ID NO. 242 (called GPGH10P herein), and combinations
thereof.
[0007] The present disclosure provides a Fab fully human antibody
fragment, having a variable domain region from a heavy chain and a
variable domain region from a light chain, wherein the heavy chain
variable domain sequence that is at least 95% identical to the
amino acid sequences selected from the group consisting of SEQ ID
NO. 1, SEQ ID NO. 3, SEQ ID NO. 5, SEQ ID NO. 7, SEQ ID NO. 9, SEQ
ID NO. 11, SEQ ID NO. 13, SEQ ID NO. 15, SEQ ID NO. 17, SEQ ID NO.
19, SEQ ID NO. 21, SEQ ID NO. 23, SEQ ID NO. 25, SEQ ID NO. 27, SEQ
ID NO. 29, SEQ ID NO. 31, SEQ ID NO. 33, SEQ ID NO. 35, SEQ ID NO.
37, SEQ ID NO. 39, SEQ ID NO. 41, SEQ ID NO. 43, SEQ ID NO. 45, SEQ
ID NO. 47, SEQ ID NO. 49, SEQ ID NO. 51, SEQ ID NO. 53, SEQ ID NO.
55, SEQ ID NO. 57, SEQ ID NO. 59, SEQ ID NO. 61, SEQ ID NO. 63, SEQ
ID NO. 65, SEQ ID NO. 67, SEQ ID NO. 69, SEQ ID NO. 71, SEQ ID NO.
73, SEQ ID NO. 75, SEQ ID NO. 77, SEQ ID NO. 79, SEQ ID NO. 81, SEQ
ID NO. 83, SEQ ID NO. 85, SEQ ID NO. 87, SEQ ID NO. 89, SEQ ID NO.
91, SEQ ID NO. 93, SEQ ID NO. 95, SEQ ID NO. 97, SEQ ID NO. 99, SEQ
ID NO. 101, SEQ ID NO. 103, SEQ ID NO. 105, SEQ ID NO. 107, SEQ ID
NO. 109, SEQ ID NO. 111, SEQ ID NO. 113, SEQ ID NO. 115, SEQ ID NO.
117, SEQ ID NO. 119, SEQ ID NO. 121, SEQ ID NO. 123, SEQ ID NO.
125, SEQ ID NO. 127, SEQ ID NO. 129, SEQ ID NO. 131, SEQ ID NO.
133, SEQ ID NO. 135, SEQ ID NO. 137, SEQ ID NO. 139, SEQ ID NO.
141, SEQ ID NO. 143, SEQ ID NO. 145, SEQ ID NO. 147, SEQ ID NO.
149, SEQ ID NO. 151, SEQ ID NO. 153, SEQ ID NO. 155, SEQ ID NO.
157, SEQ ID NO. 159, SEQ ID NO. 161, SEQ ID NO. 163, SEQ ID NO.
165, SEQ ID NO. 167, SEQ ID NO. 169, SEQ ID NO. 171, SEQ ID NO.
173, SEQ ID NO. 175, SEQ ID NO. 177, SEQ ID NO. 179, SEQ ID NO.
181, SEQ ID NO. 183, SEQ ID NO. 185, SEQ ID NO. 187, SEQ ID NO.
189, SEQ ID NO. 191, SEQ ID NO. 193, SEQ ID NO. 195, SEQ ID NO.
197, SEQ ID NO. 199, SEQ ID NO. 201, SEQ ID NO. 203, SEQ ID NO.
205, SEQ ID NO. 207, SEQ ID NO. 209, SEQ ID NO. 211, SEQ ID NO.
213, SEQ ID NO. 215, SEQ ID NO. 217, SEQ ID NO. 219, SEQ ID NO.
221, SEQ ID NO. 223, SEQ ID NO. 225, SEQ ID NO. 227, SEQ ID NO.
229, SEQ ID NO. 231, SEQ ID NO. 233, SEQ ID NO. 235, SEQ ID NO.
237, SEQ ID NO. 239, SEQ ID NO. 241, and combinations thereof, and
that has a light chain variable domain sequence that is at least
95% identical to the amino acid sequences selected from the group
consisting of SEQ ID NO. 2, SEQ ID NO. 4, SEQ ID NO. 6, SEQ ID NO.
8, SEQ ID NO. 10, SEQ ID NO. 12, SEQ ID NO. 14, SEQ ID NO. 16, SEQ
ID NO. 18, SEQ ID NO. 20, SEQ ID NO. 22, SEQ ID NO. 24, SEQ ID NO.
26, SEQ ID NO. 28, SEQ ID NO. 30, SEQ ID NO. 32, SEQ ID NO. 34, SEQ
ID NO. 36, SEQ ID NO. 38, SEQ ID NO. 40, SEQ ID NO. 42, SEQ ID NO.
44, SEQ ID NO. 46, SEQ ID NO. 48, SEQ ID NO. 50, SEQ ID NO. 52, SEQ
ID NO. 54, SEQ ID NO. 56, SEQ ID NO. 58, SEQ ID NO. 60, SEQ ID NO.
62, SEQ ID NO. 64, SEQ ID NO. 66, SEQ ID NO. 68, SEQ ID NO. 70, SEQ
ID NO. 72, SEQ ID NO. 74, SEQ ID NO. 76, SEQ ID NO. 78, SEQ ID NO.
80, SEQ ID NO. 82, SEQ ID NO. 84, SEQ ID NO. 86, SEQ ID NO. 88, SEQ
ID NO. 90, SEQ ID NO. 92, SEQ ID NO. 94, SEQ ID NO. 96, SEQ ID NO.
98, SEQ ID NO. 100, SEQ ID NO. 102, SEQ ID NO. 104, SEQ ID NO. 106,
SEQ ID NO. 108, SEQ ID NO. 110, SEQ ID NO. 112, SEQ ID NO. 114, SEQ
ID NO. 116, SEQ ID NO. 118, SEQ ID NO. 120, SEQ ID NO. 122, SEQ ID
NO. 124, SEQ ID NO. 126, SEQ ID NO. 128, SEQ ID NO. 130, SEQ ID NO.
132, SEQ ID NO. 134, SEQ ID NO. 136, SEQ ID NO. 138, SEQ ID NO.
140, SEQ ID NO. 142, SEQ ID NO. 144, SEQ ID NO. 146, SEQ ID NO.
148, SEQ ID NO. 150, SEQ ID NO. 152, SEQ ID NO. 154, SEQ ID NO.
156, SEQ ID NO. 158, SEQ ID NO. 160, SEQ ID NO. 162, SEQ ID NO.
164, SEQ ID NO. 166, SEQ ID NO. 168, SEQ ID NO. 170, SEQ ID NO.
172, SEQ ID NO. 174, SEQ ID NO. 176, SEQ ID NO. 178, SEQ ID NO.
180, SEQ ID NO. 182, SEQ ID NO. 184, SEQ ID NO. 186, SEQ ID NO.
188, SEQ ID NO. 190, SEQ ID NO. 192, SEQ ID NO. 194, SEQ ID NO.
196, SEQ ID NO. 198, SEQ ID NO. 200, SEQ ID NO. 202, SEQ ID NO.
204, SEQ ID NO. 206, SEQ ID NO. 208, SEQ ID NO. 210, SEQ ID NO.
212, SEQ ID NO. 214, SEQ ID NO. 216, SEQ ID NO. 218, SEQ ID NO.
220, SEQ ID NO. 222, SEQ ID NO. 224, SEQ ID NO. 226, SEQ ID NO.
228, SEQ ID NO. 230, SEQ ID NO. 232, SEQ ID NO. 234, SEQ ID NO.
236, SEQ ID NO. 238, SEQ ID NO. 240, SEQ ID NO. 242, and
combinations thereof. Preferably, the fully human antibody Fab
fragment has both a heavy chain variable domain region and a light
chain variable domain region wherein the antibody has a heavy
chain/light chain variable domain sequence selected from the group
consisting of SEQ ID NO. 1/SEQ ID NO. 2, SEQ ID NO. 3/SEQ ID NO. 4,
SEQ ID NO. 5/SEQ ID NO. 6, SEQ ID NO. 7/SEQ ID NO. 8, SEQ ID NO.
9/SEQ ID NO. 10, SEQ ID NO. 11/SEQ ID NO. 12, SEQ ID NO. 13/SEQ ID
NO. 14, SEQ ID NO. 15/SEQ ID NO. 16, SEQ ID NO. 17/SEQ ID NO. 18,
SEQ ID NO. 19/SEQ ID NO. 20, SEQ ID NO. 21/SEQ ID NO. 22, SEQ ID
NO. 23/SEQ ID NO. 24, SEQ ID NO. 25/SEQ ID NO. 26, SEQ ID NO.
27/SEQ ID NO. 28, SEQ ID NO. 29/SEQ ID NO. 30, SEQ ID NO. 31/SEQ ID
NO. 32, SEQ ID NO. 33/SEQ ID NO. 34, SEQ ID NO. 35/SEQ ID NO. 36,
SEQ ID NO. 37/SEQ ID NO. 38, SEQ ID NO. 39/SEQ ID NO. 40, SEQ ID
NO. 41/SEQ ID NO. 42, SEQ ID NO. 43/SEQ ID NO. 44, SEQ ID NO.
45/SEQ ID NO. 46, SEQ ID NO. 47/SEQ ID NO. 48, SEQ ID NO. 49/SEQ ID
NO. 50, SEQ ID NO. 51/SEQ ID NO. 52, SEQ ID NO. 53/SEQ ID NO. 54,
SEQ ID NO. 55/SEQ ID NO. 56, SEQ ID NO. 57/SEQ ID NO. 58, SEQ ID
NO. 59/SEQ ID NO. 60, SEQ ID NO. 61/SEQ ID NO. 62, SEQ ID NO.
63/SEQ ID NO. 64, SEQ ID NO. 65/SEQ ID NO. 66, SEQ ID NO. 67/SEQ ID
NO. 68, SEQ ID NO. 69/SEQ ID NO. 70, SEQ ID NO. 71/SEQ ID NO. 72,
SEQ ID NO. 73/SEQ ID NO. 74, SEQ ID NO. 75/SEQ ID NO. 76, SEQ ID
NO. 77/SEQ ID NO. 78, SEQ ID NO. 79/SEQ ID NO. 80, SEQ ID NO.
81/SEQ ID NO. 82, SEQ ID NO. 83/SEQ ID NO. 84, SEQ ID NO. 85/SEQ ID
NO. 86, SEQ ID NO. 87/SEQ ID NO. 88, SEQ ID NO. 89/SEQ ID NO. 90,
SEQ ID NO. 91/SEQ ID NO. 92, SEQ ID NO. 93/SEQ ID NO. 94, SEQ ID
NO. 95/SEQ ID NO. 96, SEQ ID NO. 97/SEQ ID NO. 98, SEQ ID NO.
99/SEQ ID NO. 100, SEQ ID NO. 101/SEQ ID NO. 102, SEQ ID NO.
103/SEQ ID NO. 104, SEQ ID NO. 105/SEQ ID NO. 106, SEQ ID NO.
107/SEQ ID NO. 108, SEQ ID NO. 109/SEQ ID NO. 110, SEQ ID NO.
111/SEQ ID NO. 112, SEQ ID NO. 113/SEQ ID NO. 114, SEQ ID NO.
115/SEQ ID NO. 116, SEQ ID NO. 117/SEQ ID NO. 118, SEQ ID NO.
119/SEQ ID NO. 120, SEQ ID NO. 121/SEQ ID NO. 122, SEQ ID NO.
123/SEQ ID NO. 124, SEQ ID NO. 125/SEQ ID NO. 126, SEQ ID NO.
127/SEQ ID NO. 128, SEQ ID NO. 129/SEQ ID NO. 130, SEQ ID NO.
131/SEQ ID NO. 132, SEQ ID NO. 133/SEQ ID NO. 134, SEQ ID NO.
135/SEQ ID NO. 136, SEQ ID NO. 137/SEQ ID NO. 138, SEQ ID NO.
139/SEQ ID NO. 140, SEQ ID NO. 141/SEQ ID NO. 142, SEQ ID NO.
143/SEQ ID NO. 144, SEQ ID NO. 145/SEQ ID NO. 146, SEQ ID NO.
147/SEQ ID NO. 148, SEQ ID NO. 149/SEQ ID NO. 150, SEQ ID NO.
151/SEQ ID NO. 152, SEQ ID NO. 153/SEQ ID NO. 154, SEQ ID NO.
155/SEQ ID NO. 156, SEQ ID NO. 157/SEQ ID NO. 158, SEQ ID NO.
159/SEQ ID NO. 160, SEQ ID NO. 161/SEQ ID NO. 162, SEQ ID NO.
163/SEQ ID NO. 164, SEQ ID NO. 165/SEQ ID NO. 166, SEQ ID NO.
167/SEQ ID NO. 168, SEQ ID NO. 169/SEQ ID NO. 170, SEQ ID NO.
171/SEQ ID NO. 172, SEQ ID NO. 173/SEQ ID NO. 174, SEQ ID NO.
175/SEQ ID NO. 176, SEQ ID NO. 177/SEQ ID NO. 178, SEQ ID NO.
179/SEQ ID NO. 180, SEQ ID NO. 181/SEQ ID NO. 182, SEQ ID NO.
183/SEQ ID NO. 184, SEQ ID NO. 185/SEQ ID NO. 186, SEQ ID NO.
187/SEQ ID NO. 188, SEQ ID NO. 189/SEQ ID NO. 190, SEQ ID NO.
191/SEQ ID NO. 192, SEQ ID NO. 193/SEQ ID NO. 194, SEQ ID NO.
195/SEQ ID NO. 196, SEQ ID NO. 197/SEQ ID NO. 198, SEQ ID NO.
199/SEQ ID NO. 200, SEQ ID NO. 201/SEQ ID NO. 202, SEQ ID NO.
203/SEQ ID NO. 204, SEQ ID NO. 205/SEQ ID NO. 206, SEQ ID NO.
207/SEQ ID NO. 208, SEQ ID NO. 209/SEQ ID NO. 210, SEQ ID NO.
211/SEQ ID NO. 212, SEQ ID NO. 213/SEQ ID NO. 214, SEQ ID NO.
215/SEQ ID NO. 216, SEQ ID NO. 217/SEQ ID NO. 218, SEQ ID NO.
219/SEQ ID NO. 220, SEQ ID NO. 221/SEQ ID NO. 222, SEQ ID NO.
223/SEQ ID NO. 224, SEQ ID NO. 225/SEQ ID NO. 226, SEQ ID NO.
227/SEQ ID NO. 228, SEQ ID NO. 229/SEQ ID NO. 230, SEQ ID NO.
231/SEQ ID NO. 232, SEQ ID NO. 233/SEQ ID NO. 234, SEQ ID NO.
235/SEQ ID NO. 236, SEQ ID NO. 237/SEQ ID NO. 238, SEQ ID NO.
239/SEQ ID NO. 240, SEQ ID NO. 241/SEQ ID NO. 242, and combinations
thereof.
[0008] The present disclosure provides a single chain human
antibody, having a variable domain region from a heavy chain and a
variable domain region from a light chain and a peptide linker
connection the heavy chain and light chain variable domain regions,
wherein the heavy chain variable domain sequence that is at least
95% identical to the amino acid sequences selected from the group
consisting of SEQ ID NO. 1, SEQ ID NO. 3, SEQ ID NO. 5, SEQ ID NO.
7, SEQ ID NO. 9, SEQ ID NO. 11, SEQ ID NO. 13, SEQ ID NO. 15, SEQ
ID NO. 17, SEQ ID NO. 19, SEQ ID NO. 21, SEQ ID NO. 23, SEQ ID NO.
25, SEQ ID NO. 27, SEQ ID NO. 29, SEQ ID NO. 31, SEQ ID NO. 33, SEQ
ID NO. 35, SEQ ID NO. 37, SEQ ID NO. 39, SEQ ID NO. 41, SEQ ID NO.
43, SEQ ID NO. 45, SEQ ID NO. 47, SEQ ID NO. 49, SEQ ID NO. 51, SEQ
ID NO. 53, SEQ ID NO. 55, SEQ ID NO. 57, SEQ ID NO. 59, SEQ ID NO.
61, SEQ ID NO. 63, SEQ ID NO. 65, SEQ ID NO. 67, SEQ ID NO. 69, SEQ
ID NO. 71, SEQ ID NO. 73, SEQ ID NO. 75, SEQ ID NO. 77, SEQ ID NO.
79, SEQ ID NO. 81, SEQ ID NO. 83, SEQ ID NO. 85, SEQ ID NO. 87, SEQ
ID NO. 89, SEQ ID NO. 91, SEQ ID NO. 93, SEQ ID NO. 95, SEQ ID NO.
97, SEQ ID NO. 99, SEQ ID NO. 101, SEQ ID NO. 103, SEQ ID NO. 105,
SEQ ID NO. 107, SEQ ID NO. 109, SEQ ID NO. 111, SEQ ID NO. 113, SEQ
ID NO. 115, SEQ ID NO. 117, SEQ ID NO. 119, SEQ ID NO. 121, SEQ ID
NO. 123, SEQ ID NO. 125, SEQ ID NO. 127, SEQ ID NO. 129, SEQ ID NO.
131, SEQ ID NO. 133, SEQ ID NO. 135, SEQ ID NO. 137, SEQ ID NO.
139, SEQ ID NO. 141, SEQ ID NO. 143, SEQ ID NO. 145, SEQ ID NO.
147, SEQ ID NO. 149, SEQ ID NO. 151, SEQ ID NO. 153, SEQ ID NO.
155, SEQ ID NO. 157, SEQ ID NO. 159, SEQ ID NO. 161, SEQ ID NO.
163, SEQ ID NO. 165, SEQ ID NO. 167, SEQ ID NO. 169, SEQ ID NO.
171, SEQ ID NO. 173, SEQ ID NO. 175, SEQ ID NO. 177, SEQ ID NO.
179, SEQ ID NO. 181, SEQ ID NO. 183, SEQ ID NO. 185, SEQ ID NO.
187, SEQ ID NO. 189, SEQ ID NO. 191, SEQ ID NO. 193, SEQ ID NO.
195, SEQ ID NO. 197, SEQ ID NO. 199, SEQ ID NO. 201, SEQ ID NO.
203, SEQ ID NO. 205, SEQ ID NO. 207, SEQ ID NO. 209, SEQ ID NO.
211, SEQ ID NO. 213, SEQ ID NO. 215, SEQ ID NO. 217, SEQ ID NO.
219, SEQ ID NO. 221, SEQ ID NO. 223, SEQ ID NO. 225, SEQ ID NO.
227, SEQ ID NO. 229, SEQ ID NO. 231, SEQ ID NO. 233, SEQ ID NO.
235, SEQ ID NO. 237, SEQ ID NO. 239, SEQ ID NO. 241, and
combinations thereof, and that has a light chain variable domain
sequence that is at least 95% identical to the amino acid sequences
selected from the group consisting of SEQ ID NO. 2, SEQ ID NO. 4,
SEQ ID NO. 6, SEQ ID NO. 8, SEQ ID NO. 10, SEQ ID NO. 12, SEQ ID
NO. 14, SEQ ID NO. 16, SEQ ID NO. 18, SEQ ID NO. 20, SEQ ID NO. 22,
SEQ ID NO. 24, SEQ ID NO. 26, SEQ ID NO. 28, SEQ ID NO. 30, SEQ ID
NO. 32, SEQ ID NO. 34, SEQ ID NO. 36, SEQ ID NO. 38, SEQ ID NO. 40,
SEQ ID NO. 42, SEQ ID NO. 44, SEQ ID NO. 46, SEQ ID NO. 48, SEQ ID
NO. 50, SEQ ID NO. 52, SEQ ID NO. 54, SEQ ID NO. 56, SEQ ID NO. 58,
SEQ ID NO. 60, SEQ ID NO. 62, SEQ ID NO. 64, SEQ ID NO. 66, SEQ ID
NO. 68, SEQ ID NO. 70, SEQ ID NO. 72, SEQ ID NO. 74, SEQ ID NO. 76,
SEQ ID NO. 78, SEQ ID NO. 80, SEQ ID NO. 82, SEQ ID NO. 84, SEQ ID
NO. 86, SEQ ID NO. 88, SEQ ID NO. 90, SEQ ID NO. 92, SEQ ID NO. 94,
SEQ ID NO. 96, SEQ ID NO. 98, SEQ ID NO. 100, SEQ ID NO. 102, SEQ
ID NO. 104, SEQ ID NO. 106, SEQ ID NO. 108, SEQ ID NO. 110, SEQ ID
NO. 112, SEQ ID NO. 114, SEQ ID NO. 116, SEQ ID NO. 118, SEQ ID NO.
120, SEQ ID NO. 122, SEQ ID NO. 124, SEQ ID NO. 126, SEQ ID NO.
128, SEQ ID NO. 130, SEQ ID NO. 132, SEQ ID NO. 134, SEQ ID NO.
136, SEQ ID NO. 138, SEQ ID NO. 140, SEQ ID NO. 142, SEQ ID NO.
144, SEQ ID NO. 146, SEQ ID NO. 148, SEQ ID NO. 150, SEQ ID NO.
152, SEQ ID NO. 154, SEQ ID NO. 156, SEQ ID NO. 158, SEQ ID NO.
160, SEQ ID NO. 162, SEQ ID NO. 164, SEQ ID NO. 166, SEQ ID NO.
168, SEQ ID NO. 170, SEQ ID NO. 172, SEQ ID NO. 174, SEQ ID NO.
176, SEQ ID NO. 178, SEQ ID NO. 180, SEQ ID NO. 182, SEQ ID NO.
184, SEQ ID NO. 186, SEQ ID NO. 188, SEQ ID NO. 190, SEQ ID NO.
192, SEQ ID NO. 194, SEQ ID NO. 196, SEQ ID NO. 198, SEQ ID NO.
200, SEQ ID NO. 202, SEQ ID NO. 204, SEQ ID NO. 206, SEQ ID NO.
208, SEQ ID NO. 210, SEQ ID NO. 212, SEQ ID NO. 214, SEQ ID NO.
216, SEQ ID NO. 218, SEQ ID NO. 220, SEQ ID NO. 222, SEQ ID NO.
224, SEQ ID NO. 226, SEQ ID NO. 228, SEQ ID NO. 230, SEQ ID NO.
232, SEQ ID NO. 234, SEQ ID NO. 236, SEQ ID NO. 238, SEQ ID NO.
240, SEQ ID NO. 242, and combinations thereof. Preferably, the
fully human single chain antibody has both a heavy chain variable
domain region and a light chain variable domain region, wherein the
single chain fully human antibody has a heavy chain/light chain
variable domain sequence selected from the group consisting of SEQ
ID NO. 1/SEQ ID NO. 2, SEQ ID NO. 3/SEQ ID NO. 4, SEQ ID NO. 5/SEQ
ID NO. 6, SEQ ID NO. 7/SEQ ID NO. 8, SEQ ID NO. 9/SEQ ID NO. 10,
SEQ ID NO. 11/SEQ ID NO. 12, SEQ ID NO. 13/SEQ ID NO. 14, SEQ ID
NO. 15/SEQ ID NO. 16, SEQ ID NO. 17/SEQ ID NO. 18, SEQ ID NO.
19/SEQ ID NO. 20, SEQ ID NO. 21/SEQ ID NO. 22, SEQ ID NO. 23/SEQ ID
NO. 24, SEQ ID NO. 25/SEQ ID NO. 26, SEQ ID NO. 27/SEQ ID NO. 28,
SEQ ID NO. 29/SEQ ID NO. 30, SEQ ID NO. 31/SEQ ID NO. 32, SEQ ID
NO. 33/SEQ ID NO. 34, SEQ ID NO. 35/SEQ ID NO. 36, SEQ ID NO.
37/SEQ ID NO. 38, SEQ ID NO. 39/SEQ ID NO. 40, SEQ ID NO. 41/SEQ ID
NO. 42, SEQ ID NO. 43/SEQ ID NO. 44, SEQ ID NO. 45/SEQ ID NO. 46,
SEQ ID NO. 47/SEQ ID NO. 48, SEQ ID NO. 49/SEQ ID NO. 50, SEQ ID
NO. 51/SEQ ID NO. 52, SEQ ID NO. 53/SEQ ID NO. 54, SEQ ID NO.
55/SEQ ID NO. 56, SEQ ID NO. 57/SEQ ID NO. 58, SEQ ID NO. 59/SEQ ID
NO. 60, SEQ ID NO. 61/SEQ ID NO. 62, SEQ ID NO. 63/SEQ ID NO. 64,
SEQ ID NO. 65/SEQ ID NO. 66, SEQ ID NO. 67/SEQ ID NO. 68, SEQ ID
NO. 69/SEQ ID NO. 70, SEQ ID NO. 71/SEQ ID NO. 72, SEQ ID NO.
73/SEQ ID NO. 74, SEQ ID NO. 75/SEQ ID NO. 76, SEQ ID NO. 77/SEQ ID
NO. 78, SEQ ID NO. 79/SEQ ID NO. 80, SEQ ID NO. 81/SEQ ID NO. 82,
SEQ ID NO. 83/SEQ ID NO. 84, SEQ ID NO. 85/SEQ ID NO. 86, SEQ ID
NO. 87/SEQ ID NO. 88, SEQ ID NO. 89/SEQ ID NO. 90, SEQ ID NO.
91/SEQ ID NO. 92, SEQ ID NO. 93/SEQ ID NO. 94, SEQ ID NO. 95/SEQ ID
NO. 96, SEQ ID NO. 97/SEQ ID NO. 98, SEQ ID NO. 99/SEQ ID NO. 100,
SEQ ID NO. 101/SEQ ID NO. 102, SEQ ID NO. 103/SEQ ID NO. 104, SEQ
ID NO. 105/SEQ ID NO. 106, SEQ ID NO. 107/SEQ ID NO. 108, SEQ ID
NO. 109/SEQ ID NO. 110, SEQ ID NO. 111/SEQ ID NO. 112, SEQ ID NO.
113/SEQ ID NO. 114, SEQ ID NO. 115/SEQ ID NO. 116, SEQ ID NO.
117/SEQ ID NO. 118, SEQ ID NO. 119/SEQ ID NO. 120, SEQ ID NO.
121/SEQ ID NO. 122, SEQ ID NO. 123/SEQ ID NO. 124, SEQ ID NO.
125/SEQ ID NO. 126, SEQ ID NO. 127/SEQ ID NO. 128, SEQ ID NO.
129/SEQ ID NO. 130, SEQ ID NO. 131/SEQ ID NO. 132, SEQ ID NO.
133/SEQ ID NO. 134, SEQ ID NO. 135/SEQ ID NO. 136, SEQ ID NO.
137/SEQ ID NO. 138, SEQ ID NO. 139/SEQ ID NO. 140, SEQ ID NO.
141/SEQ ID NO. 142, SEQ ID NO. 143/SEQ ID NO. 144, SEQ ID NO.
145/SEQ ID NO. 146, SEQ ID NO. 147/SEQ ID NO. 148, SEQ ID NO.
149/SEQ ID NO. 150, SEQ ID NO. 151/SEQ ID NO. 152, SEQ ID NO.
153/SEQ ID NO. 154, SEQ ID NO. 155/SEQ ID NO. 156, SEQ ID NO.
157/SEQ ID NO. 158, SEQ ID NO. 159/SEQ ID NO. 160, SEQ ID NO.
161/SEQ ID NO. 162, SEQ ID NO. 163/SEQ ID NO. 164, SEQ ID NO.
165/SEQ ID NO. 166, SEQ ID NO. 167/SEQ ID NO. 168, SEQ ID NO.
169/SEQ ID NO. 170, SEQ ID NO. 171/SEQ ID NO. 172, SEQ ID NO.
173/SEQ ID NO. 174, SEQ ID NO. 175/SEQ ID NO. 176, SEQ ID NO.
177/SEQ ID NO. 178, SEQ ID NO. 179/SEQ ID NO. 180, SEQ ID NO.
181/SEQ ID NO. 182, SEQ ID NO. 183/SEQ ID NO. 184, SEQ ID NO.
185/SEQ ID NO. 186, SEQ ID NO. 187/SEQ ID NO. 188, SEQ ID NO.
189/SEQ ID NO. 190, SEQ ID NO. 191/SEQ ID NO. 192, SEQ ID NO.
193/SEQ ID NO. 194, SEQ ID NO. 195/SEQ ID NO. 196, SEQ ID NO.
197/SEQ ID NO. 198, SEQ ID NO. 199/SEQ ID NO. 200, SEQ ID NO.
201/SEQ ID NO. 202, SEQ ID NO. 203/SEQ ID NO. 204, SEQ ID NO.
205/SEQ ID NO. 206, SEQ ID NO. 207/SEQ ID NO. 208, SEQ ID NO.
209/SEQ ID NO. 210, SEQ ID NO. 211/SEQ ID NO. 212, SEQ ID NO.
213/SEQ ID NO. 214, SEQ ID NO. 215/SEQ ID NO. 216, SEQ ID NO.
217/SEQ ID NO. 218, SEQ ID NO. 219/SEQ ID NO. 220, SEQ ID NO.
221/SEQ ID NO. 222, SEQ ID NO. 223/SEQ ID NO. 224, SEQ ID NO.
225/SEQ ID NO. 226, SEQ ID NO. 227/SEQ ID NO. 228, SEQ ID NO.
229/SEQ ID NO. 230, SEQ ID NO. 231/SEQ ID NO. 232, SEQ ID NO.
233/SEQ ID NO. 234, SEQ ID NO. 235/SEQ ID NO. 236, SEQ ID NO.
237/SEQ ID NO. 238, SEQ ID NO. 239/SEQ ID NO. 240, SEQ ID NO.
241/SEQ ID NO. 242, and combinations thereof.
[0009] The present disclosure further provides a method for
treating a broad spectrum of mammalian cancers or a broad-spectrum
of inflammatory diseases and autoimmune diseases, comprising
administering an effective amount of an anti-PD-L1 polypeptide,
wherein the anti-PD-L1 polypeptide is selected from the group
consisting of a fully human antibody of an IgG class that binds to
a PD-L1 epitope with a binding affinity of at least 10.sup.-6M, a
Fab fully human antibody fragment, having a variable domain region
from a heavy chain and a variable domain region from a light chain,
a single chain human antibody, having a variable domain region from
a heavy chain and a variable domain region from a light chain and a
peptide linker connection the heavy chain and light chain variable
domain regions, and combinations thereof;
[0010] wherein the fully human antibody has a heavy chain variable
domain sequence that is at least 95% identical to the amino acid
sequences selected from the group consisting of SEQ ID NO. 1, SEQ
ID NO. 3, SEQ ID NO. 5, SEQ ID NO. 7, SEQ ID NO. 9, SEQ ID NO. 11,
SEQ ID NO. 13, SEQ ID NO. 15, SEQ ID NO. 17, SEQ ID NO. 19, SEQ ID
NO. 21, SEQ ID NO. 23, SEQ ID NO. 25, SEQ ID NO. 27, SEQ ID NO. 29,
SEQ ID NO. 31, SEQ ID NO. 33, SEQ ID NO. 35, SEQ ID NO. 37, SEQ ID
NO. 39, SEQ ID NO. 41, SEQ ID NO. 43, SEQ ID NO. 45, SEQ ID NO. 47,
SEQ ID NO. 49, SEQ ID NO. 51, SEQ ID NO. 53, SEQ ID NO. 55, SEQ ID
NO. 57, SEQ ID NO. 59, SEQ ID NO. 61, SEQ ID NO. 63, SEQ ID NO. 65,
SEQ ID NO. 67, SEQ ID NO. 69, SEQ ID NO. 71, SEQ ID NO. 73, SEQ ID
NO. 75, SEQ ID NO. 77, SEQ ID NO. 79, SEQ ID NO. 81, SEQ ID NO. 83,
SEQ ID NO. 85, SEQ ID NO. 87, SEQ ID NO. 89, SEQ ID NO. 91, SEQ ID
NO. 93, SEQ ID NO. 95, SEQ ID NO. 97, SEQ ID NO. 99, SEQ ID NO.
101, SEQ ID NO. 103, SEQ ID NO. 105, SEQ ID NO. 107, SEQ ID NO.
109, SEQ ID NO. 111, SEQ ID NO. 113, SEQ ID NO. 115, SEQ ID NO.
117, SEQ ID NO. 119, SEQ ID NO. 121, SEQ ID NO. 123, SEQ ID NO.
125, SEQ ID NO. 127, SEQ ID NO. 129, SEQ ID NO. 131, SEQ ID NO.
133, SEQ ID NO. 135, SEQ ID NO. 137, SEQ ID NO. 139, SEQ ID NO.
141, SEQ ID NO. 143, SEQ ID NO. 145, SEQ ID NO. 147, SEQ ID NO.
149, SEQ ID NO. 151, SEQ ID NO. 153, SEQ ID NO. 155, SEQ ID NO.
157, SEQ ID NO. 159, SEQ ID NO. 161, SEQ ID NO. 163, SEQ ID NO.
165, SEQ ID NO. 167, SEQ ID NO. 169, SEQ ID NO. 171, SEQ ID NO.
173, SEQ ID NO. 175, SEQ ID NO. 177, SEQ ID NO. 179, SEQ ID NO.
181, SEQ ID NO. 183, SEQ ID NO. 185, SEQ ID NO. 187, SEQ ID NO.
189, SEQ ID NO. 191, SEQ ID NO. 193, SEQ ID NO. 195, SEQ ID NO.
197, SEQ ID NO. 199, SEQ ID NO. 201, SEQ ID NO. 203, SEQ ID NO.
205, SEQ ID NO. 207, SEQ ID NO. 209, SEQ ID NO. 211, SEQ ID NO.
213, SEQ ID NO. 215, SEQ ID NO. 217, SEQ ID NO. 219, SEQ ID NO.
221, SEQ ID NO. 223, SEQ ID NO. 225, SEQ ID NO. 227, SEQ ID NO.
229, SEQ ID NO. 231, SEQ ID NO. 233, SEQ ID NO. 235, SEQ ID NO.
237, SEQ ID NO. 239, SEQ ID NO. 241, and combinations thereof, and
that has a light chain variable domain sequence that is at least
95% identical to the amino acid sequences selected from the group
consisting of SEQ ID NO. 2, SEQ ID NO. 4, SEQ ID NO. 6, SEQ ID NO.
8, SEQ ID NO. 10, SEQ ID NO. 12, SEQ ID NO. 14, SEQ ID NO. 16, SEQ
ID NO. 18, SEQ ID NO. 20, SEQ ID NO. 22, SEQ ID NO. 24, SEQ ID NO.
26, SEQ ID NO. 28, SEQ ID NO. 30, SEQ ID NO. 32, SEQ ID NO. 34, SEQ
ID NO. 36, SEQ ID NO. 38, SEQ ID NO. 40, SEQ ID NO. 42, SEQ ID NO.
44, SEQ ID NO. 46, SEQ ID NO. 48, SEQ ID NO. 50, SEQ ID NO. 52, SEQ
ID NO. 54, SEQ ID NO. 56, SEQ ID NO. 58, SEQ ID NO. 60, SEQ ID NO.
62, SEQ ID NO. 64, SEQ ID NO. 66, SEQ ID NO. 68, SEQ ID NO. 70, SEQ
ID NO. 72, SEQ ID NO. 74, SEQ ID NO. 76, SEQ ID NO. 78, SEQ ID NO.
80, SEQ ID NO. 82, SEQ ID NO. 84, SEQ ID NO. 86, SEQ ID NO. 88, SEQ
ID NO. 90, SEQ ID NO. 92, SEQ ID NO. 94, SEQ ID NO. 96, SEQ ID NO.
98, SEQ ID NO. 100, SEQ ID NO. 102, SEQ ID NO. 104, SEQ ID NO. 106,
SEQ ID NO. 108, SEQ ID NO. 110, SEQ ID NO. 112, SEQ ID NO. 114, SEQ
ID NO. 116, SEQ ID NO. 118, SEQ ID NO. 120, SEQ ID NO. 122, SEQ ID
NO. 124, SEQ ID NO. 126, SEQ ID NO. 128, SEQ ID NO. 130, SEQ ID NO.
132, SEQ ID NO. 134, SEQ ID NO. 136, SEQ ID NO. 138, SEQ ID NO.
140, SEQ ID NO. 142, SEQ ID NO. 144, SEQ ID NO. 146, SEQ ID NO.
148, SEQ ID NO. 150, SEQ ID NO. 152, SEQ ID NO. 154, SEQ ID NO.
156, SEQ ID NO. 158, SEQ ID NO. 160, SEQ ID NO. 162, SEQ ID NO.
164, SEQ ID NO. 166, SEQ ID NO. 168, SEQ ID NO. 170, SEQ ID NO.
172, SEQ ID NO. 174, SEQ ID NO. 176, SEQ ID NO. 178, SEQ ID NO.
180, SEQ ID NO. 182, SEQ ID NO. 184, SEQ ID NO. 186, SEQ ID NO.
188, SEQ ID NO. 190, SEQ ID NO. 192, SEQ ID NO. 194, SEQ ID NO.
196, SEQ ID NO. 198, SEQ ID NO. 200, SEQ ID NO. 202, SEQ ID NO.
204, SEQ ID NO. 206, SEQ ID NO. 208, SEQ ID NO. 210, SEQ ID NO.
212, SEQ ID NO. 214, SEQ ID NO. 216, SEQ ID NO. 218, SEQ ID NO.
220, SEQ ID NO. 222, SEQ ID NO. 224, SEQ ID NO. 226, SEQ ID NO.
228, SEQ ID NO. 230, SEQ ID NO. 232, SEQ ID NO. 234, SEQ ID NO.
236, SEQ ID NO. 238, SEQ ID NO. 240, SEQ ID NO. 242, and
combinations thereof;
[0011] wherein the Fab fully human antibody fragment has the heavy
chain variable domain sequence that is at least 95% identical to
the amino acid sequences selected from the group consisting of SEQ
ID NO. 1, SEQ ID NO. 3, SEQ ID NO. 5, SEQ ID NO. 7, SEQ ID NO. 9,
SEQ ID NO. 11, SEQ ID NO. 13, SEQ ID NO. 15, SEQ ID NO. 17, SEQ ID
NO. 19, SEQ ID NO. 21, SEQ ID NO. 23, SEQ ID NO. 25, SEQ ID NO. 27,
SEQ ID NO. 29, SEQ ID NO. 31, SEQ ID NO. 33, SEQ ID NO. 35, SEQ ID
NO. 37, SEQ ID NO. 39, SEQ ID NO. 41, SEQ ID NO. 43, SEQ ID NO. 45,
SEQ ID NO. 47, SEQ ID NO. 49, SEQ ID NO. 51, SEQ ID NO. 53, SEQ ID
NO. 55, SEQ ID NO. 57, SEQ ID NO. 59, SEQ ID NO. 61, SEQ ID NO. 63,
SEQ ID NO. 65, SEQ ID NO. 67, SEQ ID NO. 69, SEQ ID NO. 71, SEQ ID
NO. 73, SEQ ID NO. 75, SEQ ID NO. 77, SEQ ID NO. 79, SEQ ID NO. 81,
SEQ ID NO. 83, SEQ ID NO. 85, SEQ ID NO. 87, SEQ ID NO. 89, SEQ ID
NO. 91, SEQ ID NO. 93, SEQ ID NO. 95, SEQ ID NO. 97, SEQ ID NO. 99,
SEQ ID NO. 101, SEQ ID NO. 103, SEQ ID NO. 105, SEQ ID NO. 107, SEQ
ID NO. 109, SEQ ID NO. 111, SEQ ID NO. 113, SEQ ID NO. 115, SEQ ID
NO. 117, SEQ ID NO. 119, SEQ ID NO. 121, SEQ ID NO. 123, SEQ ID NO.
125, SEQ ID NO. 127, SEQ ID NO. 129, SEQ ID NO. 131, SEQ ID NO.
133, SEQ ID NO. 135, SEQ ID NO. 137, SEQ ID NO. 139, SEQ ID NO.
141, SEQ ID NO. 143, SEQ ID NO. 145, SEQ ID NO. 147, SEQ ID NO.
149, SEQ ID NO. 151, SEQ ID NO. 153, SEQ ID NO. 155, SEQ ID NO.
157, SEQ ID NO. 159, SEQ ID NO. 161, SEQ ID NO. 163, SEQ ID NO.
165, SEQ ID NO. 167, SEQ ID NO. 169, SEQ ID NO. 171, SEQ ID NO.
173, SEQ ID NO. 175, SEQ ID NO. 177, SEQ ID NO. 179, SEQ ID NO.
181, SEQ ID NO. 183, SEQ ID NO. 185, SEQ ID NO. 187, SEQ ID NO.
189, SEQ ID NO. 191, SEQ ID NO. 193, SEQ ID NO. 195, SEQ ID NO.
197, SEQ ID NO. 199, SEQ ID NO. 201, SEQ ID NO. 203, SEQ ID NO.
205, SEQ ID NO. 207, SEQ ID NO. 209, SEQ ID NO. 211, SEQ ID NO.
213, SEQ ID NO. 215, SEQ ID NO. 217, SEQ ID NO. 219, SEQ ID NO.
221, SEQ ID NO. 223, SEQ ID NO. 225, SEQ ID NO. 227, SEQ ID NO.
229, SEQ ID NO. 231, SEQ ID NO. 233, SEQ ID NO. 235, SEQ ID NO.
237, SEQ ID NO. 239, SEQ ID NO. 241, and combinations thereof, and
that has the light chain variable domain sequence that is at least
95% identical to the amino acid sequences selected from the group
consisting of SEQ ID NO. 2, SEQ ID NO. 4, SEQ ID NO. 6, SEQ ID NO.
8, SEQ ID NO. 10, SEQ ID NO. 12, SEQ ID NO. 14, SEQ ID NO. 16, SEQ
ID NO. 18, SEQ ID NO. 20, SEQ ID NO. 22, SEQ ID NO. 24, SEQ ID NO.
26, SEQ ID NO. 28, SEQ ID NO. 30, SEQ ID NO. 32, SEQ ID NO. 34, SEQ
ID NO. 36, SEQ ID NO. 38, SEQ ID NO. 40, SEQ ID NO. 42, SEQ ID NO.
44, SEQ ID NO. 46, SEQ ID NO. 48, SEQ ID NO. 50, SEQ ID NO. 52, SEQ
ID NO. 54, SEQ ID NO. 56, SEQ ID NO. 58, SEQ ID NO. 60, SEQ ID NO.
62, SEQ ID NO. 64, SEQ ID NO. 66, SEQ ID NO. 68, SEQ ID NO. 70, SEQ
ID NO. 72, SEQ ID NO. 74, SEQ ID NO. 76, SEQ ID NO. 78, SEQ ID NO.
80, SEQ ID NO. 82, SEQ ID NO. 84, SEQ ID NO. 86, SEQ ID NO. 88, SEQ
ID NO. 90, SEQ ID NO. 92, SEQ ID NO. 94, SEQ ID NO. 96, SEQ ID NO.
98, SEQ ID NO. 100, SEQ ID NO. 102, SEQ ID NO. 104, SEQ ID NO. 106,
SEQ ID NO. 108, SEQ ID NO. 110, SEQ ID NO. 112, SEQ ID NO. 114, SEQ
ID NO. 116, SEQ ID NO. 118, SEQ ID NO. 120, SEQ ID NO. 122, SEQ ID
NO. 124, SEQ ID NO. 126, SEQ ID NO. 128, SEQ ID NO. 130, SEQ ID NO.
132, SEQ ID NO. 134, SEQ ID NO. 136, SEQ ID NO. 138, SEQ ID NO.
140, SEQ ID NO. 142, SEQ ID NO. 144, SEQ ID NO. 146, SEQ ID NO.
148, SEQ ID NO. 150, SEQ ID NO. 152, SEQ ID NO. 154, SEQ ID NO.
156, SEQ ID NO. 158, SEQ ID NO. 160, SEQ ID NO. 162, SEQ ID NO.
164, SEQ ID NO. 166, SEQ ID NO. 168, SEQ ID NO. 170, SEQ ID NO.
172, SEQ ID NO. 174, SEQ ID NO. 176, SEQ ID NO. 178, SEQ ID NO.
180, SEQ ID NO. 182, SEQ ID NO. 184, SEQ ID NO. 186, SEQ ID NO.
188, SEQ ID NO. 190, SEQ ID NO. 192, SEQ ID NO. 194, SEQ ID NO.
196, SEQ ID NO. 198, SEQ ID NO. 200, SEQ ID NO. 202, SEQ ID NO.
204, SEQ ID NO. 206, SEQ ID NO. 208, SEQ ID NO. 210, SEQ ID NO.
212, SEQ ID NO. 214, SEQ ID NO. 216, SEQ ID NO. 218, SEQ ID NO.
220, SEQ ID NO. 222, SEQ ID NO. 224, SEQ ID NO. 226, SEQ ID NO.
228, SEQ ID NO. 230, SEQ ID NO. 232, SEQ ID NO. 234, SEQ ID NO.
236, SEQ ID NO. 238, SEQ ID NO. 240, SEQ ID NO. 242, and
combinations thereof; and
[0012] wherein the single chain human antibody has the heavy chain
variable domain sequence that is at least 95% identical to the
amino acid sequences selected from the group consisting of SEQ ID
NO. 1, SEQ ID NO. 3, SEQ ID NO. 5, SEQ ID NO. 7, SEQ ID NO. 9, SEQ
ID NO. 11, SEQ ID NO. 13, SEQ ID NO. 15, SEQ ID NO. 17, SEQ ID NO.
19, SEQ ID NO. 21, SEQ ID NO. 23, SEQ ID NO. 25, SEQ ID NO. 27, SEQ
ID NO. 29, SEQ ID NO. 31, SEQ ID NO. 33, SEQ ID NO. 35, SEQ ID NO.
37, SEQ ID NO. 39, SEQ ID NO. 41, SEQ ID NO. 43, SEQ ID NO. 45, SEQ
ID NO. 47, SEQ ID NO. 49, SEQ ID NO. 51, SEQ ID NO. 53, SEQ ID NO.
55, SEQ ID NO. 57, SEQ ID NO. 59, SEQ ID NO. 61, SEQ ID NO. 63, SEQ
ID NO. 65, SEQ ID NO. 67, SEQ ID NO. 69, SEQ ID NO. 71, SEQ ID NO.
73, SEQ ID NO. 75, SEQ ID NO. 77, SEQ ID NO. 79, SEQ ID NO. 81, SEQ
ID NO. 83, SEQ ID NO. 85, SEQ ID NO. 87, SEQ ID NO. 89, SEQ ID NO.
91, SEQ ID NO. 93, SEQ ID NO. 95, SEQ ID NO. 97, SEQ ID NO. 99, SEQ
ID NO. 101, SEQ ID NO. 103, SEQ ID NO. 105, SEQ ID NO. 107, SEQ ID
NO. 109, SEQ ID NO. 111, SEQ ID NO. 113, SEQ ID NO. 115, SEQ ID NO.
117, SEQ ID NO. 119, SEQ ID NO. 121, SEQ ID NO. 123, SEQ ID NO.
125, SEQ ID NO. 127, SEQ ID NO. 129, SEQ ID NO. 131, SEQ ID NO.
133, SEQ ID NO. 135, SEQ ID NO. 137, SEQ ID NO. 139, SEQ ID NO.
141, SEQ ID NO. 143, SEQ ID NO. 145, SEQ ID NO. 147, SEQ ID NO.
149, SEQ ID NO. 151, SEQ ID NO. 153, SEQ ID NO. 155, SEQ ID NO.
157, SEQ ID NO. 159, SEQ ID NO. 161, SEQ ID NO. 163, SEQ ID NO.
165, SEQ ID NO. 167, SEQ ID NO. 169, SEQ ID NO. 171, SEQ ID NO.
173, SEQ ID NO. 175, SEQ ID NO. 177, SEQ ID NO. 179, SEQ ID NO.
181, SEQ ID NO. 183, SEQ ID NO. 185, SEQ ID NO. 187, SEQ ID NO.
189, SEQ ID NO. 191, SEQ ID NO. 193, SEQ ID NO. 195, SEQ ID NO.
197, SEQ ID NO. 199, SEQ ID NO. 201, SEQ ID NO. 203, SEQ ID NO.
205, SEQ ID NO. 207, SEQ ID NO. 209, SEQ ID NO. 211, SEQ ID NO.
213, SEQ ID NO. 215, SEQ ID NO. 217, SEQ ID NO. 219, SEQ ID NO.
221, SEQ ID NO. 223, SEQ ID NO. 225, SEQ ID NO. 227, SEQ ID NO.
229, SEQ ID NO. 231, SEQ ID NO. 233, SEQ ID NO. 235, SEQ ID NO.
237, SEQ ID NO. 239, SEQ ID NO. 241, and combinations thereof, and
that has the light chain variable domain sequence that is at least
95% identical to the amino acid sequences selected from the group
consisting of SEQ ID NO. 2, SEQ ID NO. 4, SEQ ID NO. 6, SEQ ID NO.
8, SEQ ID NO. 10, SEQ ID NO. 12, SEQ ID NO. 14, SEQ ID NO. 16, SEQ
ID NO. 18, SEQ ID NO. 20, SEQ ID NO. 22, SEQ ID NO. 24, SEQ ID NO.
26, SEQ ID NO. 28, SEQ ID NO. 30, SEQ ID NO. 32, SEQ ID NO. 34, SEQ
ID NO. 36, SEQ ID NO. 38, SEQ ID NO. 40, SEQ ID NO. 42, SEQ ID NO.
44, SEQ ID NO. 46, SEQ ID NO. 48, SEQ ID NO. 50, SEQ ID NO. 52, SEQ
ID NO. 54, SEQ ID NO. 56, SEQ ID NO. 58, SEQ ID NO. 60, SEQ ID NO.
62, SEQ ID NO. 64, SEQ ID NO. 66, SEQ ID NO. 68, SEQ ID NO. 70, SEQ
ID NO. 72, SEQ ID NO. 74, SEQ ID NO. 76, SEQ ID NO. 78, SEQ ID NO.
80, SEQ ID NO. 82, SEQ ID NO. 84, SEQ ID NO. 86, SEQ ID NO. 88, SEQ
ID NO. 90, SEQ ID NO. 92, SEQ ID NO. 94, SEQ ID NO. 96, SEQ ID NO.
98, SEQ ID NO. 100, SEQ ID NO. 102, SEQ ID NO. 104, SEQ ID NO. 106,
SEQ ID NO. 108, SEQ ID NO. 110, SEQ ID NO. 112, SEQ ID NO. 114, SEQ
ID NO. 116, SEQ ID NO. 118, SEQ ID NO. 120, SEQ ID NO. 122, SEQ ID
NO. 124, SEQ ID NO. 126, SEQ ID NO. 128, SEQ ID NO. 130, SEQ ID NO.
132, SEQ ID NO. 134, SEQ ID NO. 136, SEQ ID NO. 138, SEQ ID NO.
140, SEQ ID NO. 142, SEQ ID NO. 144, SEQ ID NO. 146, SEQ ID NO.
148, SEQ ID NO. 150, SEQ ID NO. 152, SEQ ID NO. 154, SEQ ID NO.
156, SEQ ID NO. 158, SEQ ID NO. 160, SEQ ID NO. 162, SEQ ID NO.
164, SEQ ID NO. 166, SEQ ID NO. 168, SEQ ID NO. 170, SEQ ID NO.
172, SEQ ID NO. 174, SEQ ID NO. 176, SEQ ID NO. 178, SEQ ID NO.
180, SEQ ID NO. 182, SEQ ID NO. 184, SEQ ID NO. 186, SEQ ID NO.
188, SEQ ID NO. 190, SEQ ID NO. 192, SEQ ID NO. 194, SEQ ID NO.
196, SEQ ID NO. 198, SEQ ID NO. 200, SEQ ID NO. 202, SEQ ID NO.
204, SEQ ID NO. 206, SEQ ID NO. 208, SEQ ID NO. 210, SEQ ID NO.
212, SEQ ID NO. 214, SEQ ID NO. 216, SEQ ID NO. 218, SEQ ID NO.
220, SEQ ID NO. 222, SEQ ID NO. 224, SEQ ID NO. 226, SEQ ID NO.
228, SEQ ID NO. 230, SEQ ID NO. 232, SEQ ID NO. 234, SEQ ID NO.
236, SEQ ID NO. 238, SEQ ID NO. 240, SEQ ID NO. 242, and
combinations thereof.
Preferably, the fully human antibody has both a heavy chain and a
light chain wherein the antibody has a heavy chain/light chain
variable domain sequence selected from the group consisting of SEQ
ID NO. 1/SEQ ID NO. 2 (called E6 herein), SEQ ID NO. 3/SEQ ID NO. 4
(called E7 herein), SEQ ID NO. 5/SEQ ID NO. 6 (called E9 herein),
SEQ ID NO. 7/SEQ ID NO. 8 (called E11 herein), SEQ ID NO. 9/SEQ ID
NO. 10 (called F1 herein), SEQ ID NO. 11/SEQ ID NO. 12 (called F4
herein), SEQ ID NO. 13/SEQ ID NO. 14 (called F7 herein), SEQ ID NO.
15/SEQ ID NO. 16 (called F8 herein), SEQ ID NO. 17/SEQ ID NO. 18
(called F11 herein), SEQ ID NO. 19/SEQ ID NO. 20 (called G4
herein), SEQ ID NO. 21/SEQ ID NO. 22 (called G9 herein), SEQ ID NO.
23/SEQ ID NO. 24 (called G11 herein), SEQ ID NO. 25/SEQ ID NO. 26
(called G12 herein), SEQ ID NO. 27/SEQ ID NO. 28 (called H1
herein), SEQ ID NO. 29/SEQ ID NO. 30 (called H3 herein), SEQ ID NO.
31/SEQ ID NO. 32 (called H4 herein), SEQ ID NO. 33/SEQ ID NO. 34
(called H5 herein), SEQ ID NO. 35/SEQ ID NO. 36 (called H6 herein),
SEQ ID NO. 37/SEQ ID NO. 38 (called H10 herein), SEQ ID NO. 39/SEQ
ID NO. 40 (called H12 herein), SEQ ID NO. 41/SEQ ID NO. 42 (called
PDL-D2 herein), SEQ ID NO. 43/SEQ ID NO. 44 (called PDL-D11
herein), SEQ ID NO. 45/SEQ ID NO. 46 (called PDL-H1 herein), SEQ ID
NO. 47/SEQ ID NO. 48 (called RB4 herein), SEQ ID NO. 49/SEQ ID NO.
50 (called RB11 herein), SEQ ID NO. 51/SEQ ID NO. 52 (called RC5
herein), SEQ ID NO. 53/SEQ ID NO. 54 (called RF5 herein), SEQ ID
NO. 55/SEQ ID NO. 56 (called RG9 herein), SEQ ID NO. 57/SEQ ID NO.
58 (called RD1 herein), SEQ ID NO. 59/SEQ ID NO. 60 (called RF11
herein), SEQ ID NO. 61/SEQ ID NO. 62 (called RH11 herein), SEQ ID
NO. 63/SEQ ID NO. 64 (called RD9 herein), SEQ ID NO. 65/SEQ ID NO.
66 (called RE10 herein), SEQ ID NO. 67/SEQ ID NO. 68 (called RA3
herein), SEQ ID NO. 69/SEQ ID NO. 70 (called RG1 herein), SEQ ID
NO. 71/SEQ ID NO. 72 (called RB1 herein), SEQ ID NO. 73/SEQ ID NO.
74 (called RG7 herein), SEQ ID NO. 75/SEQ ID NO. 76 (called RA6
herein), SEQ ID NO. 77/SEQ ID NO. 78 (called RA8 herein), SEQ ID
NO. 79/SEQ ID NO. 80 (called RA9 herein), SEQ ID NO. 81/SEQ ID NO.
82 (called RB5 herein), SEQ ID NO. 83/SEQ ID NO. 84 (called RB8
herein), SEQ ID NO. 85/SEQ ID NO. 86 (called RC8 herein), SEQ ID
NO. 87/SEQ ID NO. 88 (called RC10 herein), SEQ ID NO. 89/SEQ ID NO.
90 (called RD2 herein), SEQ ID NO. 91/SEQ ID NO. 92 (called RE8
herein), SEQ ID NO. 93/SEQ ID NO. 94 (called RE9 herein), SEQ ID
NO. 95/SEQ ID NO. 96 (called RG12 herein), SEQ ID NO. 97/SEQ ID NO.
98 (called RSA1 herein), SEQ ID NO. 99/SEQ ID NO. 100 (called R2A7
herein), SEQ ID NO. 101/SEQ ID NO. 102 (called R2B12 herein), SEQ
ID NO. 103/SEQ ID NO. 104 (called R2C9 herein), SEQ ID NO. 105/SEQ
ID NO. 106 (called R2D5 herein), SEQ ID NO. 107/SEQ ID NO. 108
(called R2D7 herein), SEQ ID NO. 109/SEQ ID NO. 110 (called R2F4
herein), SEQ ID NO. 111/SEQ ID NO. 112 (called R2A10 herein), SEQ
ID NO. 113/SEQ ID NO. 114 (called R2E2 herein), SEQ ID NO. 115/SEQ
ID NO. 116 (called R3B8 herein), SEQ ID NO. 117/SEQ ID NO. 118
(called R3C3 herein), SEQ ID NO. 119/SEQ ID NO. 120 (called R3E9
herein), SEQ ID NO. 121/SEQ ID NO. 122 (called R3E10 herein), SEQ
ID NO. 123/SEQ ID NO. 124 (called R3F7 herein), SEQ ID NO. 125/SEQ
ID NO. 126 (called R3F10 herein), SEQ ID NO. 127/SEQ ID NO. 128
(called R4B10 herein), SEQ ID NO. 129/SEQ ID NO. 130 (called R4H1
herein), SEQ ID NO. 131/SEQ ID NO. 132 (called R4A11 herein), SEQ
ID NO. 133/SEQ ID NO. 134 (called R3D2 herein), SEQ ID NO. 135/SEQ
ID NO. 136 (called R5B8 herein), SEQ ID NO. 137/SEQ ID NO. 138
(called SH1A1Q herein), SEQ ID NO. 139/SEQ ID NO. 140 (called
SH1B7B(K) herein), SEQ ID NO. 141/SEQ ID NO. 142 (called SH1C1
herein), SEQ ID NO. 143/SEQ ID NO. 144 (called SH1C8 herein), SEQ
ID NO. 145/SEQ ID NO. 146 (called SH1E10 herein), SEQ ID NO.
147/SEQ ID NO. 148 (called SH1E2 herein), SEQ ID NO. 149/SEQ ID NO.
150 (called SH1A9 herein), SEQ ID NO. 151/SEQ ID NO. 152 (called
SH1B11 herein), SEQ ID NO. 153/SEQ ID NO. 154 (called SH1E4
herein), SEQ ID NO. 155/SEQ ID NO. 156 (called SH1B3 herein), SEQ
ID NO. 157/SEQ ID NO. 158 (called SH1D1 herein), SEQ ID NO. 159/SEQ
ID NO. 160 (called SH1D2 herein), SEQ ID NO. 161/SEQ ID NO. 162
(called SH1D12 herein), SEQ ID NO. 163/SEQ ID NO. 164 (called SH1E1
herein), SEQ ID NO. 165/SEQ ID NO. 166 (called SH1G9 herein), SEQ
ID NO. 167/SEQ ID NO. 168 (called SH1A11 herein), SEQ ID NO.
169/SEQ ID NO. 170 (called SH1C2 herein), SEQ ID NO. 171/SEQ ID NO.
172 (called SH1G8 herein), SEQ ID NO. 173/SEQ ID NO. 174 (called
SH1H2 herein), SEQ ID NO. 175/SEQ ID NO. 176 (called SH1B10
herein), SEQ ID NO. 177/SEQ ID NO. 178 (called SH1B7A(L) herein),
SEQ ID NO. 179/SEQ ID NO. 180 (called SH1E6 herein), SEQ ID NO.
181/SEQ ID NO. 182 (called SH1C11 herein), SEQ ID NO. 183/SEQ ID
NO. 184 (called SH1A2 herein), SEQ ID NO. 185/SEQ ID NO. 186
(called SH1B1 herein), SEQ ID NO. 187/SEQ ID NO. 188 (called R6B2
herein), SEQ ID NO. 189/SEQ ID NO. 190 (called R6B7 herein), SEQ ID
NO. 191/SEQ ID NO. 192 (called R6B11 herein), SEQ ID NO. 193/SEQ ID
NO. 194 (called R6D1 herein), SEQ ID NO. 195/SEQ ID NO. 196 (called
R6C8 herein), SEQ ID NO. 197/SEQ ID NO. 198 (called R9G8 herein),
SEQ ID NO. 199/SEQ ID NO. 200 (called R7D1 herein), SEQ ID NO.
201/SEQ ID NO. 202 (called R7D2 herein), SEQ ID NO. 203/SEQ ID NO.
204 (called R7E7 herein), SEQ ID NO. 205/SEQ ID NO. 206 (called
R7F2 herein), SEQ ID NO. 207/SEQ ID NO. 208 (called R7F7 herein),
SEQ ID NO. 209/SEQ ID NO. 210 (called R9H2 herein), SEQ ID NO.
211/SEQ ID NO. 212 (called R9H6 herein), SEQ ID NO. 213/SEQ ID NO.
214 (called H6B1L herein), SEQ ID NO. 215/SEQ ID NO. 216 (called
H6A1 herein), SEQ ID NO. 217/SEQ ID NO. 218 (called H6B1 herein),
SEQ ID NO. 219/SEQ ID NO. 220 (called H6B2 herein), SEQ ID NO.
221/SEQ ID NO. 222 (called H19C herein), SEQ ID NO. 223/SEQ ID NO.
224 (called H110D herein), SEQ ID NO. 225/SEQ ID NO. 226 (called
H11F herein), SEQ ID NO. 227/SEQ ID NO. 228 (called H1C1 herein),
SEQ ID NO. 229/SEQ ID NO. 230 (called GPG1A2 herein), SEQ ID NO.
231/SEQ ID NO. 232 (called GPGG8 herein), SEQ ID NO. 233/SEQ ID NO.
234 (called GPGG10 herein), SEQ ID NO. 235/SEQ ID NO. 236 (called
GPGH7 herein), SEQ ID NO. 237/SEQ ID NO. 238 (called GPGH10
herein), SEQ ID NO. 239/SEQ ID NO. 240 (called GPGH11 herein), SEQ
ID NO. 241/SEQ ID NO. 242 (called GPGH10P herein), and combinations
thereof. Preferably, the fully human antibody Fab fragment has both
a heavy chain variable domain region and a light chain variable
domain region wherein the antibody has a heavy chain/light chain
variable domain sequence selected from the group consisting of SEQ
ID NO. 1/SEQ ID NO. 2 (called E6 herein), SEQ ID NO. 3/SEQ ID NO. 4
(called E7 herein), SEQ ID NO. 5/SEQ ID NO. 6 (called E9 herein),
SEQ ID NO. 7/SEQ ID NO. 8 (called E11 herein), SEQ ID NO. 9/SEQ ID
NO. 10 (called F1 herein), SEQ ID NO. 11/SEQ ID NO. 12 (called F4
herein), SEQ ID NO. 13/SEQ ID NO. 14 (called F7 herein), SEQ ID NO.
15/SEQ ID NO. 16 (called F8 herein), SEQ ID NO. 17/SEQ ID NO. 18
(called F11 herein), SEQ ID NO. 19/SEQ ID NO. 20 (called G4
herein), SEQ ID NO. 21/SEQ ID NO. 22 (called G9 herein), SEQ ID NO.
23/SEQ ID NO. 24 (called G11 herein), SEQ ID NO. 25/SEQ ID NO. 26
(called G12 herein), SEQ ID NO. 27/SEQ ID NO. 28 (called H1
herein), SEQ ID NO. 29/SEQ ID NO. 30 (called H3 herein), SEQ ID NO.
31/SEQ ID NO. 32 (called H4 herein), SEQ ID NO. 33/SEQ ID NO. 34
(called H5 herein), SEQ ID NO. 35/SEQ ID NO. 36 (called H6 herein),
SEQ ID NO. 37/SEQ ID NO. 38 (called H10 herein), SEQ ID NO. 39/SEQ
ID NO. 40 (called H12 herein), SEQ ID NO. 41/SEQ ID NO. 42 (called
PDL-D2 herein), SEQ ID NO. 43/SEQ ID NO. 44 (called PDL-D11
herein), SEQ ID NO. 45/SEQ ID NO. 46 (called PDL-H1 herein), SEQ ID
NO. 47/SEQ ID NO. 48 (called RB4 herein), SEQ ID NO. 49/SEQ ID NO.
50 (called RB11 herein), SEQ ID NO. 51/SEQ ID NO. 52 (called RC5
herein), SEQ ID NO. 53/SEQ ID NO. 54 (called RF5 herein), SEQ ID
NO. 55/SEQ ID NO. 56 (called RG9 herein), SEQ ID NO. 57/SEQ ID NO.
58 (called RD1 herein), SEQ ID NO. 59/SEQ ID NO. 60 (called RF11
herein), SEQ ID NO. 61/SEQ ID NO. 62 (called RH11 herein), SEQ ID
NO. 63/SEQ ID NO. 64 (called RD9 herein), SEQ ID NO. 65/SEQ ID NO.
66 (called RE10 herein), SEQ ID NO. 67/SEQ ID NO. 68 (called RA3
herein), SEQ ID NO. 69/SEQ ID NO. 70 (called RG1 herein), SEQ ID
NO. 71/SEQ ID NO. 72 (called RB1 herein), SEQ ID NO. 73/SEQ ID NO.
74 (called RG7 herein), SEQ ID NO. 75/SEQ ID NO. 76 (called RA6
herein), SEQ ID NO. 77/SEQ ID NO. 78 (called RA8 herein), SEQ ID
NO. 79/SEQ ID NO. 80 (called RA9 herein), SEQ ID NO. 81/SEQ ID NO.
82 (called RB5 herein), SEQ ID NO. 83/SEQ ID NO. 84 (called RB8
herein), SEQ ID NO. 85/SEQ ID NO. 86 (called RC8 herein), SEQ ID
NO. 87/SEQ ID NO. 88 (called RC10 herein), SEQ ID NO. 89/SEQ ID NO.
90 (called RD2 herein), SEQ ID NO. 91/SEQ ID NO. 92 (called RE8
herein), SEQ ID NO. 93/SEQ ID NO. 94 (called RE9 herein), SEQ ID
NO. 95/SEQ ID NO. 96 (called RG12 herein), SEQ ID NO. 97/SEQ ID NO.
98 (called RSA1 herein), SEQ ID NO. 99/SEQ ID NO. 100 (called R2A7
herein), SEQ ID NO. 101/SEQ ID NO. 102 (called R2B12 herein), SEQ
ID NO. 103/SEQ ID NO. 104 (called R2C9 herein), SEQ ID NO. 105/SEQ
ID NO. 106 (called R2D5 herein), SEQ ID NO. 107/SEQ ID NO. 108
(called R2D7 herein), SEQ ID NO. 109/SEQ ID NO. 110 (called R2F4
herein), SEQ ID NO. 111/SEQ ID NO. 112 (called R2A10 herein), SEQ
ID NO. 113/SEQ ID NO. 114 (called R2E2 herein), SEQ ID NO. 115/SEQ
ID NO. 116 (called R3B8 herein), SEQ ID NO. 117/SEQ ID NO. 118
(called R3C3 herein), SEQ ID NO. 119/SEQ ID NO. 120 (called R3E9
herein), SEQ ID NO. 121/SEQ ID NO. 122 (called R3E10 herein), SEQ
ID NO. 123/SEQ ID NO. 124 (called R3F7 herein), SEQ ID NO. 125/SEQ
ID NO. 126 (called R3F10 herein), SEQ ID NO. 127/SEQ ID NO. 128
(called R4B10 herein), SEQ ID NO. 129/SEQ ID NO. 130 (called R4H1
herein), SEQ ID NO. 131/SEQ ID NO. 132 (called R4A11 herein), SEQ
ID NO. 133/SEQ ID NO. 134 (called R3D2 herein), SEQ ID NO. 135/SEQ
ID NO. 136 (called R5B8 herein), SEQ ID NO. 137/SEQ ID NO. 138
(called SH1A1Q herein), SEQ ID NO. 139/SEQ ID NO. 140 (called
SH1B7B(K) herein), SEQ ID NO. 141/SEQ ID NO. 142 (called SH1C1
herein), SEQ ID NO. 143/SEQ ID NO. 144 (called SH1C8 herein), SEQ
ID NO. 145/SEQ ID NO. 146 (called SH1E10 herein), SEQ ID NO.
147/SEQ ID NO. 148 (called SH1E2 herein), SEQ ID NO. 149/SEQ ID NO.
150 (called SH1A9 herein), SEQ ID NO. 151/SEQ ID NO. 152 (called
SH1B11 herein), SEQ ID NO. 153/SEQ ID NO. 154 (called SH1E4
herein), SEQ ID NO. 155/SEQ ID NO. 156 (called SH1B3 herein), SEQ
ID NO. 157/SEQ ID NO. 158 (called SH1D1 herein), SEQ ID NO. 159/SEQ
ID NO. 160 (called SH1D2 herein), SEQ ID NO. 161/SEQ ID NO. 162
(called SH1D12 herein), SEQ ID NO. 163/SEQ ID NO. 164 (called SH1E1
herein), SEQ ID NO. 165/SEQ ID NO. 166 (called SH1G9 herein), SEQ
ID NO. 167/SEQ ID NO. 168 (called SH1A11 herein), SEQ ID NO.
169/SEQ ID NO. 170 (called SH1C2 herein), SEQ ID NO. 171/SEQ ID NO.
172 (called SH1G8 herein), SEQ ID NO. 173/SEQ ID NO. 174 (called
SH1H2 herein), SEQ ID NO. 175/SEQ ID NO. 176 (called SH1B10
herein), SEQ ID NO. 177/SEQ ID NO. 178 (called SH1B7A(L) herein),
SEQ ID NO. 179/SEQ ID NO. 180 (called SH1E6 herein), SEQ ID NO.
181/SEQ ID NO. 182 (called SH1C11 herein), SEQ ID NO. 183/SEQ ID
NO. 184 (called SH1A2 herein), SEQ ID NO. 185/SEQ ID NO. 186
(called SH1B1 herein), SEQ ID NO. 187/SEQ ID NO. 188 (called R6B2
herein), SEQ ID NO. 189/SEQ ID NO. 190 (called R6B7 herein), SEQ ID
NO. 191/SEQ ID NO. 192 (called R6B11 herein), SEQ ID NO. 193/SEQ ID
NO. 194 (called R6D1 herein), SEQ ID NO. 195/SEQ ID NO. 196 (called
R6C8 herein), SEQ ID NO. 197/SEQ ID NO. 198 (called R9G8 herein),
SEQ ID NO. 199/SEQ ID NO. 200 (called R7D1 herein), SEQ ID NO.
201/SEQ ID NO. 202 (called R7D2 herein), SEQ ID NO. 203/SEQ ID NO.
204 (called R7E7 herein), SEQ ID NO. 205/SEQ ID NO. 206 (called
R7F2 herein), SEQ ID NO. 207/SEQ ID NO. 208 (called R7F7 herein),
SEQ ID NO. 209/SEQ ID NO. 210 (called R9H2 herein), SEQ ID NO.
211/SEQ ID NO. 212 (called R9H6 herein), SEQ ID NO. 213/SEQ ID NO.
214 (called H6B1L herein), SEQ ID NO. 215/SEQ ID NO. 216 (called
H6A1 herein), SEQ ID NO. 217/SEQ ID NO. 218 (called H6B1 herein),
SEQ ID NO. 219/SEQ ID NO. 220 (called H6B2 herein), SEQ ID NO.
221/SEQ ID NO. 222 (called H19C herein), SEQ ID NO. 223/SEQ ID NO.
224 (called H110D herein), SEQ ID NO. 225/SEQ ID NO. 226 (called
H11F herein), SEQ ID NO. 227/SEQ ID NO. 228 (called H1C1 herein),
SEQ ID NO. 229/SEQ ID NO. 230 (called GPG1A2 herein), SEQ ID NO.
231/SEQ ID NO. 232 (called GPGG8 herein), SEQ ID NO. 233/SEQ ID NO.
234 (called GPGG10 herein), SEQ ID NO. 235/SEQ ID NO. 236 (called
GPGH7 herein), SEQ ID NO. 237/SEQ ID NO. 238 (called GPGH10
herein), SEQ ID NO. 239/SEQ ID NO. 240 (called GPGH11 herein), SEQ
ID NO. 241/SEQ ID NO. 242 (called GPGH10P herein), and combinations
thereof. Preferably, the fully human single chain antibody has both
a heavy chain variable domain region and a light chain variable
domain region, wherein the single chain fully human antibody has a
heavy chain/light chain variable domain sequence selected from the
group consisting of SEQ ID NO. 1/SEQ ID NO. 2, SEQ ID NO. 3/SEQ ID
NO. 4, SEQ ID NO. 5/SEQ ID NO. 6, SEQ ID NO. 7/SEQ ID NO. 8, SEQ ID
NO. 9/SEQ ID NO. 10, SEQ ID NO. 11/SEQ ID NO. 12, SEQ ID NO. 13/SEQ
ID NO. 14, SEQ ID NO. 15/SEQ ID NO. 16, SEQ ID NO. 17/SEQ ID NO.
18, SEQ ID NO. 19/SEQ ID NO. 20, SEQ ID NO. 21/SEQ ID NO. 22, SEQ
ID NO. 23/SEQ ID NO. 24, SEQ ID NO. 25/SEQ ID NO. 26, SEQ ID NO.
27/SEQ ID NO. 28, SEQ ID NO. 29/SEQ ID NO. 30, SEQ ID NO. 31/SEQ ID
NO. 32, SEQ ID NO. 33/SEQ ID NO. 34, SEQ ID NO. 35/SEQ ID NO. 36,
SEQ ID NO. 37/SEQ ID NO. 38, SEQ ID NO. 39/SEQ ID NO. 40, SEQ ID
NO. 41/SEQ ID NO. 42, SEQ ID NO. 43/SEQ ID NO. 44, SEQ ID NO.
45/SEQ ID NO. 46, SEQ ID NO. 47/SEQ ID NO. 48, SEQ ID NO. 49/SEQ ID
NO. 50, SEQ ID NO. 51/SEQ ID NO. 52, SEQ ID NO. 53/SEQ ID NO. 54,
SEQ ID NO. 55/SEQ ID NO. 56, SEQ ID NO. 57/SEQ ID NO. 58, SEQ ID
NO. 59/SEQ ID NO. 60, SEQ ID NO. 61/SEQ ID NO. 62, SEQ ID NO.
63/SEQ ID NO. 64, SEQ ID NO. 65/SEQ ID NO. 66, SEQ ID NO. 67/SEQ ID
NO. 68, SEQ ID NO. 69/SEQ ID NO. 70, SEQ ID NO. 71/SEQ ID NO. 72,
SEQ ID NO. 73/SEQ ID NO. 74, SEQ ID NO. 75/SEQ ID NO. 76, SEQ ID
NO. 77/SEQ ID NO. 78, SEQ ID NO. 79/SEQ ID NO. 80, SEQ ID NO.
81/SEQ ID NO. 82, SEQ ID NO. 83/SEQ ID NO. 84, SEQ ID NO. 85/SEQ ID
NO. 86, SEQ ID NO. 87/SEQ ID NO. 88, SEQ ID NO. 89/SEQ ID NO. 90,
SEQ ID NO. 91/SEQ ID NO. 92, SEQ ID NO. 93/SEQ ID NO. 94, SEQ ID
NO. 95/SEQ ID NO. 96, SEQ ID NO. 97/SEQ ID NO. 98, SEQ ID NO.
99/SEQ ID NO. 100, SEQ ID NO. 101/SEQ ID NO. 102, SEQ ID NO.
103/SEQ ID NO. 104, SEQ ID NO. 105/SEQ ID NO. 106, SEQ ID NO.
107/SEQ ID NO. 108, SEQ ID NO. 109/SEQ ID NO. 110, SEQ ID NO.
111/SEQ ID NO. 112, SEQ ID NO. 113/SEQ ID NO. 114, SEQ ID NO.
115/SEQ ID NO. 116, SEQ ID NO. 117/SEQ ID NO. 118, SEQ ID NO.
119/SEQ ID NO. 120, SEQ ID NO. 121/SEQ ID NO. 122, SEQ ID NO.
123/SEQ ID NO. 124, SEQ ID NO. 125/SEQ ID NO. 126, SEQ ID NO.
127/SEQ ID NO. 128, SEQ ID NO. 129/SEQ ID NO. 130, SEQ ID NO.
131/SEQ ID NO. 132, SEQ ID NO. 133/SEQ ID NO. 134, SEQ ID NO.
135/SEQ ID NO. 136, SEQ ID NO. 137/SEQ ID NO. 138, SEQ ID NO.
139/SEQ ID NO. 140, SEQ ID NO. 141/SEQ ID NO. 142, SEQ ID NO.
143/SEQ ID NO. 144, SEQ ID NO. 145/SEQ ID NO. 146, SEQ ID NO.
147/SEQ ID NO. 148, SEQ ID NO. 149/SEQ ID NO. 150, SEQ ID NO.
151/SEQ ID NO. 152, SEQ ID NO. 153/SEQ ID NO. 154, SEQ ID NO.
155/SEQ ID NO. 156, SEQ ID NO. 157/SEQ ID NO. 158, SEQ ID NO.
159/SEQ ID NO. 160, SEQ ID NO. 161/SEQ ID NO. 162, SEQ ID NO.
163/SEQ ID NO. 164, SEQ ID NO. 165/SEQ ID NO. 166, SEQ ID NO.
167/SEQ ID NO. 168, SEQ ID NO. 169/SEQ ID NO. 170, SEQ ID NO.
171/SEQ ID NO. 172, SEQ ID NO. 173/SEQ ID NO. 174, SEQ ID NO.
175/SEQ ID NO. 176, SEQ ID NO. 177/SEQ ID NO. 178, SEQ ID NO.
179/SEQ ID NO. 180, SEQ ID NO. 181/SEQ ID NO. 182, SEQ ID NO.
183/SEQ ID NO. 184, SEQ ID NO. 185/SEQ ID NO. 186, SEQ ID NO.
187/SEQ ID NO. 188, SEQ ID NO. 189/SEQ ID NO. 190, SEQ ID NO.
191/SEQ ID NO. 192, SEQ ID NO. 193/SEQ ID NO. 194, SEQ ID NO.
195/SEQ ID NO. 196, SEQ ID NO. 197/SEQ ID NO. 198, SEQ ID NO.
199/SEQ ID NO. 200, SEQ ID NO. 201/SEQ ID NO. 202, SEQ ID NO.
203/SEQ ID NO. 204, SEQ ID NO. 205/SEQ ID NO. 206, SEQ ID NO.
207/SEQ ID NO. 208, SEQ ID NO. 209/SEQ ID NO. 210, SEQ ID NO.
211/SEQ ID NO. 212, SEQ ID NO. 213/SEQ ID NO. 214, SEQ ID NO.
215/SEQ ID NO. 216, SEQ ID NO. 217/SEQ ID NO. 218, SEQ ID NO.
219/SEQ ID NO. 220, SEQ ID NO. 221/SEQ ID NO. 222, SEQ ID NO.
223/SEQ ID NO. 224, SEQ ID NO. 225/SEQ ID NO. 226, SEQ ID NO.
227/SEQ ID NO. 228, SEQ ID NO. 229/SEQ ID NO. 230, SEQ ID NO.
231/SEQ ID NO. 232, SEQ ID NO. 233/SEQ ID NO. 234, SEQ ID NO.
235/SEQ ID NO. 236, SEQ ID NO. 237/SEQ ID NO. 238, SEQ ID NO.
239/SEQ ID NO. 240, SEQ ID NO. 241/SEQ ID NO. 242, and combinations
thereof.
[0014] Preferably, the broad spectrum of mammalian cancers to be
treated is selected from the group consisting of ovarian, colon,
breast, lung cancers, myelomas, neuroblastic-derived CNS tumors,
monocytic leukemias, B-cell derived leukemias, T-cell derived
leukemias, B-cell derived lymphomas, T-cell derived lymphomas, mast
cell derived tumors, and combinations thereof. Preferably, the
autoimmune disease or inflammatory disease is selected from the
group consisting of intestinal mucosal inflammation, wasting
disease associated with colitis, multiple sclerosis, systemic lupus
erythematosus, viral infections, rheumatoid arthritis,
osteoarthritis, psoriasis, Cohn's disease, and inflammatory bowel
disease.
BRIEF DESCRIPTION OF THE FIGURES
[0015] FIG. 1 shows anti-PD-L1 antibodies H6 and H10 binding to
human PD-L1 expressed on human lymphocytes and the EC.sub.50
determination in the 100 pM range
[0016] FIG. 2 shows disclosed anti-PD-L1 antibodies binding to
human lymphocytes by FACSAria analysis.
[0017] FIG. 3 shows disclosed anti-PD-L1 antibodies H1, H6 and H10
inhibit lymphocyte proliferation.
[0018] FIG. 4 shows disclosed anti-PD-L1 antibody H10 inhibit NK
cell proliferation.
[0019] FIG. 5 shows disclosed anti-PD-L1 antibodies H6 and H10
enhance cell activation and that the responsive lymphocyte
population is the NK cell.
[0020] FIG. 6 shows effect of anti-PD-L1 antibodies H6 and H10 on
the progression of disease in a murine model of multiple sclerosis
(MS)
[0021] FIG. 7 shows the results of EC50 cell binding flow cytometry
experiments, demonstrating that anti-PD-L1 antibody G12 binds the
cell surface of CHO cells transfected with full length PD-L1 in a
concentration dependent manner.
[0022] FIG. 8 shows the results of EC50 cell binding flow cytometry
experiments, demonstrating that anti-PD-L1 antibody G12 binds in a
concentration dependent manner to the cell surface of ES-2 ovarian
carcinoma cells induced with IFN.gamma. to increase the level of
PD-L1 expression on these cells.
[0023] FIG. 9 shows IC50 data for the blocking of the interaction
between recombinant human PD-1 and human PD-L1 expressed on CHO
cells by anti-PD-L1 antibody G12.
[0024] FIG. 10 shows a mixed lymphocyte reaction (MLR) to evaluate
the effect of the antibodies on lymphocyte activity in lymphocyte
effector cells. IL-2 secretion was measured in the presence or
absence of the anti-PD-L1 human monoclonal antibody. The antibodies
used were the disclosed G12 antibody as compared to prior disclosed
antibodies 10A5 and 12A4 (Bristol-Myers/Medarex) that were obtained
via in-house production from prior-disclosed antibody sequences
(U.S. Patent Application 2009/0055944 the disclosure of which is
incorporated by reference herein).
[0025] FIG. 11 shows a mixed lymphocyte reaction (MLR) was employed
to demonstrate the effect of blocking the PD-L1/PD-1 pathway by the
listed anti-PD-L1 antibodies on lymphocyte effector cells.
IFN-.gamma. secretion was measured in the presence or absence of
the anti-PD-L1 human monoclonal antibody. The antibodies used were
the disclosed G12 antibody as compared to prior disclosed antibody
10A5 (Bristol-Myers/Medarex) that was obtained via in-house
production from prior-disclosed antibody sequences (see U.S. Patent
Application 2009/0055944, the disclosure of which is incorporated
by reference herein).
[0026] FIG. 12 shows a mixed lymphocyte reaction (MLR) was employed
to evaluate the effect of the antibodies on lymphocyte activity by
the anti-PD-L1 antibodies on lymphocyte effector cells. T cell
activation was measured in the presence or absence of the
anti-PD-L1 human monoclonal antibody. The antibodies used were the
disclosed G12 antibody as compared to prior disclosed antibodies
10A5 and 12A4 (Bristol-Myers/Medarex) that were obtained via
in-house production from prior-disclosed antibody sequences (U.S.
Patent Application 2009/0055944 the disclosure of which is
incorporated by reference herein).
[0027] FIG. 13 shows a mixed lymphocyte reaction (MLR) was employed
to evaluate the effect of the antibodies on lymphocyte activity by
the anti-PD-L1 antibodies on lymphocyte effector cells. T cell
activation was measured in the presence or absence of the
anti-PD-L1 human monoclonal antibody. The antibodies used were the
disclosed H6B1L, RSA1, RA3, RC5, SH1E2, SH1E4, SH1B11, and SH1C8 as
compared to prior disclosed antibodies 10A5
(Bristol-Myers-Squibb/Medarex) and YW243.55S70 (Roche/Genentech)
that were obtained via in-house production from prior-disclosed
antibody sequences (U.S. Patent Application 2009/0055944 and U.S.
Patent Application US 2010/0203056; the disclosure of which are
incorporated by reference herein).
[0028] FIG. 14 shows a mixed lymphocyte reaction (MLR) to evaluate
the effect of the antibodies on lymphocyte activity in lymphocyte
effector cells. IL-2 secretion was measured in the presence or
absence of the anti-PD-L1 human monoclonal antibody. The antibodies
used were the disclosed H6B1L, RSA1, RA3, RC5, SH1E2, SH1E4,
SH1B11, and SH1C8 as compared to prior disclosed antibodies 10A5
(Bristol-Myers-Squibb/Medarex) and YW243.55S70 (Roche/Genentech)
that were obtained via in-house production from prior-disclosed
antibody sequences (U.S. Patent Application 2009/0055944 and U.S.
Patent Application US 2010/0203056; the disclosure of which are
incorporated by reference herein).
[0029] FIG. 15 shows a mixed lymphocyte reaction (MLR) was employed
to demonstrate the effect of blocking the PD-L1/PD-1 pathway by the
listed anti-PD-L1 antibodies on lymphocyte effector cells.
IFN-.gamma. secretion was measured in the presence or absence of
the anti-PD-L1 human monoclonal antibody. The antibodies used were
the disclosed H6B1L, RSA1, RA3, RC5, SH1E2, SH1E4, SH1B11, and
SH1C8 as compared to prior disclosed antibodies 10A5
(Bristol-Myers-Squibb/Medarex) and YW243.55S70 (Roche/Genentech)
that were obtained via in-house production from prior-disclosed
antibody sequences (U.S. Patent Application 2009/0055944 and U.S.
Patent Application US 2010/0203056; the disclosure of which are
incorporated by reference herein).
DETAILED DESCRIPTION
[0030] The present disclosure provides a fully human antibody of an
IgG class that binds to a PD-L1 epitope with a binding affinity of
10.sup.-6M or less, that has a heavy chain variable domain sequence
that is at least 95% identical to the amino acid sequences selected
from the group consisting of SEQ ID NO. 1, SEQ ID NO. 3, SEQ ID NO.
5, SEQ ID NO. 7, SEQ ID NO. 9, SEQ ID NO. 11, SEQ ID NO. 13, SEQ ID
NO. 15, SEQ ID NO. 17, SEQ ID NO. 19, SEQ ID NO. 21, SEQ ID NO. 23,
SEQ ID NO. 25, SEQ ID NO. 27, SEQ ID NO. 29, SEQ ID NO. 31, SEQ ID
NO. 33, SEQ ID NO. 35, SEQ ID NO. 37, SEQ ID NO. 39, SEQ ID NO. 41,
SEQ ID NO. 43, SEQ ID NO. 45, SEQ ID NO. 47, SEQ ID NO. 49, SEQ ID
NO. 51, SEQ ID NO. 53, SEQ ID NO. 55, SEQ ID NO. 57, SEQ ID NO. 59,
SEQ ID NO. 61, SEQ ID NO. 63, SEQ ID NO. 65, SEQ ID NO. 67, SEQ ID
NO. 69, SEQ ID NO. 71, SEQ ID NO. 73, SEQ ID NO. 75, SEQ ID NO. 77,
SEQ ID NO. 79, SEQ ID NO. 81, SEQ ID NO. 83, SEQ ID NO. 85, SEQ ID
NO. 87, SEQ ID NO. 89, SEQ ID NO. 91, SEQ ID NO. 93, SEQ ID NO. 95,
SEQ ID NO. 97, SEQ ID NO. 99, SEQ ID NO. 101, SEQ ID NO. 103, SEQ
ID NO. 105, SEQ ID NO. 107, SEQ ID NO. 109, SEQ ID NO. 111, SEQ ID
NO. 113, SEQ ID NO. 115, SEQ ID NO. 117, SEQ ID NO. 119, SEQ ID NO.
121, SEQ ID NO. 123, SEQ ID NO. 125, SEQ ID NO. 127, SEQ ID NO.
129, SEQ ID NO. 131, SEQ ID NO. 133, SEQ ID NO. 135, SEQ ID NO.
137, SEQ ID NO. 139, SEQ ID NO. 141, SEQ ID NO. 143, SEQ ID NO.
145, SEQ ID NO. 147, SEQ ID NO. 149, SEQ ID NO. 151, SEQ ID NO.
153, SEQ ID NO. 155, SEQ ID NO. 157, SEQ ID NO. 159, SEQ ID NO.
161, SEQ ID NO. 163, SEQ ID NO. 165, SEQ ID NO. 167, SEQ ID NO.
169, SEQ ID NO. 171, SEQ ID NO. 173, SEQ ID NO. 175, SEQ ID NO.
177, SEQ ID NO. 179, SEQ ID NO. 181, SEQ ID NO. 183, SEQ ID NO.
185, SEQ ID NO. 187, SEQ ID NO. 189, SEQ ID NO. 191, SEQ ID NO.
193, SEQ ID NO. 195, SEQ ID NO. 197, SEQ ID NO. 199, SEQ ID NO.
201, SEQ ID NO. 203, SEQ ID NO. 205, SEQ ID NO. 207, SEQ ID NO.
209, SEQ ID NO. 211, SEQ ID NO. 213, SEQ ID NO. 215, SEQ ID NO.
217, SEQ ID NO. 219, SEQ ID NO. 221, SEQ ID NO. 223, SEQ ID NO.
225, SEQ ID NO. 227, SEQ ID NO. 229, SEQ ID NO. 231, SEQ ID NO.
233, SEQ ID NO. 235, SEQ ID NO. 237, SEQ ID NO. 239, SEQ ID NO.
241, and combinations thereof, and that has a light chain variable
domain sequence that is at least 95% identical to the amino acid
sequences selected from the group consisting of SEQ ID NO. 2, SEQ
ID NO. 4, SEQ ID NO. 6, SEQ ID NO. 8, SEQ ID NO. 10, SEQ ID NO. 12,
SEQ ID NO. 14, SEQ ID NO. 16, SEQ ID NO. 18, SEQ ID NO. 20, SEQ ID
NO. 22, SEQ ID NO. 24, SEQ ID NO. 26, SEQ ID NO. 28, SEQ ID NO. 30,
SEQ ID NO. 32, SEQ ID NO. 34, SEQ ID NO. 36, SEQ ID NO. 38, SEQ ID
NO. 40, SEQ ID NO. 42, SEQ ID NO. 44, SEQ ID NO. 46, SEQ ID NO. 48,
SEQ ID NO. 50, SEQ ID NO. 52, SEQ ID NO. 54, SEQ ID NO. 56, SEQ ID
NO. 58, SEQ ID NO. 60, SEQ ID NO. 62, SEQ ID NO. 64, SEQ ID NO. 66,
SEQ ID NO. 68, SEQ ID NO. 70, SEQ ID NO. 72, SEQ ID NO. 74, SEQ ID
NO. 76, SEQ ID NO. 78, SEQ ID NO. 80, SEQ ID NO. 82, SEQ ID NO. 84,
SEQ ID NO. 86, SEQ ID NO. 88, SEQ ID NO. 90, SEQ ID NO. 92, SEQ ID
NO. 94, SEQ ID NO. 96, SEQ ID NO. 98, SEQ ID NO. 100, SEQ ID NO.
102, SEQ ID NO. 104, SEQ ID NO. 106, SEQ ID NO. 108, SEQ ID NO.
110, SEQ ID NO. 112, SEQ ID NO. 114, SEQ ID NO. 116, SEQ ID NO.
118, SEQ ID NO. 120, SEQ ID NO. 122, SEQ ID NO. 124, SEQ ID NO.
126, SEQ ID NO. 128, SEQ ID NO. 130, SEQ ID NO. 132, SEQ ID NO.
134, SEQ ID NO. 136, SEQ ID NO. 138, SEQ ID NO. 140, SEQ ID NO.
142, SEQ ID NO. 144, SEQ ID NO. 146, SEQ ID NO. 148, SEQ ID NO.
150, SEQ ID NO. 152, SEQ ID NO. 154, SEQ ID NO. 156, SEQ ID NO.
158, SEQ ID NO. 160, SEQ ID NO. 162, SEQ ID NO. 164, SEQ ID NO.
166, SEQ ID NO. 168, SEQ ID NO. 170, SEQ ID NO. 172, SEQ ID NO.
174, SEQ ID NO. 176, SEQ ID NO. 178, SEQ ID NO. 180, SEQ ID NO.
182, SEQ ID NO. 184, SEQ ID NO. 186, SEQ ID NO. 188, SEQ ID NO.
190, SEQ ID NO. 192, SEQ ID NO. 194, SEQ ID NO. 196, SEQ ID NO.
198, SEQ ID NO. 200, SEQ ID NO. 202, SEQ ID NO. 204, SEQ ID NO.
206, SEQ ID NO. 208, SEQ ID NO. 210, SEQ ID NO. 212, SEQ ID NO.
214, SEQ ID NO. 216, SEQ ID NO. 218, SEQ ID NO. 220, SEQ ID NO.
222, SEQ ID NO. 224, SEQ ID NO. 226, SEQ ID NO. 228, SEQ ID NO.
230, SEQ ID NO. 232, SEQ ID NO. 234, SEQ ID NO. 236, SEQ ID NO.
238, SEQ ID NO. 240, SEQ ID NO. 242, and combinations thereof.
Preferably, the fully human antibody has both a heavy chain and a
light chain wherein the antibody has a heavy chain/light chain
variable domain sequence selected from the group consisting of SEQ
ID NO. 1/SEQ ID NO. 2 (called E6 herein), SEQ ID NO. 3/SEQ ID NO. 4
(called E7 herein), SEQ ID NO. 5/SEQ ID NO. 6 (called E9 herein),
SEQ ID NO. 7/SEQ ID NO. 8 (called Ell herein), SEQ ID NO. 9/SEQ ID
NO. 10 (called F1 herein), SEQ ID NO. 11/SEQ ID NO. 12 (called F4
herein), SEQ ID NO. 13/SEQ ID NO. 14 (called F7 herein), SEQ ID NO.
15/SEQ ID NO. 16 (called F8 herein), SEQ ID NO. 17/SEQ ID NO. 18
(called F11 herein), SEQ ID NO. 19/SEQ ID NO. 20 (called G4
herein), SEQ ID NO. 21/SEQ ID NO. 22 (called G9 herein), SEQ ID NO.
23/SEQ ID NO. 24 (called G11 herein), SEQ ID NO. 25/SEQ ID NO. 26
(called G12 herein), SEQ ID NO. 27/SEQ ID NO. 28 (called H1
herein), SEQ ID NO. 29/SEQ ID NO. 30 (called H3 herein), SEQ ID NO.
31/SEQ ID NO. 32 (called H4 herein), SEQ ID NO. 33/SEQ ID NO. 34
(called H5 herein), SEQ ID NO. 35/SEQ ID NO. 36 (called H6 herein),
SEQ ID NO. 37/SEQ ID NO. 38 (called H10 herein), SEQ ID NO. 39/SEQ
ID NO. 40 (called H12 herein), SEQ ID NO. 41/SEQ ID NO. 42 (called
PDL-D2 herein), SEQ ID NO. 43/SEQ ID NO. 44 (called PDL-D11
herein), SEQ ID NO. 45/SEQ ID NO. 46 (called PDL-H1 herein), SEQ ID
NO. 47/SEQ ID NO. 48 (called RB4 herein), SEQ ID NO. 49/SEQ ID NO.
50 (called RB11 herein), SEQ ID NO. 51/SEQ ID NO. 52 (called RC5
herein), SEQ ID NO. 53/SEQ ID NO. 54 (called RF5 herein), SEQ ID
NO. 55/SEQ ID NO. 56 (called RG9 herein), SEQ ID NO. 57/SEQ ID NO.
58 (called RD1 herein), SEQ ID NO. 59/SEQ ID NO. 60 (called RF11
herein), SEQ ID NO. 61/SEQ ID NO. 62 (called RH11 herein), SEQ ID
NO. 63/SEQ ID NO. 64 (called RD9 herein), SEQ ID NO. 65/SEQ ID NO.
66 (called RE10 herein), SEQ ID NO. 67/SEQ ID NO. 68 (called RA3
herein), SEQ ID NO. 69/SEQ ID NO. 70 (called RG1 herein), SEQ ID
NO. 71/SEQ ID NO. 72 (called RB1 herein), SEQ ID NO. 73/SEQ ID NO.
74 (called RG7 herein), SEQ ID NO. 75/SEQ ID NO. 76 (called RA6
herein), SEQ ID NO. 77/SEQ ID NO. 78 (called RA8 herein), SEQ ID
NO. 79/SEQ ID NO. 80 (called RA9 herein), SEQ ID NO. 81/SEQ ID NO.
82 (called RB5 herein), SEQ ID NO. 83/SEQ ID NO. 84 (called RB8
herein), SEQ ID NO. 85/SEQ ID NO. 86 (called RC8 herein), SEQ ID
NO. 87/SEQ ID NO. 88 (called RC10 herein), SEQ ID NO. 89/SEQ ID NO.
90 (called RD2 herein), SEQ ID NO. 91/SEQ ID NO. 92 (called RE8
herein), SEQ ID NO. 93/SEQ ID NO. 94 (called RE9 herein), SEQ ID
NO. 95/SEQ ID NO. 96 (called RG12 herein), SEQ ID NO. 97/SEQ ID NO.
98 (called RSA1 herein), SEQ ID NO. 99/SEQ ID NO. 100 (called R2A7
herein), SEQ ID NO. 101/SEQ ID NO. 102 (called R2B12 herein), SEQ
ID NO. 103/SEQ ID NO. 104 (called R2C9 herein), SEQ ID NO. 105/SEQ
ID NO. 106 (called R2D5 herein), SEQ ID NO. 107/SEQ ID NO. 108
(called R2D7 herein), SEQ ID NO. 109/SEQ ID NO. 110 (called R2F4
herein), SEQ ID NO. 111/SEQ ID NO. 112 (called R2A10 herein), SEQ
ID NO. 113/SEQ ID NO. 114 (called R2E2 herein), SEQ ID NO. 115/SEQ
ID NO. 116 (called R3B8 herein), SEQ ID NO. 117/SEQ ID NO. 118
(called R3C3 herein), SEQ ID NO. 119/SEQ ID NO. 120 (called R3E9
herein), SEQ ID NO. 121/SEQ ID NO. 122 (called R3E10 herein), SEQ
ID NO. 123/SEQ ID NO. 124 (called R3F7 herein), SEQ ID NO. 125/SEQ
ID NO. 126 (called R3F10 herein), SEQ ID NO. 127/SEQ ID NO. 128
(called R4B10 herein), SEQ ID NO. 129/SEQ ID NO. 130 (called R4H1
herein), SEQ ID NO. 131/SEQ ID NO. 132 (called R4A11 herein), SEQ
ID NO. 133/SEQ ID NO. 134 (called R3D2 herein), SEQ ID NO. 135/SEQ
ID NO. 136 (called R5B8 herein), SEQ ID NO. 137/SEQ ID NO. 138
(called SH1A1Q herein), SEQ ID NO. 139/SEQ ID NO. 140 (called
SH1B7B(K) herein), SEQ ID NO. 141/SEQ ID NO. 142 (called SH1C1
herein), SEQ ID NO. 143/SEQ ID NO. 144 (called SH1C8 herein), SEQ
ID NO. 145/SEQ ID NO. 146 (called SH1E10 herein), SEQ ID NO.
147/SEQ ID NO. 148 (called SH1E2 herein), SEQ ID NO. 149/SEQ ID NO.
150 (called SH1A9 herein), SEQ ID NO. 151/SEQ ID NO. 152 (called
SH1B11 herein), SEQ ID NO. 153/SEQ ID NO. 154 (called SH1E4
herein), SEQ ID NO. 155/SEQ ID NO. 156 (called SH1B3 herein), SEQ
ID NO. 157/SEQ ID NO. 158 (called SH1D1 herein), SEQ ID NO. 159/SEQ
ID NO. 160 (called SH1D2 herein), SEQ ID NO. 161/SEQ ID NO. 162
(called SH1D12 herein), SEQ ID NO. 163/SEQ ID NO. 164 (called SH1E1
herein), SEQ ID NO. 165/SEQ ID NO. 166 (called SH1G9 herein), SEQ
ID NO. 167/SEQ ID NO. 168 (called SH1A11 herein), SEQ ID NO.
169/SEQ ID NO. 170 (called SH1C2 herein), SEQ ID NO. 171/SEQ ID NO.
172 (called SH1G8 herein), SEQ ID NO. 173/SEQ ID NO. 174 (called
SH1H2 herein), SEQ ID NO. 175/SEQ ID NO. 176 (called SH1B10
herein), SEQ ID NO. 177/SEQ ID NO. 178 (called SH1B7A(L) herein),
SEQ ID NO. 179/SEQ ID NO. 180 (called SH1E6 herein), SEQ ID NO.
181/SEQ ID NO. 182 (called SH1C11 herein), SEQ ID NO. 183/SEQ ID
NO. 184 (called SH1A2 herein), SEQ ID NO. 185/SEQ ID NO. 186
(called SH1B1 herein), SEQ ID NO. 187/SEQ ID NO. 188 (called R6B2
herein), SEQ ID NO. 189/SEQ ID NO. 190 (called R6B7 herein), SEQ ID
NO. 191/SEQ ID NO. 192 (called R6B11 herein), SEQ ID NO. 193/SEQ ID
NO. 194 (called R6D1 herein), SEQ ID NO. 195/SEQ ID NO. 196 (called
R6C8 herein), SEQ ID NO. 197/SEQ ID NO. 198 (called R9G8 herein),
SEQ ID NO. 199/SEQ ID NO. 200 (called R7D1 herein), SEQ ID NO.
201/SEQ ID NO. 202 (called R7D2 herein), SEQ ID NO. 203/SEQ ID NO.
204 (called R7E7 herein), SEQ ID NO. 205/SEQ ID NO. 206 (called
R7F2 herein), SEQ ID NO. 207/SEQ ID NO. 208 (called R7F7 herein),
SEQ ID NO. 209/SEQ ID NO. 210 (called R9H2 herein), SEQ ID NO.
211/SEQ ID NO. 212 (called R9H6 herein), SEQ ID NO. 213/SEQ ID NO.
214 (called H6B1L herein), SEQ ID NO. 215/SEQ ID NO. 216 (called
H6A1 herein), SEQ ID NO. 217/SEQ ID NO. 218 (called H6B1 herein),
SEQ ID NO. 219/SEQ ID NO. 220 (called H6B2 herein), SEQ ID NO.
221/SEQ ID NO. 222 (called H19C herein), SEQ ID NO. 223/SEQ ID NO.
224 (called H110D herein), SEQ ID NO. 225/SEQ ID NO. 226 (called
H11F herein), SEQ ID NO. 227/SEQ ID NO. 228 (called H1C1 herein),
SEQ ID NO. 229/SEQ ID NO. 230 (called GPG1A2 herein), SEQ ID NO.
231/SEQ ID NO. 232 (called GPGG8 herein), SEQ ID NO. 233/SEQ ID NO.
234 (called GPGG10 herein), SEQ ID NO. 235/SEQ ID NO. 236 (called
GPGH7 herein), SEQ ID NO. 237/SEQ ID NO. 238 (called GPGH10
herein), SEQ ID NO. 239/SEQ ID NO. 240 (called GPGH11 herein), SEQ
ID NO. 241/SEQ ID NO. 242 (called GPGH10P herein), and combinations
thereof.
[0031] The present disclosure provides a Fab fully human antibody
fragment, having a variable domain region from a heavy chain and a
variable domain region from a light chain, wherein the heavy chain
variable domain sequence that is at least 95% identical to the
amino acid sequences selected from the group consisting of SEQ ID
NO. 1, SEQ ID NO. 3, SEQ ID NO. 5, SEQ ID NO. 7, SEQ ID NO. 9, SEQ
ID NO. 11, SEQ ID NO. 13, SEQ ID NO. 15, SEQ ID NO. 17, SEQ ID NO.
19, SEQ ID NO. 21, SEQ ID NO. 23, SEQ ID NO. 25, SEQ ID NO. 27, SEQ
ID NO. 29, SEQ ID NO. 31, SEQ ID NO. 33, SEQ ID NO. 35, SEQ ID NO.
37, SEQ ID NO. 39, SEQ ID NO. 41, SEQ ID NO. 43, SEQ ID NO. 45, SEQ
ID NO. 47, SEQ ID NO. 49, SEQ ID NO. 51, SEQ ID NO. 53, SEQ ID NO.
55, SEQ ID NO. 57, SEQ ID NO. 59, SEQ ID NO. 61, SEQ ID NO. 63, SEQ
ID NO. 65, SEQ ID NO. 67, SEQ ID NO. 69, SEQ ID NO. 71, SEQ ID NO.
73, SEQ ID NO. 75, SEQ ID NO. 77, SEQ ID NO. 79, SEQ ID NO. 81, SEQ
ID NO. 83, SEQ ID NO. 85, SEQ ID NO. 87, SEQ ID NO. 89, SEQ ID NO.
91, SEQ ID NO. 93, SEQ ID NO. 95, SEQ ID NO. 97, SEQ ID NO. 99, SEQ
ID NO. 101, SEQ ID NO. 103, SEQ ID NO. 105, SEQ ID NO. 107, SEQ ID
NO. 109, SEQ ID NO. 111, SEQ ID NO. 113, SEQ ID NO. 115, SEQ ID NO.
117, SEQ ID NO. 119, SEQ ID NO. 121, SEQ ID NO. 123, SEQ ID NO.
125, SEQ ID NO. 127, SEQ ID NO. 129, SEQ ID NO. 131, SEQ ID NO.
133, SEQ ID NO. 135, SEQ ID NO. 137, SEQ ID NO. 139, SEQ ID NO.
141, SEQ ID NO. 143, SEQ ID NO. 145, SEQ ID NO. 147, SEQ ID NO.
149, SEQ ID NO. 151, SEQ ID NO. 153, SEQ ID NO. 155, SEQ ID NO.
157, SEQ ID NO. 159, SEQ ID NO. 161, SEQ ID NO. 163, SEQ ID NO.
165, SEQ ID NO. 167, SEQ ID NO. 169, SEQ ID NO. 171, SEQ ID NO.
173, SEQ ID NO. 175, SEQ ID NO. 177, SEQ ID NO. 179, SEQ ID NO.
181, SEQ ID NO. 183, SEQ ID NO. 185, SEQ ID NO. 187, SEQ ID NO.
189, SEQ ID NO. 191, SEQ ID NO. 193, SEQ ID NO. 195, SEQ ID NO.
197, SEQ ID NO. 199, SEQ ID NO. 201, SEQ ID NO. 203, SEQ ID NO.
205, SEQ ID NO. 207, SEQ ID NO. 209, SEQ ID NO. 211, SEQ ID NO.
213, SEQ ID NO. 215, SEQ ID NO. 217, SEQ ID NO. 219, SEQ ID NO.
221, SEQ ID NO. 223, SEQ ID NO. 225, SEQ ID NO. 227, SEQ ID NO.
229, SEQ ID NO. 231, SEQ ID NO. 233, SEQ ID NO. 235, SEQ ID NO.
237, SEQ ID NO. 239, SEQ ID NO. 241, and combinations thereof, and
that has a light chain variable domain sequence that is at least
95% identical to the amino acid sequences selected from the group
consisting of SEQ ID NO. 2, SEQ ID NO. 4, SEQ ID NO. 6, SEQ ID NO.
8, SEQ ID NO. 10, SEQ ID NO. 12, SEQ ID NO. 14, SEQ ID NO. 16, SEQ
ID NO. 18, SEQ ID NO. 20, SEQ ID NO. 22, SEQ ID NO. 24, SEQ ID NO.
26, SEQ ID NO. 28, SEQ ID NO. 30, SEQ ID NO. 32, SEQ ID NO. 34, SEQ
ID NO. 36, SEQ ID NO. 38, SEQ ID NO. 40, SEQ ID NO. 42, SEQ ID NO.
44, SEQ ID NO. 46, SEQ ID NO. 48, SEQ ID NO. 50, SEQ ID NO. 52, SEQ
ID NO. 54, SEQ ID NO. 56, SEQ ID NO. 58, SEQ ID NO. 60, SEQ ID NO.
62, SEQ ID NO. 64, SEQ ID NO. 66, SEQ ID NO. 68, SEQ ID NO. 70, SEQ
ID NO. 72, SEQ ID NO. 74, SEQ ID NO. 76, SEQ ID NO. 78, SEQ ID NO.
80, SEQ ID NO. 82, SEQ ID NO. 84, SEQ ID NO. 86, SEQ ID NO. 88, SEQ
ID NO. 90, SEQ ID NO. 92, SEQ ID NO. 94, SEQ ID NO. 96, SEQ ID NO.
98, SEQ ID NO. 100, SEQ ID NO. 102, SEQ ID NO. 104, SEQ ID NO. 106,
SEQ ID NO. 108, SEQ ID NO. 110, SEQ ID NO. 112, SEQ ID NO. 114, SEQ
ID NO. 116, SEQ ID NO. 118, SEQ ID NO. 120, SEQ ID NO. 122, SEQ ID
NO. 124, SEQ ID NO. 126, SEQ ID NO. 128, SEQ ID NO. 130, SEQ ID NO.
132, SEQ ID NO. 134, SEQ ID NO. 136, SEQ ID NO. 138, SEQ ID NO.
140, SEQ ID NO. 142, SEQ ID NO. 144, SEQ ID NO. 146, SEQ ID NO.
148, SEQ ID NO. 150, SEQ ID NO. 152, SEQ ID NO. 154, SEQ ID NO.
156, SEQ ID NO. 158, SEQ ID NO. 160, SEQ ID NO. 162, SEQ ID NO.
164, SEQ ID NO. 166, SEQ ID NO. 168, SEQ ID NO. 170, SEQ ID NO.
172, SEQ ID NO. 174, SEQ ID NO. 176, SEQ ID NO. 178, SEQ ID NO.
180, SEQ ID NO. 182, SEQ ID NO. 184, SEQ ID NO. 186, SEQ ID NO.
188, SEQ ID NO. 190, SEQ ID NO. 192, SEQ ID NO. 194, SEQ ID NO.
196, SEQ ID NO. 198, SEQ ID NO. 200, SEQ ID NO. 202, SEQ ID NO.
204, SEQ ID NO. 206, SEQ ID NO. 208, SEQ ID NO. 210, SEQ ID NO.
212, SEQ ID NO. 214, SEQ ID NO. 216, SEQ ID NO. 218, SEQ ID NO.
220, SEQ ID NO. 222, SEQ ID NO. 224, SEQ ID NO. 226, SEQ ID NO.
228, SEQ ID NO. 230, SEQ ID NO. 232, SEQ ID NO. 234, SEQ ID NO.
236, SEQ ID NO. 238, SEQ ID NO. 240, SEQ ID NO. 242, and
combinations thereof. Preferably, the fully human antibody Fab
fragment has both a heavy chain variable domain region and a light
chain variable domain region wherein the antibody has a heavy
chain/light chain variable domain sequence selected from the group
consisting of SEQ ID NO. 1/SEQ ID NO. 2, SEQ ID NO. 3/SEQ ID NO. 4,
SEQ ID NO. 5/SEQ ID NO. 6, SEQ ID NO. 7/SEQ ID NO. 8, SEQ ID NO.
9/SEQ ID NO. 10, SEQ ID NO. 11/SEQ ID NO. 12, SEQ ID NO. 13/SEQ ID
NO. 14, SEQ ID NO. 15/SEQ ID NO. 16, SEQ ID NO. 17/SEQ ID NO. 18,
SEQ ID NO. 19/SEQ ID NO. 20, SEQ ID NO. 21/SEQ ID NO. 22, SEQ ID
NO. 23/SEQ ID NO. 24, SEQ ID NO. 25/SEQ ID NO. 26, SEQ ID NO.
27/SEQ ID NO. 28, SEQ ID NO. 29/SEQ ID NO. 30, SEQ ID NO. 31/SEQ ID
NO. 32, SEQ ID NO. 33/SEQ ID NO. 34, SEQ ID NO. 35/SEQ ID NO. 36,
SEQ ID NO. 37/SEQ ID NO. 38, SEQ ID NO. 39/SEQ ID NO. 40, SEQ ID
NO. 41/SEQ ID NO. 42, SEQ ID NO. 43/SEQ ID NO. 44, SEQ ID NO.
45/SEQ ID NO. 46, SEQ ID NO. 47/SEQ ID NO. 48, SEQ ID NO. 49/SEQ ID
NO. 50, SEQ ID NO. 51/SEQ ID NO. 52, SEQ ID NO. 53/SEQ ID NO. 54,
SEQ ID NO. 55/SEQ ID NO. 56, SEQ ID NO. 57/SEQ ID NO. 58, SEQ ID
NO. 59/SEQ ID NO. 60, SEQ ID NO. 61/SEQ ID NO. 62, SEQ ID NO.
63/SEQ ID NO. 64, SEQ ID NO. 65/SEQ ID NO. 66, SEQ ID NO. 67/SEQ ID
NO. 68, SEQ ID NO. 69/SEQ ID NO. 70, SEQ ID NO. 71/SEQ ID NO. 72,
SEQ ID NO. 73/SEQ ID NO. 74, SEQ ID NO. 75/SEQ ID NO. 76, SEQ ID
NO. 77/SEQ ID NO. 78, SEQ ID NO. 79/SEQ ID NO. 80, SEQ ID NO.
81/SEQ ID NO. 82, SEQ ID NO. 83/SEQ ID NO. 84, SEQ ID NO. 85/SEQ ID
NO. 86, SEQ ID NO. 87/SEQ ID NO. 88, SEQ ID NO. 89/SEQ ID NO. 90,
SEQ ID NO. 91/SEQ ID NO. 92, SEQ ID NO. 93/SEQ ID NO. 94, SEQ ID
NO. 95/SEQ ID NO. 96, SEQ ID NO. 97/SEQ ID NO. 98, SEQ ID NO.
99/SEQ ID NO. 100, SEQ ID NO. 101/SEQ ID NO. 102, SEQ ID NO.
103/SEQ ID NO. 104, SEQ ID NO. 105/SEQ ID NO. 106, SEQ ID NO.
107/SEQ ID NO. 108, SEQ ID NO. 109/SEQ ID NO. 110, SEQ ID NO.
111/SEQ ID NO. 112, SEQ ID NO. 113/SEQ ID NO. 114, SEQ ID NO.
115/SEQ ID NO. 116, SEQ ID NO. 117/SEQ ID NO. 118, SEQ ID NO.
119/SEQ ID NO. 120, SEQ ID NO. 121/SEQ ID NO. 122, SEQ ID NO.
123/SEQ ID NO. 124, SEQ ID NO. 125/SEQ ID NO. 126, SEQ ID NO.
127/SEQ ID NO. 128, SEQ ID NO. 129/SEQ ID NO. 130, SEQ ID NO.
131/SEQ ID NO. 132, SEQ ID NO. 133/SEQ ID NO. 134, SEQ ID NO.
135/SEQ ID NO. 136, SEQ ID NO. 137/SEQ ID NO. 138, SEQ ID NO.
139/SEQ ID NO. 140, SEQ ID NO. 141/SEQ ID NO. 142, SEQ ID NO.
143/SEQ ID NO. 144, SEQ ID NO. 145/SEQ ID NO. 146, SEQ ID NO.
147/SEQ ID NO. 148, SEQ ID NO. 149/SEQ ID NO. 150, SEQ ID NO.
151/SEQ ID NO. 152, SEQ ID NO. 153/SEQ ID NO. 154, SEQ ID NO.
155/SEQ ID NO. 156, SEQ ID NO. 157/SEQ ID NO. 158, SEQ ID NO.
159/SEQ ID NO. 160, SEQ ID NO. 161/SEQ ID NO. 162, SEQ ID NO.
163/SEQ ID NO. 164, SEQ ID NO. 165/SEQ ID NO. 166, SEQ ID NO.
167/SEQ ID NO. 168, SEQ ID NO. 169/SEQ ID NO. 170, SEQ ID NO.
171/SEQ ID NO. 172, SEQ ID NO. 173/SEQ ID NO. 174, SEQ ID NO.
175/SEQ ID NO. 176, SEQ ID NO. 177/SEQ ID NO. 178, SEQ ID NO.
179/SEQ ID NO. 180, SEQ ID NO. 181/SEQ ID NO. 182, SEQ ID NO.
183/SEQ ID NO. 184, SEQ ID NO. 185/SEQ ID NO. 186, SEQ ID NO.
187/SEQ ID NO. 188, SEQ ID NO. 189/SEQ ID NO. 190, SEQ ID NO.
191/SEQ ID NO. 192, SEQ ID NO. 193/SEQ ID NO. 194, SEQ ID NO.
195/SEQ ID NO. 196, SEQ ID NO. 197/SEQ ID NO. 198, SEQ ID NO.
199/SEQ ID NO. 200, SEQ ID NO. 201/SEQ ID NO. 202, SEQ ID NO.
203/SEQ ID NO. 204, SEQ ID NO. 205/SEQ ID NO. 206, SEQ ID NO.
207/SEQ ID NO. 208, SEQ ID NO. 209/SEQ ID NO. 210, SEQ ID NO.
211/SEQ ID NO. 212, SEQ ID NO. 213/SEQ ID NO. 214, SEQ ID NO.
215/SEQ ID NO. 216, SEQ ID NO. 217/SEQ ID NO. 218, SEQ ID NO.
219/SEQ ID NO. 220, SEQ ID NO. 221/SEQ ID NO. 222, SEQ ID NO.
223/SEQ ID NO. 224, SEQ ID NO. 225/SEQ ID NO. 226, SEQ ID NO.
227/SEQ ID NO. 228, SEQ ID NO. 229/SEQ ID NO. 230, SEQ ID NO.
231/SEQ ID NO. 232, SEQ ID NO. 233/SEQ ID NO. 234, SEQ ID NO.
235/SEQ ID NO. 236, SEQ ID NO. 237/SEQ ID NO. 238, SEQ ID NO.
239/SEQ ID NO. 240, SEQ ID NO. 241/SEQ ID NO. 242, and combinations
thereof.
[0032] The present disclosure provides a single chain human
antibody, having a variable domain region from a heavy chain and a
variable domain region from a light chain and a peptide linker
connection the heavy chain and light chain variable domain regions,
wherein the heavy chain variable domain sequence that is at least
95% identical to the amino acid sequences selected from the group
consisting of SEQ ID NO. 1, SEQ ID NO. 3, SEQ ID NO. 5, SEQ ID NO.
7, SEQ ID NO. 9, SEQ ID NO. 11, SEQ ID NO. 13, SEQ ID NO. 15, SEQ
ID NO. 17, SEQ ID NO. 19, SEQ ID NO. 21, SEQ ID NO. 23, SEQ ID NO.
25, SEQ ID NO. 27, SEQ ID NO. 29, SEQ ID NO. 31, SEQ ID NO. 33, SEQ
ID NO. 35, SEQ ID NO. 37, SEQ ID NO. 39, SEQ ID NO. 41, SEQ ID NO.
43, SEQ ID NO. 45, SEQ ID NO. 47, SEQ ID NO. 49, SEQ ID NO. 51, SEQ
ID NO. 53, SEQ ID NO. 55, SEQ ID NO. 57, SEQ ID NO. 59, SEQ ID NO.
61, SEQ ID NO. 63, SEQ ID NO. 65, SEQ ID NO. 67, SEQ ID NO. 69, SEQ
ID NO. 71, SEQ ID NO. 73, SEQ ID NO. 75, SEQ ID NO. 77, SEQ ID NO.
79, SEQ ID NO. 81, SEQ ID NO. 83, SEQ ID NO. 85, SEQ ID NO. 87, SEQ
ID NO. 89, SEQ ID NO. 91, SEQ ID NO. 93, SEQ ID NO. 95, SEQ ID NO.
97, SEQ ID NO. 99, SEQ ID NO. 101, SEQ ID NO. 103, SEQ ID NO. 105,
SEQ ID NO. 107, SEQ ID NO. 109, SEQ ID NO. 111, SEQ ID NO. 113, SEQ
ID NO. 115, SEQ ID NO. 117, SEQ ID NO. 119, SEQ ID NO. 121, SEQ ID
NO. 123, SEQ ID NO. 125, SEQ ID NO. 127, SEQ ID NO. 129, SEQ ID NO.
131, SEQ ID NO. 133, SEQ ID NO. 135, SEQ ID NO. 137, SEQ ID NO.
139, SEQ ID NO. 141, SEQ ID NO. 143, SEQ ID NO. 145, SEQ ID NO.
147, SEQ ID NO. 149, SEQ ID NO. 151, SEQ ID NO. 153, SEQ ID NO.
155, SEQ ID NO. 157, SEQ ID NO. 159, SEQ ID NO. 161, SEQ ID NO.
163, SEQ ID NO. 165, SEQ ID NO. 167, SEQ ID NO. 169, SEQ ID NO.
171, SEQ ID NO. 173, SEQ ID NO. 175, SEQ ID NO. 177, SEQ ID NO.
179, SEQ ID NO. 181, SEQ ID NO. 183, SEQ ID NO. 185, SEQ ID NO.
187, SEQ ID NO. 189, SEQ ID NO. 191, SEQ ID NO. 193, SEQ ID NO.
195, SEQ ID NO. 197, SEQ ID NO. 199, SEQ ID NO. 201, SEQ ID NO.
203, SEQ ID NO. 205, SEQ ID NO. 207, SEQ ID NO. 209, SEQ ID NO.
211, SEQ ID NO. 213, SEQ ID NO. 215, SEQ ID NO. 217, SEQ ID NO.
219, SEQ ID NO. 221, SEQ ID NO. 223, SEQ ID NO. 225, SEQ ID NO.
227, SEQ ID NO. 229, SEQ ID NO. 231, SEQ ID NO. 233, SEQ ID NO.
235, SEQ ID NO. 237, SEQ ID NO. 239, SEQ ID NO. 241, and
combinations thereof, and that has a light chain variable domain
sequence that is at least 95% identical to the amino acid sequences
selected from the group consisting of SEQ ID NO. 2, SEQ ID NO. 4,
SEQ ID NO. 6, SEQ ID NO. 8, SEQ ID NO. 10, SEQ ID NO. 12, SEQ ID
NO. 14, SEQ ID NO. 16, SEQ ID NO. 18, SEQ ID NO. 20, SEQ ID NO. 22,
SEQ ID NO. 24, SEQ ID NO. 26, SEQ ID NO. 28, SEQ ID NO. 30, SEQ ID
NO. 32, SEQ ID NO. 34, SEQ ID NO. 36, SEQ ID NO. 38, SEQ ID NO. 40,
SEQ ID NO. 42, SEQ ID NO. 44, SEQ ID NO. 46, SEQ ID NO. 48, SEQ ID
NO. 50, SEQ ID NO. 52, SEQ ID NO. 54, SEQ ID NO. 56, SEQ ID NO. 58,
SEQ ID NO. 60, SEQ ID NO. 62, SEQ ID NO. 64, SEQ ID NO. 66, SEQ ID
NO. 68, SEQ ID NO. 70, SEQ ID NO. 72, SEQ ID NO. 74, SEQ ID NO. 76,
SEQ ID NO. 78, SEQ ID NO. 80, SEQ ID NO. 82, SEQ ID NO. 84, SEQ ID
NO. 86, SEQ ID NO. 88, SEQ ID NO. 90, SEQ ID NO. 92, SEQ ID NO. 94,
SEQ ID NO. 96, SEQ ID NO. 98, SEQ ID NO. 100, SEQ ID NO. 102, SEQ
ID NO. 104, SEQ ID NO. 106, SEQ ID NO. 108, SEQ ID NO. 110, SEQ ID
NO. 112, SEQ ID NO. 114, SEQ ID NO. 116, SEQ ID NO. 118, SEQ ID NO.
120, SEQ ID NO. 122, SEQ ID NO. 124, SEQ ID NO. 126, SEQ ID NO.
128, SEQ ID NO. 130, SEQ ID NO. 132, SEQ ID NO. 134, SEQ ID NO.
136, SEQ ID NO. 138, SEQ ID NO. 140, SEQ ID NO. 142, SEQ ID NO.
144, SEQ ID NO. 146, SEQ ID NO. 148, SEQ ID NO. 150, SEQ ID NO.
152, SEQ ID NO. 154, SEQ ID NO. 156, SEQ ID NO. 158, SEQ ID NO.
160, SEQ ID NO. 162, SEQ ID NO. 164, SEQ ID NO. 166, SEQ ID NO.
168, SEQ ID NO. 170, SEQ ID NO. 172, SEQ ID NO. 174, SEQ ID NO.
176, SEQ ID NO. 178, SEQ ID NO. 180, SEQ ID NO. 182, SEQ ID NO.
184, SEQ ID NO. 186, SEQ ID NO. 188, SEQ ID NO. 190, SEQ ID NO.
192, SEQ ID NO. 194, SEQ ID NO. 196, SEQ ID NO. 198, SEQ ID NO.
200, SEQ ID NO. 202, SEQ ID NO. 204, SEQ ID NO. 206, SEQ ID NO.
208, SEQ ID NO. 210, SEQ ID NO. 212, SEQ ID NO. 214, SEQ ID NO.
216, SEQ ID NO. 218, SEQ ID NO. 220, SEQ ID NO. 222, SEQ ID NO.
224, SEQ ID NO. 226, SEQ ID NO. 228, SEQ ID NO. 230, SEQ ID NO.
232, SEQ ID NO. 234, SEQ ID NO. 236, SEQ ID NO. 238, SEQ ID NO.
240, SEQ ID NO. 242, and combinations thereof. Preferably, the
fully human single chain antibody has both a heavy chain variable
domain region and a light chain variable domain region, wherein the
single chain fully human antibody has a heavy chain/light chain
variable domain sequence selected from the group consisting of SEQ
ID NO. 1/SEQ ID NO. 2, SEQ ID NO. 3/SEQ ID NO. 4, SEQ ID NO. 5/SEQ
ID NO. 6, SEQ ID NO. 7/SEQ ID NO. 8, SEQ ID NO. 9/SEQ ID NO. 10,
SEQ ID NO. 11/SEQ ID NO. 12, SEQ ID NO. 13/SEQ ID NO. 14, SEQ ID
NO. 15/SEQ ID NO. 16, SEQ ID NO. 17/SEQ ID NO. 18, SEQ ID NO.
19/SEQ ID NO. 20, SEQ ID NO. 21/SEQ ID NO. 22, SEQ ID NO. 23/SEQ ID
NO. 24, SEQ ID NO. 25/SEQ ID NO. 26, SEQ ID NO. 27/SEQ ID NO. 28,
SEQ ID NO. 29/SEQ ID NO. 30, SEQ ID NO. 31/SEQ ID NO. 32, SEQ ID
NO. 33/SEQ ID NO. 34, SEQ ID NO. 35/SEQ ID NO. 36, SEQ ID NO.
37/SEQ ID NO. 38, SEQ ID NO. 39/SEQ ID NO. 40, SEQ ID NO. 41/SEQ ID
NO. 42, SEQ ID NO. 43/SEQ ID NO. 44, SEQ ID NO. 45/SEQ ID NO. 46,
SEQ ID NO. 47/SEQ ID NO. 48, SEQ ID NO. 49/SEQ ID NO. 50, SEQ ID
NO. 51/SEQ ID NO. 52, SEQ ID NO. 53/SEQ ID NO. 54, SEQ ID NO.
55/SEQ ID NO. 56, SEQ ID NO. 57/SEQ ID NO. 58, SEQ ID NO. 59/SEQ ID
NO. 60, SEQ ID NO. 61/SEQ ID NO. 62, SEQ ID NO. 63/SEQ ID NO. 64,
SEQ ID NO. 65/SEQ ID NO. 66, SEQ ID NO. 67/SEQ ID NO. 68, SEQ ID
NO. 69/SEQ ID NO. 70, SEQ ID NO. 71/SEQ ID NO. 72, SEQ ID NO.
73/SEQ ID NO. 74, SEQ ID NO. 75/SEQ ID NO. 76, SEQ ID NO. 77/SEQ ID
NO. 78, SEQ ID NO. 79/SEQ ID NO. 80, SEQ ID NO. 81/SEQ ID NO. 82,
SEQ ID NO. 83/SEQ ID NO. 84, SEQ ID NO. 85/SEQ ID NO. 86, SEQ ID
NO. 87/SEQ ID NO. 88, SEQ ID NO. 89/SEQ ID NO. 90, SEQ ID NO.
91/SEQ ID NO. 92, SEQ ID NO. 93/SEQ ID NO. 94, SEQ ID NO. 95/SEQ ID
NO. 96, SEQ ID NO. 97/SEQ ID NO. 98, SEQ ID NO. 99/SEQ ID NO. 100,
SEQ ID NO. 101/SEQ ID NO. 102, SEQ ID NO. 103/SEQ ID NO. 104, SEQ
ID NO. 105/SEQ ID NO. 106, SEQ ID NO. 107/SEQ ID NO. 108, SEQ ID
NO. 109/SEQ ID NO. 110, SEQ ID NO. 111/SEQ ID NO. 112, SEQ ID NO.
113/SEQ ID NO. 114, SEQ ID NO. 115/SEQ ID NO. 116, SEQ ID NO.
117/SEQ ID NO. 118, SEQ ID NO. 119/SEQ ID NO. 120, SEQ ID NO.
121/SEQ ID NO. 122, SEQ ID NO. 123/SEQ ID NO. 124, SEQ ID NO.
125/SEQ ID NO. 126, SEQ ID NO. 127/SEQ ID NO. 128, SEQ ID NO.
129/SEQ ID NO. 130, SEQ ID NO. 131/SEQ ID NO. 132, SEQ ID NO.
133/SEQ ID NO. 134, SEQ ID NO. 135/SEQ ID NO. 136, SEQ ID NO.
137/SEQ ID NO. 138, SEQ ID NO. 139/SEQ ID NO. 140, SEQ ID NO.
141/SEQ ID NO. 142, SEQ ID NO. 143/SEQ ID NO. 144, SEQ ID NO.
145/SEQ ID NO. 146, SEQ ID NO. 147/SEQ ID NO. 148, SEQ ID NO.
149/SEQ ID NO. 150, SEQ ID NO. 151/SEQ ID NO. 152, SEQ ID NO.
153/SEQ ID NO. 154, SEQ ID NO. 155/SEQ ID NO. 156, SEQ ID NO.
157/SEQ ID NO. 158, SEQ ID NO. 159/SEQ ID NO. 160, SEQ ID NO.
161/SEQ ID NO. 162, SEQ ID NO. 163/SEQ ID NO. 164, SEQ ID NO.
165/SEQ ID NO. 166, SEQ ID NO. 167/SEQ ID NO. 168, SEQ ID NO.
169/SEQ ID NO. 170, SEQ ID NO. 171/SEQ ID NO. 172, SEQ ID NO.
173/SEQ ID NO. 174, SEQ ID NO. 175/SEQ ID NO. 176, SEQ ID NO.
177/SEQ ID NO. 178, SEQ ID NO. 179/SEQ ID NO. 180, SEQ ID NO.
181/SEQ ID NO. 182, SEQ ID NO. 183/SEQ ID NO. 184, SEQ ID NO.
185/SEQ ID NO. 186, SEQ ID NO. 187/SEQ ID NO. 188, SEQ ID NO.
189/SEQ ID NO. 190, SEQ ID NO. 191/SEQ ID NO. 192, SEQ ID NO.
193/SEQ ID NO. 194, SEQ ID NO. 195/SEQ ID NO. 196, SEQ ID NO.
197/SEQ ID NO. 198, SEQ ID NO. 199/SEQ ID NO. 200, SEQ ID NO.
201/SEQ ID NO. 202, SEQ ID NO. 203/SEQ ID NO. 204, SEQ ID NO.
205/SEQ ID NO. 206, SEQ ID NO. 207/SEQ ID NO. 208, SEQ ID NO.
209/SEQ ID NO. 210, SEQ ID NO. 211/SEQ ID NO. 212, SEQ ID NO.
213/SEQ ID NO. 214, SEQ ID NO. 215/SEQ ID NO. 216, SEQ ID NO.
217/SEQ ID NO. 218, SEQ ID NO. 219/SEQ ID NO. 220, SEQ ID NO.
221/SEQ ID NO. 222, SEQ ID NO. 223/SEQ ID NO. 224, SEQ ID NO.
225/SEQ ID NO. 226, SEQ ID NO. 227/SEQ ID NO. 228, SEQ ID NO.
229/SEQ ID NO. 230, SEQ ID NO. 231/SEQ ID NO. 232, SEQ ID NO.
233/SEQ ID NO. 234, SEQ ID NO. 235/SEQ ID NO. 236, SEQ ID NO.
237/SEQ ID NO. 238, SEQ ID NO. 239/SEQ ID NO. 240, SEQ ID NO.
241/SEQ ID NO. 242, and combinations thereof.
[0033] The present disclosure further provides a method for
treating a broad spectrum of mammalian cancers or inflammatory
diseases or autoimmune diseases, comprising administering an
effective amount of an anti-PD-L1 polypeptide, wherein the
anti-PD-L1 polypeptide is selected from the group consisting of a
fully human antibody of an IgG class that binds to a PD-L1 epitope
with a binding affinity of at least 10.sup.-6M, a Fab fully human
antibody fragment, having a variable domain region from a heavy
chain and a variable domain region from a light chain, a single
chain human antibody, having a variable domain region from a heavy
chain and a variable domain region from a light chain and a peptide
linker connection the heavy chain and light chain variable domain
regions, and combinations thereof;
[0034] wherein the fully human antibody has a heavy chain variable
domain sequence that is at least 95% identical to the amino acid
sequences selected from the group consisting of SEQ ID NO. 1, SEQ
ID NO. 3, SEQ ID NO. 5, SEQ ID NO. 7, SEQ ID NO. 9, SEQ ID NO. 11,
SEQ ID NO. 13, SEQ ID NO. 15, SEQ ID NO. 17, SEQ ID NO. 19, SEQ ID
NO. 21, SEQ ID NO. 23, SEQ ID NO. 25, SEQ ID NO. 27, SEQ ID NO. 29,
SEQ ID NO. 31, SEQ ID NO. 33, SEQ ID NO. 35, SEQ ID NO. 37, SEQ ID
NO. 39, SEQ ID NO. 41, SEQ ID NO. 43, SEQ ID NO. 45, SEQ ID NO. 47,
SEQ ID NO. 49, SEQ ID NO. 51, SEQ ID NO. 53, SEQ ID NO. 55, SEQ ID
NO. 57, SEQ ID NO. 59, SEQ ID NO. 61, SEQ ID NO. 63, SEQ ID NO. 65,
SEQ ID NO. 67, SEQ ID NO. 69, SEQ ID NO. 71, SEQ ID NO. 73, SEQ ID
NO. 75, SEQ ID NO. 77, SEQ ID NO. 79, SEQ ID NO. 81, SEQ ID NO. 83,
SEQ ID NO. 85, SEQ ID NO. 87, SEQ ID NO. 89, SEQ ID NO. 91, SEQ ID
NO. 93, SEQ ID NO. 95, SEQ ID NO. 97, SEQ ID NO. 99, SEQ ID NO.
101, SEQ ID NO. 103, SEQ ID NO. 105, SEQ ID NO. 107, SEQ ID NO.
109, SEQ ID NO. 111, SEQ ID NO. 113, SEQ ID NO. 115, SEQ ID NO.
117, SEQ ID NO. 119, SEQ ID NO. 121, SEQ ID NO. 123, SEQ ID NO.
125, SEQ ID NO. 127, SEQ ID NO. 129, SEQ ID NO. 131, SEQ ID NO.
133, SEQ ID NO. 135, SEQ ID NO. 137, SEQ ID NO. 139, SEQ ID NO.
141, SEQ ID NO. 143, SEQ ID NO. 145, SEQ ID NO. 147, SEQ ID NO.
149, SEQ ID NO. 151, SEQ ID NO. 153, SEQ ID NO. 155, SEQ ID NO.
157, SEQ ID NO. 159, SEQ ID NO. 161, SEQ ID NO. 163, SEQ ID NO.
165, SEQ ID NO. 167, SEQ ID NO. 169, SEQ ID NO. 171, SEQ ID NO.
173, SEQ ID NO. 175, SEQ ID NO. 177, SEQ ID NO. 179, SEQ ID NO.
181, SEQ ID NO. 183, SEQ ID NO. 185, SEQ ID NO. 187, SEQ ID NO.
189, SEQ ID NO. 191, SEQ ID NO. 193, SEQ ID NO. 195, SEQ ID NO.
197, SEQ ID NO. 199, SEQ ID NO. 201, SEQ ID NO. 203, SEQ ID NO.
205, SEQ ID NO. 207, SEQ ID NO. 209, SEQ ID NO. 211, SEQ ID NO.
213, SEQ ID NO. 215, SEQ ID NO. 217, SEQ ID NO. 219, SEQ ID NO.
221, SEQ ID NO. 223, SEQ ID NO. 225, SEQ ID NO. 227, SEQ ID NO.
229, SEQ ID NO. 231, SEQ ID NO. 233, SEQ ID NO. 235, SEQ ID NO.
237, SEQ ID NO. 239, SEQ ID NO. 241, and combinations thereof, and
that has a light chain variable domain sequence that is at least
95% identical to the amino acid sequences selected from the group
consisting of SEQ ID NO. 2, SEQ ID NO. 4, SEQ ID NO. 6, SEQ ID NO.
8, SEQ ID NO. 10, SEQ ID NO. 12, SEQ ID NO. 14, SEQ ID NO. 16, SEQ
ID NO. 18, SEQ ID NO. 20, SEQ ID NO. 22, SEQ ID NO. 24, SEQ ID NO.
26, SEQ ID NO. 28, SEQ ID NO. 30, SEQ ID NO. 32, SEQ ID NO. 34, SEQ
ID NO. 36, SEQ ID NO. 38, SEQ ID NO. 40, SEQ ID NO. 42, SEQ ID NO.
44, SEQ ID NO. 46, SEQ ID NO. 48, SEQ ID NO. 50, SEQ ID NO. 52, SEQ
ID NO. 54, SEQ ID NO. 56, SEQ ID NO. 58, SEQ ID NO. 60, SEQ ID NO.
62, SEQ ID NO. 64, SEQ ID NO. 66, SEQ ID NO. 68, SEQ ID NO. 70, SEQ
ID NO. 72, SEQ ID NO. 74, SEQ ID NO. 76, SEQ ID NO. 78, SEQ ID NO.
80, SEQ ID NO. 82, SEQ ID NO. 84, SEQ ID NO. 86, SEQ ID NO. 88, SEQ
ID NO. 90, SEQ ID NO. 92, SEQ ID NO. 94, SEQ ID NO. 96, SEQ ID NO.
98, SEQ ID NO. 100, SEQ ID NO. 102, SEQ ID NO. 104, SEQ ID NO. 106,
SEQ ID NO. 108, SEQ ID NO. 110, SEQ ID NO. 112, SEQ ID NO. 114, SEQ
ID NO. 116, SEQ ID NO. 118, SEQ ID NO. 120, SEQ ID NO. 122, SEQ ID
NO. 124, SEQ ID NO. 126, SEQ ID NO. 128, SEQ ID NO. 130, SEQ ID NO.
132, SEQ ID NO. 134, SEQ ID NO. 136, SEQ ID NO. 138, SEQ ID NO.
140, SEQ ID NO. 142, SEQ ID NO. 144, SEQ ID NO. 146, SEQ ID NO.
148, SEQ ID NO. 150, SEQ ID NO. 152, SEQ ID NO. 154, SEQ ID NO.
156, SEQ ID NO. 158, SEQ ID NO. 160, SEQ ID NO. 162, SEQ ID NO.
164, SEQ ID NO. 166, SEQ ID NO. 168, SEQ ID NO. 170, SEQ ID NO.
172, SEQ ID NO. 174, SEQ ID NO. 176, SEQ ID NO. 178, SEQ ID NO.
180, SEQ ID NO. 182, SEQ ID NO. 184, SEQ ID NO. 186, SEQ ID NO.
188, SEQ ID NO. 190, SEQ ID NO. 192, SEQ ID NO. 194, SEQ ID NO.
196, SEQ ID NO. 198, SEQ ID NO. 200, SEQ ID NO. 202, SEQ ID NO.
204, SEQ ID NO. 206, SEQ ID NO. 208, SEQ ID NO. 210, SEQ ID NO.
212, SEQ ID NO. 214, SEQ ID NO. 216, SEQ ID NO. 218, SEQ ID NO.
220, SEQ ID NO. 222, SEQ ID NO. 224, SEQ ID NO. 226, SEQ ID NO.
228, SEQ ID NO. 230, SEQ ID NO. 232, SEQ ID NO. 234, SEQ ID NO.
236, SEQ ID NO. 238, SEQ ID NO. 240, SEQ ID NO. 242, and
combinations thereof; [0035] wherein the Fab fully human antibody
fragment has the heavy chain variable domain sequence that is at
least 95% identical to the amino acid sequences selected from the
group consisting of SEQ ID NO. 1, SEQ ID NO. 3, SEQ ID NO. 5, SEQ
ID NO. 7, SEQ ID NO. 9, SEQ ID NO. 11, SEQ ID NO. 13, SEQ ID NO.
15, SEQ ID NO. 17, SEQ ID NO. 19, SEQ ID NO. 21, SEQ ID NO. 23, SEQ
ID NO. 25, SEQ ID NO. 27, SEQ ID NO. 29, SEQ ID NO. 31, SEQ ID NO.
33, SEQ ID NO. 35, SEQ ID NO. 37, SEQ ID NO. 39, SEQ ID NO. 41, SEQ
ID NO. 43, SEQ ID NO. 45, SEQ ID NO. 47, SEQ ID NO. 49, SEQ ID NO.
51, SEQ ID NO. 53, SEQ ID NO. 55, SEQ ID NO. 57, SEQ ID NO. 59, SEQ
ID NO. 61, SEQ ID NO. 63, SEQ ID NO. 65, SEQ ID NO. 67, SEQ ID NO.
69, SEQ ID NO. 71, SEQ ID NO. 73, SEQ ID NO. 75, SEQ ID NO. 77, SEQ
ID NO. 79, SEQ ID NO. 81, SEQ ID NO. 83, SEQ ID NO. 85, SEQ ID NO.
87, SEQ ID NO. 89, SEQ ID NO. 91, SEQ ID NO. 93, SEQ ID NO. 95, SEQ
ID NO. 97, SEQ ID NO. 99, SEQ ID NO. 101, SEQ ID NO. 103, SEQ ID
NO. 105, SEQ ID NO. 107, SEQ ID NO. 109, SEQ ID NO. 111, SEQ ID NO.
113, SEQ ID NO. 115, SEQ ID NO. 117, SEQ ID NO. 119, SEQ ID NO.
121, SEQ ID NO. 123, SEQ ID NO. 125, SEQ ID NO. 127, SEQ ID NO.
129, SEQ ID NO. 131, SEQ ID NO. 133, SEQ ID NO. 135, SEQ ID NO.
137, SEQ ID NO. 139, SEQ ID NO. 141, SEQ ID NO. 143, SEQ ID NO.
145, SEQ ID NO. 147, SEQ ID NO. 149, SEQ ID NO. 151, SEQ ID NO.
153, SEQ ID NO. 155, SEQ ID NO. 157, SEQ ID NO. 159, SEQ ID NO.
161, SEQ ID NO. 163, SEQ ID NO. 165, SEQ ID NO. 167, SEQ ID NO.
169, SEQ ID NO. 171, SEQ ID NO. 173, SEQ ID NO. 175, SEQ ID NO.
177, SEQ ID NO. 179, SEQ ID NO. 181, SEQ ID NO. 183, SEQ ID NO.
185, SEQ ID NO. 187, SEQ ID NO. 189, SEQ ID NO. 191, SEQ ID NO.
193, SEQ ID NO. 195, SEQ ID NO. 197, SEQ ID NO. 199, SEQ ID NO.
201, SEQ ID NO. 203, SEQ ID NO. 205, SEQ ID NO. 207, SEQ ID NO.
209, SEQ ID NO. 211, SEQ ID NO. 213, SEQ ID NO. 215, SEQ ID NO.
217, SEQ ID NO. 219, SEQ ID NO. 221, SEQ ID NO. 223, SEQ ID NO.
225, SEQ ID NO. 227, SEQ ID NO. 229, SEQ ID NO. 231, SEQ ID NO.
233, SEQ ID NO. 235, SEQ ID NO. 237, SEQ ID NO. 239, SEQ ID NO.
241, and combinations thereof, and that has the light chain
variable domain sequence that is at least 95% identical to the
amino acid sequences selected from the group consisting of SEQ ID
NO. 2, SEQ ID NO. 4, SEQ ID NO. 6, SEQ ID NO. 8, SEQ ID NO. 10, SEQ
ID NO. 12, SEQ ID NO. 14, SEQ ID NO. 16, SEQ ID NO. 18, SEQ ID NO.
20, SEQ ID NO. 22, SEQ ID NO. 24, SEQ ID NO. 26, SEQ ID NO. 28, SEQ
ID NO. 30, SEQ ID NO. 32, SEQ ID NO. 34, SEQ ID NO. 36, SEQ ID NO.
38, SEQ ID NO. 40, SEQ ID NO. 42, SEQ ID NO. 44, SEQ ID NO. 46, SEQ
ID NO. 48, SEQ ID NO. 50, SEQ ID NO. 52, SEQ ID NO. 54, SEQ ID NO.
56, SEQ ID NO. 58, SEQ ID NO. 60, SEQ ID NO. 62, SEQ ID NO. 64, SEQ
ID NO. 66, SEQ ID NO. 68, SEQ ID NO. 70, SEQ ID NO. 72, SEQ ID NO.
74, SEQ ID NO. 76, SEQ ID NO. 78, SEQ ID NO. 80, SEQ ID NO. 82, SEQ
ID NO. 84, SEQ ID NO. 86, SEQ ID NO. 88, SEQ ID NO. 90, SEQ ID NO.
92, SEQ ID NO. 94, SEQ ID NO. 96, SEQ ID NO. 98, SEQ ID NO. 100,
SEQ ID NO. 102, SEQ ID NO. 104, SEQ ID NO. 106, SEQ ID NO. 108, SEQ
ID NO. 110, SEQ ID NO. 112, SEQ ID NO. 114, SEQ ID NO. 116, SEQ ID
NO. 118, SEQ ID NO. 120, SEQ ID NO. 122, SEQ ID NO. 124, SEQ ID NO.
126, SEQ ID NO. 128, SEQ ID NO. 130, SEQ ID NO. 132, SEQ ID NO.
134, SEQ ID NO. 136, SEQ ID NO. 138, SEQ ID NO. 140, SEQ ID NO.
142, SEQ ID NO. 144, SEQ ID NO. 146, SEQ ID NO. 148, SEQ ID NO.
150, SEQ ID NO. 152, SEQ ID NO. 154, SEQ ID NO. 156, SEQ ID NO.
158, SEQ ID NO. 160, SEQ ID NO. 162, SEQ ID NO. 164, SEQ ID NO.
166, SEQ ID NO. 168, SEQ ID NO. 170, SEQ ID NO. 172, SEQ ID NO.
174, SEQ ID NO. 176, SEQ ID NO. 178, SEQ ID NO. 180, SEQ ID NO.
182, SEQ ID NO. 184, SEQ ID NO. 186, SEQ ID NO. 188, SEQ ID NO.
190, SEQ ID NO. 192, SEQ ID NO. 194, SEQ ID NO. 196, SEQ ID NO.
198, SEQ ID NO. 200, SEQ ID NO. 202, SEQ ID NO. 204, SEQ ID NO.
206, SEQ ID NO. 208, SEQ ID NO. 210, SEQ ID NO. 212, SEQ ID NO.
214, SEQ ID NO. 216, SEQ ID NO. 218, SEQ ID NO. 220, SEQ ID NO.
222, SEQ ID NO. 224, SEQ ID NO. 226, SEQ ID NO. 228, SEQ ID NO.
230, SEQ ID NO. 232, SEQ ID NO. 234, SEQ ID NO. 236, SEQ ID NO.
238, SEQ ID NO. 240, SEQ ID NO. 242, and combinations thereof;
and
[0036] wherein the single chain human antibody has the heavy chain
variable domain sequence that is at least 95% identical to the
amino acid sequences selected from the group consisting of SEQ ID
NO. 1, SEQ ID NO. 3, SEQ ID NO. 5, SEQ ID NO. 7, SEQ ID NO. 9, SEQ
ID NO. 11, SEQ ID NO. 13, SEQ ID NO. 15, SEQ ID NO. 17, SEQ ID NO.
19, SEQ ID NO. 21, SEQ ID NO. 23, SEQ ID NO. 25, SEQ ID NO. 27, SEQ
ID NO. 29, SEQ ID NO. 31, SEQ ID NO. 33, SEQ ID NO. 35, SEQ ID NO.
37, SEQ ID NO. 39, SEQ ID NO. 41, SEQ ID NO. 43, SEQ ID NO. 45, SEQ
ID NO. 47, SEQ ID NO. 49, SEQ ID NO. 51, SEQ ID NO. 53, SEQ ID NO.
55, SEQ ID NO. 57, SEQ ID NO. 59, SEQ ID NO. 61, SEQ ID NO. 63, SEQ
ID NO. 65, SEQ ID NO. 67, SEQ ID NO. 69, SEQ ID NO. 71, SEQ ID NO.
73, SEQ ID NO. 75, SEQ ID NO. 77, SEQ ID NO. 79, SEQ ID NO. 81, SEQ
ID NO. 83, SEQ ID NO. 85, SEQ ID NO. 87, SEQ ID NO. 89, SEQ ID NO.
91, SEQ ID NO. 93, SEQ ID NO. 95, SEQ ID NO. 97, SEQ ID NO. 99, SEQ
ID NO. 101, SEQ ID NO. 103, SEQ ID NO. 105, SEQ ID NO. 107, SEQ ID
NO. 109, SEQ ID NO. 111, SEQ ID NO. 113, SEQ ID NO. 115, SEQ ID NO.
117, SEQ ID NO. 119, SEQ ID NO. 121, SEQ ID NO. 123, SEQ ID NO.
125, SEQ ID NO. 127, SEQ ID NO. 129, SEQ ID NO. 131, SEQ ID NO.
133, SEQ ID NO. 135, SEQ ID NO. 137, SEQ ID NO. 139, SEQ ID NO.
141, SEQ ID NO. 143, SEQ ID NO. 145, SEQ ID NO. 147, SEQ ID NO.
149, SEQ ID NO. 151, SEQ ID NO. 153, SEQ ID NO. 155, SEQ ID NO.
157, SEQ ID NO. 159, SEQ ID NO. 161, SEQ ID NO. 163, SEQ ID NO.
165, SEQ ID NO. 167, SEQ ID NO. 169, SEQ ID NO. 171, SEQ ID NO.
173, SEQ ID NO. 175, SEQ ID NO. 177, SEQ ID NO. 179, SEQ ID NO.
181, SEQ ID NO. 183, SEQ ID NO. 185, SEQ ID NO. 187, SEQ ID NO.
189, SEQ ID NO. 191, SEQ ID NO. 193, SEQ ID NO. 195, SEQ ID NO.
197, SEQ ID NO. 199, SEQ ID NO. 201, SEQ ID NO. 203, SEQ ID NO.
205, SEQ ID NO. 207, SEQ ID NO. 209, SEQ ID NO. 211, SEQ ID NO.
213, SEQ ID NO. 215, SEQ ID NO. 217, SEQ ID NO. 219, SEQ ID NO.
221, SEQ ID NO. 223, SEQ ID NO. 225, SEQ ID NO. 227, SEQ ID NO.
229, SEQ ID NO. 231, SEQ ID NO. 233, SEQ ID NO. 235, SEQ ID NO.
237, SEQ ID NO. 239, SEQ ID NO. 241, and combinations thereof, and
that has the light chain variable domain sequence that is at least
95% identical to the amino acid sequences selected from the group
consisting of SEQ ID NO. 2, SEQ ID NO. 4, SEQ ID NO. 6, SEQ ID NO.
8, SEQ ID NO. 10, SEQ ID NO. 12, SEQ ID NO. 14, SEQ ID NO. 16, SEQ
ID NO. 18, SEQ ID NO. 20, SEQ ID NO. 22, SEQ ID NO. 24, SEQ ID NO.
26, SEQ ID NO. 28, SEQ ID NO. 30, SEQ ID NO. 32, SEQ ID NO. 34, SEQ
ID NO. 36, SEQ ID NO. 38, SEQ ID NO. 40, SEQ ID NO. 42, SEQ ID NO.
44, SEQ ID NO. 46, SEQ ID NO. 48, SEQ ID NO. 50, SEQ ID NO. 52, SEQ
ID NO. 54, SEQ ID NO. 56, SEQ ID NO. 58, SEQ ID NO. 60, SEQ ID NO.
62, SEQ ID NO. 64, SEQ ID NO. 66, SEQ ID NO. 68, SEQ ID NO. 70, SEQ
ID NO. 72, SEQ ID NO. 74, SEQ ID NO. 76, SEQ ID NO. 78, SEQ ID NO.
80, SEQ ID NO. 82, SEQ ID NO. 84, SEQ ID NO. 86, SEQ ID NO. 88, SEQ
ID NO. 90, SEQ ID NO. 92, SEQ ID NO. 94, SEQ ID NO. 96, SEQ ID NO.
98, SEQ ID NO. 100, SEQ ID NO. 102, SEQ ID NO. 104, SEQ ID NO. 106,
SEQ ID NO. 108, SEQ ID NO. 110, SEQ ID NO. 112, SEQ ID NO. 114, SEQ
ID NO. 116, SEQ ID NO. 118, SEQ ID NO. 120, SEQ ID NO. 122, SEQ ID
NO. 124, SEQ ID NO. 126, SEQ ID NO. 128, SEQ ID NO. 130, SEQ ID NO.
132, SEQ ID NO. 134, SEQ ID NO. 136, SEQ ID NO. 138, SEQ ID NO.
140, SEQ ID NO. 142, SEQ ID NO. 144, SEQ ID NO. 146, SEQ ID NO.
148, SEQ ID NO. 150, SEQ ID NO. 152, SEQ ID NO. 154, SEQ ID NO.
156, SEQ ID NO. 158, SEQ ID NO. 160, SEQ ID NO. 162, SEQ ID NO.
164, SEQ ID NO. 166, SEQ ID NO. 168, SEQ ID NO. 170, SEQ ID NO.
172, SEQ ID NO. 174, SEQ ID NO. 176, SEQ ID NO. 178, SEQ ID NO.
180, SEQ ID NO. 182, SEQ ID NO. 184, SEQ ID NO. 186, SEQ ID NO.
188, SEQ ID NO. 190, SEQ ID NO. 192, SEQ ID NO. 194, SEQ ID NO.
196, SEQ ID NO. 198, SEQ ID NO. 200, SEQ ID NO. 202, SEQ ID NO.
204, SEQ ID NO. 206, SEQ ID NO. 208, SEQ ID NO. 210, SEQ ID NO.
212, SEQ ID NO. 214, SEQ ID NO. 216, SEQ ID NO. 218, SEQ ID NO.
220, SEQ ID NO. 222, SEQ ID NO. 224, SEQ ID NO. 226, SEQ ID NO.
228, SEQ ID NO. 230, SEQ ID NO. 232, SEQ ID NO. 234, SEQ ID NO.
236, SEQ ID NO. 238, SEQ ID NO. 240, SEQ ID NO. 242, and
combinations thereof.
[0037] Preferably, the fully human antibody has both a heavy chain
and a light chain wherein the antibody has a heavy chain/light
chain variable domain sequence selected from the group consisting
of SEQ ID NO. 1/SEQ ID NO. 2, SEQ ID NO. 3/SEQ ID NO. 4, SEQ ID NO.
5/SEQ ID NO. 6, SEQ ID NO. 7/SEQ ID NO. 8, SEQ ID NO. 9/SEQ ID NO.
10, SEQ ID NO. 11/SEQ ID NO. 12, SEQ ID NO. 13/SEQ ID NO. 14, SEQ
ID NO. 15/SEQ ID NO. 16, SEQ ID NO. 17/SEQ ID NO. 18, SEQ ID NO.
19/SEQ ID NO. 20, SEQ ID NO. 21/SEQ ID NO. 22, SEQ ID NO. 23/SEQ ID
NO. 24, SEQ ID NO. 25/SEQ ID NO. 26, SEQ ID NO. 27/SEQ ID NO. 28,
SEQ ID NO. 29/SEQ ID NO. 30, SEQ ID NO. 31/SEQ ID NO. 32, SEQ ID
NO. 33/SEQ ID NO. 34, SEQ ID NO. 35/SEQ ID NO. 36, SEQ ID NO.
37/SEQ ID NO. 38, SEQ ID NO. 39/SEQ ID NO. 40, SEQ ID NO. 41/SEQ ID
NO. 42, SEQ ID NO. 43/SEQ ID NO. 44, SEQ ID NO. 45/SEQ ID NO. 46,
SEQ ID NO. 47/SEQ ID NO. 48, SEQ ID NO. 49/SEQ ID NO. 50, SEQ ID
NO. 51/SEQ ID NO. 52, SEQ ID NO. 53/SEQ ID NO. 54, SEQ ID NO.
55/SEQ ID NO. 56, SEQ ID NO. 57/SEQ ID NO. 58, SEQ ID NO. 59/SEQ ID
NO. 60, SEQ ID NO. 61/SEQ ID NO. 62, SEQ ID NO. 63/SEQ ID NO. 64,
SEQ ID NO. 65/SEQ ID NO. 66, SEQ ID NO. 67/SEQ ID NO. 68, SEQ ID
NO. 69/SEQ ID NO. 70, SEQ ID NO. 71/SEQ ID NO. 72, SEQ ID NO.
73/SEQ ID NO. 74, SEQ ID NO. 75/SEQ ID NO. 76, SEQ ID NO. 77/SEQ ID
NO. 78, SEQ ID NO. 79/SEQ ID NO. 80, SEQ ID NO. 81/SEQ ID NO. 82,
SEQ ID NO. 83/SEQ ID NO. 84, SEQ ID NO. 85/SEQ ID NO. 86, SEQ ID
NO. 87/SEQ ID NO. 88, SEQ ID NO. 89/SEQ ID NO. 90, SEQ ID NO.
91/SEQ ID NO. 92, SEQ ID NO. 93/SEQ ID NO. 94, SEQ ID NO. 95/SEQ ID
NO. 96, SEQ ID NO. 97/SEQ ID NO. 98, SEQ ID NO. 99/SEQ ID NO. 100,
SEQ ID NO. 101/SEQ ID NO. 102, SEQ ID NO. 103/SEQ ID NO. 104, SEQ
ID NO. 105/SEQ ID NO. 106, SEQ ID NO. 107/SEQ ID NO. 108, SEQ ID
NO. 109/SEQ ID NO. 110, SEQ ID NO. 111/SEQ ID NO. 112, SEQ ID NO.
113/SEQ ID NO. 114, SEQ ID NO. 115/SEQ ID NO. 116, SEQ ID NO.
117/SEQ ID NO. 118, SEQ ID NO. 119/SEQ ID NO. 120, SEQ ID NO.
121/SEQ ID NO. 122, SEQ ID NO. 123/SEQ ID NO. 124, SEQ ID NO.
125/SEQ ID NO. 126, SEQ ID NO. 127/SEQ ID NO. 128, SEQ ID NO.
129/SEQ ID NO. 130, SEQ ID NO. 131/SEQ ID NO. 132, SEQ ID NO.
133/SEQ ID NO. 134, SEQ ID NO. 135/SEQ ID NO. 136, SEQ ID NO.
137/SEQ ID NO. 138, SEQ ID NO. 139/SEQ ID NO. 140, SEQ ID NO.
141/SEQ ID NO. 142, SEQ ID NO. 143/SEQ ID NO. 144, SEQ ID NO.
145/SEQ ID NO. 146, SEQ ID NO. 147/SEQ ID NO. 148, SEQ ID NO.
149/SEQ ID NO. 150, SEQ ID NO. 151/SEQ ID NO. 152, SEQ ID NO.
153/SEQ ID NO. 154, SEQ ID NO. 155/SEQ ID NO. 156, SEQ ID NO.
157/SEQ ID NO. 158, SEQ ID NO. 159/SEQ ID NO. 160, SEQ ID NO.
161/SEQ ID NO. 162, SEQ ID NO. 163/SEQ ID NO. 164, SEQ ID NO.
165/SEQ ID NO. 166, SEQ ID NO. 167/SEQ ID NO. 168, SEQ ID NO.
169/SEQ ID NO. 170, SEQ ID NO. 171/SEQ ID NO. 172, SEQ ID NO.
173/SEQ ID NO. 174, SEQ ID NO. 175/SEQ ID NO. 176, SEQ ID NO.
177/SEQ ID NO. 178, SEQ ID NO. 179/SEQ ID NO. 180, SEQ ID NO.
181/SEQ ID NO. 182, SEQ ID NO. 183/SEQ ID NO. 184, SEQ ID NO.
185/SEQ ID NO. 186, SEQ ID NO. 187/SEQ ID NO. 188, SEQ ID NO.
189/SEQ ID NO. 190, SEQ ID NO. 191/SEQ ID NO. 192, SEQ ID NO.
193/SEQ ID NO. 194, SEQ ID NO. 195/SEQ ID NO. 196, SEQ ID NO.
197/SEQ ID NO. 198, SEQ ID NO. 199/SEQ ID NO. 200, SEQ ID NO.
201/SEQ ID NO. 202, SEQ ID NO. 203/SEQ ID NO. 204, SEQ ID NO.
205/SEQ ID NO. 206, SEQ ID NO. 207/SEQ ID NO. 208, SEQ ID NO.
209/SEQ ID NO. 210, SEQ ID NO. 211/SEQ ID NO. 212, SEQ ID NO.
213/SEQ ID NO. 214, SEQ ID NO. 215/SEQ ID NO. 216, SEQ ID NO.
217/SEQ ID NO. 218, SEQ ID NO. 219/SEQ ID NO. 220, SEQ ID NO.
221/SEQ ID NO. 222, SEQ ID NO. 223/SEQ ID NO. 224, SEQ ID NO.
225/SEQ ID NO. 226, SEQ ID NO. 227/SEQ ID NO. 228, SEQ ID NO.
229/SEQ ID NO. 230, SEQ ID NO. 231/SEQ ID NO. 232, SEQ ID NO.
233/SEQ ID NO. 234, SEQ ID NO. 235/SEQ ID NO. 236, SEQ ID NO.
237/SEQ ID NO. 238, SEQ ID NO. 239/SEQ ID NO. 240, SEQ ID NO.
241/SEQ ID NO. 242, and combinations thereof. Preferably, the fully
human antibody Fab fragment has both a heavy chain variable domain
region and a light chain variable domain region wherein the
antibody has a heavy chain/light chain variable domain sequence
selected from the group consisting of SEQ ID NO. 1/SEQ ID NO. 2,
SEQ ID NO. 3/SEQ ID NO. 4, SEQ ID NO. 5/SEQ ID NO. 6, SEQ ID NO.
7/SEQ ID NO. 8, SEQ ID NO. 9/SEQ ID NO. 10, SEQ ID NO. 11/SEQ ID
NO. 12, SEQ ID NO. 13/SEQ ID NO. 14, SEQ ID NO. 15/SEQ ID NO. 16,
SEQ ID NO. 17/SEQ ID NO. 18, SEQ ID NO. 19/SEQ ID NO. 20, SEQ ID
NO. 21/SEQ ID NO. 22, SEQ ID NO. 23/SEQ ID NO. 24, SEQ ID NO.
25/SEQ ID NO. 26, SEQ ID NO. 27/SEQ ID NO. 28, SEQ ID NO. 29/SEQ ID
NO. 30, SEQ ID NO. 31/SEQ ID NO. 32, SEQ ID NO. 33/SEQ ID NO. 34,
SEQ ID NO. 35/SEQ ID NO. 36, SEQ ID NO. 37/SEQ ID NO. 38, SEQ ID
NO. 39/SEQ ID NO. 40, SEQ ID NO. 41/SEQ ID NO. 42, SEQ ID NO.
43/SEQ ID NO. 44, SEQ ID NO. 45/SEQ ID NO. 46, SEQ ID NO. 47/SEQ ID
NO. 48, SEQ ID NO. 49/SEQ ID NO. 50, SEQ ID NO. 51/SEQ ID NO. 52,
SEQ ID NO. 53/SEQ ID NO. 54, SEQ ID NO. 55/SEQ ID NO. 56, SEQ ID
NO. 57/SEQ ID NO. 58, SEQ ID NO. 59/SEQ ID NO. 60, SEQ ID NO.
61/SEQ ID NO. 62, SEQ ID NO. 63/SEQ ID NO. 64, SEQ ID NO. 65/SEQ ID
NO. 66, SEQ ID NO. 67/SEQ ID NO. 68, SEQ ID NO. 69/SEQ ID NO. 70,
SEQ ID NO. 71/SEQ ID NO. 72, SEQ ID NO. 73/SEQ ID NO. 74, SEQ ID
NO. 75/SEQ ID NO. 76, SEQ ID NO. 77/SEQ ID NO. 78, SEQ ID NO.
79/SEQ ID NO. 80, SEQ ID NO. 81/SEQ ID NO. 82, SEQ ID NO. 83/SEQ ID
NO. 84, SEQ ID NO. 85/SEQ ID NO. 86, SEQ ID NO. 87/SEQ ID NO. 88,
SEQ ID NO. 89/SEQ ID NO. 90, SEQ ID NO. 91/SEQ ID NO. 92, SEQ ID
NO. 93/SEQ ID NO. 94, SEQ ID NO. 95/SEQ ID NO. 96, SEQ ID NO.
97/SEQ ID NO. 98, SEQ ID NO. 99/SEQ ID NO. 100, SEQ ID NO. 101/SEQ
ID NO. 102, SEQ ID NO. 103/SEQ ID NO. 104, SEQ ID NO. 105/SEQ ID
NO. 106, SEQ ID NO. 107/SEQ ID NO. 108, SEQ ID NO. 109/SEQ ID NO.
110, SEQ ID NO. 111/SEQ ID NO. 112, SEQ ID NO. 113/SEQ ID NO. 114,
SEQ ID NO. 115/SEQ ID NO. 116, SEQ ID NO. 117/SEQ ID NO. 118, SEQ
ID NO. 119/SEQ ID NO. 120, SEQ ID NO. 121/SEQ ID NO. 122, SEQ ID
NO. 123/SEQ ID NO. 124, SEQ ID NO. 125/SEQ ID NO. 126, SEQ ID NO.
127/SEQ ID NO. 128, SEQ ID NO. 129/SEQ ID NO. 130, SEQ ID NO.
131/SEQ ID NO. 132, SEQ ID NO. 133/SEQ ID NO. 134, SEQ ID NO.
135/SEQ ID NO. 136, SEQ ID NO. 137/SEQ ID NO. 138, SEQ ID NO.
139/SEQ ID NO. 140, SEQ ID NO. 141/SEQ ID NO. 142, SEQ ID NO.
143/SEQ ID NO. 144, SEQ ID NO. 145/SEQ ID NO. 146, SEQ ID NO.
147/SEQ ID NO. 148, SEQ ID NO. 149/SEQ ID NO. 150, SEQ ID NO.
151/SEQ ID NO. 152, SEQ ID NO. 153/SEQ ID NO. 154, SEQ ID NO.
155/SEQ ID NO. 156, SEQ ID NO. 157/SEQ ID NO. 158, SEQ ID NO.
159/SEQ ID NO. 160, SEQ ID NO. 161/SEQ ID NO. 162, SEQ ID NO.
163/SEQ ID NO. 164, SEQ ID NO. 165/SEQ ID NO. 166, SEQ ID NO.
167/SEQ ID NO. 168, SEQ ID NO. 169/SEQ ID NO. 170, SEQ ID NO.
171/SEQ ID NO. 172, SEQ ID NO. 173/SEQ ID NO. 174, SEQ ID NO.
175/SEQ ID NO. 176, SEQ ID NO. 177/SEQ ID NO. 178, SEQ ID NO.
179/SEQ ID NO. 180, SEQ ID NO. 181/SEQ ID NO. 182, SEQ ID NO.
183/SEQ ID NO. 184, SEQ ID NO. 185/SEQ ID NO. 186, SEQ ID NO.
187/SEQ ID NO. 188, SEQ ID NO. 189/SEQ ID NO. 190, SEQ ID NO.
191/SEQ ID NO. 192, SEQ ID NO. 193/SEQ ID NO. 194, SEQ ID NO.
195/SEQ ID NO. 196, SEQ ID NO. 197/SEQ ID NO. 198, SEQ ID NO.
199/SEQ ID NO. 200, SEQ ID NO. 201/SEQ ID NO. 202, SEQ ID NO.
203/SEQ ID NO. 204, SEQ ID NO. 205/SEQ ID NO. 206, SEQ ID NO.
207/SEQ ID NO. 208, SEQ ID NO. 209/SEQ ID NO. 210, SEQ ID NO.
211/SEQ ID NO. 212, SEQ ID NO. 213/SEQ ID NO. 214, SEQ ID NO.
215/SEQ ID NO. 216, SEQ ID NO. 217/SEQ ID NO. 218, SEQ ID NO.
219/SEQ ID NO. 220, SEQ ID NO. 221/SEQ ID NO. 222, SEQ ID NO.
223/SEQ ID NO. 224, SEQ ID NO. 225/SEQ ID NO. 226, SEQ ID NO.
227/SEQ ID NO. 228, SEQ ID NO. 229/SEQ ID NO. 230, SEQ ID NO.
231/SEQ ID NO. 232, SEQ ID NO. 233/SEQ ID NO. 234, SEQ ID NO.
235/SEQ ID NO. 236, SEQ ID NO. 237/SEQ ID NO. 238, SEQ ID NO.
239/SEQ ID NO. 240, SEQ ID NO. 241/SEQ ID NO. 242, and combinations
thereof. Preferably, the fully human single chain antibody has both
a heavy chain variable domain region and a light chain variable
domain region, wherein the single chain fully human antibody has a
heavy chain/light chain variable domain sequence selected from the
group consisting of SEQ ID NO. 1/SEQ ID NO. 2, SEQ ID NO. 3/SEQ ID
NO. 4, SEQ ID NO. 5/SEQ ID NO. 6, SEQ ID NO. 7/SEQ ID NO. 8, SEQ ID
NO. 9/SEQ ID NO. 10, SEQ ID NO. 11/SEQ ID NO. 12, SEQ ID NO. 13/SEQ
ID NO. 14, SEQ ID NO. 15/SEQ ID NO. 16, SEQ ID NO. 17/SEQ ID NO.
18, SEQ ID NO. 19/SEQ ID NO. 20, SEQ ID NO. 21/SEQ ID NO. 22, SEQ
ID NO. 23/SEQ ID NO. 24, SEQ ID NO. 25/SEQ ID NO. 26, SEQ ID NO.
27/SEQ ID NO. 28, SEQ ID NO. 29/SEQ ID NO. 30, SEQ ID NO. 31/SEQ ID
NO. 32, SEQ ID NO. 33/SEQ ID NO. 34, SEQ ID NO. 35/SEQ ID NO. 36,
SEQ ID NO. 37/SEQ ID NO. 38, SEQ ID NO. 39/SEQ ID NO. 40, SEQ ID
NO. 41/SEQ ID NO. 42, SEQ ID NO. 43/SEQ ID NO. 44, SEQ ID NO.
45/SEQ ID NO. 46, SEQ ID NO. 47/SEQ ID NO. 48, SEQ ID NO. 49/SEQ ID
NO. 50, SEQ ID NO. 51/SEQ ID NO. 52, SEQ ID NO. 53/SEQ ID NO. 54,
SEQ ID NO. 55/SEQ ID NO. 56, SEQ ID NO. 57/SEQ ID NO. 58, SEQ ID
NO. 59/SEQ ID NO. 60, SEQ ID NO. 61/SEQ ID NO. 62, SEQ ID NO.
63/SEQ ID NO. 64, SEQ ID NO. 65/SEQ ID NO. 66, SEQ ID NO. 67/SEQ ID
NO. 68, SEQ ID NO. 69/SEQ ID NO. 70, SEQ ID NO. 71/SEQ ID NO. 72,
SEQ ID NO. 73/SEQ ID NO. 74, SEQ ID NO. 75/SEQ ID NO. 76, SEQ ID
NO. 77/SEQ ID NO. 78, SEQ ID NO. 79/SEQ ID NO. 80, SEQ ID NO.
81/SEQ ID NO. 82, SEQ ID NO. 83/SEQ ID NO. 84, SEQ ID NO. 85/SEQ ID
NO. 86, SEQ ID NO. 87/SEQ ID NO. 88, SEQ ID NO. 89/SEQ ID NO. 90,
SEQ ID NO. 91/SEQ ID NO. 92, SEQ ID NO. 93/SEQ ID NO. 94, SEQ ID
NO. 95/SEQ ID NO. 96, SEQ ID NO. 97/SEQ ID NO. 98, SEQ ID NO.
99/SEQ ID NO. 100, SEQ ID NO. 101/SEQ ID NO. 102, SEQ ID NO.
103/SEQ ID NO. 104, SEQ ID NO. 105/SEQ ID NO. 106, SEQ ID NO.
107/SEQ ID NO. 108, SEQ ID NO. 109/SEQ ID NO. 110, SEQ ID NO.
111/SEQ ID NO. 112, SEQ ID NO. 113/SEQ ID NO. 114, SEQ ID NO.
115/SEQ ID NO. 116, SEQ ID NO. 117/SEQ ID NO. 118, SEQ ID NO.
119/SEQ ID NO. 120, SEQ ID NO. 121/SEQ ID NO. 122, SEQ ID NO.
123/SEQ ID NO. 124, SEQ ID NO. 125/SEQ ID NO. 126, SEQ ID NO.
127/SEQ ID NO. 128, SEQ ID NO. 129/SEQ ID NO. 130, SEQ ID NO.
131/SEQ ID NO. 132, SEQ ID NO. 133/SEQ ID NO. 134, SEQ ID NO.
135/SEQ ID NO. 136, SEQ ID NO. 137/SEQ ID NO. 138, SEQ ID NO.
139/SEQ ID NO. 140, SEQ ID NO. 141/SEQ ID NO. 142, SEQ ID NO.
143/SEQ ID NO. 144, SEQ ID NO. 145/SEQ ID NO. 146, SEQ ID NO.
147/SEQ ID NO. 148, SEQ ID NO. 149/SEQ ID NO. 150, SEQ ID NO.
151/SEQ ID NO. 152, SEQ ID NO. 153/SEQ ID NO. 154, SEQ ID NO.
155/SEQ ID NO. 156, SEQ ID NO. 157/SEQ ID NO. 158, SEQ ID NO.
159/SEQ ID NO. 160, SEQ ID NO. 161/SEQ ID NO. 162, SEQ ID NO.
163/SEQ ID NO. 164, SEQ ID NO. 165/SEQ ID NO. 166, SEQ ID NO.
167/SEQ ID NO. 168, SEQ ID NO. 169/SEQ ID NO. 170, SEQ ID NO.
171/SEQ ID NO. 172, SEQ ID NO. 173/SEQ ID NO. 174, SEQ ID NO.
175/SEQ ID NO. 176, SEQ ID NO. 177/SEQ ID NO. 178, SEQ ID NO.
179/SEQ ID NO. 180, SEQ ID NO. 181/SEQ ID NO. 182, SEQ ID NO.
183/SEQ ID NO. 184, SEQ ID NO. 185/SEQ ID NO. 186, SEQ ID NO.
187/SEQ ID NO. 188, SEQ ID NO. 189/SEQ ID NO. 190, SEQ ID NO.
191/SEQ ID NO. 192, SEQ ID NO. 193/SEQ ID NO. 194, SEQ ID NO.
195/SEQ ID NO. 196, SEQ ID NO. 197/SEQ ID NO. 198, SEQ ID NO.
199/SEQ ID NO. 200, SEQ ID NO. 201/SEQ ID NO. 202, SEQ ID NO.
203/SEQ ID NO. 204, SEQ ID NO. 205/SEQ ID NO. 206, SEQ ID NO.
207/SEQ ID NO. 208, SEQ ID NO. 209/SEQ ID NO. 210, SEQ ID NO.
211/SEQ ID NO. 212, SEQ ID NO. 213/SEQ ID NO. 214, SEQ ID NO.
215/SEQ ID NO. 216, SEQ ID NO. 217/SEQ ID NO. 218, SEQ ID NO.
219/SEQ ID NO. 220, SEQ ID NO. 221/SEQ ID NO. 222, SEQ ID NO.
223/SEQ ID NO. 224, SEQ ID NO. 225/SEQ ID NO. 226, SEQ ID NO.
227/SEQ ID NO. 228, SEQ ID NO. 229/SEQ ID NO. 230, SEQ ID NO.
231/SEQ ID NO. 232, SEQ ID NO. 233/SEQ ID NO. 234, SEQ ID NO.
235/SEQ ID NO. 236, SEQ ID NO. 237/SEQ ID NO. 238, SEQ ID NO.
239/SEQ ID NO. 240, SEQ ID NO. 241/SEQ ID NO. 242, and combinations
thereof.
[0038] Preferably, the broad spectrum of mammalian cancers to be
treated is selected from the group consisting of ovarian, colon,
breast, lung cancers, myelomas, neuroblastic-derived CNS tumors,
monocytic leukemias, B-cell derived leukemias, T-cell derived
leukemias, B-cell derived lymphomas, T-cell derived lymphomas, mast
cell derived tumors, and combinations thereof. Preferably, the
autoimmune disease or inflammatory disease is selected from the
group consisting of intestinal mucosal inflammation, wasting
disease associated with colitis, multiple sclerosis, systemic lupus
erythematosus, viral infections, rheumatoid arthritis,
osteoarthritis, psoriasis, Cohn's disease, and inflammatory bowel
disease.
[0039] An "antigen binding protein" is a protein comprising a
portion that binds to an antigen and, optionally, a scaffold or
framework portion that allows the antigen binding portion to adopt
a conformation that promotes binding of the antigen binding protein
to the antigen. Examples of antigen binding proteins include
antibodies, antibody fragments (e.g., an antigen binding portion of
an antibody), antibody derivatives, and antibody analogs. The
antigen binding protein can comprise, for example, an alternative
protein scaffold or artificial scaffold with grafted CDRs or CDR
derivatives. Such scaffolds include, but are not limited to,
antibody-derived scaffolds comprising mutations introduced to, for
example, stabilize the three-dimensional structure of the antigen
binding protein as well as wholly synthetic scaffolds comprising,
for example, a biocompatible polymer. See, for example, Korndorfer
et al., 2003, Proteins: Structure, Function, and Bioinformatics,
Volume 53, Issue 1:121-129; Roque et al., 2004, Biotechnol. Prog.
20:639-654. In addition, peptide antibody mimetics ("PAMs") can be
used, as well as scaffolds based on antibody mimetics utilizing
fibronection components as a scaffold.
[0040] An antigen binding protein can have, for example, the
structure of a naturally occurring immunoglobulin. An
"immunoglobulin" is a tetrameric molecule. In a naturally occurring
immunoglobulin, each tetramer is composed of two identical pairs of
polypeptide chains, each pair having one "light" (about 25 kDa) and
one "heavy" chain (about 50-70 kDa). The amino-terminal portion of
each chain includes a variable region of about 100 to 110 or more
amino acids primarily responsible for antigen recognition. The
carboxy-terminal portion of each chain defines a constant region
primarily responsible for effector function. Human light chains are
classified as kappa or lambda light chains. Heavy chains are
classified as mu, delta, gamma, alpha, or epsilon, and define the
antibody's isotype as IgM, IgD, IgG, IgA, and IgE, respectively.
Within light and heavy chains, the variable and constant regions
are joined by a "J" region of about 12 or more amino acids, with
the heavy chain also including a "D" region of about 10 more amino
acids. See generally, Fundamental Immunology Ch. 7 (Paul, W., ed.,
2nd ed. Raven Press, N.Y. (1989)) (incorporated by reference in its
entirety for all purposes). The variable regions of each
light/heavy chain pair form the antibody binding site such that an
intact immunoglobulin has two binding sites.
[0041] The variable regions of naturally occurring immunoglobulin
chains exhibit the same general structure of relatively conserved
framework regions (FR) joined by three hypervariable regions, also
called complementarity determining regions or CDRs. From N-terminus
to C-terminus, both light and heavy chains comprise the domains
FR1, CDR1, FR2, CDR2, FR3, CDR3 and FR4. The assignment of amino
acids to each domain is in accordance with the definitions of Kabat
et al. in Sequences of Proteins of Immunological Interest, 5.sup.th
Ed., US Dept. of Health and Human Services, PHS, NIH, NIH
Publication no. 91-3242, 1991. Other numbering systems for the
amino acids in immunoglobulin chains include IMGT.RTM.
(international ImMunoGeneTics information system; Lefranc et al,
Dev. Comp. Immunol. 29:185-203; 2005) and AHo (Honegger and
Pluckthun, J. Mol. Biol. 309(3):657-670; 2001).
[0042] Antibodies can be obtained from sources such as serum or
plasma that contain immunoglobulins having varied antigenic
specificity. If such antibodies are subjected to affinity
purification, they can be enriched for a particular antigenic
specificity. Such enriched preparations of antibodies usually are
made of less than about 10% antibody having specific binding
activity for the particular antigen. Subjecting these preparations
to several rounds of affinity purification can increase the
proportion of antibody having specific binding activity for the
antigen. Antibodies prepared in this manner are often referred to
as "monospecific." Monospecific antibody preparations can be made
up of about 10%, 20%, 30%, 40%, 50%, 60%, 70%, 75%, 80%, 85%, 90%,
95%, 97%, 99%, or 99.9% antibody having specific binding activity
for the particular antigen.
[0043] An "antibody" refers to an intact immunoglobulin or to an
antigen binding portion thereof that competes with the intact
antibody for specific binding, unless otherwise specified. Antigen
binding portions may be produced by recombinant DNA techniques or
by enzymatic or chemical cleavage of intact antibodies. Antigen
binding portions include, inter alia, Fab, Fab', F(ab').sub.2, Fv,
domain antibodies (dAbs), and complementarity determining region
(CDR) fragments, single-chain antibodies (scFv), chimeric
antibodies, diabodies, triabodies, tetrabodies, and polypeptides
that contain at least a portion of an immunoglobulin that is
sufficient to confer specific antigen binding to the
polypeptide.
[0044] A Fab fragment is a monovalent fragment having the V.sub.L,
V.sub.H, C.sub.L and C.sub.H1 domains; a F(ab').sub.2 fragment is a
bivalent fragment having two Fab fragments linked by a disulfide
bridge at the hinge region; a Fd fragment has the V.sub.H and
C.sub.H1 domains; an Fv fragment has the V.sub.L and V.sub.H
domains of a single arm of an antibody; and a dAb fragment has a
V.sub.H domain, a V.sub.L domain, or an antigen-binding fragment of
a V.sub.H or VL domain (U.S. Pat. Nos. 6,846,634; 6,696,245, US
App. Pub. 20/0202512; 2004/0202995; 2004/0038291; 2004/0009507;
2003/0039958, and Ward et al., Nature 341:544-546, 1989).
[0045] A single-chain antibody (scFv) is an antibody in which a
V.sub.L and a V.sub.H region are joined via a linker (e.g., a
synthetic sequence of amino acid residues) to form a continuous
protein chain wherein the linker is long enough to allow the
protein chain to fold back on itself and form a monovalent antigen
binding site (see, e.g., Bird et al., 1988, Science 242:423-26 and
Huston et al., 1988, Proc. Natl. Acad. Sci. USA 85:5879-83).
Diabodies are bivalent antibodies comprising two polypeptide
chains, wherein each polypeptide chain comprises V.sub.H and
V.sub.L domains joined by a linker that is too short to allow for
pairing between two domains on the same chain, thus allowing each
domain to pair with a complementary domain on another polypeptide
chain (see, e.g., Holliger et al., 1993, Proc. Natl. Acad. Sci. USA
90:6444-48, and Poljak et al., 1994, Structure 2:1121-23). If the
two polypeptide chains of a diabody are identical, then a diabody
resulting from their pairing will have two identical antigen
binding sites. Polypeptide chains having different sequences can be
used to make a diabody with two different antigen binding sites.
Similarly, tribodies and tetrabodies are antibodies comprising
three and four polypeptide chains, respectively, and forming three
and four antigen binding sites, respectively, which can be the same
or different.
[0046] Complementarity determining regions (CDRs) and framework
regions (FR) of a given antibody may be identified using the system
described by Kabat et al. supra; Lefranc et al., supra and/or
Honegger and Pluckthun, supra. One or more CDRs may be incorporated
into a molecule either covalently or noncovalently to make it an
antigen binding protein. An antigen binding protein may incorporate
the CDR(s) as part of a larger polypeptide chain, may covalently
link the CDR(s) to another polypeptide chain, or may incorporate
the CDR(s) noncovalently. The CDRs permit the antigen binding
protein to specifically bind to a particular antigen of
interest.
[0047] An antigen binding protein may have one or more binding
sites. If there is more than one binding site, the binding sites
may be identical to one another or may be different. For example, a
naturally occurring human immunoglobulin typically has two
identical binding sites, while a "bispecific" or "bifunctional"
antibody has two different binding sites.
[0048] The term "human antibody" includes all antibodies that have
one or more variable and constant regions derived from human
immunoglobulin sequences. In one embodiment, all of the variable
and constant domains are derived from human immunoglobulin
sequences (a fully human antibody). These antibodies may be
prepared in a variety of ways, examples of which are described
below, including through the immunization with an antigen of
interest of a mouse that is genetically modified to express
antibodies derived from human heavy and/or light chain-encoding
genes.
[0049] A humanized antibody has a sequence that differs from the
sequence of an antibody derived from a non-human species by one or
more amino acid substitutions, deletions, and/or additions, such
that the humanized antibody is less likely to induce an immune
response, and/or induces a less severe immune response, as compared
to the non-human species antibody, when it is administered to a
human subject. In one embodiment, certain amino acids in the
framework and constant domains of the heavy and/or light chains of
the non-human species antibody are mutated to produce the humanized
antibody. In another embodiment, the constant domain(s) from a
human antibody are fused to the variable domain(s) of a non-human
species. In another embodiment, one or more amino acid residues in
one or more CDR sequences of a non-human antibody are changed to
reduce the likely immunogenicity of the non-human antibody when it
is administered to a human subject, wherein the changed amino acid
residues either are not critical for immunospecific binding of the
antibody to its antigen, or the changes to the amino acid sequence
that are made are conservative changes, such that the binding of
the humanized antibody to the antigen is not significantly worse
than the binding of the non-human antibody to the antigen. Examples
of how to make humanized antibodies may be found in U.S. Pat. Nos.
6,054,297, 5,886,152 and 5,877,293.
[0050] The term "chimeric antibody" refers to an antibody that
contains one or more regions from one antibody and one or more
regions from one or more other antibodies. In one embodiment, one
or more of the CDRs are derived from a human anti-PD-L1 antibody.
In another embodiment, all of the CDRs are derived from a human
anti-PD-L1 antibody. In another embodiment, the CDRs from more than
one human anti-PD-L1 antibodies are mixed and matched in a chimeric
antibody. For instance, a chimeric antibody may comprise a CDR1
from the light chain of a first human anti-PAR-2 antibody, a CDR2
and a CDR3 from the light chain of a second human anti-PD-L1
antibody, and the CDRs from the heavy chain from a third anti-PD-L1
antibody. Other combinations are possible.
[0051] Further, the framework regions may be derived from one of
the same anti-PD-L1 antibodies, from one or more different
antibodies, such as a human antibody, or from a humanized antibody.
In one example of a chimeric antibody, a portion of the heavy
and/or light chain is identical with, homologous to, or derived
from an antibody from a particular species or belonging to a
particular antibody class or subclass, while the remainder of the
chain(s) is/are identical with, homologous to, or derived from an
antibody (-ies) from another species or belonging to another
antibody class or subclass. Also included are fragments of such
antibodies that exhibit the desired biological activity (i.e., the
ability to specifically bind PD-L1).
[0052] A "neutralizing antibody" or an "inhibitory antibody" is an
antibody that inhibits the proteolytic activation of PD-L1 when an
excess of the anti-PD-L1 antibody reduces the amount of activation
by at least about 20% using an assay such as those described herein
in the Examples. In various embodiments, the antigen binding
protein reduces the amount of amount of proteolytic activation of
PD-L1 by at least 30%, 40%, 50%, 60%, 70%, 75%, 80%, 85%, 90%, 95%,
97%, 99%, and 99.9%.
[0053] Fragments or analogs of antibodies can be readily prepared
by those of ordinary skill in the art following the teachings of
this specification and using techniques known in the art. Preferred
amino- and carboxy-termini of fragments or analogs occur near
boundaries of functional domains. Structural and functional domains
can be identified by comparison of the nucleotide and/or amino acid
sequence data to public or proprietary sequence databases.
Computerized comparison methods can be used to identify sequence
motifs or predicted protein conformation domains that occur in
other proteins of known structure and/or function. Methods to
identify protein sequences that fold into a known three-dimensional
structure are known. See, Bowie et al., 1991, Science 253:164.
[0054] A "CDR grafted antibody" is an antibody comprising one or
more CDRs derived from an antibody of a particular species or
isotype and the framework of another antibody of the same or
different species or isotype.
[0055] A "multi-specific antibody" is an antibody that recognizes
more than one epitope on one or more antigens. A subclass of this
type of antibody is a "bi-specific antibody" which recognizes two
distinct epitopes on the same or different antigens.
[0056] An antigen binding protein "specifically binds" to an
antigen (e.g., human PD-L1) if it binds to the antigen with a
dissociation constant of 1 nanomolar or less.
[0057] An "antigen binding domain," "antigen binding region," or
"antigen binding site" is a portion of an antigen binding protein
that contains amino acid residues (or other moieties) that interact
with an antigen and contribute to the antigen binding protein's
specificity and affinity for the antigen. For an antibody that
specifically binds to its antigen, this will include at least part
of at least one of its CDR domains.
[0058] An "epitope" is the portion of a molecule that is bound by
an antigen binding protein (e.g., by an antibody). An epitope can
comprise non-contiguous portions of the molecule (e.g., in a
polypeptide, amino acid residues that are not contiguous in the
polypeptide's primary sequence but that, in the context of the
polypeptide's tertiary and quaternary structure, are near enough to
each other to be bound by an antigen binding protein).
[0059] The "percent identity" of two polynucleotide or two
polypeptide sequences is determined by comparing the sequences
using the GAP computer program (a part of the GCG Wisconsin
Package, version 10.3 (Accelrys, San Diego, Calif.)) using its
default parameters.
[0060] The terms "polynucleotide," "oligonucleotide" and "nucleic
acid" are used interchangeably throughout and include DNA molecules
(e.g., cDNA or genomic DNA), RNA molecules (e.g., mRNA), analogs of
the DNA or RNA generated using nucleotide analogs (e.g., peptide
nucleic acids and non-naturally occurring nucleotide analogs), and
hybrids thereof. The nucleic acid molecule can be single-stranded
or double-stranded. In one embodiment, the nucleic acid molecules
of the invention comprise a contiguous open reading frame encoding
an antibody, or a fragment, derivative, mutein, or variant
thereof.
[0061] Two single-stranded polynucleotides are "the complement" of
each other if their sequences can be aligned in an anti-parallel
orientation such that every nucleotide in one polynucleotide is
opposite its complementary nucleotide in the other polynucleotide,
without the introduction of gaps, and without unpaired nucleotides
at the 5' or the 3' end of either sequence. A polynucleotide is
"complementary" to another polynucleotide if the two
polynucleotides can hybridize to one another under moderately
stringent conditions. Thus, a polynucleotide can be complementary
to another polynucleotide without being its complement.
[0062] A "vector" is a nucleic acid that can be used to introduce
another nucleic acid linked to it into a cell. One type of vector
is a "plasmid," which refers to a linear or circular double
stranded DNA molecule into which additional nucleic acid segments
can be ligated. Another type of vector is a viral vector (e.g.,
replication defective retroviruses, adenoviruses and
adeno-associated viruses), wherein additional DNA segments can be
introduced into the viral genome. Certain vectors are capable of
autonomous replication in a host cell into which they are
introduced (e.g., bacterial vectors comprising a bacterial origin
of replication and episomal mammalian vectors). Other vectors
(e.g., non-episomal mammalian vectors) are integrated into the
genome of a host cell upon introduction into the host cell, and
thereby are replicated along with the host genome. An "expression
vector" is a type of vector that can direct the expression of a
chosen polynucleotide.
[0063] A nucleotide sequence is "operably linked" to a regulatory
sequence if the regulatory sequence affects the expression (e.g.,
the level, timing, or location of expression) of the nucleotide
sequence. A "regulatory sequence" is a nucleic acid that affects
the expression (e.g., the level, timing, or location of expression)
of a nucleic acid to which it is operably linked. The regulatory
sequence can, for example, exert its effects directly on the
regulated nucleic acid, or through the action of one or more other
molecules (e.g., polypeptides that bind to the regulatory sequence
and/or the nucleic acid). Examples of regulatory sequences include
promoters, enhancers and other expression control elements (e.g.,
polyadenylation signals). Further examples of regulatory sequences
are described in, for example, Goeddel, 1990, Gene Expression
Technology: Methods in Enzymology 185, Academic Press, San Diego,
Calif. and Baron et al., 1995, Nucleic Acids Res. 23:3605-06.
[0064] A "host cell" is a cell that can be used to express a
nucleic acid, e.g., a nucleic acid of the invention. A host cell
can be a prokaryote, for example, E. coli, or it can be a
eukaryote, for example, a single-celled eukaryote (e.g., a yeast or
other fungus), a plant cell (e.g., a tobacco or tomato plant cell),
an animal cell (e.g., a human cell, a monkey cell, a hamster cell,
a rat cell, a mouse cell, or an insect cell) or a hybridoma.
Examples of host cells include the COS-7 line of monkey kidney
cells (ATCC CRL 1651) (see Gluzman et al., 1981, Cell 23:175), L
cells, C127 cells, 3T3 cells (ATCC CCL 163), Chinese hamster ovary
(CHO) cells or their derivatives such as Veggie CHO and related
cell lines which grow in serum-free media (see Rasmussen et al.,
1998, Cytotechnology 28:31) or CHO strain DX-B11, which is
deficient in DHFR (see Urlaub et al., 1980, Proc. Natl. Acad. Sci.
USA 77:4216-20), HeLa cells, BHK (ATCC CRL 10) cell lines, the
CV1/EBNA cell line derived from the African green monkey kidney
cell line CV1 (ATCC CCL 70) (see McMahan et al., 1991, EMBO J.
10:2821), human embryonic kidney cells such as 293,293 EBNA or MSR
293, human epidermal A431 cells, human Colo205 cells, other
transformed primate cell lines, normal diploid cells, cell strains
derived from in vitro culture of primary tissue, primary explants,
HL-60, U937, HaK or Jurkat cells. Typically, a host cell is a
cultured cell that can be transformed or transfected with a
polypeptide-encoding nucleic acid, which can then be expressed in
the host cell. The phrase "recombinant host cell" can be used to
denote a host cell that has been transformed or transfected with a
nucleic acid to be expressed. A host cell also can be a cell that
comprises the nucleic acid but does not express it at a desired
level unless a regulatory sequence is introduced into the host cell
such that it becomes operably linked with the nucleic acid. It is
understood that the term host cell refers not only to the
particular subject cell but also to the progeny or potential
progeny of such a cell. Because certain modifications may occur in
succeeding generations due to, e.g., mutation or environmental
influence, such progeny may not, in fact, be identical to the
parent cell, but are still included within the scope of the term as
used herein.
[0065] Preferably, the mammalian cancer to be treated is selected
from the group consisting of ovarian, colon, breast or hepatic
carcinoma cell lines, myelomas, neuroblastic-derived CNS tumors,
monocytic leukemias, B-cell derived leukemia's, T-cell derived
leukemias, B-cell derived lymphomas, T-cell derived lymphomas, mast
cell derived tumors, and combinations thereof.
[0066] Polypeptides of the present disclosure can be produced using
any standard methods known in the art. In one example, the
polypeptides are produced by recombinant DNA methods by inserting a
nucleic acid sequence (e.g., a cDNA) encoding the polypeptide into
a recombinant expression vector and expressing the DNA sequence
under conditions promoting expression.
[0067] Nucleic acids encoding any of the various polypeptides
disclosed herein may be synthesized chemically. Codon usage may be
selected so as to improve expression in a cell. Such codon usage
will depend on the cell type selected. Specialized codon usage
patterns have been developed for E. coli and other bacteria, as
well as mammalian cells, plant cells, yeast cells and insect cells.
See for example: Mayfield et al., Proc. Natl. Acad. Sci. USA. 2003
100(2):438-42; Sinclair et al. Protein Expr. Purif. 2002
(1):96-105; Connell N D. Curr. Opin. Biotechnol. 2001 12(5):446-9;
Makrides et al. Microbiol. Rev. 1996 60(3):512-38; and Sharp et al.
Yeast. 1991 7(7):657-78.
[0068] General techniques for nucleic acid manipulation are
described for example in Sambrook et al., Molecular Cloning: A
Laboratory Manual, Vols. 1-3, Cold Spring Harbor Laboratory Press,
2 ed., 1989, or F. Ausubel et al., Current Protocols in Molecular
Biology (Green Publishing and Wiley-Interscience: New York, 1987)
and periodic updates, herein incorporated by reference. The DNA
encoding the polypeptide is operably linked to suitable
transcriptional or translational regulatory elements derived from
mammalian, viral, or insect genes. Such regulatory elements include
a transcriptional promoter, an optional operator sequence to
control transcription, a sequence encoding suitable mRNA ribosomal
binding sites, and sequences that control the termination of
transcription and translation. The ability to replicate in a host,
usually conferred by an origin of replication, and a selection gene
to facilitate recognition of transformants is additionally
incorporated.
[0069] The recombinant DNA can also include any type of protein tag
sequence that may be useful for purifying the protein. Examples of
protein tags include but are not limited to a histidine tag, a FLAG
tag, a myc tag, an HA tag, or a GST tag. Appropriate cloning and
expression vectors for use with bacterial, fungal, yeast, and
mammalian cellular hosts can be found in Cloning Vectors: A
Laboratory Manual, (Elsevier, N.Y., 1985).
[0070] The expression construct is introduced into the host cell
using a method appropriate to the host cell. A variety of methods
for introducing nucleic acids into host cells are known in the art,
including, but not limited to, electroporation; transfection
employing calcium chloride, rubidium chloride, calcium phosphate,
DEAE-dextran, or other substances; microprojectile bombardment;
lipofection; and infection (where the vector is an infectious
agent). Suitable host cells include prokaryotes, yeast, mammalian
cells, or bacterial cells.
[0071] Suitable bacteria include gram negative or gram positive
organisms, for example, E. coli or Bacillus spp. Yeast, preferably
from the Saccharomyces species, such as S. cerevisiae, may also be
used for production of polypeptides. Various mammalian or insect
cell culture systems can also be employed to express recombinant
proteins. Baculovirus systems for production of heterologous
proteins in insect cells are reviewed by Luckow and Summers,
(Bio/Technology, 6:47, 1988). Examples of suitable mammalian host
cell lines include endothelial cells, COS-7 monkey kidney cells,
CV-1, L cells, C127, 3T3, Chinese hamster ovary (CHO), human
embryonic kidney cells, HeLa, 293, 293T, and BHK cell lines.
Purified polypeptides are prepared by culturing suitable
host/vector systems to express the recombinant proteins. For many
applications, the small size of many of the polypeptides disclosed
herein would make expression in E. coli as the preferred method for
expression. The protein is then purified from culture media or cell
extracts.
[0072] Proteins disclosed herein can also be produced using
cell-translation systems. For such purposes the nucleic acids
encoding the polypeptide must be modified to allow in vitro
transcription to produce mRNA and to allow cell-free translation of
the mRNA in the particular cell-free system being utilized
(eukaryotic such as a mammalian or yeast cell-free translation
system or prokaryotic such as a bacterial cell-free translation
system.
[0073] PD-L1-binding polypeptides can also be produced by chemical
synthesis (e.g., by the methods described in Solid Phase Peptide
Synthesis, 2nd ed., 1984, The Pierce Chemical Co., Rockford, Ill.).
Modifications to the protein can also be produced by chemical
synthesis.
[0074] The polypeptides of the present disclosure can be purified
by isolation/purification methods for proteins generally known in
the field of protein chemistry. Non-limiting examples include
extraction, recrystallization, salting out (e.g., with ammonium
sulfate or sodium sulfate), centrifugation, dialysis,
ultrafiltration, adsorption chromatography, ion exchange
chromatography, hydrophobic chromatography, normal phase
chromatography, reversed-phase chromatography, gel filtration, gel
permeation chromatography, affinity chromatography,
electrophoresis, countercurrent distribution or any combinations of
these. After purification, polypeptides may be exchanged into
different buffers and/or concentrated by any of a variety of
methods known to the art, including, but not limited to, filtration
and dialysis.
[0075] The purified polypeptide is preferably at least 85% pure,
more preferably at least 95% pure, and most preferably at least 98%
pure. Regardless of the exact numerical value of the purity, the
polypeptide is sufficiently pure for use as a pharmaceutical
product.
Post-Translational Modifications of Polypeptides
[0076] In certain embodiments, the binding polypeptides of the
invention may further comprise post-translational modifications.
Exemplary post-translational protein modifications include
phosphorylation, acetylation, methylation, ADP-ribosylation,
ubiquitination, glycosylation, carbonylation, sumoylation,
biotinylation or addition of a polypeptide side chain or of a
hydrophobic group. As a result, the modified soluble polypeptides
may contain non-amino acid elements, such as lipids, poly- or
mono-saccharide, and phosphates. A preferred form of glycosylation
is sialylation, which conjugates one or more sialic acid moieties
to the polypeptide. Sialic acid moieties improve solubility and
serum half-life while also reducing the possible immunogeneticity
of the protein. See Raju et al. Biochemistry. 2001 31;
40(30):8868-76. Effects of such non-amino acid elements on the
functionality of a polypeptide may be tested for its antagonizing
role in PD-L1 or PD-1 function, e.g., its inhibitory effect on
angiogenesis or on tumor growth.
[0077] In one specific embodiment, modified forms of the subject
soluble polypeptides comprise linking the subject soluble
polypeptides to nonproteinaceous polymers. In one specific
embodiment, the polymer is polyethylene glycol ("PEG"),
polypropylene glycol, or polyoxyalkylenes, in the manner as set
forth in U.S. Pat. No. 4,640,835; 4,496,689; 4,301,144; 4,670,417;
4,791,192 or 4,179,337.
[0078] PEG is a water soluble polymer that is commercially
available or can be prepared by ring-opening polymerization of
ethylene glycol according to methods well known in the art (Sandler
and Karo, Polymer Synthesis, Academic Press, New York, Vol. 3,
pages 138-161). The term "PEG" is used broadly to encompass any
polyethylene glycol molecule, without regard to size or to
modification at an end of the PEG, and can be represented by the
formula: X--O(CH.sub.2CH.sub.2O).sub.n-1CH.sub.2CH.sub.2OH (1),
where n is 20 to 2300 and X is H or a terminal modification, e.g.,
a C.sub.14 alkyl. In one embodiment, the PEG of the invention
terminates on one end with hydroxy or methoxy, i.e., X is H or
CH.sub.3 ("methoxy PEG"). A PEG can contain further chemical groups
which are necessary for binding reactions; which results from the
chemical synthesis of the molecule; or which is a spacer for
optimal distance of parts of the molecule. In addition, such a PEG
can consist of one or more PEG side-chains which are linked
together. PEGs with more than one PEG chain are called multiarmed
or branched PEGs. Branched PEGs can be prepared, for example, by
the addition of polyethylene oxide to various polyols, including
glycerol, pentaerythriol, and sorbitol. For example, a four-armed
branched PEG can be prepared from pentaerythriol and ethylene
oxide. Branched PEG are described in, for example, EP-A 0 473 084
and U.S. Pat. No. 5,932,462. One form of PEGs includes two PEG
side-chains (PEG2) linked via the primary amino groups of a lysine
(Monfardini et al., Bioconjugate Chem. 6 (1995) 62-69).
[0079] Although PEG is well-known, this is, to our knowledge, the
first demonstration that a pegylated.sup.10Fn3 polypeptide can be
pegylated and retain ligand binding activity. In a preferred
embodiment, the pegylated.sup.10Fn3 polypeptide is produced by
site-directed pegylation, particularly by conjugation of PEG to a
cysteine moiety at the N- or C-terminus. Accordingly, the present
disclosure provides a target-binding .sup.10Fn3 polypeptide with
improved pharmacokinetic properties, the polypeptide comprising: a
.sup.10Fn3 domain having from about 80 to about 150 amino acids,
wherein at least one of the loops of said .sup.10Fn3 domain
participate in target binding; and a covalently bound PEG moiety,
wherein said .sup.10Fn3 polypeptide binds to the target with a
K.sub.D of less than 100 nM and has a clearance rate of less than
30 mL/hr/kg in a mammal. The PEG moiety may be attached to the
.sup.10Fn3 polypeptide by site directed pegylation, such as by
attachment to a Cys residue, where the Cys residue may be
positioned at the N-terminus of the .sup.0Fn3 polypeptide or
between the N-terminus and the most N-terminal beta or beta-like
strand or at the C-terminus of the .sup.10Fn3 polypeptide or
between the C-terminus and the most C-terminal beta or beta-like
strand. A Cys residue may be situated at other positions as well,
particularly any of the loops that do not participate in target
binding. A PEG moiety may also be attached by other chemistry,
including by conjugation to amines.
[0080] PEG conjugation to peptides or proteins generally involves
the activation of PEG and coupling of the activated
PEG-intermediates directly to target proteins/peptides or to a
linker, which is subsequently activated and coupled to target
proteins/peptides (see Abuchowski et al., J. Biol. Chem., 252, 3571
(1977) and J. Biol. Chem., 252, 3582 (1977), Zalipsky, et al., and
Harris et. al., in: Poly(ethylene glycol)Chemistry: Biotechnical
and Biomedical Applications; (J. M. Harris ed.) Plenum Press: New
York, 1992; Chap. 21 and 22). It is noted that a binding
polypeptide containing a PEG molecule is also known as a conjugated
protein, whereas the protein lacking an attached PEG molecule can
be referred to as unconjugated.
[0081] A variety of molecular mass forms of PEG can be selected,
e.g., from about 1,000 Daltons (Da) to 100,000 Da (n is 20 to
2300), for conjugating to PD-L1-binding polypeptides. The number of
repeating units "n" in the PEG is approximated for the molecular
mass described in Daltons. It is preferred that the combined
molecular mass of PEG on an activated linker is suitable for
pharmaceutical use. Thus, in one embodiment, the molecular mass of
the PEG molecules does not exceed 100,000 Da. For example, if three
PEG molecules are attached to a linker, where each PEG molecule has
the same molecular mass of 12,000 Da (each n is about 270), then
the total molecular mass of PEG on the linker is about 36,000 Da
(total n is about 820). The molecular masses of the PEG attached to
the linker can also be different, e.g., of three molecules on a
linker two PEG molecules can be 5,000 Da each (each n is about 110)
and one PEG molecule can be 12,000 Da (n is about 270).
[0082] In a specific embodiment of the disclosure an PD-L1 binding
polypeptide is covalently linked to one poly(ethylene glycol) group
of the formula:
--CO--(CH.sub.2).sub.x--(OCH.sub.2CH.sub.2).sub.m--OR, with the
--CO (i.e. carbonyl) of the poly(ethylene glycol) group forming an
amide bond with one of the amino groups of the binding polypeptide;
R being lower alkyl; x being 2 or 3; m being from about 450 to
about 950; and n and m being chosen so that the molecular weight of
the conjugate minus the binding polypeptide is from about 10 to 40
kDa. In one embodiment, a binding polypeptide's 6-amino group of a
lysine is the available (free) amino group.
[0083] The above conjugates may be more specifically presented by
formula (II):
P--NHCO--(CH.sub.2).sub.x--(OCH.sub.2CH.sub.2).sub.m--OR (II),
wherein P is the group of a binding polypeptide as described
herein, (i.e. without the amino group or amino groups which form an
amide linkage with the carbonyl shown in formula (II); and wherein
R is lower alkyl; x is 2 or 3; m is from about 450 to about 950 and
is chosen so that the molecular weight of the conjugate minus the
binding polypeptide is from about 10 to about 40 kDa. As used
herein, the given ranges of "m" have an orientational meaning. The
ranges of "m" are determined in any case, and exactly, by the
molecular weight of the PEG group.
[0084] One skilled in the art can select a suitable molecular mass
for PEG, e.g., based on how the pegylated binding polypeptide will
be used therapeutically, the desired dosage, circulation time,
resistance to proteolysis, immunogenicity, and other
considerations. For a discussion of PEG and its use to enhance the
properties of proteins, see Katre, Advanced Drug Delivery Reviews
10: 91-114 (1993).
[0085] In one embodiment, PEG molecules may be activated to react
with amino groups on a binding polypeptide, such as with lysines
(Bencham et al., Anal. Biochem., 131, 25 (1983); Veronese et al.,
Appl. Biochem., 11, 141 (1985).; Zalipsky et al., Polymeric Drugs
and Drug Delivery Systems, adrs 9-110 ACS Symposium Series 469
(1999); Zalipsky et al., Europ. Polym. J., 19, 1177-1183 (1983);
Delgado et al., Biotechnology and Applied Biochemistry, 12, 119-128
(1990)).
[0086] In one specific embodiment, carbonate esters of PEG are used
to form the PEG-binding polypeptide conjugates.
N,N'-disuccinimidylcarbonate (DSC) may be used in the reaction with
PEG to form active mixed PEG-succinimidyl carbonate that may be
subsequently reacted with a nucleophilic group of a linker or an
amino group of a binding polypeptide (see U.S. Pat. Nos. 5,281,698
and 5,932,462). In a similar type of reaction,
1,1'-(dibenzotriazolyl)carbonate and di-(2-pyridyl)carbonate may be
reacted with PEG to form PEG-benzotriazolyl and PEG-pyridyl mixed
carbonate (U.S. Pat. No. 5,382,657), respectively.
[0087] Pegylation of a .sup.10Fn3 polypeptide can be performed
according to the methods of the state of the art, for example by
reaction of the binding polypeptide with electrophilically active
PEGs (supplier: Shearwater Corp., USA, www.shearwatercorp.com).
Preferred PEG reagents of the present invention are, e.g.,
N-hydroxysuccinimidyl propionates (PEG-SPA), butanoates (PEG-SBA),
PEG-succinimidyl propionate or branched N-hydroxysuccinimides such
as mPEG2-NHS (Monfardini et al., Bioconjugate Chem. 6 (1995)
62-69). Such methods may used to pegylated at an f-amino group of a
binding polypeptide lysine or the N-terminal amino group of the
binding polypeptide.
[0088] In another embodiment, PEG molecules may be coupled to
sulfhydryl groups on a binding polypeptide (Sartore et al., Appl.
Biochem. Biotechnol., 27, 45 (1991); Morpurgo et al., Biocon.
Chem., 7, 363-368 (1996); Goodson et al., Bio/Technology (1990) 8,
343; U.S. Pat. No. 5,766,897). U.S. Pat. Nos. 6,610,281 and
5,766,897 describes exemplary reactive PEG species that may be
coupled to sulfhydryl groups.
[0089] In some embodiments where PEG molecules are conjugated to
cysteine residues on a binding polypeptide, the cysteine residues
are native to the binding polypeptide, whereas in other
embodiments, one or more cysteine residues are engineered into the
binding polypeptide. Mutations may be introduced into a binding
polypeptide coding sequence to generate cysteine residues. This
might be achieved, for example, by mutating one or more amino acid
residues to cysteine. Preferred amino acids for mutating to a
cysteine residue include serine, threonine, alanine and other
hydrophilic residues. Preferably, the residue to be mutated to
cysteine is a surface-exposed residue. Algorithms are well-known in
the art for predicting surface accessibility of residues based on
primary sequence or a protein. Alternatively, surface residues may
be predicted by comparing the amino acid sequences of binding
polypeptides, given that the crystal structure of the framework
based on which binding polypeptides are designed and evolved has
been solved (see Himanen et al., Nature. (2001) 20-27;
414(6866):933-8) and thus the surface-exposed residues identified.
In one embodiment, cysteine residues are introduced into binding
polypeptides at or near the N- and/or C-terminus, or within loop
regions.
[0090] In some embodiments, the pegylated binding polypeptide
comprises a PEG molecule covalently attached to the alpha amino
group of the N-terminal amino acid. Site specific N-terminal
reductive amination is described in Pepinsky et al., (2001) JPET,
297, 1059, and U.S. Pat. No. 5,824,784. The use of a PEG-aldehyde
for the reductive amination of a protein utilizing other available
nucleophilic amino groups is described in U.S. Pat. No. 4,002,531,
in Wieder et al., (1979) J. Biol. Chem. 254,12579, and in Chamow et
al., (1994) Bioconjugate Chem. 5, 133.
[0091] In another embodiment, pegylated binding polypeptide
comprises one or more PEG molecules covalently attached to a
linker, which in turn is attached to the alpha amino group of the
amino acid residue at the N-terminus of the binding polypeptide.
Such an approach is disclosed in U.S. Patent Publication
2002/0044921 and in WO094/01451.
[0092] In one embodiment, a binding polypeptide is pegylated at the
C-terminus. In a specific embodiment, a protein is pegylated at the
C-terminus by the introduction of C-terminal azido-methionine and
the subsequent conjugation of a methyl-PEG-triarylphosphine
compound via the Staudinger reaction. This C-terminal conjugation
method is described in Cazalis et al., Bioconjug. Chem. 2004;
15(5):1005-1009.
[0093] Monopegylation of a binding polypeptide can also be produced
according to the general methods described in WO 94/01451. WO
94/01451 describes a method for preparing a recombinant polypeptide
with a modified terminal amino acid alpha-carbon reactive group.
The steps of the method involve forming the recombinant polypeptide
and protecting it with one or more biologically added protecting
groups at the N-terminal alpha-amine and C-terminal alpha-carboxyl.
The polypeptide can then be reacted with chemical protecting agents
to selectively protect reactive side chain groups and thereby
prevent side chain groups from being modified. The polypeptide is
then cleaved with a cleavage reagent specific for the biological
protecting group to form an unprotected terminal amino acid
alpha-carbon reactive group. The unprotected terminal amino acid
alpha-carbon reactive group is modified with a chemical modifying
agent. The side chain protected terminally modified single copy
polypeptide is then deprotected at the side chain groups to form a
terminally modified recombinant single copy polypeptide. The number
and sequence of steps in the method can be varied to achieve
selective modification at the N- and/or C-terminal amino acid of
the polypeptide.
[0094] The ratio of a binding polypeptide to activated PEG in the
conjugation reaction can be from about 1:0.5 to 1:50, between from
about 1:1 to 1:30, or from about 1:5 to 1:15. Various aqueous
buffers can be used in the present method to catalyze the covalent
addition of PEG to the binding polypeptide. In one embodiment, the
pH of a buffer used is from about 7.0 to 9.0. In another
embodiment, the pH is in a slightly basic range, e.g., from about
7.5 to 8.5. Buffers having a pKa close to neutral pH range may be
used, e.g., phosphate buffer.
[0095] Conventional separation and purification techniques known in
the art can be used to purify PEGylated binding polypeptide, such
as size exclusion (e.g. gel filtration) and ion exchange
chromatography. Products may also be separated using SDS-PAGE.
Products that may be separated include mono-, di-, tri- poly- and
un-pegylated binding polypeptide, as well as free PEG. The
percentage of mono-PEG conjugates can be controlled by pooling
broader fractions around the elution peak to increase the
percentage of mono-PEG in the composition. About ninety percent
mono-PEG conjugates represents a good balance of yield and
activity. Compositions in which, for example, at least ninety-two
percent or at least ninety-six percent of the conjugates are
mono-PEG species may be desired. In an embodiment of this invention
the percentage of mono-PEG conjugates is from ninety percent to
ninety-six percent.
[0096] In one embodiment, PEGylated binding polypeptide of the
invention contain one, two or more PEG moieties. In one embodiment,
the PEG moiety(ies) are bound to an amino acid residue which is on
the surface of the protein and/or away from the surface that
contacts the target ligand. In one embodiment, the combined or
total molecular mass of PEG in PEG-binding polypeptide is from
about 3,000 Da to 60,000 Da, optionally from about 10,000 Da to
36,000 Da. In a one embodiment, the PEG in pegylated binding
polypeptide is a substantially linear, straight-chain PEG.
[0097] In one embodiment of the invention, the PEG in pegylated
binding polypeptide is not hydrolyzed from the pegylated amino acid
residue using a hydroxylamine assay, e.g., 450 mM hydroxylamine (pH
6.5) over 8 to 16 hours at room temperature, and is thus stable. In
one embodiment, greater than 80% of the composition is stable
mono-PEG-binding polypeptide, more preferably at least 90%, and
most preferably at least 95%.
[0098] In another embodiment, the pegylated binding polypeptides of
the invention will preferably retain at least 25%, 50%, 60%, 70%,
80%, 85%, 90%, 95% or 100% of the biological activity associated
with the unmodified protein. In one embodiment, biological activity
refers to its ability to bind to PD-L1, as assessed by KD, k.sub.on
or k.sub.off. In one specific embodiment, the pegylated binding
polypeptide protein shows an increase in binding to PD-L1 relative
to unpegylated binding polypeptide.
[0099] The serum clearance rate of PEG-modified polypeptide may be
decreased by about 10%, 20%, 30%, 40%, 50%, 60%, 70%, 80%, or even
90%, relative to the clearance rate of the unmodified binding
polypeptide. The PEG-modified polypeptide may have a half-life
(t.sub.1/2) which is enhanced relative to the half-life of the
unmodified protein. The half-life of PEG-binding polypeptide may be
enhanced by at least 10%, 20%, 30%, 40%, 50%, 60%, 70%, 80%, 90%,
100%, 125%, 150%, 175%, 200%, 250%, 300%, 400% or 500%, or even by
1000% relative to the half-life of the unmodified binding
polypeptide. In some embodiments, the protein half-life is
determined in vitro, such as in a buffered saline solution or in
serum. In other embodiments, the protein half-life is an in vivo
half life, such as the half-life of the protein in the serum or
other bodily fluid of an animal.
Therapeutic Formulations and Modes of Administration
[0100] The present disclosure features methods for treating
conditions or preventing pre-conditions which respond to an
inhibition of PD-L1 biological activity. Preferred examples are
conditions that are characterized by inflammation or cellular
hyperproliferation. Techniques and dosages for administration vary
depending on the type of specific polypeptide and the specific
condition being treated but can be readily determined by the
skilled artisan. In general, regulatory agencies require that a
protein reagent to be used as a therapeutic is formulated so as to
have acceptably low levels of pyrogens. Accordingly, therapeutic
formulations will generally be distinguished from other
formulations in that they are substantially pyrogen free, or at
least contain no more than acceptable levels of pyrogen as
determined by the appropriate regulatory agency (e.g., FDA).
[0101] Therapeutic compositions of the present disclosure may be
administered with a pharmaceutically acceptable diluent, carrier,
or excipient, in unit dosage form. Administration may be parenteral
(e.g., intravenous, subcutaneous), oral, or topical, as
non-limiting examples. In addition, any gene therapy technique,
using nucleic acids encoding the polypeptides of the invention, may
be employed, such as naked DNA delivery, recombinant genes and
vectors, cell-based delivery, including ex vivo manipulation of
patients' cells, and the like.
[0102] The composition can be in the form of a pill, tablet,
capsule, liquid, or sustained release tablet for oral
administration; or a liquid for intravenous, subcutaneous or
parenteral administration; gel, lotion, ointment, cream, or a
polymer or other sustained release vehicle for local
administration.
[0103] Methods well known in the art for making formulations are
found, for example, in "Remington: The Science and Practice of
Pharmacy" (20th ed., ed. A. R. Gennaro A R., 2000, Lippincott
Williams & Wilkins, Philadelphia, Pa.). Formulations for
parenteral administration may, for example, contain excipients,
sterile water, saline, polyalkylene glycols such as polyethylene
glycol, oils of vegetable origin, or hydrogenated napthalenes.
Biocompatible, biodegradable lactide polymer, lactide/glycolide
copolymer, or polyoxyethylene-polyoxypropylene copolymers may be
used to control the release of the compounds. Nanoparticulate
formulations (e.g., biodegradable nanoparticles, solid lipid
nanoparticles, liposomes) may be used to control the
biodistribution of the compounds. Other potentially useful
parenteral delivery systems include ethylene-vinyl acetate
copolymer particles, osmotic pumps, implantable infusion systems,
and liposomes. The concentration of the compound in the formulation
varies depending upon a number of factors, including the dosage of
the drug to be administered, and the route of administration.
[0104] The polypeptide may be optionally administered as a
pharmaceutically acceptable salt, such as non-toxic acid addition
salts or metal complexes that are commonly used in the
pharmaceutical industry. Examples of acid addition salts include
organic acids such as acetic, lactic, pamoic, maleic, citric,
malic, ascorbic, succinic, benzoic, palmitic, suberic, salicylic,
tartaric, methanesulfonic, toluenesulfonic, or trifluoroacetic
acids or the like; polymeric acids such as tannic acid,
carboxymethyl cellulose, or the like; and inorganic acid such as
hydrochloric acid, hydrobromic acid, sulfuric acid phosphoric acid,
or the like. Metal complexes include zinc, iron, and the like. In
one example, the polypeptide is formulated in the presence of
sodium acetate to increase thermal stability.
[0105] Formulations for oral use include tablets containing the
active ingredient(s) in a mixture with non-toxic pharmaceutically
acceptable excipients. These excipients may be, for example, inert
diluents or fillers (e.g., sucrose and sorbitol), lubricating
agents, glidants, and anti-adhesives (e.g., magnesium stearate,
zinc stearate, stearic acid, silicas, hydrogenated vegetable oils,
or talc).
[0106] Formulations for oral use may also be provided as chewable
tablets, or as hard gelatin capsules wherein the active ingredient
is mixed with an inert solid diluent, or as soft gelatin capsules
wherein the active ingredient is mixed with water or an oil
medium.
[0107] A therapeutically effective dose refers to a dose that
produces the therapeutic effects for which it is administered. The
exact dose will depend on the disorder to be treated, and may be
ascertained by one skilled in the art using known techniques. In
general, the polypeptide is administered at about 0.01 .mu.g/kg to
about 50 mg/kg per day, preferably 0.01 mg/kg to about 30 mg/kg per
day, most preferably 0.1 mg/kg to about 20 mg/kg per day. The
polypeptide may be given daily (e.g., once, twice, three times, or
four times daily) or preferably less frequently (e.g., weekly,
every two weeks, every three weeks, monthly, or quarterly). In
addition, as is known in the art, adjustments for age as well as
the body weight, general health, sex, diet, time of administration,
drug interaction, and the severity of the disease may be necessary,
and will be ascertainable with routine experimentation by those
skilled in the art.
Pharmaceutical Formulations of Disclosed Antibodies with Tumor
Vaccines
[0108] A combined therapeutic product or formulation of a disclosed
anti-PD-L1 antibody with a therapeutic vaccine provides synergistic
oncologic therapeutic benefit. For example, the present disclosure
provides a combination of a disclosed anti-PD-L1 antibody with
"Neuvax" which is a E75-derived 9 mer synthetic peptide isolated
from HER2/neu combined with GM-CSF as an adjuvant as described in
U.S. Pat. No. 8,222,214, the disclosure of which is incorporated by
reference herein. In addition, the present disclosure provides a
combination of a disclosed anti-PD-L1 antibody with ALVAC-CEA
vaccine, which is a canary pox virus combined with carcinoembryonic
antigen.
Exemplary Uses
[0109] The PD-L1 binding proteins described herein and their
related variants are useful in a number of therapeutic and
diagnostic applications. These include the inhibition of the
biological activity of PD-L1 by competing for or blocking the
binding to a PD-L1 as well as the delivery of cytotoxic or imaging
moieties to cells, preferably cells expressing PD-L1. The small
size and stable structure of these molecules can be particularly
valuable with respect to manufacturing of the drug, rapid clearance
from the body for certain applications where rapid clearance is
desired or formulation into novel delivery systems that are
suitable or improved using a molecule with such
characteristics.
[0110] On the basis of their efficacy as inhibitors of PD-L1
biological activity, the polypeptides of this disclosure are
effective against a number of cancer conditions as well as
complications arising from cancer, such as pleural effusion and
ascites. Preferably, the PD-L1-binding polypeptides of the
disclosure can be used for the treatment of prevention of
hyperproliferative diseases or cancer and the metastatic spread of
cancers. Preferred indications for the disclosed anti-PD-L1
antibodies include colorectal cancers, head and neck cancers, small
cell lung cancer, non-small cell lung cancer (NSCLC) and pancreatic
cancer. Non-limiting examples of cancers include bladder, blood,
bone, brain, breast, cartilage, colon kidney, liver, lung, lymph
node, nervous tissue, ovary, pancreatic, prostate, skeletal muscle,
skin, spinal cord, spleen, stomach, testes, thymus, thyroid,
trachea, urogenital tract, ureter, urethra, uterus, or vaginal
cancer.
[0111] In addition, various inflammatory disorders can be treated
with the disclosed anti-PD-L1 binding polypeptides disclosed
herein. Such inflammatory disorders include, for example,
intestinal mucosa inflammation wasting diseases associated with
colitis, multiple sclerosis, systemic lupus erythematosus, viral
infections, rheumatoid arthritis, osteoarthritis, psoriasis, and
Crohn's disease.
[0112] A PD-L1 binding polypeptide can be administered alone or in
combination with one or more additional therapies such as
chemotherapy radiotherapy, immunotherapy, surgical intervention, or
any combination of these. Long-term therapy is equally possible as
is adjuvant therapy in the context of other treatment strategies,
as described above.
[0113] In certain embodiments of such methods, one or more
polypeptide therapeutic agents can be administered, together
(simultaneously) or at different times (sequentially). In addition,
polypeptide therapeutic agents can be administered with another
type of compounds for treating cancer or for inhibiting
angiogenesis.
[0114] In certain embodiments, the subject anti-PD-L1 antibodies
agents of the invention can be used alone. Alternatively, the
subject agents may be used in combination with other conventional
anti-cancer therapeutic approaches directed to treatment or
prevention of proliferative disorders (e.g., tumor). For example,
such methods can be used in prophylactic cancer prevention,
prevention of cancer recurrence and metastases after surgery, and
as an adjuvant of other conventional cancer therapy. The present
disclosure recognizes that the effectiveness of conventional cancer
therapies (e.g., chemotherapy, radiation therapy, phototherapy,
immunotherapy, and surgery) can be enhanced through the use of a
subject polypeptide therapeutic agent.
[0115] A wide array of conventional compounds have been shown to
have anti-neoplastic activities. These compounds have been used as
pharmaceutical agents in chemotherapy to shrink solid tumors,
prevent metastases and further growth, or decrease the number of
malignant cells in leukemic or bone marrow malignancies. Although
chemotherapy has been effective in treating various types of
malignancies, many anti-neoplastic compounds induce undesirable
side effects. It has been shown that when two or more different
treatments are combined, the treatments may work synergistically
and allow reduction of dosage of each of the treatments, thereby
reducing the detrimental side effects exerted by each compound at
higher dosages. In other instances, malignancies that are
refractory to a treatment may respond to a combination therapy of
two or more different treatments.
[0116] When a polypeptide therapeutic agent of the present
invention is administered in combination with another conventional
anti-neoplastic agent, either concomitantly or sequentially, such
therapeutic agent may be found to enhance the therapeutic effect of
the anti-neoplastic agent or overcome cellular resistance to such
anti-neoplastic agent. This allows decrease of dosage of an
anti-neoplastic agent, thereby reducing the undesirable side
effects, or restores the effectiveness of an anti-neoplastic agent
in resistant cells.
[0117] Pharmaceutical compounds that may be used for combinatory
anti-tumor therapy include, merely to illustrate:
aminoglutethimide, amsacrine, anastrozole, asparaginase, bcg,
bicalutamide, bleomycin, buserelin, busulfan, campothecin,
capecitabine, carboplatin, carmustine, chlorambucil, cisplatin,
cladribine, clodronate, colchicine, cyclophosphamide, cyproterone,
cytarabine, dacarbazine, dactinomycin, daunorubicin, dienestrol,
diethylstilbestrol, docetaxel, doxorubicin, epirubicin, estradiol,
estramustine, etoposide, exemestane, filgrastim, fludarabine,
fludrocortisone, fluorouracil, fluoxymesterone, flutamide,
gemcitabine, genistein, goserelin, hydroxyurea, idarubicin,
ifosfamide, imatinib, interferon, irinotecan, ironotecan,
letrozole, leucovorin, leuprolide, levamisole, lomustine,
mechlorethamine, medroxyprogesterone, megestrol, melphalan,
mercaptopurine, mesna, methotrexate, mitomycin, mitotane,
mitoxantrone, nilutamide, nocodazole, octreotide, oxaliplatin,
paclitaxel, pamidronate, pentostatin, plicamycin, porfimer,
procarbazine, raltitrexed, rituximab, streptozocin, suramin,
tamoxifen, temozolomide, teniposide, testosterone, thioguanine,
thiotepa, titanocene dichloride, topotecan, trastuzumab, tretinoin,
vinblastine, vincristine, vindesine, and vinorelbine.
[0118] Certain chemotherapeutic anti-tumor compounds may be
categorized by their mechanism of action into, for example,
following groups: anti-metabolites/anti-cancer agents, such as
pyrimidine analogs (5-fluorouracil, floxuridine, capecitabine,
gemcitabine and cytarabine) and purine analogs, folate antagonists
and related inhibitors (mercaptopurine, thioguanine, pentostatin
and 2-chlorodeoxyadenosine (cladribine));
antiproliferative/antimitotic agents including natural products
such as vinca alkaloids (vinblastine, vincristine, and
vinorelbine), microtubule disruptors such as taxane (paclitaxel,
docetaxel), vincristin, vinblastin, nocodazole, epothilones and
navelbine, epidipodophyllotoxins (etoposide, teniposide), DNA
damaging agents (actinomycin, amsacrine, anthracyclines, bleomycin,
busulfan, camptothecin, carboplatin, chlorambucil, cisplatin,
cyclophosphamide, cytoxan, dactinomycin, daunorubicin, doxorubicin,
epirubicin, hexamethylmelamineoxaliplatin, iphosphamide, melphalan,
merchlorehtamine, mitomycin, mitoxantrone, nitrosourea, plicamycin,
procarbazine, taxol, taxotere, teniposide,
triethylenethiophosphoramide and etoposide (VP16)); antibiotics
such as dactinomycin (actinomycin D), daunorubicin, doxorubicin
(adriamycin), idarubicin, anthracyclines, mitoxantrone, bleomycins,
plicamycin (mithramycin) and mitomycin; enzymes (L-asparaginase
which systemically metabolizes L-asparagine and deprives cells
which do not have the capacity to synthesize their own asparagine);
antiplatelet agents; antiproliferative/antimitotic alkylating
agents such as nitrogen mustards (mechlorethamine, cyclophosphamide
and analogs, melphalan, chlorambucil), ethylenimines and
methylmelamines (hexamethylmelamine and thiotepa), alkyl
sulfonates-busulfan, nitrosoureas (carmustine (BCNU) and analogs,
streptozocin), trazenes-dacarbazinine (DTIC);
antiproliferative/antimitotic antimetabolites such as folic acid
analogs (methotrexate); platinum coordination complexes (cisplatin,
carboplatin), procarbazine, hydroxyurea, mitotane,
aminoglutethimide; hormones, hormone analogs (estrogen, tamoxifen,
goserelin, bicalutamide, nilutamide) and aromatase inhibitors
(letrozole, anastrozole); anticoagulants (heparin, synthetic
heparin salts and other inhibitors of thrombin); fibrinolytic
agents (such as tissue plasminogen activator, streptokinase and
urokinase), aspirin, dipyridamole, ticlopidine, clopidogrel,
abciximab; antimigratory agents; antisecretory agents (breveldin);
immunosuppressives (cyclosporine, tacrolimus (FK-506), sirolimus
(rapamycin), azathioprine, mycophenolate mofetil); anti-angiogenic
compounds (TNP-470, genistein) and growth factor inhibitors (e.g.,
VEGF inhibitors, fibroblast growth factor (FGF) inhibitors);
angiotensin receptor blocker; nitric oxide donors; anti-sense
oligonucleotides; antibodies (trastuzumab); cell cycle inhibitors
and differentiation inducers (tretinoin); mTOR inhibitors,
topoisomerase inhibitors (doxorubicin (adriamycin), amsacrine,
camptothecin, daunorubicin, dactinomycin, eniposide, epirubicin,
etoposide, idarubicin and mitoxantrone, topotecan, irinotecan),
corticosteroids (cortisone, dexamethasone, hydrocortisone,
methylpednisolone, prednisone, and prenisolone); growth factor
signal transduction kinase inhibitors; mitochondrial dysfunction
inducers and caspase activators; and chromatin disruptors.
[0119] Depending on the nature of the combinatory therapy,
administration of the polypeptide therapeutic agents may be
continued while the other therapy is being administered and/or
thereafter. Administration of the polypeptide therapeutic agents
may be made in a single dose, or in multiple doses. In some
instances, administration of the polypeptide therapeutic agents is
commenced at least several days prior to the conventional therapy,
while in other instances, administration is begun either
immediately before or at the time of the administration of the
conventional therapy.
[0120] In one example of a diagnostic application, a biological
sample, such as serum or a tissue biopsy, from a patient suspected
of having a condition characterized by inappropriate angiogenesis
is contacted with a detectably labeled polypeptide of the
disclosure to detect levels of PD-L1. The levels of PD-L1 detected
are then compared to levels of PD-L1 detected in a normal sample
also contacted with the labeled polypeptide. An increase of at
least 10%, 20%, 30%, 40%, 50%, 60%, 70%, 80%, or 90% in the levels
of the PD-L1 may be considered a diagnostic indicator.
[0121] In certain embodiments, the PD-L1 binding polypeptides are
further attached to a label that is able to be detected (e.g., the
label can be a radioisotope, fluorescent compound, enzyme or enzyme
co-factor). The active moiety may be a radioactive agent, such as:
radioactive heavy metals such as iron chelates, radioactive
chelates of gadolinium or manganese, positron emitters of oxygen,
nitrogen, iron, carbon, or gallium, .sup.43K, .sup.52Fe, .sup.57Co,
.sup.67Cu, .sup.67Ga, .sup.68Ga, .sup.123I, .sup.125I, .sup.131I,
.sup.132I, or .sup.99Tc. A binding agent affixed to such a moiety
may be used as an imaging agent and is administered in an amount
effective for diagnostic use in a mammal such as a human and the
localization and accumulation of the imaging agent is then
detected. The localization and accumulation of the imaging agent
may be detected by radioscintigraphy, nuclear magnetic resonance
imaging, computed tomography or positron emission tomography.
Immunoscintigraphy using PD-L1 binding polypeptides directed at
PD-L1 may be used to detect and/or diagnose cancers and
vasculature. For example, any of the binding polypeptide against a
PD-L1 marker labeled with .sup.99Technetium, .sup.111Indium, or
.sup.125Iodine may be effectively used for such imaging. As will be
evident to the skilled artisan, the amount of radioisotope to be
administered is dependent upon the radioisotope. Those having
ordinary skill in the art can readily formulate the amount of the
imaging agent to be administered based upon the specific activity
and energy of a given radionuclide used as the active moiety.
Typically 0.1-100 millicuries per dose of imaging agent, preferably
1-10 millicuries, most often 2-5 millicuries are administered.
Thus, compositions according to the present invention useful as
imaging agents comprising a targeting moiety conjugated to a
radioactive moiety comprise 0.1-100 millicuries, in some
embodiments preferably 1-10 millicuries, in some embodiments
preferably 2-5 millicuries, in some embodiments more preferably 1-5
millicuries.
[0122] The PD-L1 binding polypeptides can also be used to deliver
additional therapeutic agents (including but not limited to drug
compounds, chemotherapeutic compounds, and radiotherapeutic
compounds) to a cell or tissue expressing PD-L1. In one example,
the PD-L1 binding polypeptide is fused to a chemotherapeutic agent
for targeted delivery of the chemotherapeutic agent to a tumor cell
or tissue expressing PD-L1.
[0123] The PD-L1 binding polypeptides are useful in a variety of
applications, including research, diagnostic and therapeutic
applications. For instance, they can be used to isolate and/or
purify receptor or portions thereof, and to study receptor
structure (e.g., conformation) and function.
[0124] In certain aspects, the various binding polypeptides can be
used to detect or measure the expression of PD-L1, for example, on
endothelial cells (e.g., venous endothelial cells), or on cells
transfected with a PD-L1 gene. Thus, they also have utility in
applications such as cell sorting and imaging (e.g., flow
cytometry, and fluorescence activated cell sorting), for diagnostic
or research purposes.
[0125] In certain embodiments, the binding polypeptides of
fragments thereof can be labeled or unlabeled for diagnostic
purposes. Typically, diagnostic assays entail detecting the
formation of a complex resulting from the binding of a binding
polypeptide to PD-L1. The binding polypeptides or fragments can be
directly labeled, similar to antibodies. A variety of labels can be
employed, including, but not limited to, radionuclides,
fluorescers, enzymes, enzyme substrates, enzyme cofactors, enzyme
inhibitors and ligands (e.g., biotin, haptens). Numerous
appropriate immunoassays are known to the skilled artisan (U.S.
Pat. Nos. 3,817,827; 3,850,752; 3,901,654; and 4,098,876). When
unlabeled, the binding polypeptides can be used in assays, such as
agglutination assays. Unlabeled binding polypeptides can also be
used in combination with another (one or more) suitable reagent
which can be used to detect the binding polypeptide, such as a
labeled antibody reactive with the binding polypeptide or other
suitable reagent (e.g., labeled protein A).
[0126] In one embodiment, the binding polypeptides of the present
invention can be utilized in enzyme immunoassays, wherein the
subject polypeptides are conjugated to an enzyme. When a biological
sample comprising a PD-L1 protein is combined with the subject
binding polypeptides, binding occurs between the binding
polypeptides and the PD-L1 protein. In one embodiment, a sample
containing cells expressing a PD-L1 protein (e.g., endothelial
cells) is combined with the subject antibodies, and binding occurs
between the binding polypeptides and cells bearing a PD-L1 protein
recognized by the binding polypeptide. These bound cells can be
separated from unbound reagents and the presence of the binding
polypeptide-enzyme conjugate specifically bound to the cells can be
determined, for example, by contacting the sample with a substrate
of the enzyme which produces a color or other detectable change
when acted on by the enzyme. In another embodiment, the subject
binding polypeptides can be unlabeled, and a second, labeled
polypeptide (e.g., an antibody) can be added which recognizes the
subject binding polypeptide.
[0127] In certain aspects, kits for use in detecting the presence
of a PD-L1 protein in a biological sample can also be prepared.
Such kits will include a PD-L1 binding polypeptide which binds to a
PD-L1 protein or portion of said receptor, as well as one or more
ancillary reagents suitable for detecting the presence of a complex
between the binding polypeptide and the receptor protein or
portions thereof. The polypeptide compositions of the present
invention can be provided in lyophilized form, either alone or in
combination with additional antibodies specific for other epitopes.
The binding polypeptides and/or antibodies, which can be labeled or
unlabeled, can be included in the kits with adjunct ingredients
(e.g., buffers, such as Tris, phosphate and carbonate, stabilizers,
excipients, biocides and/or inert proteins, e.g., bovine serum
albumin). For example, the binding polypeptides and/or antibodies
can be provided as a lyophilized mixture with the adjunct
ingredients, or the adjunct ingredients can be separately provided
for combination by the user. Generally these adjunct materials will
be present in less than about 5% weight based on the amount of
active binding polypeptide or antibody, and usually will be present
in a total amount of at least about 0.001% weight based on
polypeptide or antibody concentration. Where a second antibody
capable of binding to the binding polypeptide is employed, such
antibody can be provided in the kit, for instance in a separate
vial or container. The second antibody, if present, is typically
labeled, and can be formulated in an analogous manner with the
antibody formulations described above.
[0128] Similarly, the present disclosure also provides a method of
detecting and/or quantitating expression of PD-L1, wherein a
composition comprising a cell or fraction thereof (e.g., membrane
fraction) is contacted with a binding polypeptide which binds to a
PD-L1 or portion of the receptor under conditions appropriate for
binding thereto, and the binding is monitored. Detection of the
binding polypeptide, indicative of the formation of a complex
between binding polypeptide and PD-L1 or a portion thereof,
indicates the presence of the receptor. Binding of a polypeptide to
the cell can be determined by standard methods, such as those
described in the working examples. The method can be used to detect
expression of PD-L1 on cells from an individual. Optionally, a
quantitative expression of PD-L1 on the surface of endothelial
cells can be evaluated, for instance, by flow cytometry, and the
staining intensity can be correlated with disease susceptibility,
progression or risk.
[0129] The present disclosure also provides a method of detecting
the susceptibility of a mammal to certain diseases. To illustrate,
the method can be used to detect the susceptibility of a mammal to
diseases which progress based on the amount of PD-L1 present on
cells and/or the number of PD-L1-positive cells in a mammal.
[0130] Polypeptide sequences are indicated using standard one- or
three-letter abbreviations. Unless otherwise indicated, each
polypeptide sequence has amino termini at the left and a carboxy
termini at the right; each single-stranded nucleic acid sequence,
and the top strand of each double-stranded nucleic acid sequence,
has a 5' termini at the left and a 3' termini at the right. A
particular polypeptide sequence also can be described by explaining
how it differs from a reference sequence.
[0131] The terms "PD-L1 inhibitor" and "PD-L1 antagonist" are used
interchangeably. Each is a molecule that detectably inhibits at
least one function of PD-L1. Conversely, a "PD-L1 agonist" is a
molecule that detectably increases at least one function of PD-L1.
The inhibition caused by a PD-L1 inhibitor need not be complete so
long as it is detectable using an assay. Any assay of a function of
PD-L1 can be used, examples of which are provided herein. Examples
of functions of PD-L1 that can be inhibited by a PD-L1 inhibitor,
or increased by a PD-L1 agonist, include cancer cell growth or
apoptosis (programmed cell death), and so on. Examples of types of
PD-L1 inhibitors and PD-L1 agonists include, but are not limited
to, PD-L1 binding polypeptides such as antigen binding proteins
(e.g., PD-L1 inhibiting antigen binding proteins), antibodies,
antibody fragments, and antibody derivatives.
[0132] The terms "peptide," "polypeptide" and "protein" each refers
to a molecule comprising two or more amino acid residues joined to
each other by peptide bonds. These terms encompass, e.g., native
and artificial proteins, protein fragments and polypeptide analogs
(such as muteins, variants, and fusion proteins) of a protein
sequence as well as post-translationally, or otherwise covalently
or non-covalently, modified proteins. A peptide, polypeptide, or
protein may be monomeric or polymeric.
[0133] A "variant" of a polypeptide (for example, an antibody)
comprises an amino acid sequence wherein one or more amino acid
residues are inserted into, deleted from and/or substituted into
the amino acid sequence relative to another polypeptide sequence.
Disclosed variants include, for example, fusion proteins.
[0134] A "derivative" of a polypeptide is a polypeptide (e.g., an
antibody) that has been chemically modified, e.g., via conjugation
to another chemical moiety (such as, for example, polyethylene
glycol or albumin, e.g., human serum albumin), phosphorylation, and
glycosylation. Unless otherwise indicated, the term "antibody"
includes, in addition to antibodies comprising two full-length
heavy chains and two full-length light chains, derivatives,
variants, fragments, and muteins thereof, examples of which are
described below.
[0135] An "antigen binding protein" is a protein comprising a
portion that binds to an antigen and, optionally, a scaffold or
framework portion that allows the antigen binding portion to adopt
a conformation that promotes binding of the antigen binding protein
to the antigen. Examples of antigen binding proteins include
antibodies, antibody fragments (e.g., an antigen binding portion of
an antibody), antibody derivatives, and antibody analogs. The
antigen binding protein can comprise, for example, an alternative
protein scaffold or artificial scaffold with grafted CDRs or CDR
derivatives. Such scaffolds include, but are not limited to,
antibody-derived scaffolds comprising mutations introduced to, for
example, stabilize the three-dimensional structure of the antigen
binding protein as well as wholly synthetic scaffolds comprising,
for example, a biocompatible polymer. See, for example, Korndorfer
et al., 2003, Proteins: Structure, Function, and Bioinformatics,
Volume 53, Issue 1:121-129; Roque et al., 2004, Biotechnol. Prog.
20:639-654. In addition, peptide antibody mimetics ("PAMs") can be
used, as well as scaffolds based on antibody mimetics utilizing
fibronection components as a scaffold.
[0136] An antigen binding protein can have, for example, the
structure of a naturally occurring immunoglobulin. An
"immunoglobulin" is a tetrameric molecule. In a naturally occurring
immunoglobulin, each tetramer is composed of two identical pairs of
polypeptide chains, each pair having one "light" (about 25 kDa) and
one "heavy" chain (about 50-70 kDa). The amino-terminal portion of
each chain includes a variable region of about 100 to 110 or more
amino acids primarily responsible for antigen recognition. The
carboxy-terminal portion of each chain defines a constant region
primarily responsible for effector function. Human light chains are
classified as kappa or lambda light chains. Heavy chains are
classified as mu, delta, gamma, alpha, or epsilon, and define the
antibody's isotype as IgM, IgD, IgG, IgA, and IgE, respectively.
Preferably, the anti-PD-L1 antibodies disclosed herein are
characterized by their variable domain region sequences in the
heavy V.sub.H and light V.sub.L amino acid sequences. The preferred
antibody is A6 which is a kappa IgG antibody. Within light and
heavy chains, the variable and constant regions are joined by a "J"
region of about 12 or more amino acids, with the heavy chain also
including a "D" region of about 10 more amino acids. See generally,
Fundamental Immunology Ch. 7 (Paul, W., ed., 2nd ed. Raven Press,
N.Y. (1989)). The variable regions of each light/heavy chain pair
form the antibody binding site such that an intact immunoglobulin
has two binding sites.
[0137] A "multi-specific antibody" is an antibody that recognizes
more than one epitope on one or more antigens. A subclass of this
type of antibody is a "bi-specific antibody" which recognizes two
distinct epitopes on the same or different antigens.
[0138] An antigen binding protein "specifically binds" to an
antigen (e.g., human PD-L1) if it binds to the antigen with a
dissociation constant of 1 nanomolar or less.
[0139] An "antigen binding domain, "antigen binding region," or
"antigen binding site" is a portion of an antigen binding protein
that contains amino acid residues (or other moieties) that interact
with an antigen and contribute to the antigen binding protein's
specificity and affinity for the antigen. For an antibody that
specifically binds to its antigen, this will include at least part
of at least one of its CDR domains.
[0140] An "epitope" is the portion of a molecule that is bound by
an antigen binding protein (e.g., by an antibody). An epitope can
comprise non-contiguous portions of the molecule (e.g., in a
polypeptide, amino acid residues that are not contiguous in the
polypeptide's primary sequence but that, in the context of the
polypeptide's tertiary and quaternary structure, are near enough to
each other to be bound by an antigen binding protein).
[0141] The "percent homology" of two polynucleotide or two
polypeptide sequences is determined by comparing the sequences
using the GAP computer program (a part of the GCG Wisconsin
Package, version 10.3 (Accelrys, San Diego, Calif.)) using its
default parameters.
[0142] A "host cell" is a cell that can be used to express a
nucleic acid. A host cell can be a prokaryote, for example, E.
coli, or it can be a eukaryote, for example, a single-celled
eukaryote (e.g., a yeast or other fungus), a plant cell (e.g., a
tobacco or tomato plant cell), an animal cell (e.g., a human cell,
a monkey cell, a hamster cell, a rat cell, a mouse cell, or an
insect cell) or a hybridoma. Examples of host cells include the
COS-7 line of monkey kidney cells (ATCC CRL 1651) (Gluzman et al.,
1981, Cell 23:175), L cells, C127 cells, 3T3 cells (ATCC CCL 163),
Chinese hamster ovary (CHO) cells or their derivatives such as
Veggie CHO and related cell lines which grow in serum-free media
(Rasmussen et al., 1998, Cytotechnology 28:31) or CHO strain
DX-B11, which is deficient in DHFR (Urlaub et al., 1980, Proc.
Natl. Acad. Sci. USA 77:4216-20), HeLa cells, BHK (ATCC CRL 10)
cell lines, the CV1/EBNA cell line derived from the African green
monkey kidney cell line CV1 (ATCC CCL 70) (McMahan et al., 1991,
EMBO J. 10:2821), human embryonic kidney cells such as 293,293 EBNA
or MSR 293, human epidermal A431 cells, human Colo205 cells, other
transformed primate cell lines, normal diploid cells, cell strains
derived from in vitro culture of primary tissue, primary explants,
HL-60, U937, HaK or Jurkat cells. Typically, a host cell is a
cultured cell that can be transformed or transfected with a
polypeptide-encoding nucleic acid, which can then be expressed in
the host cell. The phrase "recombinant host cell" can be used to
denote a host cell that has been transformed or transfected with a
nucleic acid to be expressed. A host cell also can be a cell that
comprises the nucleic acid but does not express it at a desired
level unless a regulatory sequence is introduced into the host cell
such that it becomes operably linked with the nucleic acid. It is
understood that the term host cell refers not only to the
particular subject cell but also to the progeny or potential
progeny of such a cell. Because certain modifications may occur in
succeeding generations due to, e.g., mutation or environmental
influence, such progeny may not, in fact, be identical to the
parent cell, but are still included within the scope of the term as
used herein.
Antigen Binding Proteins
[0143] Antigen binding proteins (e.g., antibodies, antibody
fragments, antibody derivatives, antibody muteins, and antibody
variants) are polypeptides that bind to PD-L1, (preferably, human
PD-L1). Antigen binding proteins include antigen binding proteins
that inhibit a biological activity of PD-L1.
[0144] Oligomers that contain one or more antigen binding proteins
may be employed as PD-L1 antagonists. Oligomers may be in the form
of covalently-linked or non-covalently-linked dimers, trimers, or
higher oligomers. Oligomers comprising two or more antigen binding
protein are contemplated for use, with one example being a
homodimer. Other oligomers include heterodimers, homotrimers,
heterotrimers, homotetramers, heterotetramers, etc.
[0145] One embodiment is directed to oligomers comprising multiple
antigen binding proteins joined via covalent or non-covalent
interactions between peptide moieties fused to the antigen binding
proteins. Such peptides may be peptide linkers (spacers), or
peptides that have the property of promoting oligomerization.
Leucine zippers and certain polypeptides derived from antibodies
are among the peptides that can promote oligomerization of antigen
binding proteins attached thereto, as described in more detail
below.
[0146] In particular embodiments, the oligomers comprise from two
to four antigen binding proteins. The antigen binding proteins of
the oligomer may be in any form, such as any of the forms described
above, e.g., variants or fragments. Preferably, the oligomers
comprise antigen binding proteins that have PD-L1 binding
activity.
[0147] In one embodiment, an oligomer is prepared using
polypeptides derived from immunoglobulins. Preparation of Fusion
Proteins Comprising Certain Heterologous Polypeptides Fused to
Various Portions of antibody-derived polypeptides (including the Fc
domain) has been described, e.g., by Ashkenazi et al., 1991, Proc.
Natl. Acad. Sci. USA 88:10535; Byrn et al., 1990, Nature 344:677;
and Hollenbaugh et al., 1992 "Construction of Immunoglobulin Fusion
Proteins", in Current Protocols in Immunology, Suppl. 4, pages
10.19.1-10.19.11.
[0148] One embodiment is directed to a dimer comprising two fusion
proteins created by fusing a PD-L1 binding fragment of an
anti-PD-L1 antibody to the Fc region of an antibody. The dimer can
be made by, for example, inserting a gene fusion encoding the
fusion protein into an appropriate expression vector, expressing
the gene fusion in host cells transformed with the recombinant
expression vector, and allowing the expressed fusion protein to
assemble much like antibody molecules, whereupon interchain
disulfide bonds form between the Fc moieties to yield the
dimer.
[0149] The term "Fc polypeptide" includes native and mutein forms
of polypeptides derived from the Fc region of an antibody.
Truncated forms of such polypeptides containing the hinge region
that promotes dimerization also are included. Fusion proteins
comprising Fc moieties (and oligomers formed therefrom) offer the
advantage of facile purification by affinity chromatography over
Protein A or Protein G columns.
[0150] Another method for preparing oligomeric antigen binding
proteins involves use of a leucine zipper. Leucine zipper domains
are peptides that promote oligomerization of the proteins in which
they are found. Leucine zippers were originally identified in
several DNA-binding proteins (Landschulz et al., 1988, Science
240:1759), and have since been found in a variety of different
proteins. Among the known leucine zippers are naturally occurring
peptides and derivatives thereof that dimerize or trimerize.
Examples of leucine zipper domains suitable for producing soluble
oligomeric proteins are described in WO 94/10308, and the leucine
zipper derived from lung surfactant protein D (SPD) described in
Hoppe et al., 1994, FEBS Letters 344:191. The use of a modified
leucine zipper that allows for stable trimerization of a
heterologous protein fused thereto is described in Fanslow et al.,
1994, Semin. Immunol. 6:267-78. In one approach, recombinant fusion
proteins comprising an anti-PD-L1 antibody fragment or derivative
fused to a leucine zipper peptide are expressed in suitable host
cells, and the soluble oligomeric anti-PD-L1 antibody fragments or
derivatives that form are recovered from the culture
supernatant.
[0151] Antigen-binding fragments of antigen binding proteins of the
invention may be produced by conventional techniques. Examples of
such fragments include, but are not limited to, Fab and
F(ab').sub.2 fragments.
[0152] The present disclosure provides monoclonal antibodies that
bind to PD-L1. Monoclonal antibodies may be produced using any
technique known in the art, e.g., by immortalizing spleen cells
harvested from the transgenic animal after completion of the
immunization schedule. The spleen cells can be immortalized using
any technique known in the art, e.g., by fusing them with myeloma
cells to produce hybridomas. Myeloma cells for use in
hybridoma-producing fusion procedures preferably are
non-antibody-producing, have high fusion efficiency, and enzyme
deficiencies that render them incapable of growing in certain
selective media which support the growth of only the desired fused
cells (hybridomas). Examples of suitable cell lines for use in
mouse fusions include Sp-20, P3-X63/Ag8, P3-X63-Ag8.653, NS1/1.Ag 4
1, Sp210-Ag14, FO, NSO/U, MPC-11, MPC11-X45-GTG 1.7 and S194/5XX0
Bul; examples of cell lines used in rat fusions include R210.RCY3,
Y3-Ag 1.2.3, IR983F and 48210. Other cell lines useful for cell
fusions are U-266, GM1500-GRG2, LICR-LON-HMy2 and UC729-6.
[0153] Antigen binding proteins directed against PD-L1 can be used,
for example, in assays to detect the presence of PD-L1
polypeptides, either in vitro or in vivo. The antigen binding
proteins also may be employed in purifying PD-L1 proteins by
immunoaffinity chromatography. Blocking antigen binding proteins
can be used in the methods disclosed herein. Such antigen binding
proteins that function as PD-L1 antagonists may be employed in
treating any PD-L1-induced condition, including but not limited to
various cancers.
[0154] Antigen binding proteins may be employed in an in vitro
procedure, or administered in vivo to inhibit PD-L1-induced
biological activity. Disorders caused or exacerbated (directly or
indirectly) by the proteolytic activation of PD-L1, examples of
which are provided herein, thus may be treated. In one embodiment,
the present invention provides a therapeutic method comprising in
vivo administration of a PD-L1 blocking antigen binding protein to
a mammal in need thereof in an amount effective for reducing an
PD-L1-induced biological activity.
[0155] Antigen binding proteins include fully human monoclonal
antibodies that inhibit a biological activity of PD-L1.
[0156] Antigen binding proteins may be prepared by any of a number
of conventional techniques. For example, they may be purified from
cells that naturally express them (e.g., an antibody can be
purified from a hybridoma that produces it), or produced in
recombinant expression systems, using any technique known in the
art. See, for example, Monoclonal Antibodies, Hybridomas: A New
Dimension in Biological Analyses, Kennet et al. (eds.), Plenum
Press, New York (1980); and Antibodies: A Laboratory Manual, Harlow
and Land (eds.), Cold Spring Harbor Laboratory Press, Cold Spring
Harbor, N.Y., (1988).
[0157] Any expression system known in the art can be used to make
the recombinant polypeptides of the invention. In general, host
cells are transformed with a recombinant expression vector that
comprises DNA encoding a desired polypeptide. Among the host cells
that may be employed are prokaryotes, yeast or higher eukaryotic
cells. Prokaryotes include gram negative or gram positive
organisms, for example E. coli or bacilli. Higher eukaryotic cells
include insect cells and established cell lines of mammalian
origin. Examples of suitable mammalian host cell lines include the
COS-7 line of monkey kidney cells (ATCC CRL 1651) (Gluzman et al.,
1981, Cell 23:175), L cells, 293 cells, C127 cells, 3T3 cells (ATCC
CCL 163), Chinese hamster ovary (CHO) cells, HeLa cells, BHK (ATCC
CRL 10) cell lines, and the CV1/EBNA cell line derived from the
African green monkey kidney cell line CV1 (ATCC CCL 70) as
described by McMahan et al., 1991, EMBO J. 10: 2821. Appropriate
cloning and expression vectors for use with bacterial, fungal,
yeast, and mammalian cellular hosts are described by Pouwels et al.
(Cloning Vectors: A Laboratory Manual, Elsevier, N.Y., 1985).
[0158] The transformed cells can be cultured under conditions that
promote expression of the polypeptide, and the polypeptide
recovered by conventional protein purification procedures. One such
purification procedure includes the use of affinity chromatography,
e.g., over a matrix having all or a portion (e.g., the
extracellular domain) of PD-L1 bound thereto. Polypeptides
contemplated for use herein include substantially homogeneous
recombinant mammalian anti-PD-L1 antibody polypeptides
substantially free of contaminating endogenous materials.
[0159] Antigen binding proteins may be prepared, and screened for
desired properties, by any of a number of known techniques. Certain
of the techniques involve isolating a nucleic acid encoding a
polypeptide chain (or portion thereof) of an antigen binding
protein of interest (e.g., an anti-PD-L1 antibody), and
manipulating the nucleic acid through recombinant DNA technology.
The nucleic acid may be fused to another nucleic acid of interest,
or altered (e.g., by mutagenesis or other conventional techniques)
to add, delete, or substitute one or more amino acid residues, for
example.
[0160] Single chain antibodies may be formed by linking heavy and
light chain variable domain (Fv region) fragments via an amino acid
bridge (short peptide linker), resulting in a single polypeptide
chain. Such single-chain Fvs (scFvs) have been prepared by fusing
DNA encoding a peptide linker between DNAs encoding the two
variable domain polypeptides (V.sub.L and V.sub.H). The resulting
polypeptides can fold back on themselves to form antigen-binding
monomers, or they can form multimers (e.g., dimers, trimers, or
tetramers), depending on the length of a flexible linker between
the two variable domains (Kortt et al., 1997, Prot. Eng. 10:423;
Kortt et al., 2001, Biomol. Eng. 18:95-108). By combining different
V.sub.L and V.sub.H-comprising polypeptides, one can form
multimeric scFvs that bind to different epitopes (Kriangkum et al.,
2001, Biomol. Eng. 18:31-40). Techniques developed for the
production of single chain antibodies include those described in
U.S. Pat. No. 4,946,778; Bird, 1988, Science 242:423; Huston et
al., 1988, Proc. Natl. Acad. Sci. USA 85:5879; Ward et al., 1989,
Nature 334:544, de Graaf et al., 2002, Methods Mol. Biol.
178:379-87.
[0161] Techniques are known for deriving an antibody of a different
subclass or isotype from an antibody of interest, i.e., subclass
switching. Thus, IgG antibodies may be derived from an IgM
antibody, for example, and vice versa. Such techniques allow the
preparation of new antibodies that possess the antigen-binding
properties of a given antibody (the parent antibody), but also
exhibit biological properties associated with an antibody isotype
or subclass different from that of the parent antibody. Recombinant
DNA techniques may be employed. Cloned DNA encoding particular
antibody polypeptides may be employed in such procedures, e.g., DNA
encoding the constant domain of an antibody of the desired isotype
(Lantto et al., 2002, Methods Mol. Biol. 178:303-16). Moreover, if
an IgG4 is desired, it may also be desired to introduce a point
mutation (CPSCP->CPPCP) in the hinge region (Bloom et al., 1997,
Protein Science 6:407) to alleviate a tendency to form intra-H
chain disulfide bonds that can lead to heterogeneity in the IgG4
antibodies.
[0162] In particular embodiments, antigen binding proteins of the
present invention have a binding affinity (K.sub.a) for PD-L1 of at
least 10.sup.6. In other embodiments, the antigen binding proteins
exhibit a K.sub.a of at least 10.sup.7, at least 10.sup.8, at least
10.sup.9, or at least 10.sup.10. In another embodiment, the antigen
binding protein exhibits a K.sub.a substantially the same as that
of an antibody described herein in the Examples.
[0163] In another embodiment, the present disclosure provides an
antigen binding protein that has a low dissociation rate from
PD-L1. In one embodiment, the antigen binding protein has a
K.sub.off of 1.times.10.sup.-4 to .sup.-1 or lower. In another
embodiment, the K.sub.off is 5.times.10.sup.-5 to .sup.-1 or lower.
In another embodiment, the K.sub.off is substantially the same as
an antibody described herein. In another embodiment, the antigen
binding protein binds to PD-L1 with substantially the same
K.sub.off as an antibody described herein.
[0164] In another aspect, the present disclosure provides an
antigen binding protein that inhibits an activity of PD-L1. In one
embodiment, the antigen binding protein has an IC.sub.50 of 1000 nM
or lower. In another embodiment, the IC.sub.50 is 100 nM or lower;
in another embodiment, the IC.sub.50 is 10 nM or lower. In another
embodiment, the IC.sub.50 is substantially the same as that of an
antibody described herein in the Examples. In another embodiment,
the antigen binding protein inhibits an activity of PD-L1 with
substantially the same IC.sub.50 as an antibody described
herein.
[0165] In another aspect, the present disclosure provides an
antigen binding protein that binds to human PD-L1 expressed on the
surface of a cell and, when so bound, inhibits PD-L1 signaling
activity in the cell without causing a significant reduction in the
amount of PD-L1 on the surface of the cell. Any method for
determining or estimating the amount of PD-L1 on the surface and/or
in the interior of the cell can be used. In other embodiments,
binding of the antigen binding protein to the PD-L1-expressing cell
causes less than about 75%, 50%, 40%, 30%, 20%, 15%, 10%, 5%, 1%,
or 0.1% of the cell-surface PD-L1 to be internalized.
[0166] In another aspect, the present disclosure provides an
antigen binding protein having a half-life of at least one day in
vitro or in vivo (e.g., when administered to a human subject). In
one embodiment, the antigen binding protein has a half-life of at
least three days. In another embodiment, the antigen binding
protein has a half-life of four days or longer. In another
embodiment, the antigen binding protein has a half-life of eight
days or longer. In another embodiment, the antigen binding protein
is derivatized or modified such that it has a longer half-life as
compared to the underivatized or unmodified antigen binding
protein. In another embodiment, the antigen binding protein
contains one or more point mutations to increase serum half life,
such as described in WO00/09560, incorporated by reference
herein.
[0167] The present disclosure further provides multi-specific
antigen binding proteins, for example, bispecific antigen binding
protein, e.g., antigen binding protein that bind to two different
epitopes of PD-L1, or to an epitope of PD-L1 and an epitope of
another molecule, via two different antigen binding sites or
regions. Moreover, bispecific antigen binding protein as disclosed
herein can comprise a PD-L1 binding site from one of the
herein-described antibodies and a second PD-L1 binding region from
another of the herein-described antibodies, including those
described herein by reference to other publications. Alternatively,
a bispecific antigen binding protein may comprise an antigen
binding site from one of the herein described antibodies and a
second antigen binding site from another PD-L1 antibody that is
known in the art, or from an antibody that is prepared by known
methods or the methods described herein.
[0168] Numerous methods of preparing bispecific antibodies are
known in the art. Such methods include the use of hybrid-hybridomas
as described by Milstein et al., 1983, Nature 305:537, and chemical
coupling of antibody fragments (Brennan et al., 1985, Science
229:81; Glennie et al., 1987, J. Immunol. 139:2367; U.S. Pat. No.
6,010,902). Moreover, bispecific antibodies can be produced via
recombinant means, for example by using leucine zipper moieties
(i.e., from the Fos and Jun proteins, which preferentially form
heterodimers; Kostelny et al., 1992, J. Immunol. 148:1547) or other
lock and key interactive domain structures as described in U.S.
Pat. No. 5,582,996. Additional useful techniques include those
described in U.S. Pat. Nos. 5,959,083; and 5,807,706.
[0169] In another aspect, the antigen binding protein comprises a
derivative of an antibody. The derivatized antibody can comprise
any molecule or substance that imparts a desired property to the
antibody, such as increased half-life in a particular use. The
derivatized antibody can comprise, for example, a detectable (or
labeling) moiety (e.g., a radioactive, colorimetric, antigenic or
enzymatic molecule, a detectable bead (such as a magnetic or
electrodense (e.g., gold bead), or a molecule that binds to another
molecule (e.g., biotin or streptavidin), a therapeutic or
diagnostic moiety (e.g., a radioactive, cytotoxic, or
pharmaceutically active moiety), or a molecule that increases the
suitability of the antibody for a particular use (e.g.,
administration to a subject, such as a human subject, or other in
vivo or in vitro uses). Examples of molecules that can be used to
derivatize an antibody include albumin (e.g., human serum albumin)
and polyethylene glycol (PEG). Albumin-linked and PEGylated
derivatives of antibodies can be prepared using techniques well
known in the art. In one embodiment, the antibody is conjugated or
otherwise linked to transthyretin (TTR) or a TTR variant. The TTR
or TTR variant can be chemically modified with, for example, a
chemical selected from the group consisting of dextran,
poly(n-vinyl pyurrolidone), polyethylene glycols, propropylene
glycol homopolymers, polypropylene oxide/ethylene oxide
co-polymers, polyoxyethylated polyols and polyvinyl alcohols.
Indications
[0170] In one aspect, the present disclosure provides methods of
treating a subject. The method can, for example, have a generally
salubrious effect on the subject, e.g., it can increase the
subject's expected longevity. Alternatively, the method can, for
example, treat, prevent, cure, relieve, or ameliorate ("treat") a
disease, disorder, condition, or illness ("a condition"). Among the
conditions to be treated are conditions characterized by
inappropriate expression or activity of PD-L1. In some such
conditions, the expression or activity level is too high, and the
treatment comprises administering a PD-L1 antagonist as described
herein. The disorders or conditions are cancer-related. In
particular, those cancers include, but are not limited to, lung,
ovarian and colon carcinoma and various myelomas.
[0171] Specific medical conditions and diseases that are treatable
or preventable with the antigen binding proteins of this disclosure
include various cancers.
[0172] Therapeutic Methods and Administration of Antigen Binding
Proteins
[0173] Certain methods provided herein comprise administering a
PD-L1 binding antigen binding protein to a subject, thereby
reducing a PD-L1-induced biological response that plays a role in a
particular condition. In particular embodiments, methods of the
invention involve contacting endogenous PD-L1 with a PD-L1 binding
antigen binding protein, e.g., via administration to a subject or
in an ex vivo procedure.
[0174] The term "treatment" encompasses alleviation or prevention
of at least one symptom or other aspect of a disorder, or reduction
of disease severity, and the like. An antigen binding protein need
not effect a complete cure, or eradicate every symptom or
manifestation of a disease, to constitute a viable therapeutic
agent. As is recognized in the pertinent field, drugs employed as
therapeutic agents may reduce the severity of a given disease
state, but need not abolish every manifestation of the disease to
be regarded as useful therapeutic agents. Similarly, a
prophylactically administered treatment need not be completely
effective in preventing the onset of a condition in order to
constitute a viable prophylactic agent. Simply reducing the impact
of a disease (for example, by reducing the number or severity of
its symptoms, or by increasing the effectiveness of another
treatment, or by producing another beneficial effect), or reducing
the likelihood that the disease will occur or worsen in a subject,
is sufficient. One embodiment of the invention is directed to a
method comprising administering to a patient a PD-L1 antagonist in
an amount and for a time sufficient to induce a sustained
improvement over baseline of an indicator that reflects the
severity of the particular disorder.
[0175] As is understood in the pertinent field, pharmaceutical
compositions comprising the antibodies and fragments thereof of the
disclosure are administered to a subject in a manner appropriate to
the indication. Pharmaceutical compositions may be administered by
any suitable technique, including but not limited to, parenterally,
topically, or by inhalation. If injected, the pharmaceutical
composition can be administered, for example, via intra-articular,
intravenous, intramuscular, intralesional, intraperitoneal or
subcutaneous routes, by bolus injection, or continuous infusion.
Localized administration, e.g. at a site of disease or injury is
contemplated, as are transdermal delivery and sustained release
from implants. Delivery by inhalation includes, for example, nasal
or oral inhalation, use of a nebulizer, inhalation of the
antagonist in aerosol form, and the like. Other alternatives
include eyedrops; oral preparations including pills, syrups,
lozenges or chewing gum; and topical preparations such as lotions,
gels, sprays, and ointments.
[0176] Use of antigen binding proteins in ex vivo procedures also
is contemplated. For example, a patient's blood or other bodily
fluid may be contacted with an antigen binding protein that binds
PD-L1 ex vivo. The antigen binding protein may be bound to a
suitable insoluble matrix or solid support material.
[0177] Advantageously, antigen binding proteins are administered in
the form of a composition comprising one or more additional
components such as a physiologically acceptable carrier, excipient
or diluent. Optionally, the composition additionally comprises one
or more physiologically active agents, for example, a second
inflammation- or immune-inhibiting substance, an anti-angiogenic
substance, an analgesic substance, etc., non-exclusive examples of
which are provided herein. In various particular embodiments, the
composition comprises one, two, three, four, five, or six
physiologically active agents in addition to a PD-L1 binding
antigen binding protein
Combination Therapy
[0178] In another aspect, the present disclosure provides a method
of treating a subject with a PD-L1 inhibiting antigen binding
protein and one or more other treatments. In one embodiment, such a
combination therapy achieves synergy or an additive effect by, for
example, attacking multiple sites or molecular targets in a tumor.
Types of combination therapies that can be used in connection with
the present invention include inhibiting or activating (as
appropriate) multiple nodes in a single disease-related pathway,
multiple pathways in a target cell, and multiple cell types within
a target tissue.
[0179] In another embodiment, a combination therapy method
comprises administering to the subject two, three, four, five, six,
or more of the PD-L1 agonists or antagonists described herein. In
another embodiment, the method comprises administering to the
subject two or more treatments that together inhibit or activate
(directly or indirectly) PD-L1-mediated signal transduction.
Examples of such methods include using combinations of two or more
PD-L1 inhibiting antigen binding proteins, of a PD-L1 inhibiting
antigen binding protein and one or more other therapeutic moiety
having anti-cancer properties (for example, cytotoxic agents,
and/or immunomodulators), or of a PD-L1 inhibiting antigen binding
protein and one or more other treatments (e.g., surgery, or
radiation). Furthermore, one or more anti-PD-L1 antibodies or
antibody derivatives can be used in combination with one or more
molecules or other treatments, wherein the other molecule(s) and/or
treatment(s) do not directly bind to or affect PD-L1, but which
combination is effective for treating or preventing the condition
being treated. In one embodiment, one or more of the molecule(s)
and/or treatment(s) treats or prevents a condition that is caused
by one or more of the other molecule(s) or treatment(s) in the
course of therapy, e.g., nausea, fatigue, alopecia, cachexia,
insomnia, etc. In every case where a combination of molecules
and/or other treatments is used, the individual molecule(s) and/or
treatment(s) can be administered in any order, over any length of
time, which is effective, e.g., simultaneously, consecutively, or
alternately. In one embodiment, the method of treatment comprises
completing a first course of treatment with one molecule or other
treatment before beginning a second course of treatment. The length
of time between the end of the first course of treatment and
beginning of the second course of treatment can be any length of
time that allows the total course of therapy to be effective, e.g.,
seconds, minutes, hours, days, weeks, months, or even years.
[0180] In another embodiment, the method comprises administering
one or more of the PD-L1 antagonists described herein and one or
more other treatments (e.g., a therapeutic or palliative
treatment). Where a method comprises administering more than one
treatment to a subject, it is to be understood that the order,
timing, number, concentration, and volume of the administrations is
limited only by the medical requirements and limitations of the
treatment, i.e., two treatments can be administered to the subject,
e.g., simultaneously, consecutively, alternately, or according to
any other regimen.
Example 1
[0181] This example provides a characterization of the disclosed
anti-PD-L1 antibodies binding to human PD-L1 expressed on human
lymphocytes. Human peripheral blood mononuclear cells were
activated by culture with anti-CD3 for three days to promote
expression of PD-L1. Binding was assessed by adding serial
dilutions of the antibody to the activated lymphocytes. After
washing, binding was detected by staining with a phycoerythrin
labeled anti-human Ig reagent followed by analysis using a FACS
Aria (Becton Dickinson, San Jose, Calif.). Since the anti-human Ig
reagent reacts with immunoglobulin on B lymphocytes the cells were
co-staining with an anti-human CD19 APC-Cy5 reagent. Data were
obtained by gating on the CD19 negative lymphocytes and the results
are shown in FIG. 1. Both H6 and H10 antibodies show potent binding
activity with an EC.sub.50 in the 100 pM range.
Example 2
[0182] This example provides the results from binding the disclosed
anti-PD-L1 antibodies to human lymphocytes. Anti-PD-L1 antibodies
were assayed for binding to non-activated lymphocytes. Peripheral
blood mononuclear cells were incubated with anti-PD-L1 antibodies
(1 .mu.g/ml) followed by washing. Binding of the anti-PD-L1
antibody was detected by staining with a phycoerythrin conjugated
and human Ig reagent. To identify the stained populations the cells
were co-stained with an anti-CD3 FITC or an anti-CD56 APC reagent.
Since the anti-human Ig reagent reacts with immunoglobulin on B
lymphocytes the cells were also stained with an anti-human CD19
APC-Cy5 reagent. The data in FIG. 2 were derived from the CD19
negative lymphocytes following analysis using a FACSAria (Becton
Dickinson, San Jose, Calif.). The results show that CD56 positive
NK cells, but not CD3+ T cells, react with the anti-PD-L1
antibodies.
Example 3
[0183] This example provides a showing of the effect of disclosed
anti-PD-L1 antibodies on lymphocyte proliferation. Anti-PD-L1
antibodies were assayed for their ability to modulate the response
of lymphocytes to stimulation. The anti-PD-L1 antibodies H1, H6 and
H10 were added at 10 .mu.g/ml to cultures of peripheral blood
mononuclear cells labeled with the fluorescent dye
carboxyfluorescein (CFSE) and stimulated with anti-CD3 (1 ng/ml).
After three days of culture, the cells were assayed for
proliferative activity by flow cytometry using a FACS Aria (Becton
Dickinson, San Jose, Calif.). The results, shown in FIG. 3, show
that the anti-PD-L1 antibodies inhibited lymphocyte
proliferation.
Example 4
[0184] This example provides a showing of the effect of NK cells on
the disclosed anti-PD-L1 antibodies on mediated inhibition of
proliferation. With the anti-PD-L1 antibodies showing a
preferential binding to NK cells, the significance of this in the
inhibition of proliferation was tested. By cell sorting using a
FACS Aria (Becton Dickinson, Dan Jose, Calif.) purified population
of CD4+, CD8+, CD56+ (NK) and monocytes were obtained. As a base
culture, 1.5.times.10.sup.5 CD4+ cells and 3.times.10.sup.4
monocytes were stimulated with anti-CD3 (1 ng/ml) with or without
H10 anti-PD-L1 antibody (10 .mu.g/ml). In separate cultures, either
CD8+ cells or NK cells (both at 3.times.10.sup.4) were added to
this base culture. After three days of culture, cells were stained
for expression of CD25 as a measure of lymphocyte activation as
measured by flow cytometry. The results shown in FIG. 4 were
compared to those obtained using whole, unfractionated PBMC
(1.5.times.10.sup.5). The anti-PD-L1 antibody inhibited the
activation of lymphocytes in the cultures containing whole PBMC and
those where NK cells were added, but not in the absence of NK
cells.
Example 5
[0185] This example provides a showing of an effect of anti-PD-L1
on NK cell activation. Disclosed anti-PD-L1 antibodies were assayed
for their ability to promote the activation of lymphocytes.
Peripheral blood mononuclear cells or purified populations of
lymphocyte subsets isolated by cell sorting were cultured with IL-2
(100 U/ml) in the presence or absence of added anti-PD-L1
antibodies (10 .mu.g/ml). After five days of culture, cells were
stained for expression of CD25 as a measure of cell activation and
analyzed by flow cytometry. The results shown in FIG. 5 reveal that
H6 and H10 enhance cell activation and that the responsive
lymphocyte population is the NK cell.
Example 6
[0186] This example provides a showing of an effect of disclosed
anti-PD-L1 antibodies on the progression of disease in a murine
model of multiple sclerosis (MS). Anti-PD-L1 antibodies were
assayed for their ability to modulate the course of disease in mice
induced to develop experimental autoimmune encephalitis (EAE) as a
model of MS. Disease was induced in C57Bl/6 mice following
injection of myelin oligodendrocyte glycoprotein (MOG) peptide and
pertussis toxin. Once symptoms of disease developed, the mice were
treated every second day with an intraperitoneal injection of
anti-PD-L1 antibody (0.1 mg). The results shown in FIG. 6 provide
that both anti-PD-L1 antibodies H6 and H10 impacted the course of
disease development with H6 greatly reducing disease severity.
Example 7
[0187] This example provides a characterization of the disclosed
G12 anti-PD-L1 antibody. rhPD-L1 was immobilized on CMS sensor chip
using standard NHS/EDC coupling methodology. All measurements were
conducted in HBS-EP buffer with a flow rate of 30 .mu.L/min.
Antibody was diluted so as to obtain a series of concentrations. A
1:1 (Langmuir) binding model was used to fit the data.
[0188] Table 1 provides the binding data for G12.
TABLE-US-00001 G12 Biacore k.sub.on (M.sup.-1 s.sup.-1) 1.31E+07
k.sub.off (s.sup.-1) 4.90E-04 Kd (M) 3.74E-11
Example 8
[0189] This example provides the results from an experiment showing
that G12 blocks the interaction between rhPD-1 and rhPD-L1. A
96-well ELISA plate was coated with 1 ng/.mu.L PD1/His at 4.degree.
C. overnight, then blocked with casein in PBS. Pre-mixed 20 .mu.l
serial 2-fold diluted IgGs (started from 20 .mu.g/ml) and 20 .mu.l
0.25 .mu.l/ml PD-L1/Fc and incubated the mixtures 30 min. washed
the plate with PBS-Tween (PBST) 3 times. Transferred 25 .mu.l the
mixtures to the ELISA plate and incubated 30 min with shaking.
Washed 3 times with PBST. Added HRP conjugated Goat anti-human Fc
(1:500 in casein), used TMB as substrate and developed 30 min. 2M
H.sub.2SO.sub.4 was added to stop the reaction. Read the OD at 450
nm.
TABLE-US-00002 TABLE 2 G12 Blocking PD-1/PD-L1 interaction (M)
IC.sub.50 7.288E-11
Example 9
[0190] This example illustrates in vitro EC.sub.50 data for the
binding of G12 to human PD-L1 expressed on the surface of CHO
cells. This example shows the binding characteristic for this
antibody in terms of the maximal cell binding and the concentration
at which 50% binding saturation (EC.sub.50) is reached. In this
example, the experimental procedure is as follows: 50,000 CHO-PD-L1
cells were aliquoted into the wells of a 96-well, v-bottom plate in
100 .mu.l FACS Buffer (PBS+2% FBS). A dilution curve of the
antibody was made in FACS Buffer encompassing the concentrations
shown in FIG. 7. Cells were spun down, washed 1.times. with FACS
Buffer, and then resuspended in 25 .mu.l of antibody solution in
triplicate. After 0.5 hr incubation, cells were washed 1.times.
with FACS Buffer and resuspended in 50 .mu.l PE-conjugated, goat
anti-human IgG (.gamma.-chain specific) secondary antibody
(Southern Biotech Cat #2040-09). Cells were further incubated for
0.5 hr and then washed 1.times. with FACS Buffer. Cells were
resuspended in 25 .mu.l FACS Buffer and the median fluorescence
intensity in the FL2-H channel was determined using the Intellicyt
HTFC flow cytometer.
[0191] Results: As shown in FIG. 7 and Table 3, the cell binding
EC.sub.50 for the G12 anti-PD-L1 antibody on CHO-PD-L1 cells was
1.71E-09 M. Data was collected on the Intellicyt HTFC flow
cytometer, processed using FlowJo software, and analyzed and
plotted in Graph Pad Prizm using non-linear regression fit. Data
points are shown as the median fluorescence intensity (MFI) of
positively labeled cells+/-Std Error.
TABLE-US-00003 TABLE 3 G12 Cell Binding EC50 (M) CHO-PD-L1
1.71E-09
Example 10
[0192] This example provides in vitro IC.sub.50 data for the
blocking of the interaction between recombinant human PD-1 (PD-1-Fc
Chimera; Sino Biologics) and human PD-L1 expressed CHO cells by
anti-PD-L1 antibody G12. Here, CHO cells expressing PD-L1 were
pre-incubated with G12 prior to the addition of rhPD-1-Fc chimeric
protein. After incubation and washing, PD-1 binding to cell surface
expressed PD-L1 was detected using an Alexa-Fluor 647 tagged
anti-PD-1 antibody by flow cytometry (Intellicyt HTFC; FL-4H). This
example shows that anti-PD-L1 monoclonal antibody G12 was able to
inhibit efficiently the binding of PD-1 to PD-L1 expressed on the
surface of CHO cells.
[0193] Results: As shown in FIG. 8 and Table 4, the IC.sub.50 for
blocking of the PD-1/PD-L1 cellular interaction by G12 is 1.76E-09
M. Data was collected on the Intellicyt HTFC flow cytometer,
processed using FlowJo software, and analyzed and plotted in Graph
Pad Prizm using non-linear regression fit. Data points are shown as
the median fluorescence detected in the FL-4H channel+/-Std
Error.
TABLE-US-00004 TABLE 4 G12 Inhibition of PD-1/PD-L1 CHO-PD-L1/
1.76E-09 Interaction IC50 (M) rhPD-1-Fc
Example 11
[0194] This example illustrates in vitro EC.sub.50 data for the
binding of G12 to PD-L1 expressed on the surface of ES-2 human
ovarian carcinoma cells. This example shows the binding
characteristic for this antibody in terms of the maximal cell
binding and the concentration at which 50% binding saturation
(EC.sub.50) is reached. In this example, the experimental procedure
is as follows: ES-2 cells were treated with 500 IU/ml IFN.gamma.
for 18 hours to increase PD-L1 levels above basal expression. After
induction, 50,000 ES-2 cells were aliquoted into the wells of a
96-well, v-bottom plate in 100 .mu.l FACS Buffer (PBS+2% FBS). A
dilution curve of the antibody was made in FACS Buffer encompassing
the concentrations shown in FIG. 9. Cells were spun down, washed
1.times. with FACS Buffer, and then resuspended in 25 .mu.l of
antibody solution in triplicate. After 0.5 hr incubation, cells
were washed 1.times. with FACS Buffer and resuspended in 50 .mu.l
PE-conjugated, goat anti-human IgG (.gamma.-chain specific)
secondary antibody (Southern Biotech Cat #2040-09). Cells were
further incubated for 0.5 hr and then washed 1.times. with FACS
Buffer. Cells were resuspended in 25 .mu.l FACS Buffer and the
median fluorescence intensity in the FL2-H channel was determined
using the Intellicyt HTFC flow cytometer.
[0195] Results: As shown in FIG. 9 and Table 5, the cell binding
EC.sub.50 for the G12 anti-PD-L1 antibody on ES-2 ovarian carcinoma
cells was 4.58E-11 M. Data was collected on the Intellicyt HTFC
flow cytometer, processed using FlowJo software, and analyzed and
plotted in Graph Pad Prizm using non-linear regression fit. Data
points are shown as the median fluorescence detected in the FL-2H
channel+/-Std Error. Cell binding EC.sub.50 for anti-PD-L1 mAb G12
against human PD-L1 expressed on ES-2 ovarian cancer cells after
treatment with 500 IU/ml recombinant hIFN.gamma. for 18 hr is shown
in Table 5.
TABLE-US-00005 TABLE 5 G12 Cell Binding EC50 (M) ES-2 4.58E-11
Example 12
[0196] This example provides a mixed lymphocyte reaction (MLR) to
evaluate the effect of the antibodies on lymphocyte activity in
lymphocyte effector cells. IL-2 secretion was measured in the
presence or absence of an anti-PD-L1 human monoclonal antibody
(FIG. 10). The functional activity of the antibodies was assessed
in an allogeneic mixed lymphocyte reaction (MLR) consisting of
purified CD4+ T lymphocytes and allogeneic dendritic cells. The
antibodies used were the disclosed G12 antibody as compared to
prior disclosed antibodies 10A5 and 12A4 (Bristol-Myers/Medarex)
that were obtained via in-house production from prior-disclosed
antibody sequences (U.S. Patent Application 2009/0055944 the
disclosure of which is incorporated by reference herein). To
prepare the dendritic cells, monocytes, purified using a
discontinuous Percoll gradient, were cultured with GM-CSF (1,000
U/ml) plus IL-4 (500 U/ml) for seven days. The CD4+ cells were
prepared by negative selection using biotinylated antibodies
reactive with CD8, CD16, CD19 and CD20. Removal of the reactive
cells was achieved using biotin binding magnetic beads. The
antibodies were added at the indicated concentrations to wells
containing 10.sup.5 CD4+ cells labeled with carboxyfluorecein
(CFSE) and 10.sup.4 dendritic cells. After five days of culture,
supernatants were harvested for cytokine determination.
Example 13
[0197] This example provides a mixed lymphocyte reaction (MLR) was
employed to demonstrate the effect of blocking the PD-L1/PD-1
pathway by the anti-PD-L1 antibodies on lymphocyte effector cells.
T cell activation was measured in the presence or absence of the
anti-PD-L1 human monoclonal antibody (FIG. 12). The functional
activity of the antibodies was assessed in an allogeneic mixed
lymphocyte reaction (MLR) consisting of purified CD4+ T lymphocytes
and allogeneic dendritic cells. The antibodies used were the
disclosed H6B1L, RSA1, RA3, RC5, SH1E2, SH1E4, SH1B11, and SH1C8 as
compared to prior disclosed antibodies 10A5
(Bristol-Myers-Squibb/Medarex) and YW243.55S70 (Roche/Genentech)
that were obtained via in-house production from prior-disclosed
antibody sequences (U.S. Patent Application 2009/0055944 and U.S.
Patent Application US 2010/0203056; the disclosure of which are
incorporated by reference herein). To prepare the dendritic cells,
monocytes, purified using a discontinuous Percoll gradient, were
cultured with GM-CSF (1,000 U/ml) plus IL-4 (500 U/ml) for seven
days. The CD4+ cells were prepared by negative selection using
biotinylated antibodies reactive with CD8, CD16, CD19 and CD20.
Removal of the reactive cells was achieved using biotin binding
magnetic beads. The antibodies were added at the indicated
concentrations to wells containing 10.sup.5 CD4+ cells labeled with
carboxyfluorecein (CFSE) and 10.sup.4 dendritic cells. After five
days of culture, the cells were collected and stained for CD25
expression as a measure of cell activation. Cell activation was
measured by flow cytometry.
[0198] The results for cell activation are shown in FIG. 13. With
all anti-PD-L1 antibodies there was an increase in cell activation.
In FIG. 13, the data are expressed as a percentage of test value
with of the respect to that obtained in the absence of any added
antibody. In this way, the percent increase in cell activation was
realized.
Example 14
[0199] The ability of anti-PD-L1 antibodies to modulate immune
responsiveness was assessed using a mixed lymphocyte reaction
(MLR). With this assay, the effects anti-PD-L1 antibodies on cell
activation and the production of IL-2 were measured. The MLR was
performed by culturing 10.sup.5 purified human CD4+ cells from one
donor with 10.sup.4 monocyte derived dendritic cells prepared from
another donor. To prepare the dendritic cells, purified monocytes
were cultured with GM-CSF (1,000 U/ml) and IL-4 (500 U/ml) for
seven days. Anti-PD-L1 or control antibodies were added to the
allogeneic MLR cultures at 10 .mu.g/ml unless stated otherwise.
Parallel plates were set up to allow collection of supernatants at
day 3 and at day 5 to measure IL-2 using a commercial ELISA kit
(Biolegend). The antibodies used were the disclosed H6B1L, RSA1,
RA3, RC5, SH1E2, SH1E4, SH1B11, and SH1C8 as compared to prior
disclosed antibodies 10A5 (Bristol-Myers-Squibb/Medarex) and
YW243.55S70 (Roche/Genentech) that were obtained via in-house
production from prior-disclosed antibody sequences (U.S. Patent
Application 2009/0055944 and U.S. Patent Application US
2010/0203056; the disclosure of which are incorporated by reference
herein).
[0200] Production of IL-2 was enhanced by the addition of the
anti-PD-L1 antibodies.
Example 15
[0201] This example provides a mixed lymphocyte reaction (MLR) was
employed to demonstrate the effect of blocking the PD-L1/PD-1
pathway by the anti-PD-L1 antibodies on lymphocyte effector cells.
IFN-.gamma. secretion was measured in the presence or absence of
the anti-PD-L1 human monoclonal antibody (FIG. 11). The functional
activity of the antibodies was assessed in an allogeneic mixed
lymphocyte reaction (MLR) consisting of purified CD4+ T lymphocytes
and allogeneic dendritic cells. The antibodies used were the
disclosed H6B1L, RSA1, RA3, RC5, SH1E2, SH1E4, SH1B11, and SH1C8 as
compared to prior disclosed antibodies 10A5
(Bristol-Myers-Squibb/Medarex) and YW243.55S70 (Roche/Genentech)
that were obtained via in-house production from prior-disclosed
antibody sequences (U.S. Patent Application 2009/0055944 and U.S.
Patent Application US 2010/0203056; the disclosure of which are
incorporated by reference herein).
To prepare the dendritic cells, monocytes, purified using a
discontinuous Percoll gradient, were cultured with GM-CSF (1,000
U/ml) plus IL-4 (500 U/ml) for seven days. The CD4+ cells were
prepared by negative selection using biotinylated antibodies
reactive with CD8, CD16, CD19 and CD20. Removal of the reactive
cells was achieved using biotin binding magnetic beads. The
antibodies were added at the indicated concentrations to wells
containing 10.sup.5 CD4+ cells labeled with carboxyfluorecein
(CFSE) and 10.sup.4 dendritic cells. After five days of culture,
supernatants were harvested for cytokine determination.
[0202] Production of IFN-.gamma. was enhanced by the addition of
the anti-PD-L1 antibodies.
TABLE-US-00006 Sequence Listing Heavy chain variable domain region
Light chain variable domain region
QMQLVQSGAEVKKPGSSVKVSCKASGGTFNTYAIS DIVMTQTPYSVSASVGDRVTITCRASQEVSR
WVRQAPGQGLEWMGGIIPLFGKADYAQKFQDRVT WVAWYQQKPGQAPKSLIYASSRLQSGVPS
ITADESTSTAYMELSSLRSEDTAVYYCARDKGREELG
RFTASGSGTDFTLVISSLQPEDFATYYCQQYS GNYYYAVDVWGPGTTVTVSS SEQ ID NO. 1
RFPLTFGGGTKVEIK SEQ ID NO. 2 QVQLQQLGPGLVKPSQTLSLTCAISGDSVSSNSAA
QPVLTQPASVSGSPGQSITISCTGTSSDVGG WNWIRQSPSRGLEWLGRTYYRSKWYTNYAVSMRS
YNYVSWYQQHPGKAPKLMVYDVSKRPSGV RITINPDTSKNQFSLQLNSVTPEDTAVYFCAGGNSSS
SNRFSGSKSGNTASLTISGLQTEDEADYYCSS HDDYWGQGTLVTVSS SEQ ID NO. 3
YTSSNTRVFGTGTKLTVL SEQ ID NO. 4
EVQLVQSGAEVKKPGASVKVSCKASGYTFTSYGISW
DIVMTQSPSTLSASVGDRVTITCRASQSFTT VRQAPGQGLEWMGWISAYNGNTNYAQKLQGRVT
YLAWYQQKPGKAPKLLIYQTSNLESGVPSRF
MTTDTSTSTAYMELRSLRSDDTAVYYCARDLFPTIF
SGSGSGTEFTLTISSLQPDDFATYYCQQYSRY WEGGAFDIWGQGTMVTVSS SEQ ID NO. 5
WWSFGQGTRLEIK SEQ ID NO. 6 E11 EVQLVQSGAEVKKPGASLKVSCKASGYTFNSYDINW
AIQMTQSPSSLSASVGDRVTITCRASQSISSY VRQAPGQGLEWMGWINPNSGGTNYAQKFQGRV
LNWYQQKPGKAPKLLIYAASSLQSGVPSRFS
TMTRDTSTSTVYMELSSLTSEDTAVYYCARDLFPHIY
GSGSGTDFTLTISSLQPEDFATYYCQQSSSTP GNYYGMDIWGQGTTVTVSS SEQ ID NO. 7
LTFGQGTKVEIK SEQ ID NO. 8 F1 QVQLVESGGGVVQPGRSLRLSCAASGFTFSSYAMH
QAVLTQPRSVSGSPGQSVTISCTGTSSDVG WVRQAPGKGLEWVAVISFDGSNKYYADSVRGRFTI
GYNYVSWYQQHPGKAPKLMIYDVRTRPSG SRDNSKNTLYLQMNSLRTEDTAVYYCARGWLDRDI
VSDRFSGSKSGNTASLSISGLQAEDEADYYC DYWGQGTLVTVSS SEQ ID NO. 9
SSHSSSTTVIFGGGTKLTVL SEQ ID NO. 10 F4
EVQLVQSGAEVKKPGASVKVSCKASGYTFTGYYMH
DIVMTQSPSSLSASVGDRVTITCRASQSISSY WVRQAPGQGLEWMGWINPNSDNTGSAQKFQGR
LNWYQQKPGKAPKLLIYAASSLQSGVPSRFS
VFMTKTTSLNTAYMELSGLRSEDTAIYYCARERSSGY
GSGSGTDFTLTISSLQPEDFATYYCQQSYSTP FDFWGQGTLVTVSS SEQ ID NO. 11
ITFGQGTRLEIK SEQ ID NO. 12 F7 EVQLVESGGGVVQPGRSLRLSCAASGFTFSSYWMS
QAVLTQPPSVSAAPGQRVTISCSGSNSNIAD WVRQAPGKGLEWVANIKQDGSEKYYVDSVKGRFTI
TYVSWYQQLPGTAPRLLIYDNDQRPSGIPD SRDNAKNSLYLQMNSLRAEDTAVYYCAREGEHDAF
RFSGSKSGTSATLGITGLQTGDEADYYCGT DIWGQGTMVTVSS SEQ ID NO. 13
WDSSLSGVFGTGTKVTVL SEQ ID NO. 14 F8
QVQLVQSGGGVVQPGRSPRLSCAASGFTFNTYGM QSVLTQPASVSGSPGQSVTISCTGTSSDVGG
HWVRQAPGKGLEWVAVISDGGNNKKYADSVKGRF FNSVSWYQQHPGKAPKLMIYDVSKRPSEIS
TISRDNAKNSLYLQMNSLRAEDTALYYCAKDIGESYY
DRFSGSKSGNTASLTISGLQPEDEADYYCSSY YYMDVWGKGTTVTVSS SEQ ID NO. 15
TSSSTLVFGGGTKLTVL SEQ ID NO. 16 F11
QVQLQQSGPGLVKPSQSLSLTCAISGDSLSSNSAAW
SYVLTQPPSVSVSPGQTASISCSGYKLENKYV
NWIRQSPSGGLEWLGRTYYRSKWYNEYVESLKSRIT SWYQQRAGQSPVLVIYQDNKRPSGIPERFS
INSDISRNQFSLHLNSVTPEDTAVYYCASGTGARGM GSNSGNTASLTITGLQPEDEADYYCSAWDS
DVWGQGTTVTVSS SEQ ID NO. 17 SLRAWVFGGGTQLTVL SEQ ID NO. 18 G4
QVQLQQSGPGLVKPSETLSLTCAISGDSVSENSAAW
QPVLTQPPSVSVSPGQTASITCSGDELGNKY
NWIRQSPSGGLEWLGRTYYRSKWYNEYVESLKSRIT VYWYQQKPGRSPVLVIYQDSKRPSGFPARF
INSDISRNQFSLHLNSVTPEDTAVYYCASGTGARGM SGANSGNTATLTISGTQAMDEADYFCQAW
DVWGQGTTVTVSS SEQ ID NO. 19 DSSTAWVFGGGTKLTVL SEQ ID NO. 20 G9
EVQLVQSGAEVKKPGASVKVSCKASGYTFTGYYMH
DIVMTQSPSSLSASVGDRVTITCRASQSISSY WVRQAPGQGLEWMGWINPNSDNTGSAQKFQGR
LNWYQQKPGKAPKLLIYAASSLQSGVPSRFS
VFMTKTTSLNTAYMELSGLRSEDTAIYYCARERSSGY
GSGSGTDFTLTISSLQPEDFATYYCQQSYSTP FDFWGQGTLVTVSS SEQ ID NO. 21
ITFGQGTRLEIK SEQ ID NO. 22 G11 QVQLVQSGAEVKKPGSSVKVSCKASGGTFSRYGVH
LPVLTQPASVSGSPGQSVTISCTGTSSDVGG WVRQAPGQGLEWMGRLIPIVSMTNYAQKFQDRV
HNYVSWYQQHPGKAPKLMIYEVNKRPSGV SITTDKSTGTAYMELRSLTSEDTALYYCASVGQQLP
PDRFSGSKSDYTASLTISGLQPDDEADYFCSS WVFFAWGQGTLVTVSS SEQ ID NO. 23
YTATTTGVVFGTGTKVTVL SEQ ID NO. 24 G12
EVQLVQSGAEVKKPGASVKVSCKASGYTFTGYYMH
DIVMTQSPSSLSASVGDRVTITCRASQSISSY WVRQAPGQGLEWMGWINPNSDNTGSAQKFQGR
LNWYQQKPGKAPKLLIYAASSLQSGVPSRFS
VFMTKTTSLNTAYMELSGLRSEDTAIYYCARERSSGY
GSGSGTDFTLTISSLQPEDFATYYCQQSYSTP FDFWGQGTLVTVSS SEQ ID NO. 25
ITFGQGTRLEIK SEQ ID NO. 26 H1 QVQLVQSGAEVKKPGASVKVSCKTSGNTFTNYYMH
DIVMTQSPPSLSASVGDRVTITCRASQSISSY WVRQAPGQGLEWMGIMNPSGGSTSYAQKFQGR
LNWYQQKPGKAPKLLIYAASSLQSGVPSRFS
VTMTRDKSTSTVYMELSSLTSEDTAVYYCARDLFPHI
GSGSGTDFTLTISSLQPEDFATYYCQQSYSTP YGNYYGMDIWGQGTTVTVSS SEQ ID NO. 27
YTFGQGTKVEIK SEQ ID NO. 28 H3 QVQLVQSGAEVKKPGSSVKVSCKASGGTFSSYAISW
QSVVTQPPSVSAAPGQKVTISCSGSTSNIEN VRQAPGQGLEWMGGIIPIFGTASYAQKFQGRVTIT
YSVSWYQQLPGTAPKLLIYDNNKRPSGIPDR
ADESTTTAYMELSSLRSEDTAVYYCAREGPEYCSGG FSGSKSGTSATLGITGLQTGDEADYYCGTW
TCYSADAFDIWGQGTMVTVSS SEQ ID NO. 29 DNRLSSVVFGGGTKVTVL SEQ ID NO.
30 H4 QVQLVQSGAEVKKPGSSVKVSCKASGGTFSSYAISW
QPVLTQPPSVSAAPGQKVTISCSGSSSNIGN
VRQAPGQGLEWMGRIIPILGIANYAQKFQGRVTITA SHVSWFQQLPGTAPKLVIYDNDKRPSGIAD
DKSTSTAYMELSSLRSEDTAVYYCARSESGSYSHDY RFSGSKSGTSATLGITGLQTGDEADYYCGT
WGQGTTVTVSS SEQ ID NO. 31 WDSSLSAGVFGGGTKLTVL SEQ ID NO. 32 H5
QVQLVESGAEVKKPGASVKVSCKASGYTFTSYYIHW QAVVTQPPSASGTPGQRVTISCSGSSSNVG
VRQAPGQGLEWMGIINPSGGSTTYAQKFQGRVSM VNHVFWYQHLPGMAPKLLIHRTNQWPSG
TRDTSTRTVYMELSGLISDDTAIYYCARDDDFYSGYP
VPDRFSGSKSGTSATLGITGLQTGDEADYYC GDYWGQGTLVTVSS SEQ ID NO. 33
GTWDSSLSAVFGGGTKLTVL SEQ ID NO. 34 H6
QMQLVQSGAEVKKPGSSVKVSCKASGGTFSSYAIS SYELMQPPSVSVAPGKTATIACGGENIGRKT
WVRQAPGQGLEWMGGIIPIFGTANYAQKFQGRVT VHWYQQKPGQAPVLVIYYDSDRPSGIPERF
ITADESTSTAYMELSSLRSEDTAVYYCARGNIVATITP
SGSNSGNTATLTISRVEAGDEADYYCQVWD LDYWGQGTLVTVSS SEQ ID NO. 35
SSSDHRIFGGGTKLTVL SEQ ID NO. 36 H10
EVQLVQSGGGLVQPGGSLRLSCAASGFTFSSYSMN
EIVLTQSPSSLSASIGDRVTLTCRASQSIRRFL
WVRQAPGKGLEWVSYISSSSSTIYYADSVKGRFTISR
NWYQQKPGKAPELLIYTASSLQSGVPSRFSG DNAKNSLYLQMNSLRDEDTAVYYCARGDYYYGMD
SGSGTDFTLTINSLQPEDFATYYCQQSYAVS VWGQGTTVTVSS SEQ ID NO. 37
PYTFGQGTKVEIR SEQ ID NO. 38 H12 QMQLVQSGAEVKKPGSSVKVSCKASGGTFSSYAIS
QSVVTQPPSVSAAPGQKVTISCSGSSSNIGN WVRQAPGQGLEWMGGIIPIFGTANYAQKFQGRVT
NYVSWYQQLPGTAPKLLIYDNNKRPSGIPD ITADESTSTAYMELSSLRSEDTAVYYCARGDFWSGY
RFSGSKSGTSATLGITGLQTGDEADYYCGT RTYYYYYGMDVWGQGTMVTVSS SEQ ID NO. 39
WDSSLSAVVFGGGTKLTVL SEQ ID NO. 40 PDL-D2
QVQLVQSGAEVKKPGASVKVSCKTSGYTFTSNAIG
ALTQPASVSGSLGQSITISCTGSSSDVGGYKY WVRQAPGQGLEWMGWISAYNGNTNYAQNLQGR
VSWYQQHPGKAPKLMIYDVINRPSGVSSRF VTMTTDTSTSTAYMELRSLRSDDTAVFYCARKGTGL
SGSKSANTASLTISGLQAEDEADYYCFSYSSR HFDYWGQGTLVTVSS SEQ ID NO. 41
STRIFGSGTKVTVL SEQ ID NO. 42 PDL-D11
QVQLQQSGPGLVKPSQTLSLTCAISGDSVSSNSAA QTVVTQPPSVSKDLGQTATLTCTGNNNNV
WNWIRQSPSRGLEWLGRTYYRSKWYNDYAVSVKS GNHGAAWLQQHQGHPPKLLSYRNNNRPS
RITINPDTSKNQFSLQLNSVTPEDTAVYYCARGAAG
GISERLSASRSGNTASLTITGLQPEDEADYYC RAFDIWGQGTMVTVSS SEQ ID NO. 43
SAWDRSLSAWVFGGGTKLTVL SEQ ID NO. 44 PDL-H1
EVQLVQSGGGLVQPGGSLRLSCAASGFTFSSYSMN
EIVLTQSPSSLSASIGDRVTLTCRASQSIRRFL
WVRQAPGKGLEWVSYISSSSSTIYYADSVKGRFTISR
NWYQQKPGKAPELLIYTASSLQSGVPSRFSG DNAKNSLYLQMNSLRDEDTAVYYCARGDYYYGMD
SGSGTDFTLTINSLQPEDFATYYCQQSYAVS VWGQGTTVTVSS SEQ ID NO. 45
PYTFGQGTKVEIK SEQ ID NO. 46 RB4 EVQLVESGGGLVQPGGSLRLSCAASGFYLGSYWMA
QSVLTQPASVSGSPGQSISVSCTGTSSDVGR
WVRQAPGKGLEWVAAIRQDGSETIYVDSVKGRFIIS YNFVSWYQQHPGKAPKLMVFDVSNRPSGI
RDNGGNSVTLQMTTLRAGDTAVYYCARAHYFGFD SNRFSGSKSGNTASLTISGLQAEDEADYYCS
NWGQGTLVTVSS SEQ ID NO. 47 SYTTNSTYVFGSGTKVTVL SEQ ID NO. 48 RB11
QMQLVQSGAEVKKPGASVKISCKASGYPFRNYYIH QPVLTQPPSVSAAPGQKVTISCSGSSSNIAN
WVRQAPGQGLEWVGIINPDGGTITYAGKFQGRVS NYVSWYQQLPGTAPKLLIFANNKRPSGIPD
MTRDTSTSTVYMELSSLTSEDTAVYYCARDLFPHIYG
RFSGSKSGTSAALDITGLQTGDEADYYCGT NYYGMDIWGQGTTVTVSS SEQ ID NO. 49
WDSDLRAGVFGGGTKLTVL SEQ ID NO. 50 RC5
EVQLLESGGGVVQPGGSLRLSCAASGFTFSSYWMS
AIRMTQSPSSLSASVGDRVTITCRASQSISSY
WVRQAPGKGLEWVANIKQDGSEKYYVDSVKGRFTI LNWYQQKPGKAPKLLIYTTSSLKSGVPSRFS
SRDNSKNTVSLQMNSLRAEDTAVYYCAKDRYYNFP
GSGSGTDFTLTISRLQPEDFATYYCQQSYSST LGMDVWGQGTTVTVSS SEQ ID NO. 51
WTFGRGTKVEIK SEQ ID NO. 52 RF5
EVQLLESGAEVKKPGSSVKVSCKSSGDTFTNFAINWI
QSVLTQPASVSGSPGQSITISCTGTSSDVGSY
RQAPGQGLEWMGRIIPLFGTTNYAQKFQGRVTITA NLVSWYQQYPGKAPKLMIYEVSERPSGVPD
DESTSTAFMDLNSLTSEDTAVYYCARTLGGDYYDSR
RFSGSKSGNTASLTVSGLQAEDEADYYCSSY GYYNWGQGTLVTVSS SEQ ID NO. 53
TDSNNFRVFGGGTKLTVL SEQ ID NO. 54 RG9
QVQLQQSGPGLVKPSQTLSLTCAISGDSVSSNSVV
EIVMTQSPSSLYASVGDRVTITCRASQSISSY WNWFRQSPSRGLEWLGRAYYRSKWYNDYAVSVKS
LNWYQQKPGKVPKLLIYAASSLQSGVPSRFS
RITINPDTSKNQLSLQLNSVTPEDTAVYYCAKGLDV
GSGSGTDFTLTISGLQPEDFATYYCQQSYTP WGQGTTVTVSS SEQ ID NO. 55
AWTFGQGTKLEIK SEQ ID NO. 56 RD1
QVQLVQSGAEVKKPGSSVKVSCKASGGTFSSYAISW
QSVVTQPPSVSAAPGQKVTISCSGSSSNIGN VRQAPGQGLEWMGGIIPIFGTANYAQKFQGRVTIT
NYVSWYQQVPGTAPKLLIYDNDKRPSGIPD ADESTSTAYMELSSLRSEDTAVYYCARDGIVADFQH
RFSGSKSGTSATLAITGLQTGDEADYYCGT WGQGTLVTVSS SEQ ID NO. 57
WDSSLNAWVFGGGTKLTVL SEQ ID NO. 58 RF11
QVQLVQSGAEVKKPGASVRVSCKASGGTFSSYAIS QSVLTQPPSVSAAPGQKVTISCSGSSSNIEN
WVRQAPGQGLEWMGGIIPIFGTANYAQKFQGRVT NYVSWYQHLPGTAPKLLIYDDFKRPSGIPDR
ITADESTSTAYMELSSLRSEDTAVYYCARDGIVADFQ
FSGSKSGTSATLGITGLQTGDEADYYCGTW HWGQGTLVTVSS SEQ ID NO. 59
DSSLSAVVFGGGTKLTVL SEQ ID NO. 60 RH11
QMQLVQSGAEVKKPGSSVKVSCKASGGTFNSYPIS QSVLTQPPSASGSPGQSVTISCTGTSSDVGG
WVRQAPGQGLEWMGGIIPIFGTANYAQKFQGRVT YNYVSWYQQHPGKAPKLMIYEVSKRPSGV
ITADESTSTAYMELSSLRSEDTAMYYCAKNHPTATL
PDRFSGSKSGNTASLTVSGLQAEDEADYYCS DYWGQGTLVTVSS SEQ ID NO. 61
SYAGSNNLGVFGGGTKLTVL SEQ ID NO. 62 RD9
QVQLVQSGGNLVKPGGSLRLSCAASGFSFSSYDMN DIQLTQSPSSLSASVGDRVTITCRASQGISS
WVRQAPGRGLEWVSSISGTGRYEYYSPSVKGRFTIS WLAWYQQKPGKAPKLLIYAASSLQSGVPSR
RDNANTSLYLQMNSLTADDTAVYFCTRGDILTGASA
FSGSGSGTDFTLTISSLQPEDFATYYCQQAN MDVWGQGTTVTVSS SEQ ID NO. 63
SFPLTFGGGTKVEIK SEQ ID NO. 64 RE10
EVQLLESGGNLVKPGGSLRLSCAASGFSFSSYDMN DVVMTQSPSTLSASVGDRVTITCRASQSIGT
WVRQAPGRGLEWVSSISGTGRYEYYSPSVKGRFTIS WLAWYQQKPGKAPNLLIYKASSLESGVPSR
RDNANTSLYLQMNSLTADDTAVYFCTRGDILTGASA
FSGSGSGTEFTLTISSLQPDDFATYYCQQAN MDVWGQGTTVTVSS SEQ ID NO. 65
SFPLTFGGGTKVEIK SEQ ID NO. 66 RA3
QMQLVQSGAEVKKPGSSVKVSCKASGGTFSRYGVH DIQMTQSPSSLSASVGDRVTITCQASQDISN
WVRQAPGQGLEWMGRLIPIVSMTNYAQKFQDRV YLNWYQQKPGKAPKLLIYDASTLQSGVPSR
SITTDKSTGTAYMELRSLTSEDTALYYCASVGQQLP
FSGSGSGTDFTLTISSLQPEDFATYYCQQSYS WVFFAWGQGTLVTVSS SEQ ID NO. 67
SHWTFGQGTKVEIK SEQ ID NO. 68 RG1
EVQLVQSGAEVKKPGSSVKVSCKASGGTFSRYGVH QSVVTQPPSVSGAPGQRVTISCTGSSSNIGA
WVRQAPGQGLEWMGRLIPIVSMTNYAQKFQDRV GYGVHWYQHLPGSAPKLLIYGNSNRPSGVT
SITTDKSTGTAYMELRSLTSEDTALYYCASVGQQLP
DRISGSKSGTSASLAITGLQAEDEAVYYCQSY WVFFAWGQGTLVTVSS SEQ ID NO. 69
DSSLSTSVVFGGGTKLTVL SEQ ID NO. 70 RB1
QMQLVQSGGGLIQPGGSLRLSCAASGFTFSSYAMH QAGLTQPASVSGSPGQSITISCTGTSSDVGG
WVRQAPGKGLEWVAVISFDGSNKYYADSVRGRFTI YNYVSWYQQHPGKAPKLMIYDVTKRPSGV
SRDNSKNTLYLQMNSLRTEDTAVYYCARGWLDRDI SNRFSGSKSGNTASLTISGLQAEDEANYYCS
DYWGQGTLVTVSS SEQ ID NO. 71 SYTSRSTSVLFGGGTKLTVL SEQ ID NO. 72 RG7
EVQLVESGGGVVLPGRSLRLSCAASGFTFSSYAMH QPVLTQPPSVSEAPRQRVTISCSGSSSNIGH
WVRQAPGKGLEWVAVISFDGSNKYYADSVRGRFTI NAVTWYQQVPGKAPKLLIYYDDLLPSGVSD
SRDNSKNTLYLQMNSLRTEDTAVYYCARGWLDRDI RFSGSKSGTSASLAISGLQSEDEADYYCAAW
DYWGQGTLVTVSS SEQ ID NO. 73 DDSLNGWVFGGGTKLTVL SEQ ID NO. 74 RA6
QVQLVESGGGVVQPGRSLRLSCAASGFTFSSYAMH QAGLTQPASVSGSPGQSITISCTGTSSDVGG
WVRQAPGKGLEWVAVISFDGSNKYYADSVRGRFTI YNYVSWYQQHPGKAPKLMIYDVSNRPSGV
SRDNSKNTLYLQMNSLRTEDTAVYYCARGWLDRDI PDRFSGSKSGNTASLTISGLQAEDDADYYCA
DYWGQGTLVTVSS SEQ ID NO. 75 SYTSTSTLGVVFGGGTKLTVL SEQ ID NO. 76 RA8
QVQLVESGGGVVQPGRSLRLSCAASGFTFSSYAMH QPVLTQPASVSGSPGQSITISCTGTSSDVGG
WVRQAPGKGLEWVAVISFDGSNKYYADSVRGRFTI YNYVSWYQHHPGKAPKLMIFDVNKRPSGV
SRDNSKNTLYLQMNSLRTEDTAVYYCARGWLDRDI SNRFSGSKSGNTASLTISGLQAEDEADYYCN
DYWGQGTLVTVSS SEQ ID NO. 77 SYTTSSTYVVFGGGTKLTVL SEQ ID NO. 78 RA9
QVQLVESGGGVVQPGRSLRLSCAASGFTFSSYAMH QSVLTQPPSASGTPGQRVTISCSGSSSNIGS
WVRQAPGKGLEWVAVISFDGSNKYYADSVRGRFTI NTVHWYQQLPGTAPKVLIYTNNQRPSGVP
SRDNSKNTLYLQMNSLRTEDTAVYYCARGWLDRDI DRFSGSKSGTSASLAISGLQSEDEADYYCAA
DYWGQGTLVTVSS SEQ ID NO. 79 WDGRLQGWVFGGGTKLTVL SEQ ID NO. 80 RB5
QVQLVESGGGVVQPGRSLRLSCAASGFTFSSYAMH QSVVTQPPSVSAAPGQKVTISCSGSNSNIAN
WVRQAPGKGLEWVAVISFDGSNKYYADSVRGRFTI NYVSWYQQLPGTAPKLLIYDSNKRPSGIPDR
SRDNSKNTLYLQMNSLRTEDTAVYYCARGWLDRDI FSGSKSGTSATLGITGLQTGDEADYYCGSW
DYWGQGTLVTVSS SEQ ID NO. 81 DSSLSVWMFGGGTKLTVL SEQ ID NO. 82 RB8
QVQLVESGGGVVQPGRSLRLSCAASGFTFSSYAMH LPVLTQPRSVSGSPGQSVTISCTGTSSDVGG
WVRQAPGKGLEWVAVISFDGSNKYYADSVRGRFTI YNYVSWYQQHPGKAPKLMIYDVTKRPSGV
SRDNSKNTLYLQMNSLRTEDTAVYYCARGWLDRDI PDRFSGSKSGNTASLTISGLQAEDEADYYCS
DYWGQGTLVTVSS SEQ ID NO. 83 SYTGSSTLGPVFGGGTKLTVL SEQ ID NO. 84 RC8
EVQLVESGGGVVQPGRSLRLSCAASGFTFSSYAMH QSVLTQPPSVSAAPGQKVTISCSGNSSNIGN
WVRQAPGKGLEWVAVISFDGSNKYYADSVRGRFTI NYVSWYQQLPGTAPKLLIYDNDKRPSGIPD
SRDNSKNTLYLQMNSLRTEDTAVYYCARGWLDRDI RFSGSKSGTSASLAISELRFEDEADYYCAAW
DYWGQGTLVTVSS SEQ ID NO. 85 DDTLSGHVFGPGTKLTVL SEQ ID NO. 86 RC10
EVQLVESGGGVVQPGRSLRLSCAASGFTFSSYAMH SYELMQPPSVSVPPGETARITCGGNNIGNK
WVRQAPGKGLEWVAVISFDGSNKYYADSVRGRFTI NVHWYQQKPGQAPVLVVREDSARPAGIPE
SRDNSKNTLYLQMNSLRTEDTAVYYCARGWLDRDI RFSGSNSGNSATLTISRVEAGDEADYYCQV
DYWGQGTLVTVSS SEQ ID NO. 87 WDNTSDHVVFGGGTKLTVL SEQ ID NO. 88 RD2
QVQLVESGGGVVQPGRSLRLSCAASGFTFSSYAMH SYELMQPPSVSEVPGQRVTISCSGSSSNIGN
WVRQAPGKGLEWVAVISFDGSNKYYADSVRGRFTI NAVNWFQQLPGKAPKLLVYYDDWVPSGIS
SRDNSKNTLYLQMNSLRTEDTAVYYCARGWLDRDI GRFSASKSGTSASLAISGLQSGDEGDYYCAV
DYWGQGTLVTVSS SEQ ID NO. 89 WDDRLSGVVFGGGTKLTVL SEQ ID NO. 90 RE8
QVQLVESGGGVVQPGRSLRLSCAASGFTFSSYAMH QSVVTQPPSVSAAPGQKVTISCSGSSSNIGN
WVRQAPGKGLEWVAVISFDGSNKYYADSVRGRFTI NYVSWYQQLPGTAPTLLIYDSNKRPSVIPDR
SRDNSKNTLYLQMNSLRTEDTAVYYCARGWLDRDI FSGSKSGTSATLGITGLQTGDEADYYCGTW
DYWGQGTLVTVSS SEQ ID NO. 91 DDSLNGWVFGGGTKLTVL SEQ ID NO. 92 RE9
EVQLVESGGGVVQPGRSLRLSCAASGFTFSSYAMH QSALTQPASVSGSPGQSITISCTGTSSDVGG
WVRQAPGKGLEWVAVISFDGSNKYYADSVRGRFTI YNYVSWYQQHPGKAPKLMIYDVSNRPSGV
SRDNSKNTLYLQMNSLRTEDTAVYYCARGWLDRDI SNRFSGSKSGNTASLTISGLQAEDEADYYCS
DYWGQGTMVTVSS SEQ ID NO. 93 SYRSSTLGPVFGGGTKLTVL SEQ ID NO. 94 RG12
QVQLVESGGGVVQPGRSLRLSCAASGFTFSSYAMH QAGLTQPPSASGSPGQSVTISCTGTSSDVG
WVRQAPGKGLEWVAVISFDGSNKYYADSVRGRFTI GYNYVSWYQQHPGKAPKLMIYDVSNRPSG
SRDNSKNTLYLQMNSLRTEDTAVYYCARGWLDRDI VPDRFSGSKSGNTASLTISGLQAEDEADYYC
DYWGQGTLVTVSS SEQ ID NO. 95 SSYTSSSTLVVFGGGTKLTVL SEQ ID NO. 96
RSA1 EVQLVQSGGGLVQPGGSLRLSCAASGFTFSSYSMNN
IQMTQSPSSVSASVGDRVTITCRASQDISR
WVRQAPGKGLEWVSYISSSSSTIYYADSVKGRFTISR
WLAWYQQKPGKAPKLLIYAASSLQSGVPSR DNAKNSLYLQMNSLRDEDTAVYYCARGDYYYGMD
FSGSGSGTDFALTISSLQPEDFATYYCQQAD
VWGQGTTVTVSS SEQ ID NO. 97 SFFSITFGQGTRLEIK SEQ ID NO. 98 R2A7
QVQLVQSGSEVKKPGASVKVSCRASGYLFTNYGIS
AIQLTQSPATLSLSPGERATLSCRASQSVGVY WVRQAPGQGLEWMGWVSAHGEFTKYAPSLQDR
LAWYQQKPGQSPRLLIYDTSKRATGIPDRFS VTMTSDISTTTAYMELRSLRSDDAGVYYCARDRGA
ASGSGTDFTLTISRLEPEDFAVYYCHQRHSW DHFDTWGQGTLVTVSS SEQ ID NO. 99
PTTFGQGTRLEIK SEQ ID NO. 100 R2B12
EVQLVQSGAEVKKPGASVKVSCKASGYTFTSYYMH
NIQMTQSPSSLSASVGDRVTITCRASQSISSY WVRQAPGQGLEWMGMINPSSATTTYTQKFQGRV
LNWYQQKPGKAPKLLIYAASSLQSGVPSRFS
SMTRDTSTSTVYMELSSLTSEDTAVYYCARDLFPHIY
GSGSGTDFTLTISSLQPEDFATYYCQQSYSTL GNYYGMDIWGQGTTVTVSS SEQ ID NO. 101
TFGGGTKVEIK SEQ ID NO. 102 R2C9
EVQLVQSGAEVKKPGSSVKVSCKASGGTFSSHVISW
QSVLTQPASVSGSPGQSITISCTGTSSDVGD VRQAPGQGLEWMGGIIPIFGTANYAQKFQGRVTIT
YNLVSWYQQHPGKAPKLIIYEVNKRPSGVS ADESTSTAYMELSSMRSEDTAVYYCATSGVVAATHF
NRFSGSKSGNTASLTISGLQAEDEADYYCSS GYWGQGTLVTVSS SEQ ID NO. 103
YAGYNNLYVFGTGTKVTVL SEQ ID NO. 104 R2D5
QVQLVQSGAEVKKPGSSVKVSCKASGGTFSSYAISW
QSALTQPPSASGSPGQSVTISCTGTSSDVGG VRQAPGQGLEWMGGIIPIFGTANYAQKFQGRVTIT
YNYVSWYQQHPGKAPKLIIYDVNMRPSGV ADESTSTAYMELSSLRSEDTAVYYCARGASGSYFITT
PDRFSGSKSGNTASLTISGLQAEDEADYYCS YVDYWGQGTLVTVSS SEQ ID NO. 105
SYAGLYFPLFGGGTQLTVL SEQ ID NO. 106 R2D7
EVQLVESGGGLVQPGGPLRLSCAASGFTLSSYWMS
DIVMTQSPSSLSASVGDRVTITCRASQSISSY
WVRQAPGKGLEWVANIKYDGSETYYADSVKGRFTI LNWYQQKPGKAPKLLIYAASSLQSGVPSRFS
SRDNAKNSLYLQMNRLRLEDTAVYYCAREVSSAATS
GSGSGTDFTLTISSLQPEDFATYYCQQSHSS PLDRWGRGTLVTVSS SEQ ID NO. 107
RYTFGQGTKLEIK SEQ ID NO. 108 R2F4
EVQLVQSGAEVKKPGSSVKVSCKASGGTFSRYGVH QSVVTQPPSVSGAPGQRVTISCTGSSSNIGA
WVRQAPGQGLEWMGRLIPIVSMTNYAQKFQDRV GYGVHWYQHLPGSAPKLLIYGNSNRPSGVT
SITTDKSTGTAYMELRSLTSEDTALYYCASVGQQLP
DRISGSKSGTSASLAITGLQAEDEAVYYCQSY WVFFAWGQGTLVTVSS SEQ ID NO. 109
DSSLSTSVVFGGGTKLTVL SEQ ID NO. 110 R2A10
EVQLVESGGGVVQPGGSLRLSCAASGFTFSSYAMH QSVLTQPPSASGTPGQRVTISCSGSSSNIGS
WVRQAPGKGLEWVAVISFDGSNKYYADSVRGRFTI NTVHWYQQLPGTAPKVLIYTNNQRPSGVP
SRDNSKNTLYLQMNSLRTEDTAVYYCARGWLDRDI DRFSGSKSGTSASLAISGLQSEDEADYYCAA
DYWGQGTLVTVSS SEQ ID NO. 111 WDGRLQGWVFGGGTQLTVL SEQ ID NO. 112
R2E2 EVQLVESGGGVVQPGRSLRLSCAASGFTFSSYAMH
QAGLTQPPSASGTPGQRVTISCFGSSSDIGS WVRQAPGKGLEWVAVISFDGSNKYYADSVRGRFTI
NTVNWYQQVSGRAPKLLLYTNGQRPSGVP SRDNSKNTLYLQMNSLRTEDTAVYYCARGWLDRDI
DRFSGSKSGSSASLAISGLQSEDEADYYCAS DYWGQGTLVTVSS SEQ ID NO. 113
WDDSLKGYVFGTGTKVTVL SEQ ID NO. 114 R3B8
EVQLVQSGAEVKKPGSSVKVSCKASGGTFSSYAISW
QSVLTQPPSVSAAPGQKVTISCSGSSSNIGN
VRQAPGQGLEWMGRIIPILGIANYAQKFQGRVTITA
SYVSWYQHLPGTAPKLLIYDNNKRPSGIPDR
DKSTSTAYMELSSLRSEDTAVYYCARVGGGAQTPFD FSGSKSATSATLGITGLQTADEADYYCGTW
YWGQGTLVTVSS SEQ ID NO. 115 DSSLGVVFGGGTKLTVL SEQ ID NO. 116 R3C3
QVQLVQSGSEVKRPGASVRVSCKASGYIFSQYTIHW
QSALTQPASVSGSPGQSITISCTGTSSDVGG VRQAPGERLEWLGWINAVTGNTKYAQKFQGRVTIT
YNYVSWYQQHPGKAPKLMIYNVSKRPSGV MDSSASTAFMEMSSLRSEDAGVYFCARDMVPFGG
SNRFSGSKSGNTASLTISGLQAEDEADYYCS EIKYGFDFWGQGTMITVSS SEQ ID NO. 117
SYTSSSTFVFGTGTKVTVL SEQ ID NO. 118 R3E9
QVQLVESGGGVVQPGRSLRLSCAASGFTFSSYGMH SYELMQPPSVSVAPGETARITCGGNNIGSKS
WVRQAPGKGLEWVALISYDGSNKYYADSMKGRFTI VHWYQQKPGQAPILVIYYDSGRPSGIPERFS
SRDNSKNTLFLQMNSLRAEDTAVYYCAKTLMPASI GSNSGNTATLTISRAEAGDEADYYCHVWDS
MGYFTHWGQGTLVTVSS SEQ ID NO. 119 YTDHVVFGGGTKLTVL SEQ ID NO. 120
R3E10 QVQLVQSGAEVKKPGASVKVSCKASGYTFTSYYMH
QPVLTQPPSLSVAPGKTASIACGGNNIGSKR WVRQAPGQGLEWMGIINPSDGSTSYAQKFQGRVT
VHWYQQKPGQAPVLVIYYESDRPSGIPERF MTRDTSTSTVYMELSSLRSEDTAVYYCARGYYGSGI
SGTISQNTATLSISRVEAGDEADYYCQVWD AMDVWGQGTTVTVSS SEQ ID NO. 121
RSSAHVVFGGGTKVTVL SEQ ID NO. 122 R3F7
QVQLVQSGAEVKKPGSSVKVSCKASGGTFSSYAISW
AIQMTQSPSSLSASVGDRVTITCRASQSISTY
VRQAPGQGLEWMGGIIPIFGTANYAQKFQGRVTIT LNWYQQKPGKAPKLLIYAASSLQNGVPSRF
ADESTSTAYMELSSLRPEDTAVYYCARDNGDLGFDY
SGSGSGTDFTLTISSLQPEDFATYYCQQSYST WGQGTLVTVSS SEQ ID NO. 123
PRTFGPGTKVDIK SEQ ID NO. 124 R3F10
EVQLVESGGGLIQPGGSLRLSCAASGFTVSSNYMS DIQMTQSPSSLSASVGDRVTITCQASQDISN
WVRQAPGKGLEWVSVIYSGGTIYYADSVKGRFTISR YLNWYQQKPGKAPKLLIFAGSNLQSGVPSR
DSSKNTLYLHMNSLRAEDTGVYYCAKGVGSWSIFD
FSGSGSGTDFTLTITSLQPEDFATYYCQQSYT YWGQGTLVTVSS SEQ ID NO. 125
TPTFGQGTKVEIK SEQ ID NO. 126 R4B10
EVQLVESGAELKKPGSSMKVSCKASGGTFSSYAISW
QSVVTQPASVSGSPGQSITISCTGTSSDVGS
VRQAPGQGLEYIGRIIPIFGVTYYAQKFQGRVTISAD
YNLVSWYQQHPGKAPKLMIYEGSKRPSGVS KSTSTVYLDLRSLRSEDTAVYYCARDLGGGDGDWG
TRFSGSKSGNTASLTISGLQAEDESDYYCSSY QGTLVTVSS SEQ ID NO. 127
TGSAWVFGGGTKLTVL SEQ ID NO. 128 R4H1
EVQLVQSGAEVKKPGSSVKVSCKASGYTFTGYYMH QSVVTQPPSVSATPGQKVTISCSGSDSNIGN
WVRQAPGQGLEWMGRIIPIFGTANYAQKFQGRVT NYVSWFLQLPGTAPKLLIHNNDQRPSGVPD
ITADESTSTAYMELSSLRSEDTAVYFCVTSAWSDWG
RFSGSKSGTSASLAITGLQAEDEADYYCQSF QGTLVTVSS SEQ ID NO. 129
DDSLRGYLFGTGTKVTVL SEQ ID NO. 130 R4A11
EVQLVESGGGLVQPGGSLRLSCAASGFTFSSYWMS QAVLTQPPSVSAAPGQKVTISCSGGSSNIAN
WVRQAPGKGLEWVANIKQDGSEKYYVDSVKGRFTI NYVSWYQHLPGTAPKLLIYDDNKRPSGIPD
SRDNSKNTLYLQMNSLGAEDTAVYYCAKGFYYPDH RFSGSKSGTSATLGITGLQTGDGADYYCGT
WGQGTLVTVSS SEQ ID NO. 131 WDNSLNSDWVFGGGTKL SEQ ID NO. 132 R3D2
EVQLVESGGGVVQPGGSLRLSCEVSGFIFSDYGMH QSVLTQPPSVSVAPGKTARITCGGNNIGSKS
WVRQAPGKGLEWVSSISSSSSYIYYADSVKGRFTISR
VHWYQQKPGQAPVLVIYYDSDRPSGIPERF DNAKNSLYLQMNSLRAEDTAMYYCARSWNYGRFF
SGSNSGNTATLTISRVEAGDEADYYCQVWD DYWDQGTLVTVSS SEQ ID NO. 133
SSSDHYVFGTGTKLTVL SEQ ID NO. 134 R5B8
EVQLVESGGGLVQPGGSLRLSCAASGFTSSRNWM VIWMTQSPSSLSASVGDRVTITCRASQTISS
HWVRLAPGKGLVWVSLIAPDGSLTTYADSVKGRFTI
YLNWYQQKPGKAPKLLIYAASSLQSGVPSRF
SRDTAKNSVQLLLNSLRAEDTGLYFCAREAGVSGGL
SGSGSGTDFTLTISSLQPEDFATYYCQQANS DVWGQGTLVTVSS SEQ ID NO. 135
FPLTFGGGTKVEIK SEQ ID NO. 136 SH1A1Q
EVQLVQSGAEVKKPGSSVKVSCKASGGTFSSYAISW QSVLTQPPSVSAAPGQKVTISCSGNNSNIA
VRQAPGQGLEWMGGIIPIFGTANYAQKFQGRVTIT NNYVSWYQQLPGTAPKLLIYDNNYRPSGIP
ADKSTSTAYMELSSLRSEDTAVYYCAREGTIYDSSGY
DRFSGSKSGTSATLDITGLQTGDEADYYCGV SFDYWGQGTLVTVSS SEQ ID NO. 137
WDGSLTTGVFGGGTKLTVL SEQ ID NO. 138 SH1B7B(K)
EVQLVQSGAEVKKPGSSVKVSCKASGGTFSSYAISW
AIQMTQSPSSLSASVGDRVTITCRASQGISN VRQAPGQGLEWMGIINPSGGSTSYAQKFQGRVSM
YLAWYQQKPGKVPKLLIYAASTLESGVPSRF
TRDTSTSTVYMELSSLTSEDTAVYYCARDLFPHIYGN
SGSGSGTDFTLTISSLQPEDLATYYCQQLHTF YYGMDIWGQGTTVTVSS SEQ ID NO. 139
PLTFGGGTKVEIK SEQ ID NO. 140 SH1C1
QVQLVQSGAEVKKPGSSVKVSCKASGGTFSSYAISW
QPVLTQPPSASGSPGQSVTISCTGTSSDVGA VRQAPGQGLEWMGGIIPIFGTANYAQKFQGRVTIT
YNFVSWYRQHPGKAPKLMIYEVNKRPSGV ADKSTSTAYMELSSLRSEDTAVYYCARLAVPGAFDI
PDRFSGSKSGNTASLTVSGLQAEDEADYYCS WGQGTMVTVSS SEQ ID NO. 141
SYAGTNSLGIFGTGTKLTVL SEQ ID NO. 142 SH1C8
EVQLVESGGGVVQPGRSLRLSCAASGFTFSSYAMH QSVVTQPPSVSAAPGQKVTISCSGSSSDIGN
WVRQAPGKGLEWVAVISYDGSNKYYADSVKGRFTI HYVSWYQQLPGTAPKLLIYDNNQRPSGIPD
SRDNSKNTLYLQMNSLRAEDTAVYYCARGQWLVTE RFSGSKSGTSATLAITGLQTGDEADYYCGT
LDYWGQGTLVTVSS SEQ ID NO. 143 WDNSLSPHLLFGGGTKLTVL SEQ ID NO. 144
SH1E10 EVQLVESGSEVEKPGSSVKVSCKASGGTFSDSGISW
QSVLTQPPSVSAAPGQKVTISCSGSSSNMG VRQAPGQGLEWMGGIIPMFATPYYAQKFQDRVTI
NNYVSWYKQVPGTAPKLLIYENDKRPSGIP TADESTSTVYMELSGLRSDDTAVFYCARDRGRGHLP
DRFSGSKSGTSATLGITGLQTGDEADYYCGT WYFDLWGRGTLVTVSS SEQ ID NO. 145
WDNSLSGFVFASGTKVTVL SEQ ID NO. 146 SH1E2
EVQLVESGAEVKKPGSSVKVSCKASGGTFSSYAISW
QSALTQPASVSGSLGQSVTISCTGSSSDVGS VRQAPGQGLEWMGGIIPIFGTANYAQKFQGRVTIT
YNLVSWYQQHPGKAPNLMIYDVSKRSGVS ADESTSTAYMELSSLRSEDTAVYYCARAPYYYYYMD
NRFSGSKSGNTASLTISGLQAEDEADYYCSS VWGQGTTVTVSS SEQ ID NO. 147
YTGISTVVFGGGTKLTVL SEQ ID NO. 148 SH1A9
EVQLLESGAEVKKPGSSVKVSCKASGGTLSRYALSW
QSVLTQPASVSGSPGQSITISCTGTSSDVGSY
VRQAPGQGPEWVGAIIPIFGTPHYSKKFQDRVIITV NLVSWYQQHPGKAPKLMIYEVSKRPSGVS
DTSTNTAFMELSSLRFEDTALYFCARGHDEYDISGYH
NRFSGSKSGNTASLTISGLQAEDEADYYCSS RLDYWGQGTLVTVSS SEQ ID NO. 149
YGGFNNLLFGGGTKLTVL SEQ ID NO. 150 SH1B11
QVQLVQSGSELKKPGSSVKVSCKASGYSFSGYYIHW
DIVMTQSPSSLSASIGDRVTITCRASQRISAY VRQAPGQGLEWMGWIDPNSGVTNYVRRFQGRVT
VNWYQQKPGKAPKVLIYAASSLRSGVPSRF MTRDTSLSTAYMELSGLTADDTAVYYCARDENLWQ
SGSGSGTDFTLTISSLQPEDFATYYCQQTYSS FGYLDYWGQGTLVTVSS SEQ ID NO. 151
PWTFGQGTKVEIK SEQ ID NO. 152 SH1E4
QVQLVQSGAEVKKPGSSVKVSCKASGGTFSRYGVH QSVLTQPPSASGSPGQSVTISCTGTSSDIGG
WVRQAPGQGLEWMGRLIPIVSMTNYAQKFQDRV YDSVSWYQQHPGKAPKLMIYDVSKRPSGV
SITTDKSTGTAYMELRSLTSEDTALYYCASVGQQLP
SNRFSGSKSGNTASLTISGLQAEDEADYYCS WVFFAWGQGTLVTVSS SEQ ID NO. 153
SYTSSSIFFYVFGTGTKVTVL SEQ ID NO. 154 SH1B3
QVQLVESGGGVVQPGRSLRLSCAASGFTFSSYAMH
LPVLTQPASVSGSPGQSITISCTGTTSDIGGY
WVRQAPGKGLEWVAVISFDGSNKYYADSVRGRFTI DYVSWYQQHPGKAPKLMIYDVSKRPSGVS
SRDNSKNTLYLQMNSLRTEDTAVYYCARGWLDRDI NRFSGSKSGNTASLTISGLQAEDEADYYCSS
DYWGQGTLVTVSS SEQ ID NO. 155 YTSSSTHVFGTGTKLTVL SEQ ID NO. 156
SH1D1 EVQLVESGGGVVQPGRSLRLSCAASGFTFSSYAMH
QSALTQPASVSGSPGQSITISCTGTSSDVGG WVRQAPGKGLEWVAVISFDGSNKYYADSVRGRFTI
YNYVSWYQQHPGKAPKLMIYDVSNRPSGV SRDNSKNTLYLQMNSLRTEDTAVYYCARGWLDRDI
SNRFSGSKSGNTASLTISGLQAEDEADYYCS DYWGQGTLVTVSS SEQ ID NO. 157
SYRSSTLGPVFGGGTKLTVL SEQ ID NO. 158 SH1D2
QVQLVESGGGVVQPGRSLRLSCAASGFTFSSYAMH QAGLTQPPSVSEAPRQRVTISCSGSSSNIGN
WVRQAPGKGLEWVAVISFDGSNKYYADSVRGRFTI NAVNWYQQLPGKAPKLLIYYDDLLPSGVSD
SRDNSKNTLYLQMNSLRTEDTAVYYCARGWLDRDI RFSGSKSGTSASLAISGLQSEDEADYYCAAW
DYWGQGTLVTVSS SEQ ID NO. 159 DDSLNGYVFGTGTKLTVL SEQ ID NO. 160
SH1D12 EVQLVESGGGVVQPGRSLRLSCAASGFTFSSYAMH
QSALTQPRSVSGSPGQSVTISCTGTSSDVGG WVRQAPGKGLEWVAVISFDGSNKYYADSVRGRFTI
YNYVSWYQQHPGKAPKLMIYDVSKRPSGV SRDNSKNTLYLQMNSLRTEDTAVYYCARGWLDRDI
PDRFSGSKSGNTASLTISGLQAEDEADYYCS DYWGQGTLVTVSS SEQ ID NO. 161
SYTSSTTHVFGTGTKVTVL SEQ ID NO. 162 SH1E1
EVQLVESGGGVVQPGRSLRLSCAASGFTFSSYAMH QSVVTQPPSVSAAPGQKVTISCSGSSSNIGN
WVRQAPGKGLEWVAVISFDGSNKYYADSVRGRFTI NYVSWYQQLPGTAPKLLIYDNNKRPSGIPD
SRDNSKNTLYLQMNSLRTEDTAVYYCARGWLDRDI RFSGSKSGTSATLGITGLQTGDEADYYCGT
DYWGQGTLVTVSS SEQ ID NO. 163 WDSSLSVWVFGGGTQLTVL SEQ ID NO. 164
SH1G9 QVQLVESGGGVVQPGRSLRLSCAASGFTFSSYAMH
QSVLTQPASVSGSPGQSITISCTGTSSDVGG WVRQAPGKGLEWVAVISFDGSNKYYADSVRGRFTI
YNYVSWYQQHPGRAPRLMIYDVSNRPSGV SRDNSKNTLYLQMNSLRTEDTAVYYCARGWLDRDI
SNRFSGSKSGNTASLTISGLQAEDEGDYYCS DYWGQGTLVTVSS SEQ ID NO. 165
SYTSGGTLGPVFGGGTKLTVL SEQ ID NO. 166 SH1A11
EVQLVQSGGGLVQPGGSLRLSCAASGFTFSDYGMH QAGLTQPPSASGTPGQRVTISCSGSSSNIGS
WVRQPPGKGLEWLAVISYDGSYKIHADSVQGRFTIS NTVNWYQQLPGTAPKLLIYSNNQRPSGVP
RDNAKNSVFLQMNSLKTEDTAVYYCTTDRKWLAW DRFSGSKSGTSASLAISGLQSEDEADYYCAA
HGMDVWGQGTTVTVSS SEQ ID NO. 167 WDDSLNGWVFGGGTKLTVL SEQ ID NO. 168
SH1C2 EVQLVQSGAEVKKPGSSVKVSCKASGGTFSSYAISW
AIRMTQSPSSLSASVGDRVTITCRASQSISNY
VRQAPGQGLEWMGGIIPIFGTANYAQKFQGRVTIT LNWYQQRPGKAPNLLIYAASSLQSGVPSRF
ADESTSTAYMELSSLRSEDTAVYYCARDGIVADFQH
SGSGSGTDFTLTISSLQPEDFATYYCQQTYST WGQGTLVTVSS SEQ ID NO. 169
PYTFGQGTKLEIK SEQ ID NO. 170 SH1G8
EVQLVESGAEVKKPGASVKVSCKASGDTFSRYGITW
QSVLTQPASVSGSPGQSITISCTGTSSDVGG VRQAPGRGLEWMGNIVPFFGATNYAQKFQGRLTIT
YNYVSWYRQHPGKAPKLMIYDVSYRPSGVS ADKSSYTSYMDLSSLRSDDTAVYYCARDHFYGSGGY
NRFSGSKSGNTASLTISGLQAEDEADYYCSS FDYWGQGTLVTVSS SEQ ID NO. 171
YTDSSTRYVFGTGTKLTVL SEQ ID NO. 172 SH1H2
EVQLLESGAEVKKPGASVKVSCKASGYTFNSYDINW
QPVLTQPPSASGTPGQRVAISCSGSRSNIEI VRQAPGQGLEWMGGIIPVFGTANYAESFQGRVTM
NSVNWYQQLPGTAPKLLIYDNNKRPSGIPD TADHSTSTAYMELNNLRSEDTAVYYCARDRWHYES
RFSGSKSGTSATLGITGLQTGDEADYYCGS RPMDVWGQGTTVTVSS SEQ ID NO. 173
WDSSLSADVFGTGTKLTVL SEQ ID NO. 174 SH1B10
EVQLVESGGGLVRPGGSLRLACAASGFSFSDYYMT QSVLTQPPSVSAAPGKKVTISCSGSSSNIGN
WIRQAPGRGLEWIAYISDSGQTVHYADSVKGRFTIS NYVSWYQQLPGTAPKLLIYRNNQRPSGVPD
RDNTKNSLFLQVNTLRAEDTAVYYCAREDLLGYYLQ
RFSGSKSGTSASLAISGLQSEDEADYYCATW SWGQGTLVTVSS SEQ ID NO. 175
DDSLNGWVFGGGTKLTVL SEQ ID NO. 176 SH1B7A(L)
QVQLQQSGPGLVKPSQTLSLTCAISGDSVSSNSAA QSVVTQPPSVSGAPGQRVTISCTGSSSNIGA
WNWIRQSPSRGLEWLGRTYYRSKWYNDYAVSVKS GYDVHWYQQLPGTAPKLLIYGNNNRHSGV
RITINPDTSKNQFSLQLNSVTPEDTAVYYCARDEPRA
PDRFSGSKSGTSASLAITGLQAEDEAEFFCG VAGSQAYYYYGMDVWGQGTTVTVSS SEQ ID
NO. 177 TWDSRLTTYVFGSGTKLTVL SEQ ID NO. 178 SH1E6
QVQLVQSGAEVKKPGSSVKVSCKASGGTFSRYGVH QSVVTQPPSVSAAPGQKVTISCSGSSSNIGN
WVRQAPGQGLEWMGRLIPIVSMTNYAQKFQDRV NYVSWYQQLPGTAPKLLIYDNNKRPSGIPD
SITTDKSTGTAYMELRSLTSEDTALYYCASVGQQLP RFSGSKSGTSATLGITGLQTGDEADYYCGT
WVFFAWGQGTLVTVSS SEQ ID NO. 179 WDSSLSAVVFGGGTKLTVL SEQ ID NO. 180
SH1C11 EVQLVQSGAEVKKPGASVKVSCKASGYTFTSYYMH
VIWMTQSPSSLSASVGDRVTITCRASQSISS WVRQAPGQGLEWMGIINPSDGSTSYAQKFQGRVT
YLNWYQQKPGKAPKLLIYEASTLESGVPSRF
MTRDTSTSTVHMELSSLRSEDTAVYYCARDLFPHIY
SGSGSGTEFTLTISSLQPEDFATYYCQQSYST GNYYGMDIWGQGTTVTVSS SEQ ID NO. 181
PYTFGQGTKLEIK SEQ ID NO. 182 SH1A2
QMQLVQSGGGVVQPGRSLRLSCAASGFTFSSYAM QSVVTQPPSVSAAPGQKVTISCSGSSSNIGN
HWVRQAPGKGLEWVAVISFDGSNKYYADSVRGRF NYVSWYQQVPGTAPKLLIYDNNKRPSGIPD
TISRDNSKNTLYLQMNSLRTEDTAVYYCARGWLDR RFSGSNSDTSATLGITGLQTGDEADYYCGT
DIDYWGQGTLVTVSS SEQ ID NO. 183 WDSSLSAWVFGGGTKLTVL SEQ ID NO. 184
SH1B1 QVQLVQSGGGVVQPGRSLRLSCAASGFTFSSYAMH
QSVVTQPPSVSAAPGQKVTISCSGSSSNIGN WVRQAPGKGLEWVAVISFDGSNKYYADSVRGRFTI
NYVSWYQQLPGTAPKLLIYDNNKRPSGIPD SRDNSKNTLYLQMNSLRTEDTAVYYCARGWLDRDI
RFSGSKSGTSATLGITGLQTGDEADYYCGT DYWGQGTLVTVSS SEQ ID NO. 185
WDSSLSAGSVVFGGGTKLTVL SEQ ID NO. 186 R6B2
EVQLVQSGAEVKKPGSSVKVSCKASGGTFSSYAISW
QPVLTQPRSVSGSPGQSVTISCTGTSSDVGG VRQAPGQGLEWMGGIIPIFGTANYAQKFQGRVTIT
YNFVSWYQQNPGKAPKLMIYDVSKRPSGV ADESTSTAYMELSSLRSEDTAVYYCARDGIVADFQH
PDRFSGSKSGNTASLTVSGLRAEDEADYYCA WGQGTLVTVSS SEQ ID NO. 187
SYAGGRTFVFGGGTKVTVL SEQ ID NO. 188 R6B7
QMQLVQSGAEVKKPGSSVKVSCKASGGTFNSYPIS
QSVLTQSPSSFSASTGDRVTITCRASQGISSY WVRQAPGQGLEWMGGIIPIFGTANYAQKFQGRVT
LAWYQQKPGKAPKLLIYAASTLQSGVPSRFS
ITADESTSTAYMELSSLRSEDTAMYYCAKNHPTATL
GSGSGTDFTLTISCLQSEDFATYYCQQYYSYP DYWGQGTLVTVSS SEQ ID NO. 189
LTFGGGTKVTVL SEQ ID NO. 190
R6B11 QVQLVQSGGGVVQPGRSLRLSCAASGFPFRSYDM
LPVLTQPASVSASAGQSIAISCTGISSDIGDY
HWVRQAPGEGLEWVALISSDGSNKYYLDSVKGRFT NSVSWYQRHPGKAPKLIIYDVSSRPSGVAD
ISRDNSKNTLYLQMNSLRAEDTAVYYCAKDLLPYSSS
RFSGSKSGSTASLSISGLQAEDEADYYCASYT WDYYYYYGMDVWGQGTTVTVSS SEQ ID NO.
191 ASDNPVFGGGTKLTVL SEQ ID NO. 192 R6D1
EVQLVESGGGLVQPGGSLRLSCAASGFNIKDTYIHW
SYELMQPPSVSVAPGKTATIACGGENIGRKT
VRQAPGKGLEWVARIYPTNGYTRYADSVKGRFTISA VHWYQQKPGQAPVLVIYYDSDRPSGIPERF
DTSKNTAYLQMNSLRAEDTAVYYCSRWGGDGFYA SGSNSGNTATLTISRVEAGDEADYYCQVWD
MDYWGQGTLVTVSS SEQ ID NO. 193 SSSDHRIFGGGTKLTVL SEQ ID NO. 194 R6C8
EVQLVESGGGLVKPGGSRKLSCAASGFTFSNYGMH QSVLTQPPSVSAAPGQEVTISCSGSNSNIGN
WVRQAPEKGLEWVAYISSGSSTIYYADTVKGRFTISR
NYVSWYQQLPGTAPKLLIYDNNERPSGIPD DNAKNTLFLQMTSLRSEDTAMYYCARRGLLLDYWG
RFSGSKSGTSATLGITGLQTGDEADYYCGT QGTTLTVSS SEQ ID NO. 195
WDSSLSAGVFGGGTKLTVL SEQ ID NO. 196 R9G8
EVQLVQSGAEVKKPGASVKVSCKASGYTFTSYGISW
QSVLTQPPSVSAAPGQEVTISCSGSNSNIGN VRQAPGQGLEWMGWISAYNGNTNYAQKLQGRVT
NYVSWYQQLPGTAPKLLIYDNNERPSGIPD MTTDTSTSTAYMELRSLRSDDTAVYYCARDLFPTIF
RFSGSKSGTSATLGITGLQTGDEADYYCGT WEGGAFDIWGQGTMVTVSS SEQ ID NO. 197
WDSSLSAGVFGGGTKLTVL SEQ ID NO. 198 R7D1
QVQLVQSGSEVEKPGSSVKVSCKASGGTFSDSGISW
QSVLTQPPSVSAAPGQEVTISCSGSNSNIGN VRQAPGQGLEWMGGIIPMFATPYYAQKFQDRVTI
NYVSWYQQLPGTAPKLLIYDNNERPSGIPD TADESTSTVYMELSGLRSDDTAVFYCARDRGRGHLP
RFSGSKSGTSATLGITGLQTGDEADYYCGT WYFDLWGRGTLVTVSS SEQ ID NO. 199
WDSSLSAGVFGGGTKLTVL SEQ ID NO. 200 R7D2
QVQLVQSGAEVKKPGSSVKVSCKASGGTFSSYAISW
AIRMTQSPSSLSASVGDRVTITCRASQSISNY
VRQAPGQGLEWMGGIIPIFGTANYAQKFQGRVTIT LNWYQQRPGKAPNLLIYAASSLQSGVPSRF
ADESTSTAYMELSSLRSEDTAVYYCARDGIVADFQH
SGSGSGTDFTLTISSLQPEDFATYYCQQTYST WGQGTLVTVSS SEQ ID NO. 201
PYTFGQGTKLEIK SEQ ID NO. 202 R7E7
EVQLLESGAEVKKPGSSVKVSCKASGGTFSSYAISWV
QSVLTQPPSVSAAPGQEVTISCSGSNSNIGN
RQAPGQGLEWMGRIIPILGIADYAQKFQGRVTITAD NYVSWYQQLPGTAPKLLIYDNNERPSGIPD
KFTSTAYMELSSLRSEDTAVYYCATVEGWGAVTTFD RFSGSKSGTSATLGITGLQTGDEADYYCGT
YWGQGTLVTVSS SEQ ID NO. 203 WDSSLSAGVFGGGTKLTVL SEQ ID NO. 204 R7F2
QVQLVQSGAEVKKPGSSVKVSCKASGGTLSSYAISW
QSVLTQPPSVSGAPGQRVTISCTGSSSNIGA VRQVPGHGLEWMGRIISMLGVSNYAQNFQGRVTI
GYDVYWYQHLLGKAPKLLIYGNSNRPSGVS
TADKSTSTAYMELRSLTSDDTAVYYCATVTIFDGDYY
DRFSASKSGTSVSLAITGLQAEDEADYYCQS AMDVWGQGTTVTVSS SEQ ID NO. 205
YDSSLSGYVFGTGTKLTVL SEQ ID NO. 206 R7F7
EVQLVQSGAEVKKPGSSVKVSCKASGGTFSSHVISW
QPVLTQPASVSGSPGQSITISCTGTSSDVGS
VRQAPGQGLEWMGIILPSFGKTNYAQKFQGRVTMYN LVSWYQQHPGKAPKLMIYEVSKRPSGVS
TGDTSTSTVYMELSSLTSEDTAVYYCVREFSGGYFDY
NRFSGSKSGNTASLTISGLQAEDEADYYCNT WGQGTLVTVSS SEQ ID NO. 207
YTSSGTYVIGTGTKVTVL SEQ ID NO. 208 R9H2
QVQLVQSGAEVKKPGASVKVSCKASGYTFTSYVIH
QPVLTQPASVSGSPGQSITISCTGTSSDIGRY WVRQAPGQRLEWMGWIHAGNGHTKYAQNFQGR
NYVSWYQQHPGKAPKVMIYDVSNRPSGVS
VTITRDTSATTAYVEVSSLGSEDTALYYCAREGSDIGL
NRFSGSKSGNTASLTISGLQAEDEADYYCSS DLHYWGQGTLVTVSS SEQ ID NO. 209
YTSSSTWVFGGGTKLTVL SEQ ID NO. 210 R9H6
QSVVTQPPSVSAAPGQKVTISCSGSSSNIGN EVQLVQSGGGVVQPGRSLRLSCEASGFTFRNFAMH
WVRQAPGKGLEWAAVISVDGSREHYADSVKGRFTI NYVSWYQQLPGTAPKILIYDNDKRPSGIPDR
SRDNSQNTVYLQMNGLRPEDTAEYYCAREGEGST FSGSKSGTSATLGITGLQTGDEADYYCGTW
WSSFDYWGQGTLVTVSS SEQ ID NO. 211 DRSLSGYVFGTGTKVTVL SEQ ID NO. 212
H6B1L QMQLVQSGAEVKKPGSSVKVSCKASGGTFSSYAYS
SYELMQPPSVSVAPGKTATIACGGENIGRKT WVRQAPGQGLEWMGGIIPSFGTANYAQKFQGRV
VHWYQQKPGQAPVLVIYYDSDRPSGIPERF
TITADESTSTAYMELSSLRSEDTAVYYCARGPIVATIT
SGSNSGNTATLTISRVEAGDEADYYCLVWD PLDYWGQGTLVTVSS SEQ ID NO. 213
SSSDHRIFGGGTKLTVL SEQ ID NO. 214 H6A1
QMQLVQSGAEVKKPGSSVKVSCKASGGTFSSYAYS SYELMQPPSVSVAPGKTATIACGGENIGRKT
WVRQAPGQGLEWMGGIIPIFGTANYAQKFQGRVT VHWYQQKPGQAPVLVIYYDSDRPSGIPERF
ITADESTSTAYMELSSLRSEDTAVYYCARGPIVATITP
SGSNSGNTATLTISRVEAGDEADYYCQVWD LDYWGQGTLVTVSS SEQ ID NO. 215
SSSDHRIFGGGTKLTVL SEQ ID NO. 216 H6B1
QMQLVQSGAEVKKPGSSVKVSCKASGGTFSSYAYS SYELMQPPSVSVAPGKTATIACGGENIGRKT
WVRQAPGQGLEWMGGIIPSFGTANYAQKFQGRV VHWYQQKPGQAPVLVIYYDSDRPSGIPERF
TITADESTSTAYMELSSLRSEDTAVYYCARGPIVATIT
SGSNSGNTATLTISRVEAGDEADYYCQVWD PLDYWGQGTLVTVSS SEQ ID NO. 217
SSSDHRIFGGGTKLTVL SEQ ID NO. 218 H6B2
QMQLVQSGAEVKKPGSSVKVSCKASGGTFSSYAIS SYELMQPPSVSVAPGKTATIACGGENIGRKT
WVRQAPGQGLEWMGGIIPAFGTANYAQKFQGRV VHWYQQKPGQAPVLVIYYDSDRPSGIPERF
TITADESTSTAYMELSSLRSEDTAVYYCARGPIVATIT
SGSNSGNTATLTISRVEAGDEADYYCQVWD PLDYWGQGTLVTVSS SEQ ID NO. 219
SSSDHRIFGGGTKLTVL SEQ ID NO. 220 H19C
QVQLVQSGAEVKKPGASVKVSCKTSGNTFTNYALH
DIVMTQSPPSLSASVGDRVTITCRASQSISSY WVRQAPGQGLEWMGGMKPSGGSTSIAQKFQGR
LNWYQQKPGKAPKLLIYATSSLQYGVPSRFS
VTMTRDKSTSTVYMELSSLTSEDTAVYYCARDLFPHI
GSGSGTDFTLTISSLQPEDFATYYCQGSYSTP FGNYYGMDIWGQGTTVTVSS SEQ ID NO.
221 YTFGQGTKVEIK SEQ ID NO. 222 H110D
QVQLVQSGAEVKKPGASVKVSCKTSGNTFTNYYMH
DIVMTQSPPSLSASVGDRVTITCRASQSISSY WVRQAPGQGLEWMGSMQPSGGSTSLAQKFQGR
LNWYQQKPGKAPKLLIYAASSLQSGVPSRFS
VTMTRDKSTSTVYMELSSLTSEDTAVYYCARDLFPHI
GSGSGTDFTLTISSLQPEDFATYYCQGSYSTP LGNYYGMDIWGQGTTVTVSS SEQ ID NO.
223 YTFGQGTKVEIK SEQ ID NO. 224 H11F
QVQLVQSGAEVKKPGASVKVSCKTSGNTFTNYPM DIVMTQSPPSLSASVGDRVTITCRASQSISSY
HWVRQAPGQGLEWMGSMKPSGGSTSLAPKFQGR LNWYQQKPGKAPKLLIYAASSLQYGVPSRFS
VTMTRDKSTSTVYMELSSLTSEDTAVYYCARDLFPHI
GSGSGTDFTLTISSLQPEDFATYYCQGSYSTP IGNYYGMDIWGQGTTVTVSS SEQ ID NO.
225 YTFGQGTKVEIK SEQ ID NO. 226 H1C1
QVQLVQSGAEVKKPGASVKVSCKTSGNTFTNYSMH
DIVMTQSPPSLSASVGDRVTITCRASQSISSY WVRQAPGQGLEWMGIMNPSGGSTSYAQKFQGR
LNWYQQKPGKAPKLLIYAASSLQSGVPSRFS
VTMTRDKSTSTVYMELSSLTSEDTAVYYCARDLFPHI
GSGSGTDFTLTISSLQPEDFATYYCQQSYSTP YGNYYGMDIWGQGTTVTVSS SEQ ID NO.
227 YTFGQGTKVEIK SEQ ID NO. 228 GPG1A2
EVQLVQSGAEVKKPGASVKVSCKASGYTFTGYYMH
DIVMTQSPSSLSASVGDRVTITCRASQSISSF WVRQAPGQGLEWMGWINPNSDNTGSAQKFQGR
LNWYQQKPGKAPKLLIYAASSLQSGVPSRFS
VFMTKTTSLNTAYMELSGLRSEDTAIYYCARERSSGY
GSGSGTDFTLTISSLQPEDFATYYCQQSYSTP FDFWGQGTLVTVSS SEQ ID NO. 229
ITFGQGTKVEIK SEQ ID NO. 230 GPGG8
QVQLVQSGAEVKKLGASVKVSCKASGYPFTGYYMH
DIVMTQSPSSLSASVGDRVTITCRATPSTSSY WVRQAPGQGLEWMGWINPNGDNTGLAQKFQGR
LNWYQQKPGKAPKLLIYAASSLQSGVPSRFS
VFMTKTTSLNTAYMELSGLRSEDTAIYYCARERSSGY
GSGSGTDFTLTISSLQPEDFATYYCQQSYSTP FDFWGQGTLVTVSS SEQ ID NO. 231
ITFGQGTKLEIK SEQ ID NO. 232 GPGG10
QVQLVQSGAEVKKPGASVKVSCKTSGYPFTGYYMH
DIVMTQSPSSLSASVGDRVTITCRASQSISSY WVRQAPGQGLEWMGWINPLSDTTGSAQKFQGR
LNWYQQKPGKAPKLLIYAASSLQSGVPSRFS
VFMTKTTSLNTAYMELSGLRSEDTAIYYCARERSSGY
GSGSGTDFTLTISSLQPEDFATYYCQQSYSTP FDFWGQGTLVTVSS SEQ ID NO. 233
ITFGQGTKLEIK SEQ ID NO. 234 GPGH7
QVQLVQSGAEVKKPGASVKVSCKASGYTFTGYYMH
DIVMTQSPSSLSASVGDRVTITCRASQSISSF WVRQAPGQGLEWMGWINPLSDNTGSAQKFQGR
LNWYQQKPGKAPKLLIYLASSLQSGVPSRFS
VFMTKTTSLNTAYMELSGLRSEDTAIYYCARERSSGY
GSGSGTDFTLTISSLQPEDFATYYCQQSYSTP FDFWGQGTLVTVSS SEQ ID NO. 235
ITFGQGTKVEIK SEQ ID NO. 236 GPGH10
QVQLVQSGAEVKKPGASVKVSCKTSGYTFTGYYMH
DIVMTQSPSSLSASVGDRVTITCRASQSISSF WVRQAPGQGLEWMGWINPNSDNTGYAQKFQGR
LNWYQQKPGKAPKLLIYAASSLQSGVPSRFS
VFMTKTTSLNTAYMELSGLRSEDTAIYYCARERSSGY
GSGSGTDFTLTISSLQPEDFATYYCQQAYST FDFWGQGTLVTVSS SEQ ID NO. 237
PITFGQGTKVEIK SEQ ID NO. 238 GPGH11
QVQLVQSGAEVKKPGASVKVSCKASGYPFTGYYMH
DIVMTQSPSSLSASVGDRVTITCRASQSISSY WVRQAPGQGLEWMGWINPLSDSTGSAQKFQGRV
LNWYQQKPGKAPKLLIYAASSLQSGVPSRFS
FMTKTTSLNTAYMELSGLRSEDTAIYYCARERSSGYF
GSGSGTDFTLTISSLQPEDFATYYCQQSYSTP DFWGQGTLVTVSS SEQ ID NO. 2 SEQ ID
NO. 239 ITFGQGTKLEIK SEQ ID NO. 240 GPGH10P
QVQLVQSGAEVKKPGASVKVSCKTSGYTFTGYYMH
DIVMTQSPSSLSASVGDRVTITCRASQSISSF WVRQAPGQGLEWMGWINPNSDNTGYAQKFQGR
LNWYQQKPGKAPKLLIYAASSLQSGVPSRFS
VFMTKTTSLNTAYMELSGLRSEDTAIYYCARERSSGY
GSGSGTDFTLTISSLQPEDFATYYCQQPYSTP FDFWGQGTLVTVSS SEQ ID NO. 241
ITFGQGTKVEIK SEQ ID NO. 242
Sequence CWU 1
1
2421126PRTArtificial SequenceE6-VH 1Gln Met Gln Leu Val Gln Ser Gly
Ala Glu Val Lys Lys Pro Gly Ser 1 5 10 15 Ser Val Lys Val Ser Cys
Lys Ala Ser Gly Gly Thr Phe Asn Thr Tyr 20 25 30 Ala Ile Ser Trp
Val Arg Gln Ala Pro Gly Gln Gly Leu Glu Trp Met 35 40 45 Gly Gly
Ile Ile Pro Leu Phe Gly Lys Ala Asp Tyr Ala Gln Lys Phe 50 55 60
Gln Asp Arg Val Thr Ile Thr Ala Asp Glu Ser Thr Ser Thr Ala Tyr 65
70 75 80 Met Glu Leu Ser Ser Leu Arg Ser Glu Asp Thr Ala Val Tyr
Tyr Cys 85 90 95 Ala Arg Asp Lys Gly Arg Glu Glu Leu Gly Gly Asn
Tyr Tyr Tyr Ala 100 105 110 Val Asp Val Trp Gly Pro Gly Thr Thr Val
Thr Val Ser Ser 115 120 125 2107PRTArtificial SequenceE6-VL 2Asp
Ile Val Met Thr Gln Thr Pro Tyr Ser Val Ser Ala Ser Val Gly 1 5 10
15 Asp Arg Val Thr Ile Thr Cys Arg Ala Ser Gln Glu Val Ser Arg Trp
20 25 30 Val Ala Trp Tyr Gln Gln Lys Pro Gly Gln Ala Pro Lys Ser
Leu Ile 35 40 45 Tyr Ala Ser Ser Arg Leu Gln Ser Gly Val Pro Ser
Arg Phe Thr Ala 50 55 60 Ser Gly Ser Gly Thr Asp Phe Thr Leu Val
Ile Ser Ser Leu Gln Pro 65 70 75 80 Glu Asp Phe Ala Thr Tyr Tyr Cys
Gln Gln Tyr Ser Arg Phe Pro Leu 85 90 95 Thr Phe Gly Gly Gly Thr
Lys Val Glu Ile Lys 100 105 3 121PRTArtificial SequenceE7-VH 3Gln
Val Gln Leu Gln Gln Leu Gly Pro Gly Leu Val Lys Pro Ser Gln 1 5 10
15 Thr Leu Ser Leu Thr Cys Ala Ile Ser Gly Asp Ser Val Ser Ser Asn
20 25 30 Ser Ala Ala Trp Asn Trp Ile Arg Gln Ser Pro Ser Arg Gly
Leu Glu 35 40 45 Trp Leu Gly Arg Thr Tyr Tyr Arg Ser Lys Trp Tyr
Thr Asn Tyr Ala 50 55 60 Val Ser Met Arg Ser Arg Ile Thr Ile Asn
Pro Asp Thr Ser Lys Asn 65 70 75 80 Gln Phe Ser Leu Gln Leu Asn Ser
Val Thr Pro Glu Asp Thr Ala Val 85 90 95 Tyr Phe Cys Ala Gly Gly
Asn Ser Ser Ser His Asp Asp Tyr Trp Gly 100 105 110 Gln Gly Thr Leu
Val Thr Val Ser Ser 115 120 4110PRTArtificial SequenceE7-VL 4Gln
Pro Val Leu Thr Gln Pro Ala Ser Val Ser Gly Ser Pro Gly Gln 1 5 10
15 Ser Ile Thr Ile Ser Cys Thr Gly Thr Ser Ser Asp Val Gly Gly Tyr
20 25 30 Asn Tyr Val Ser Trp Tyr Gln Gln His Pro Gly Lys Ala Pro
Lys Leu 35 40 45 Met Val Tyr Asp Val Ser Lys Arg Pro Ser Gly Val
Ser Asn Arg Phe 50 55 60 Ser Gly Ser Lys Ser Gly Asn Thr Ala Ser
Leu Thr Ile Ser Gly Leu 65 70 75 80 Gln Thr Glu Asp Glu Ala Asp Tyr
Tyr Cys Ser Ser Tyr Thr Ser Ser 85 90 95 Asn Thr Arg Val Phe Gly
Thr Gly Thr Lys Leu Thr Val Leu 100 105 110 5 124PRTArtificial
SequenceE9-VH 5Glu Val Gln Leu Val Gln Ser Gly Ala Glu Val Lys Lys
Pro Gly Ala 1 5 10 15 Ser Val Lys Val Ser Cys Lys Ala Ser Gly Tyr
Thr Phe Thr Ser Tyr 20 25 30 Gly Ile Ser Trp Val Arg Gln Ala Pro
Gly Gln Gly Leu Glu Trp Met 35 40 45 Gly Trp Ile Ser Ala Tyr Asn
Gly Asn Thr Asn Tyr Ala Gln Lys Leu 50 55 60 Gln Gly Arg Val Thr
Met Thr Thr Asp Thr Ser Thr Ser Thr Ala Tyr 65 70 75 80 Met Glu Leu
Arg Ser Leu Arg Ser Asp Asp Thr Ala Val Tyr Tyr Cys 85 90 95 Ala
Arg Asp Leu Phe Pro Thr Ile Phe Trp Glu Gly Gly Ala Phe Asp 100 105
110 Ile Trp Gly Gln Gly Thr Met Val Thr Val Ser Ser 115 120
6107PRTArtificial SequenceE9-VL 6Asp Ile Val Met Thr Gln Ser Pro
Ser Thr Leu Ser Ala Ser Val Gly 1 5 10 15 Asp Arg Val Thr Ile Thr
Cys Arg Ala Ser Gln Ser Phe Thr Thr Tyr 20 25 30 Leu Ala Trp Tyr
Gln Gln Lys Pro Gly Lys Ala Pro Lys Leu Leu Ile 35 40 45 Tyr Gln
Thr Ser Asn Leu Glu Ser Gly Val Pro Ser Arg Phe Ser Gly 50 55 60
Ser Gly Ser Gly Thr Glu Phe Thr Leu Thr Ile Ser Ser Leu Gln Pro 65
70 75 80 Asp Asp Phe Ala Thr Tyr Tyr Cys Gln Gln Tyr Ser Arg Tyr
Trp Trp 85 90 95 Ser Phe Gly Gln Gly Thr Arg Leu Glu Ile Lys 100
105 7 124PRTArtificial SequenceE11-VH 7Glu Val Gln Leu Val Gln Ser
Gly Ala Glu Val Lys Lys Pro Gly Ala 1 5 10 15 Ser Leu Lys Val Ser
Cys Lys Ala Ser Gly Tyr Thr Phe Asn Ser Tyr 20 25 30 Asp Ile Asn
Trp Val Arg Gln Ala Pro Gly Gln Gly Leu Glu Trp Met 35 40 45 Gly
Trp Ile Asn Pro Asn Ser Gly Gly Thr Asn Tyr Ala Gln Lys Phe 50 55
60 Gln Gly Arg Val Thr Met Thr Arg Asp Thr Ser Thr Ser Thr Val Tyr
65 70 75 80 Met Glu Leu Ser Ser Leu Thr Ser Glu Asp Thr Ala Val Tyr
Tyr Cys 85 90 95 Ala Arg Asp Leu Phe Pro His Ile Tyr Gly Asn Tyr
Tyr Gly Met Asp 100 105 110 Ile Trp Gly Gln Gly Thr Thr Val Thr Val
Ser Ser 115 120 8107PRTArtificial SequenceE11-VL 8Ala Ile Gln Met
Thr Gln Ser Pro Ser Ser Leu Ser Ala Ser Val Gly 1 5 10 15 Asp Arg
Val Thr Ile Thr Cys Arg Ala Ser Gln Ser Ile Ser Ser Tyr 20 25 30
Leu Asn Trp Tyr Gln Gln Lys Pro Gly Lys Ala Pro Lys Leu Leu Ile 35
40 45 Tyr Ala Ala Ser Ser Leu Gln Ser Gly Val Pro Ser Arg Phe Ser
Gly 50 55 60 Ser Gly Ser Gly Thr Asp Phe Thr Leu Thr Ile Ser Ser
Leu Gln Pro 65 70 75 80 Glu Asp Phe Ala Thr Tyr Tyr Cys Gln Gln Ser
Ser Ser Thr Pro Leu 85 90 95 Thr Phe Gly Gln Gly Thr Lys Val Glu
Ile Lys 100 105 9 118PRTArtificial SequenceF1-VH 9Gln Val Gln Leu
Val Glu Ser Gly Gly Gly Val Val Gln Pro Gly Arg 1 5 10 15 Ser Leu
Arg Leu Ser Cys Ala Ala Ser Gly Phe Thr Phe Ser Ser Tyr 20 25 30
Ala Met His Trp Val Arg Gln Ala Pro Gly Lys Gly Leu Glu Trp Val 35
40 45 Ala Val Ile Ser Phe Asp Gly Ser Asn Lys Tyr Tyr Ala Asp Ser
Val 50 55 60 Arg Gly Arg Phe Thr Ile Ser Arg Asp Asn Ser Lys Asn
Thr Leu Tyr 65 70 75 80 Leu Gln Met Asn Ser Leu Arg Thr Glu Asp Thr
Ala Val Tyr Tyr Cys 85 90 95 Ala Arg Gly Trp Leu Asp Arg Asp Ile
Asp Tyr Trp Gly Gln Gly Thr 100 105 110 Leu Val Thr Val Ser Ser 115
10110PRTArtificial SequenceF1-VL 10Gln Ala Val Leu Thr Gln Pro Arg
Ser Val Ser Gly Ser Pro Gly Gln 1 5 10 15 Ser Val Thr Ile Ser Cys
Thr Gly Thr Ser Ser Asp Val Gly Gly Tyr 20 25 30 Asn Tyr Val Ser
Trp Tyr Gln Gln His Pro Gly Lys Ala Pro Lys Leu 35 40 45 Met Ile
Tyr Asp Val Arg Thr Arg Pro Ser Gly Val Ser Asp Arg Phe 50 55 60
Ser Gly Ser Lys Ser Gly Asn Thr Ala Ser Leu Ser Ile Ser Gly Leu 65
70 75 80 Gln Ala Glu Asp Glu Ala Asp Tyr Tyr Cys Ser Ser His Ser
Ser Ser 85 90 95 Thr Thr Val Ile Phe Gly Gly Gly Thr Lys Leu Thr
Val Leu 100 105 110 11118PRTArtificial SequenceF4-VH 11Glu Val Gln
Leu Val Gln Ser Gly Ala Glu Val Lys Lys Pro Gly Ala 1 5 10 15 Ser
Val Lys Val Ser Cys Lys Ala Ser Gly Tyr Thr Phe Thr Gly Tyr 20 25
30 Tyr Met His Trp Val Arg Gln Ala Pro Gly Gln Gly Leu Glu Trp Met
35 40 45 Gly Trp Ile Asn Pro Asn Ser Asp Asn Thr Gly Ser Ala Gln
Lys Phe 50 55 60 Gln Gly Arg Val Phe Met Thr Lys Thr Thr Ser Leu
Asn Thr Ala Tyr 65 70 75 80 Met Glu Leu Ser Gly Leu Arg Ser Glu Asp
Thr Ala Ile Tyr Tyr Cys 85 90 95 Ala Arg Glu Arg Ser Ser Gly Tyr
Phe Asp Phe Trp Gly Gln Gly Thr 100 105 110 Leu Val Thr Val Ser Ser
115 12107PRTArtificial SequenceF4-VL 12Asp Ile Val Met Thr Gln Ser
Pro Ser Ser Leu Ser Ala Ser Val Gly 1 5 10 15 Asp Arg Val Thr Ile
Thr Cys Arg Ala Ser Gln Ser Ile Ser Ser Tyr 20 25 30 Leu Asn Trp
Tyr Gln Gln Lys Pro Gly Lys Ala Pro Lys Leu Leu Ile 35 40 45 Tyr
Ala Ala Ser Ser Leu Gln Ser Gly Val Pro Ser Arg Phe Ser Gly 50 55
60 Ser Gly Ser Gly Thr Asp Phe Thr Leu Thr Ile Ser Ser Leu Gln Pro
65 70 75 80 Glu Asp Phe Ala Thr Tyr Tyr Cys Gln Gln Ser Tyr Ser Thr
Pro Ile 85 90 95 Thr Phe Gly Gln Gly Thr Arg Leu Glu Ile Lys 100
105 13118PRTArtificial SequenceF7-VH 13Glu Val Gln Leu Val Glu Ser
Gly Gly Gly Val Val Gln Pro Gly Arg 1 5 10 15 Ser Leu Arg Leu Ser
Cys Ala Ala Ser Gly Phe Thr Phe Ser Ser Tyr 20 25 30 Trp Met Ser
Trp Val Arg Gln Ala Pro Gly Lys Gly Leu Glu Trp Val 35 40 45 Ala
Asn Ile Lys Gln Asp Gly Ser Glu Lys Tyr Tyr Val Asp Ser Val 50 55
60 Lys Gly Arg Phe Thr Ile Ser Arg Asp Asn Ala Lys Asn Ser Leu Tyr
65 70 75 80 Leu Gln Met Asn Ser Leu Arg Ala Glu Asp Thr Ala Val Tyr
Tyr Cys 85 90 95 Ala Arg Glu Gly Glu His Asp Ala Phe Asp Ile Trp
Gly Gln Gly Thr 100 105 110 Met Val Thr Val Ser Ser 115
14109PRTArtificial SequenceF7-VL 14Gln Ala Val Leu Thr Gln Pro Pro
Ser Val Ser Ala Ala Pro Gly Gln 1 5 10 15 Arg Val Thr Ile Ser Cys
Ser Gly Ser Asn Ser Asn Ile Ala Asp Thr 20 25 30 Tyr Val Ser Trp
Tyr Gln Gln Leu Pro Gly Thr Ala Pro Arg Leu Leu 35 40 45 Ile Tyr
Asp Asn Asp Gln Arg Pro Ser Gly Ile Pro Asp Arg Phe Ser 50 55 60
Gly Ser Lys Ser Gly Thr Ser Ala Thr Leu Gly Ile Thr Gly Leu Gln 65
70 75 80 Thr Gly Asp Glu Ala Asp Tyr Tyr Cys Gly Thr Trp Asp Ser
Ser Leu 85 90 95 Ser Gly Val Phe Gly Thr Gly Thr Lys Val Thr Val
Leu 100 105 15121PRTArtificial SequenceF8-VH 15Gln Val Gln Leu Val
Gln Ser Gly Gly Gly Val Val Gln Pro Gly Arg 1 5 10 15 Ser Pro Arg
Leu Ser Cys Ala Ala Ser Gly Phe Thr Phe Asn Thr Tyr 20 25 30 Gly
Met His Trp Val Arg Gln Ala Pro Gly Lys Gly Leu Glu Trp Val 35 40
45 Ala Val Ile Ser Asp Gly Gly Asn Asn Lys Lys Tyr Ala Asp Ser Val
50 55 60 Lys Gly Arg Phe Thr Ile Ser Arg Asp Asn Ala Lys Asn Ser
Leu Tyr 65 70 75 80 Leu Gln Met Asn Ser Leu Arg Ala Glu Asp Thr Ala
Leu Tyr Tyr Cys 85 90 95 Ala Lys Asp Ile Gly Glu Ser Tyr Tyr Tyr
Tyr Met Asp Val Trp Gly 100 105 110 Lys Gly Thr Thr Val Thr Val Ser
Ser 115 120 16110PRTArtificial SequenceF8-VL 16Gln Ser Val Leu Thr
Gln Pro Ala Ser Val Ser Gly Ser Pro Gly Gln 1 5 10 15 Ser Val Thr
Ile Ser Cys Thr Gly Thr Ser Ser Asp Val Gly Gly Phe 20 25 30 Asn
Ser Val Ser Trp Tyr Gln Gln His Pro Gly Lys Ala Pro Lys Leu 35 40
45 Met Ile Tyr Asp Val Ser Lys Arg Pro Ser Glu Ile Ser Asp Arg Phe
50 55 60 Ser Gly Ser Lys Ser Gly Asn Thr Ala Ser Leu Thr Ile Ser
Gly Leu 65 70 75 80 Gln Pro Glu Asp Glu Ala Asp Tyr Tyr Cys Ser Ser
Tyr Thr Ser Ser 85 90 95 Ser Thr Leu Val Phe Gly Gly Gly Thr Lys
Leu Thr Val Leu 100 105 110 17121PRTArtificial SequenceF11-VH 17Gln
Val Gln Leu Gln Gln Ser Gly Pro Gly Leu Val Lys Pro Ser Gln 1 5 10
15 Ser Leu Ser Leu Thr Cys Ala Ile Ser Gly Asp Ser Leu Ser Ser Asn
20 25 30 Ser Ala Ala Trp Asn Trp Ile Arg Gln Ser Pro Ser Gly Gly
Leu Glu 35 40 45 Trp Leu Gly Arg Thr Tyr Tyr Arg Ser Lys Trp Tyr
Asn Glu Tyr Val 50 55 60 Glu Ser Leu Lys Ser Arg Ile Thr Ile Asn
Ser Asp Ile Ser Arg Asn 65 70 75 80 Gln Phe Ser Leu His Leu Asn Ser
Val Thr Pro Glu Asp Thr Ala Val 85 90 95 Tyr Tyr Cys Ala Ser Gly
Thr Gly Ala Arg Gly Met Asp Val Trp Gly 100 105 110 Gln Gly Thr Thr
Val Thr Val Ser Ser 115 120 18108PRTArtificial SequenceF11-VL 18Ser
Tyr Val Leu Thr Gln Pro Pro Ser Val Ser Val Ser Pro Gly Gln 1 5 10
15 Thr Ala Ser Ile Ser Cys Ser Gly Tyr Lys Leu Glu Asn Lys Tyr Val
20 25 30 Ser Trp Tyr Gln Gln Arg Ala Gly Gln Ser Pro Val Leu Val
Ile Tyr 35 40 45 Gln Asp Asn Lys Arg Pro Ser Gly Ile Pro Glu Arg
Phe Ser Gly Ser 50 55 60 Asn Ser Gly Asn Thr Ala Ser Leu Thr Ile
Thr Gly Leu Gln Pro Glu 65 70 75 80 Asp Glu Ala Asp Tyr Tyr Cys Ser
Ala Trp Asp Ser Ser Leu Arg Ala 85 90 95 Trp Val Phe Gly Gly Gly
Thr Gln Leu Thr Val Leu 100 105 19121PRTArtificial SequenceG4-VH
19Gln Val Gln Leu Gln Gln Ser Gly Pro Gly Leu Val Lys Pro Ser Glu 1
5 10 15 Thr Leu Ser Leu Thr Cys Ala Ile Ser Gly Asp Ser Val Ser Glu
Asn 20 25 30 Ser Ala Ala Trp Asn Trp Ile Arg Gln Ser Pro Ser Gly
Gly Leu Glu 35 40 45 Trp Leu Gly Arg Thr Tyr Tyr Arg Ser Lys Trp
Tyr Asn Glu Tyr Val 50 55 60 Glu Ser Leu Lys Ser Arg Ile Thr Ile
Asn Ser Asp Ile Ser Arg Asn 65 70 75 80 Gln Phe Ser Leu His Leu Asn
Ser Val Thr Pro Glu Asp Thr Ala Val 85 90 95 Tyr Tyr Cys Ala Ser
Gly Thr Gly Ala Arg Gly Met Asp Val Trp Gly 100 105 110 Gln Gly Thr
Thr Val Thr Val Ser Ser 115 120 20107PRTArtificial SequenceG4-VL
20Gln Pro Val Leu Thr Gln Pro Pro Ser
Val Ser Val Ser Pro Gly Gln 1 5 10 15 Thr Ala Ser Ile Thr Cys Ser
Gly Asp Glu Leu Gly Asn Lys Tyr Val 20 25 30 Tyr Trp Tyr Gln Gln
Lys Pro Gly Arg Ser Pro Val Leu Val Ile Tyr 35 40 45 Gln Asp Ser
Lys Arg Pro Ser Gly Phe Pro Ala Arg Phe Ser Gly Ala 50 55 60 Asn
Ser Gly Asn Thr Ala Thr Leu Thr Ile Ser Gly Thr Gln Ala Met 65 70
75 80 Asp Glu Ala Asp Tyr Phe Cys Gln Ala Trp Asp Ser Ser Thr Ala
Trp 85 90 95 Val Phe Gly Gly Gly Thr Lys Leu Thr Val Leu 100 105
21118PRTArtificial SequenceG9-VH 21Glu Val Gln Leu Val Gln Ser Gly
Ala Glu Val Lys Lys Pro Gly Ala 1 5 10 15 Ser Val Lys Val Ser Cys
Lys Ala Ser Gly Tyr Thr Phe Thr Gly Tyr 20 25 30 Tyr Met His Trp
Val Arg Gln Ala Pro Gly Gln Gly Leu Glu Trp Met 35 40 45 Gly Trp
Ile Asn Pro Asn Ser Asp Asn Thr Gly Ser Ala Gln Lys Phe 50 55 60
Gln Gly Arg Val Phe Met Thr Lys Thr Thr Ser Leu Asn Thr Ala Tyr 65
70 75 80 Met Glu Leu Ser Gly Leu Arg Ser Glu Asp Thr Ala Ile Tyr
Tyr Cys 85 90 95 Ala Arg Glu Arg Ser Ser Gly Tyr Phe Asp Phe Trp
Gly Gln Gly Thr 100 105 110 Leu Val Thr Val Ser Ser 115
22107PRTArtificial SequenceG9-VL 22Asp Ile Val Met Thr Gln Ser Pro
Ser Ser Leu Ser Ala Ser Val Gly 1 5 10 15 Asp Arg Val Thr Ile Thr
Cys Arg Ala Ser Gln Ser Ile Ser Ser Tyr 20 25 30 Leu Asn Trp Tyr
Gln Gln Lys Pro Gly Lys Ala Pro Lys Leu Leu Ile 35 40 45 Tyr Ala
Ala Ser Ser Leu Gln Ser Gly Val Pro Ser Arg Phe Ser Gly 50 55 60
Ser Gly Ser Gly Thr Asp Phe Thr Leu Thr Ile Ser Ser Leu Gln Pro 65
70 75 80 Glu Asp Phe Ala Thr Tyr Tyr Cys Gln Gln Ser Tyr Ser Thr
Pro Ile 85 90 95 Thr Phe Gly Gln Gly Thr Arg Leu Glu Ile Lys 100
105 23120PRTArtificial SequenceG11-VH 23Gln Val Gln Leu Val Gln Ser
Gly Ala Glu Val Lys Lys Pro Gly Ser 1 5 10 15 Ser Val Lys Val Ser
Cys Lys Ala Ser Gly Gly Thr Phe Ser Arg Tyr 20 25 30 Gly Val His
Trp Val Arg Gln Ala Pro Gly Gln Gly Leu Glu Trp Met 35 40 45 Gly
Arg Leu Ile Pro Ile Val Ser Met Thr Asn Tyr Ala Gln Lys Phe 50 55
60 Gln Asp Arg Val Ser Ile Thr Thr Asp Lys Ser Thr Gly Thr Ala Tyr
65 70 75 80 Met Glu Leu Arg Ser Leu Thr Ser Glu Asp Thr Ala Leu Tyr
Tyr Cys 85 90 95 Ala Ser Val Gly Gln Gln Leu Pro Trp Val Phe Phe
Ala Trp Gly Gln 100 105 110 Gly Thr Leu Val Thr Val Ser Ser 115 120
24111PRTArtificial SequenceG11-VL 24Leu Pro Val Leu Thr Gln Pro Ala
Ser Val Ser Gly Ser Pro Gly Gln 1 5 10 15 Ser Val Thr Ile Ser Cys
Thr Gly Thr Ser Ser Asp Val Gly Gly His 20 25 30 Asn Tyr Val Ser
Trp Tyr Gln Gln His Pro Gly Lys Ala Pro Lys Leu 35 40 45 Met Ile
Tyr Glu Val Asn Lys Arg Pro Ser Gly Val Pro Asp Arg Phe 50 55 60
Ser Gly Ser Lys Ser Asp Tyr Thr Ala Ser Leu Thr Ile Ser Gly Leu 65
70 75 80 Gln Pro Asp Asp Glu Ala Asp Tyr Phe Cys Ser Ser Tyr Thr
Ala Thr 85 90 95 Thr Thr Gly Val Val Phe Gly Thr Gly Thr Lys Val
Thr Val Leu 100 105 110 25118PRTArtificial SequenceG12-VH 25Glu Val
Gln Leu Val Gln Ser Gly Ala Glu Val Lys Lys Pro Gly Ala 1 5 10 15
Ser Val Lys Val Ser Cys Lys Ala Ser Gly Tyr Thr Phe Thr Gly Tyr 20
25 30 Tyr Met His Trp Val Arg Gln Ala Pro Gly Gln Gly Leu Glu Trp
Met 35 40 45 Gly Trp Ile Asn Pro Asn Ser Asp Asn Thr Gly Ser Ala
Gln Lys Phe 50 55 60 Gln Gly Arg Val Phe Met Thr Lys Thr Thr Ser
Leu Asn Thr Ala Tyr 65 70 75 80 Met Glu Leu Ser Gly Leu Arg Ser Glu
Asp Thr Ala Ile Tyr Tyr Cys 85 90 95 Ala Arg Glu Arg Ser Ser Gly
Tyr Phe Asp Phe Trp Gly Gln Gly Thr 100 105 110 Leu Val Thr Val Ser
Ser 115 26107PRTArtificial SequenceG12-VL 26Asp Ile Val Met Thr Gln
Ser Pro Ser Ser Leu Ser Ala Ser Val Gly 1 5 10 15 Asp Arg Val Thr
Ile Thr Cys Arg Ala Ser Gln Ser Ile Ser Ser Tyr 20 25 30 Leu Asn
Trp Tyr Gln Gln Lys Pro Gly Lys Ala Pro Lys Leu Leu Ile 35 40 45
Tyr Ala Ala Ser Ser Leu Gln Ser Gly Val Pro Ser Arg Phe Ser Gly 50
55 60 Ser Gly Ser Gly Thr Asp Phe Thr Leu Thr Ile Ser Ser Leu Gln
Pro 65 70 75 80 Glu Asp Phe Ala Thr Tyr Tyr Cys Gln Gln Ser Tyr Ser
Thr Pro Ile 85 90 95 Thr Phe Gly Gln Gly Thr Arg Leu Glu Ile Lys
100 105 27124PRTArtificial SequenceH1-VH 27Gln Val Gln Leu Val Gln
Ser Gly Ala Glu Val Lys Lys Pro Gly Ala 1 5 10 15 Ser Val Lys Val
Ser Cys Lys Thr Ser Gly Asn Thr Phe Thr Asn Tyr 20 25 30 Tyr Met
His Trp Val Arg Gln Ala Pro Gly Gln Gly Leu Glu Trp Met 35 40 45
Gly Ile Met Asn Pro Ser Gly Gly Ser Thr Ser Tyr Ala Gln Lys Phe 50
55 60 Gln Gly Arg Val Thr Met Thr Arg Asp Lys Ser Thr Ser Thr Val
Tyr 65 70 75 80 Met Glu Leu Ser Ser Leu Thr Ser Glu Asp Thr Ala Val
Tyr Tyr Cys 85 90 95 Ala Arg Asp Leu Phe Pro His Ile Tyr Gly Asn
Tyr Tyr Gly Met Asp 100 105 110 Ile Trp Gly Gln Gly Thr Thr Val Thr
Val Ser Ser 115 120 28107PRTArtificial SequenceH1-VL 28Asp Ile Val
Met Thr Gln Ser Pro Pro Ser Leu Ser Ala Ser Val Gly 1 5 10 15 Asp
Arg Val Thr Ile Thr Cys Arg Ala Ser Gln Ser Ile Ser Ser Tyr 20 25
30 Leu Asn Trp Tyr Gln Gln Lys Pro Gly Lys Ala Pro Lys Leu Leu Ile
35 40 45 Tyr Ala Ala Ser Ser Leu Gln Ser Gly Val Pro Ser Arg Phe
Ser Gly 50 55 60 Ser Gly Ser Gly Thr Asp Phe Thr Leu Thr Ile Ser
Ser Leu Gln Pro 65 70 75 80 Glu Asp Phe Ala Thr Tyr Tyr Cys Gln Gln
Ser Tyr Ser Thr Pro Tyr 85 90 95 Thr Phe Gly Gln Gly Thr Lys Val
Glu Ile Lys 100 105 29128PRTArtificial SequenceH3-VH 29Gln Val Gln
Leu Val Gln Ser Gly Ala Glu Val Lys Lys Pro Gly Ser 1 5 10 15 Ser
Val Lys Val Ser Cys Lys Ala Ser Gly Gly Thr Phe Ser Ser Tyr 20 25
30 Ala Ile Ser Trp Val Arg Gln Ala Pro Gly Gln Gly Leu Glu Trp Met
35 40 45 Gly Gly Ile Ile Pro Ile Phe Gly Thr Ala Ser Tyr Ala Gln
Lys Phe 50 55 60 Gln Gly Arg Val Thr Ile Thr Ala Asp Glu Ser Thr
Thr Thr Ala Tyr 65 70 75 80 Met Glu Leu Ser Ser Leu Arg Ser Glu Asp
Thr Ala Val Tyr Tyr Cys 85 90 95 Ala Arg Glu Gly Pro Glu Tyr Cys
Ser Gly Gly Thr Cys Tyr Ser Ala 100 105 110 Asp Ala Phe Asp Ile Trp
Gly Gln Gly Thr Met Val Thr Val Ser Ser 115 120 125
30110PRTArtificial SequenceH3-VL 30Gln Ser Val Val Thr Gln Pro Pro
Ser Val Ser Ala Ala Pro Gly Gln 1 5 10 15 Lys Val Thr Ile Ser Cys
Ser Gly Ser Thr Ser Asn Ile Glu Asn Tyr 20 25 30 Ser Val Ser Trp
Tyr Gln Gln Leu Pro Gly Thr Ala Pro Lys Leu Leu 35 40 45 Ile Tyr
Asp Asn Asn Lys Arg Pro Ser Gly Ile Pro Asp Arg Phe Ser 50 55 60
Gly Ser Lys Ser Gly Thr Ser Ala Thr Leu Gly Ile Thr Gly Leu Gln 65
70 75 80 Thr Gly Asp Glu Ala Asp Tyr Tyr Cys Gly Thr Trp Asp Asn
Arg Leu 85 90 95 Ser Ser Val Val Phe Gly Gly Gly Thr Lys Val Thr
Val Leu 100 105 110 31119PRTArtificial SequenceH4-VH 31Gln Val Gln
Leu Val Gln Ser Gly Ala Glu Val Lys Lys Pro Gly Ser 1 5 10 15 Ser
Val Lys Val Ser Cys Lys Ala Ser Gly Gly Thr Phe Ser Ser Tyr 20 25
30 Ala Ile Ser Trp Val Arg Gln Ala Pro Gly Gln Gly Leu Glu Trp Met
35 40 45 Gly Arg Ile Ile Pro Ile Leu Gly Ile Ala Asn Tyr Ala Gln
Lys Phe 50 55 60 Gln Gly Arg Val Thr Ile Thr Ala Asp Lys Ser Thr
Ser Thr Ala Tyr 65 70 75 80 Met Glu Leu Ser Ser Leu Arg Ser Glu Asp
Thr Ala Val Tyr Tyr Cys 85 90 95 Ala Arg Ser Glu Ser Gly Ser Tyr
Ser His Asp Tyr Trp Gly Gln Gly 100 105 110 Thr Thr Val Thr Val Ser
Ser 115 32110PRTArtificial SequenceH4-VL 32Gln Pro Val Leu Thr Gln
Pro Pro Ser Val Ser Ala Ala Pro Gly Gln 1 5 10 15 Lys Val Thr Ile
Ser Cys Ser Gly Ser Ser Ser Asn Ile Gly Asn Ser 20 25 30 His Val
Ser Trp Phe Gln Gln Leu Pro Gly Thr Ala Pro Lys Leu Val 35 40 45
Ile Tyr Asp Asn Asp Lys Arg Pro Ser Gly Ile Ala Asp Arg Phe Ser 50
55 60 Gly Ser Lys Ser Gly Thr Ser Ala Thr Leu Gly Ile Thr Gly Leu
Gln 65 70 75 80 Thr Gly Asp Glu Ala Asp Tyr Tyr Cys Gly Thr Trp Asp
Ser Ser Leu 85 90 95 Ser Ala Gly Val Phe Gly Gly Gly Thr Lys Leu
Thr Val Leu 100 105 110 33121PRTArtificial SequenceH5-VH 33Gln Val
Gln Leu Val Glu Ser Gly Ala Glu Val Lys Lys Pro Gly Ala 1 5 10 15
Ser Val Lys Val Ser Cys Lys Ala Ser Gly Tyr Thr Phe Thr Ser Tyr 20
25 30 Tyr Ile His Trp Val Arg Gln Ala Pro Gly Gln Gly Leu Glu Trp
Met 35 40 45 Gly Ile Ile Asn Pro Ser Gly Gly Ser Thr Thr Tyr Ala
Gln Lys Phe 50 55 60 Gln Gly Arg Val Ser Met Thr Arg Asp Thr Ser
Thr Arg Thr Val Tyr 65 70 75 80 Met Glu Leu Ser Gly Leu Ile Ser Asp
Asp Thr Ala Ile Tyr Tyr Cys 85 90 95 Ala Arg Asp Asp Asp Phe Tyr
Ser Gly Tyr Pro Gly Asp Tyr Trp Gly 100 105 110 Gln Gly Thr Leu Val
Thr Val Ser Ser 115 120 34109PRTArtificial SequenceH5-VL 34Gln Ala
Val Val Thr Gln Pro Pro Ser Ala Ser Gly Thr Pro Gly Gln 1 5 10 15
Arg Val Thr Ile Ser Cys Ser Gly Ser Ser Ser Asn Val Gly Val Asn 20
25 30 His Val Phe Trp Tyr Gln His Leu Pro Gly Met Ala Pro Lys Leu
Leu 35 40 45 Ile His Arg Thr Asn Gln Trp Pro Ser Gly Val Pro Asp
Arg Phe Ser 50 55 60 Gly Ser Lys Ser Gly Thr Ser Ala Thr Leu Gly
Ile Thr Gly Leu Gln 65 70 75 80 Thr Gly Asp Glu Ala Asp Tyr Tyr Cys
Gly Thr Trp Asp Ser Ser Leu 85 90 95 Ser Ala Val Phe Gly Gly Gly
Thr Lys Leu Thr Val Leu 100 105 35121PRTArtificial SequenceH6-VH
35Gln Met Gln Leu Val Gln Ser Gly Ala Glu Val Lys Lys Pro Gly Ser 1
5 10 15 Ser Val Lys Val Ser Cys Lys Ala Ser Gly Gly Thr Phe Ser Ser
Tyr 20 25 30 Ala Ile Ser Trp Val Arg Gln Ala Pro Gly Gln Gly Leu
Glu Trp Met 35 40 45 Gly Gly Ile Ile Pro Ile Phe Gly Thr Ala Asn
Tyr Ala Gln Lys Phe 50 55 60 Gln Gly Arg Val Thr Ile Thr Ala Asp
Glu Ser Thr Ser Thr Ala Tyr 65 70 75 80 Met Glu Leu Ser Ser Leu Arg
Ser Glu Asp Thr Ala Val Tyr Tyr Cys 85 90 95 Ala Arg Gly Asn Ile
Val Ala Thr Ile Thr Pro Leu Asp Tyr Trp Gly 100 105 110 Gln Gly Thr
Leu Val Thr Val Ser Ser 115 120 36108PRTArtificial SequenceH6-VL
36Ser Tyr Glu Leu Met Gln Pro Pro Ser Val Ser Val Ala Pro Gly Lys 1
5 10 15 Thr Ala Thr Ile Ala Cys Gly Gly Glu Asn Ile Gly Arg Lys Thr
Val 20 25 30 His Trp Tyr Gln Gln Lys Pro Gly Gln Ala Pro Val Leu
Val Ile Tyr 35 40 45 Tyr Asp Ser Asp Arg Pro Ser Gly Ile Pro Glu
Arg Phe Ser Gly Ser 50 55 60 Asn Ser Gly Asn Thr Ala Thr Leu Thr
Ile Ser Arg Val Glu Ala Gly 65 70 75 80 Asp Glu Ala Asp Tyr Tyr Cys
Gln Val Trp Asp Ser Ser Ser Asp His 85 90 95 Arg Ile Phe Gly Gly
Gly Thr Lys Leu Thr Val Leu 100 105 37118PRTArtificial
SequenceH10-VH 37Glu Val Gln Leu Val Gln Ser Gly Gly Gly Leu Val
Gln Pro Gly Gly 1 5 10 15 Ser Leu Arg Leu Ser Cys Ala Ala Ser Gly
Phe Thr Phe Ser Ser Tyr 20 25 30 Ser Met Asn Trp Val Arg Gln Ala
Pro Gly Lys Gly Leu Glu Trp Val 35 40 45 Ser Tyr Ile Ser Ser Ser
Ser Ser Thr Ile Tyr Tyr Ala Asp Ser Val 50 55 60 Lys Gly Arg Phe
Thr Ile Ser Arg Asp Asn Ala Lys Asn Ser Leu Tyr 65 70 75 80 Leu Gln
Met Asn Ser Leu Arg Asp Glu Asp Thr Ala Val Tyr Tyr Cys 85 90 95
Ala Arg Gly Asp Tyr Tyr Tyr Gly Met Asp Val Trp Gly Gln Gly Thr 100
105 110 Thr Val Thr Val Ser Ser 115 38108PRTArtificial
SequenceH10-VL 38Glu Ile Val Leu Thr Gln Ser Pro Ser Ser Leu Ser
Ala Ser Ile Gly 1 5 10 15 Asp Arg Val Thr Leu Thr Cys Arg Ala Ser
Gln Ser Ile Arg Arg Phe 20 25 30 Leu Asn Trp Tyr Gln Gln Lys Pro
Gly Lys Ala Pro Glu Leu Leu Ile 35 40 45 Tyr Thr Ala Ser Ser Leu
Gln Ser Gly Val Pro Ser Arg Phe Ser Gly 50 55 60 Ser Gly Ser Gly
Thr Asp Phe Thr Leu Thr Ile Asn Ser Leu Gln Pro 65 70 75 80 Glu Asp
Phe Ala Thr Tyr Tyr Cys Gln Gln Ser Tyr Ala Val Ser Pro 85 90 95
Tyr Thr Phe Gly Gln Gly Thr Lys Val Glu Ile Arg 100 105
39127PRTArtificial SequenceH12-VH 39Gln Met Gln Leu Val Gln Ser Gly
Ala Glu Val Lys Lys Pro Gly Ser 1 5 10 15 Ser Val Lys Val Ser Cys
Lys Ala Ser Gly Gly Thr Phe Ser Ser Tyr 20 25
30 Ala Ile Ser Trp Val Arg Gln Ala Pro Gly Gln Gly Leu Glu Trp Met
35 40 45 Gly Gly Ile Ile Pro Ile Phe Gly Thr Ala Asn Tyr Ala Gln
Lys Phe 50 55 60 Gln Gly Arg Val Thr Ile Thr Ala Asp Glu Ser Thr
Ser Thr Ala Tyr 65 70 75 80 Met Glu Leu Ser Ser Leu Arg Ser Glu Asp
Thr Ala Val Tyr Tyr Cys 85 90 95 Ala Arg Gly Asp Phe Trp Ser Gly
Tyr Arg Thr Tyr Tyr Tyr Tyr Tyr 100 105 110 Gly Met Asp Val Trp Gly
Gln Gly Thr Met Val Thr Val Ser Ser 115 120 125 40110PRTArtificial
SequenceH12-VL 40Gln Ser Val Val Thr Gln Pro Pro Ser Val Ser Ala
Ala Pro Gly Gln 1 5 10 15 Lys Val Thr Ile Ser Cys Ser Gly Ser Ser
Ser Asn Ile Gly Asn Asn 20 25 30 Tyr Val Ser Trp Tyr Gln Gln Leu
Pro Gly Thr Ala Pro Lys Leu Leu 35 40 45 Ile Tyr Asp Asn Asn Lys
Arg Pro Ser Gly Ile Pro Asp Arg Phe Ser 50 55 60 Gly Ser Lys Ser
Gly Thr Ser Ala Thr Leu Gly Ile Thr Gly Leu Gln 65 70 75 80 Thr Gly
Asp Glu Ala Asp Tyr Tyr Cys Gly Thr Trp Asp Ser Ser Leu 85 90 95
Ser Ala Val Val Phe Gly Gly Gly Thr Lys Leu Thr Val Leu 100 105 110
41118PRTArtificial SequencePDL-D2-VH 41Gln Val Gln Leu Val Gln Ser
Gly Ala Glu Val Lys Lys Pro Gly Ala 1 5 10 15 Ser Val Lys Val Ser
Cys Lys Thr Ser Gly Tyr Thr Phe Thr Ser Asn 20 25 30 Ala Ile Gly
Trp Val Arg Gln Ala Pro Gly Gln Gly Leu Glu Trp Met 35 40 45 Gly
Trp Ile Ser Ala Tyr Asn Gly Asn Thr Asn Tyr Ala Gln Asn Leu 50 55
60 Gln Gly Arg Val Thr Met Thr Thr Asp Thr Ser Thr Ser Thr Ala Tyr
65 70 75 80 Met Glu Leu Arg Ser Leu Arg Ser Asp Asp Thr Ala Val Phe
Tyr Cys 85 90 95 Ala Arg Lys Gly Thr Gly Leu His Phe Asp Tyr Trp
Gly Gln Gly Thr 100 105 110 Leu Val Thr Val Ser Ser 115
42108PRTArtificial SequencePDL-D2-VL 42Ala Leu Thr Gln Pro Ala Ser
Val Ser Gly Ser Leu Gly Gln Ser Ile 1 5 10 15 Thr Ile Ser Cys Thr
Gly Ser Ser Ser Asp Val Gly Gly Tyr Lys Tyr 20 25 30 Val Ser Trp
Tyr Gln Gln His Pro Gly Lys Ala Pro Lys Leu Met Ile 35 40 45 Tyr
Asp Val Ile Asn Arg Pro Ser Gly Val Ser Ser Arg Phe Ser Gly 50 55
60 Ser Lys Ser Ala Asn Thr Ala Ser Leu Thr Ile Ser Gly Leu Gln Ala
65 70 75 80 Glu Asp Glu Ala Asp Tyr Tyr Cys Phe Ser Tyr Ser Ser Arg
Ser Thr 85 90 95 Arg Ile Phe Gly Ser Gly Thr Lys Val Thr Val Leu
100 105 43121PRTArtificial SequencePDL-D11-VH 43Gln Val Gln Leu Gln
Gln Ser Gly Pro Gly Leu Val Lys Pro Ser Gln 1 5 10 15 Thr Leu Ser
Leu Thr Cys Ala Ile Ser Gly Asp Ser Val Ser Ser Asn 20 25 30 Ser
Ala Ala Trp Asn Trp Ile Arg Gln Ser Pro Ser Arg Gly Leu Glu 35 40
45 Trp Leu Gly Arg Thr Tyr Tyr Arg Ser Lys Trp Tyr Asn Asp Tyr Ala
50 55 60 Val Ser Val Lys Ser Arg Ile Thr Ile Asn Pro Asp Thr Ser
Lys Asn 65 70 75 80 Gln Phe Ser Leu Gln Leu Asn Ser Val Thr Pro Glu
Asp Thr Ala Val 85 90 95 Tyr Tyr Cys Ala Arg Gly Ala Ala Gly Arg
Ala Phe Asp Ile Trp Gly 100 105 110 Gln Gly Thr Met Val Thr Val Ser
Ser 115 120 44110PRTArtificial SequencePDL-D11-VL 44Gln Thr Val Val
Thr Gln Pro Pro Ser Val Ser Lys Asp Leu Gly Gln 1 5 10 15 Thr Ala
Thr Leu Thr Cys Thr Gly Asn Asn Asn Asn Val Gly Asn His 20 25 30
Gly Ala Ala Trp Leu Gln Gln His Gln Gly His Pro Pro Lys Leu Leu 35
40 45 Ser Tyr Arg Asn Asn Asn Arg Pro Ser Gly Ile Ser Glu Arg Leu
Ser 50 55 60 Ala Ser Arg Ser Gly Asn Thr Ala Ser Leu Thr Ile Thr
Gly Leu Gln 65 70 75 80 Pro Glu Asp Glu Ala Asp Tyr Tyr Cys Ser Ala
Trp Asp Arg Ser Leu 85 90 95 Ser Ala Trp Val Phe Gly Gly Gly Thr
Lys Leu Thr Val Leu 100 105 110 45118PRTArtificial
SequencePDL-H1-VH 45Glu Val Gln Leu Val Gln Ser Gly Gly Gly Leu Val
Gln Pro Gly Gly 1 5 10 15 Ser Leu Arg Leu Ser Cys Ala Ala Ser Gly
Phe Thr Phe Ser Ser Tyr 20 25 30 Ser Met Asn Trp Val Arg Gln Ala
Pro Gly Lys Gly Leu Glu Trp Val 35 40 45 Ser Tyr Ile Ser Ser Ser
Ser Ser Thr Ile Tyr Tyr Ala Asp Ser Val 50 55 60 Lys Gly Arg Phe
Thr Ile Ser Arg Asp Asn Ala Lys Asn Ser Leu Tyr 65 70 75 80 Leu Gln
Met Asn Ser Leu Arg Asp Glu Asp Thr Ala Val Tyr Tyr Cys 85 90 95
Ala Arg Gly Asp Tyr Tyr Tyr Gly Met Asp Val Trp Gly Gln Gly Thr 100
105 110 Thr Val Thr Val Ser Ser 115 46108PRTArtificial
SequencePDL-H1-VL 46Glu Ile Val Leu Thr Gln Ser Pro Ser Ser Leu Ser
Ala Ser Ile Gly 1 5 10 15 Asp Arg Val Thr Leu Thr Cys Arg Ala Ser
Gln Ser Ile Arg Arg Phe 20 25 30 Leu Asn Trp Tyr Gln Gln Lys Pro
Gly Lys Ala Pro Glu Leu Leu Ile 35 40 45 Tyr Thr Ala Ser Ser Leu
Gln Ser Gly Val Pro Ser Arg Phe Ser Gly 50 55 60 Ser Gly Ser Gly
Thr Asp Phe Thr Leu Thr Ile Asn Ser Leu Gln Pro 65 70 75 80 Glu Asp
Phe Ala Thr Tyr Tyr Cys Gln Gln Ser Tyr Ala Val Ser Pro 85 90 95
Tyr Thr Phe Gly Gln Gly Thr Lys Val Glu Ile Lys 100 105
47117PRTArtificial SequenceRB4-VH 47Glu Val Gln Leu Val Glu Ser Gly
Gly Gly Leu Val Gln Pro Gly Gly 1 5 10 15 Ser Leu Arg Leu Ser Cys
Ala Ala Ser Gly Phe Tyr Leu Gly Ser Tyr 20 25 30 Trp Met Ala Trp
Val Arg Gln Ala Pro Gly Lys Gly Leu Glu Trp Val 35 40 45 Ala Ala
Ile Arg Gln Asp Gly Ser Glu Thr Ile Tyr Val Asp Ser Val 50 55 60
Lys Gly Arg Phe Ile Ile Ser Arg Asp Asn Gly Gly Asn Ser Val Thr 65
70 75 80 Leu Gln Met Thr Thr Leu Arg Ala Gly Asp Thr Ala Val Tyr
Tyr Cys 85 90 95 Ala Arg Ala His Tyr Phe Gly Phe Asp Asn Trp Gly
Gln Gly Thr Leu 100 105 110 Val Thr Val Ser Ser 115
48110PRTArtificial SequenceRB4-VL 48Gln Ser Val Leu Thr Gln Pro Ala
Ser Val Ser Gly Ser Pro Gly Gln 1 5 10 15 Ser Ile Ser Val Ser Cys
Thr Gly Thr Ser Ser Asp Val Gly Arg Tyr 20 25 30 Asn Phe Val Ser
Trp Tyr Gln Gln His Pro Gly Lys Ala Pro Lys Leu 35 40 45 Met Val
Phe Asp Val Ser Asn Arg Pro Ser Gly Ile Ser Asn Arg Phe 50 55 60
Ser Gly Ser Lys Ser Gly Asn Thr Ala Ser Leu Thr Ile Ser Gly Leu 65
70 75 80 Gln Ala Glu Asp Glu Ala Asp Tyr Tyr Cys Ser Ser Tyr Thr
Thr Asn 85 90 95 Ser Thr Tyr Val Phe Gly Ser Gly Thr Lys Val Thr
Val Leu 100 105 110 49124PRTArtificial SequenceRB11-VH 49Gln Met
Gln Leu Val Gln Ser Gly Ala Glu Val Lys Lys Pro Gly Ala 1 5 10 15
Ser Val Lys Ile Ser Cys Lys Ala Ser Gly Tyr Pro Phe Arg Asn Tyr 20
25 30 Tyr Ile His Trp Val Arg Gln Ala Pro Gly Gln Gly Leu Glu Trp
Val 35 40 45 Gly Ile Ile Asn Pro Asp Gly Gly Thr Ile Thr Tyr Ala
Gly Lys Phe 50 55 60 Gln Gly Arg Val Ser Met Thr Arg Asp Thr Ser
Thr Ser Thr Val Tyr 65 70 75 80 Met Glu Leu Ser Ser Leu Thr Ser Glu
Asp Thr Ala Val Tyr Tyr Cys 85 90 95 Ala Arg Asp Leu Phe Pro His
Ile Tyr Gly Asn Tyr Tyr Gly Met Asp 100 105 110 Ile Trp Gly Gln Gly
Thr Thr Val Thr Val Ser Ser 115 120 50110PRTArtificial
SequenceRB11-VL 50Gln Pro Val Leu Thr Gln Pro Pro Ser Val Ser Ala
Ala Pro Gly Gln 1 5 10 15 Lys Val Thr Ile Ser Cys Ser Gly Ser Ser
Ser Asn Ile Ala Asn Asn 20 25 30 Tyr Val Ser Trp Tyr Gln Gln Leu
Pro Gly Thr Ala Pro Lys Leu Leu 35 40 45 Ile Phe Ala Asn Asn Lys
Arg Pro Ser Gly Ile Pro Asp Arg Phe Ser 50 55 60 Gly Ser Lys Ser
Gly Thr Ser Ala Ala Leu Asp Ile Thr Gly Leu Gln 65 70 75 80 Thr Gly
Asp Glu Ala Asp Tyr Tyr Cys Gly Thr Trp Asp Ser Asp Leu 85 90 95
Arg Ala Gly Val Phe Gly Gly Gly Thr Lys Leu Thr Val Leu 100 105 110
51121PRTArtificial SequenceRC5-VH 51Glu Val Gln Leu Leu Glu Ser Gly
Gly Gly Val Val Gln Pro Gly Gly 1 5 10 15 Ser Leu Arg Leu Ser Cys
Ala Ala Ser Gly Phe Thr Phe Ser Ser Tyr 20 25 30 Trp Met Ser Trp
Val Arg Gln Ala Pro Gly Lys Gly Leu Glu Trp Val 35 40 45 Ala Asn
Ile Lys Gln Asp Gly Ser Glu Lys Tyr Tyr Val Asp Ser Val 50 55 60
Lys Gly Arg Phe Thr Ile Ser Arg Asp Asn Ser Lys Asn Thr Val Ser 65
70 75 80 Leu Gln Met Asn Ser Leu Arg Ala Glu Asp Thr Ala Val Tyr
Tyr Cys 85 90 95 Ala Lys Asp Arg Tyr Tyr Asn Phe Pro Leu Gly Met
Asp Val Trp Gly 100 105 110 Gln Gly Thr Thr Val Thr Val Ser Ser 115
120 52107PRTArtificial SequenceRC5-VL 52Ala Ile Arg Met Thr Gln Ser
Pro Ser Ser Leu Ser Ala Ser Val Gly 1 5 10 15 Asp Arg Val Thr Ile
Thr Cys Arg Ala Ser Gln Ser Ile Ser Ser Tyr 20 25 30 Leu Asn Trp
Tyr Gln Gln Lys Pro Gly Lys Ala Pro Lys Leu Leu Ile 35 40 45 Tyr
Thr Thr Ser Ser Leu Lys Ser Gly Val Pro Ser Arg Phe Ser Gly 50 55
60 Ser Gly Ser Gly Thr Asp Phe Thr Leu Thr Ile Ser Arg Leu Gln Pro
65 70 75 80 Glu Asp Phe Ala Thr Tyr Tyr Cys Gln Gln Ser Tyr Ser Ser
Thr Trp 85 90 95 Thr Phe Gly Arg Gly Thr Lys Val Glu Ile Lys 100
105 53123PRTArtificial SequenceRF5-VH 53Glu Val Gln Leu Leu Glu Ser
Gly Ala Glu Val Lys Lys Pro Gly Ser 1 5 10 15 Ser Val Lys Val Ser
Cys Lys Ser Ser Gly Asp Thr Phe Thr Asn Phe 20 25 30 Ala Ile Asn
Trp Ile Arg Gln Ala Pro Gly Gln Gly Leu Glu Trp Met 35 40 45 Gly
Arg Ile Ile Pro Leu Phe Gly Thr Thr Asn Tyr Ala Gln Lys Phe 50 55
60 Gln Gly Arg Val Thr Ile Thr Ala Asp Glu Ser Thr Ser Thr Ala Phe
65 70 75 80 Met Asp Leu Asn Ser Leu Thr Ser Glu Asp Thr Ala Val Tyr
Tyr Cys 85 90 95 Ala Arg Thr Leu Gly Gly Asp Tyr Tyr Asp Ser Arg
Gly Tyr Tyr Asn 100 105 110 Trp Gly Gln Gly Thr Leu Val Thr Val Ser
Ser 115 120 54111PRTArtificial SequenceRF5-VL 54Gln Ser Val Leu Thr
Gln Pro Ala Ser Val Ser Gly Ser Pro Gly Gln 1 5 10 15 Ser Ile Thr
Ile Ser Cys Thr Gly Thr Ser Ser Asp Val Gly Ser Tyr 20 25 30 Asn
Leu Val Ser Trp Tyr Gln Gln Tyr Pro Gly Lys Ala Pro Lys Leu 35 40
45 Met Ile Tyr Glu Val Ser Glu Arg Pro Ser Gly Val Pro Asp Arg Phe
50 55 60 Ser Gly Ser Lys Ser Gly Asn Thr Ala Ser Leu Thr Val Ser
Gly Leu 65 70 75 80 Gln Ala Glu Asp Glu Ala Asp Tyr Tyr Cys Ser Ser
Tyr Thr Asp Ser 85 90 95 Asn Asn Phe Arg Val Phe Gly Gly Gly Thr
Lys Leu Thr Val Leu 100 105 110 55116PRTArtificial SequenceRG9-VH
55Gln Val Gln Leu Gln Gln Ser Gly Pro Gly Leu Val Lys Pro Ser Gln 1
5 10 15 Thr Leu Ser Leu Thr Cys Ala Ile Ser Gly Asp Ser Val Ser Ser
Asn 20 25 30 Ser Val Val Trp Asn Trp Phe Arg Gln Ser Pro Ser Arg
Gly Leu Glu 35 40 45 Trp Leu Gly Arg Ala Tyr Tyr Arg Ser Lys Trp
Tyr Asn Asp Tyr Ala 50 55 60 Val Ser Val Lys Ser Arg Ile Thr Ile
Asn Pro Asp Thr Ser Lys Asn 65 70 75 80 Gln Leu Ser Leu Gln Leu Asn
Ser Val Thr Pro Glu Asp Thr Ala Val 85 90 95 Tyr Tyr Cys Ala Lys
Gly Leu Asp Val Trp Gly Gln Gly Thr Thr Val 100 105 110 Thr Val Ser
Ser 115 56107PRTArtificial SequenceRG9-VL 56Glu Ile Val Met Thr Gln
Ser Pro Ser Ser Leu Tyr Ala Ser Val Gly 1 5 10 15 Asp Arg Val Thr
Ile Thr Cys Arg Ala Ser Gln Ser Ile Ser Ser Tyr 20 25 30 Leu Asn
Trp Tyr Gln Gln Lys Pro Gly Lys Val Pro Lys Leu Leu Ile 35 40 45
Tyr Ala Ala Ser Ser Leu Gln Ser Gly Val Pro Ser Arg Phe Ser Gly 50
55 60 Ser Gly Ser Gly Thr Asp Phe Thr Leu Thr Ile Ser Gly Leu Gln
Pro 65 70 75 80 Glu Asp Phe Ala Thr Tyr Tyr Cys Gln Gln Ser Tyr Thr
Pro Ala Trp 85 90 95 Thr Phe Gly Gln Gly Thr Lys Leu Glu Ile Lys
100 105 57118PRTArtificial SequenceRD1-VH 57Gln Val Gln Leu Val Gln
Ser Gly Ala Glu Val Lys Lys Pro Gly Ser 1 5 10 15 Ser Val Lys Val
Ser Cys Lys Ala Ser Gly Gly Thr Phe Ser Ser Tyr 20 25 30 Ala Ile
Ser Trp Val Arg Gln Ala Pro Gly Gln Gly Leu Glu Trp Met 35 40 45
Gly Gly Ile Ile Pro Ile Phe Gly Thr Ala Asn Tyr Ala Gln Lys Phe 50
55 60 Gln Gly Arg Val Thr Ile Thr Ala Asp Glu Ser Thr Ser Thr Ala
Tyr 65 70 75 80 Met Glu Leu Ser Ser Leu Arg Ser Glu Asp Thr Ala Val
Tyr Tyr Cys 85 90 95 Ala Arg Asp Gly Ile Val Ala Asp Phe Gln His
Trp Gly Gln Gly Thr 100 105 110 Leu Val Thr Val Ser Ser 115
58110PRTArtificial SequenceRD1-VL 58Gln Ser Val Val Thr Gln Pro Pro
Ser Val Ser Ala Ala Pro Gly Gln 1 5 10 15 Lys Val Thr Ile Ser Cys
Ser Gly Ser Ser Ser Asn Ile Gly Asn Asn 20 25 30 Tyr Val Ser Trp
Tyr Gln Gln Val Pro Gly Thr Ala Pro Lys Leu Leu
35 40 45 Ile Tyr Asp Asn Asp Lys Arg Pro Ser Gly Ile Pro Asp Arg
Phe Ser 50 55 60 Gly Ser Lys Ser Gly Thr Ser Ala Thr Leu Ala Ile
Thr Gly Leu Gln 65 70 75 80 Thr Gly Asp Glu Ala Asp Tyr Tyr Cys Gly
Thr Trp Asp Ser Ser Leu 85 90 95 Asn Ala Trp Val Phe Gly Gly Gly
Thr Lys Leu Thr Val Leu 100 105 110 59118PRTArtificial
SequenceRF11-VH 59Gln Val Gln Leu Val Gln Ser Gly Ala Glu Val Lys
Lys Pro Gly Ala 1 5 10 15 Ser Val Arg Val Ser Cys Lys Ala Ser Gly
Gly Thr Phe Ser Ser Tyr 20 25 30 Ala Ile Ser Trp Val Arg Gln Ala
Pro Gly Gln Gly Leu Glu Trp Met 35 40 45 Gly Gly Ile Ile Pro Ile
Phe Gly Thr Ala Asn Tyr Ala Gln Lys Phe 50 55 60 Gln Gly Arg Val
Thr Ile Thr Ala Asp Glu Ser Thr Ser Thr Ala Tyr 65 70 75 80 Met Glu
Leu Ser Ser Leu Arg Ser Glu Asp Thr Ala Val Tyr Tyr Cys 85 90 95
Ala Arg Asp Gly Ile Val Ala Asp Phe Gln His Trp Gly Gln Gly Thr 100
105 110 Leu Val Thr Val Ser Ser 115 60110PRTArtificial
SequenceRF11-VL 60Gln Ser Val Leu Thr Gln Pro Pro Ser Val Ser Ala
Ala Pro Gly Gln 1 5 10 15 Lys Val Thr Ile Ser Cys Ser Gly Ser Ser
Ser Asn Ile Glu Asn Asn 20 25 30 Tyr Val Ser Trp Tyr Gln His Leu
Pro Gly Thr Ala Pro Lys Leu Leu 35 40 45 Ile Tyr Asp Asp Phe Lys
Arg Pro Ser Gly Ile Pro Asp Arg Phe Ser 50 55 60 Gly Ser Lys Ser
Gly Thr Ser Ala Thr Leu Gly Ile Thr Gly Leu Gln 65 70 75 80 Thr Gly
Asp Glu Ala Asp Tyr Tyr Cys Gly Thr Trp Asp Ser Ser Leu 85 90 95
Ser Ala Val Val Phe Gly Gly Gly Thr Lys Leu Thr Val Leu 100 105 110
61118PRTArtificial SequenceRH11-VH 61Gln Met Gln Leu Val Gln Ser
Gly Ala Glu Val Lys Lys Pro Gly Ser 1 5 10 15 Ser Val Lys Val Ser
Cys Lys Ala Ser Gly Gly Thr Phe Asn Ser Tyr 20 25 30 Pro Ile Ser
Trp Val Arg Gln Ala Pro Gly Gln Gly Leu Glu Trp Met 35 40 45 Gly
Gly Ile Ile Pro Ile Phe Gly Thr Ala Asn Tyr Ala Gln Lys Phe 50 55
60 Gln Gly Arg Val Thr Ile Thr Ala Asp Glu Ser Thr Ser Thr Ala Tyr
65 70 75 80 Met Glu Leu Ser Ser Leu Arg Ser Glu Asp Thr Ala Met Tyr
Tyr Cys 85 90 95 Ala Lys Asn His Pro Thr Ala Thr Leu Asp Tyr Trp
Gly Gln Gly Thr 100 105 110 Leu Val Thr Val Ser Ser 115
62111PRTArtificial SequenceRH11-VL 62Gln Ser Val Leu Thr Gln Pro
Pro Ser Ala Ser Gly Ser Pro Gly Gln 1 5 10 15 Ser Val Thr Ile Ser
Cys Thr Gly Thr Ser Ser Asp Val Gly Gly Tyr 20 25 30 Asn Tyr Val
Ser Trp Tyr Gln Gln His Pro Gly Lys Ala Pro Lys Leu 35 40 45 Met
Ile Tyr Glu Val Ser Lys Arg Pro Ser Gly Val Pro Asp Arg Phe 50 55
60 Ser Gly Ser Lys Ser Gly Asn Thr Ala Ser Leu Thr Val Ser Gly Leu
65 70 75 80 Gln Ala Glu Asp Glu Ala Asp Tyr Tyr Cys Ser Ser Tyr Ala
Gly Ser 85 90 95 Asn Asn Leu Gly Val Phe Gly Gly Gly Thr Lys Leu
Thr Val Leu 100 105 110 63121PRTArtificial SequenceRD9-VH 63Gln Val
Gln Leu Val Gln Ser Gly Gly Asn Leu Val Lys Pro Gly Gly 1 5 10 15
Ser Leu Arg Leu Ser Cys Ala Ala Ser Gly Phe Ser Phe Ser Ser Tyr 20
25 30 Asp Met Asn Trp Val Arg Gln Ala Pro Gly Arg Gly Leu Glu Trp
Val 35 40 45 Ser Ser Ile Ser Gly Thr Gly Arg Tyr Glu Tyr Tyr Ser
Pro Ser Val 50 55 60 Lys Gly Arg Phe Thr Ile Ser Arg Asp Asn Ala
Asn Thr Ser Leu Tyr 65 70 75 80 Leu Gln Met Asn Ser Leu Thr Ala Asp
Asp Thr Ala Val Tyr Phe Cys 85 90 95 Thr Arg Gly Asp Ile Leu Thr
Gly Ala Ser Ala Met Asp Val Trp Gly 100 105 110 Gln Gly Thr Thr Val
Thr Val Ser Ser 115 120 64107PRTArtificial SequenceRD9-VL 64Asp Ile
Gln Leu Thr Gln Ser Pro Ser Ser Leu Ser Ala Ser Val Gly 1 5 10 15
Asp Arg Val Thr Ile Thr Cys Arg Ala Ser Gln Gly Ile Ser Ser Trp 20
25 30 Leu Ala Trp Tyr Gln Gln Lys Pro Gly Lys Ala Pro Lys Leu Leu
Ile 35 40 45 Tyr Ala Ala Ser Ser Leu Gln Ser Gly Val Pro Ser Arg
Phe Ser Gly 50 55 60 Ser Gly Ser Gly Thr Asp Phe Thr Leu Thr Ile
Ser Ser Leu Gln Pro 65 70 75 80 Glu Asp Phe Ala Thr Tyr Tyr Cys Gln
Gln Ala Asn Ser Phe Pro Leu 85 90 95 Thr Phe Gly Gly Gly Thr Lys
Val Glu Ile Lys 100 105 65121PRTArtificial SequenceRE10-VH 65Glu
Val Gln Leu Leu Glu Ser Gly Gly Asn Leu Val Lys Pro Gly Gly 1 5 10
15 Ser Leu Arg Leu Ser Cys Ala Ala Ser Gly Phe Ser Phe Ser Ser Tyr
20 25 30 Asp Met Asn Trp Val Arg Gln Ala Pro Gly Arg Gly Leu Glu
Trp Val 35 40 45 Ser Ser Ile Ser Gly Thr Gly Arg Tyr Glu Tyr Tyr
Ser Pro Ser Val 50 55 60 Lys Gly Arg Phe Thr Ile Ser Arg Asp Asn
Ala Asn Thr Ser Leu Tyr 65 70 75 80 Leu Gln Met Asn Ser Leu Thr Ala
Asp Asp Thr Ala Val Tyr Phe Cys 85 90 95 Thr Arg Gly Asp Ile Leu
Thr Gly Ala Ser Ala Met Asp Val Trp Gly 100 105 110 Gln Gly Thr Thr
Val Thr Val Ser Ser 115 120 66107PRTArtificial SequenceRE10-VL
66Asp Val Val Met Thr Gln Ser Pro Ser Thr Leu Ser Ala Ser Val Gly 1
5 10 15 Asp Arg Val Thr Ile Thr Cys Arg Ala Ser Gln Ser Ile Gly Thr
Trp 20 25 30 Leu Ala Trp Tyr Gln Gln Lys Pro Gly Lys Ala Pro Asn
Leu Leu Ile 35 40 45 Tyr Lys Ala Ser Ser Leu Glu Ser Gly Val Pro
Ser Arg Phe Ser Gly 50 55 60 Ser Gly Ser Gly Thr Glu Phe Thr Leu
Thr Ile Ser Ser Leu Gln Pro 65 70 75 80 Asp Asp Phe Ala Thr Tyr Tyr
Cys Gln Gln Ala Asn Ser Phe Pro Leu 85 90 95 Thr Phe Gly Gly Gly
Thr Lys Val Glu Ile Lys 100 105 67120PRTArtificial SequenceRA3-VH
67Gln Met Gln Leu Val Gln Ser Gly Ala Glu Val Lys Lys Pro Gly Ser 1
5 10 15 Ser Val Lys Val Ser Cys Lys Ala Ser Gly Gly Thr Phe Ser Arg
Tyr 20 25 30 Gly Val His Trp Val Arg Gln Ala Pro Gly Gln Gly Leu
Glu Trp Met 35 40 45 Gly Arg Leu Ile Pro Ile Val Ser Met Thr Asn
Tyr Ala Gln Lys Phe 50 55 60 Gln Asp Arg Val Ser Ile Thr Thr Asp
Lys Ser Thr Gly Thr Ala Tyr 65 70 75 80 Met Glu Leu Arg Ser Leu Thr
Ser Glu Asp Thr Ala Leu Tyr Tyr Cys 85 90 95 Ala Ser Val Gly Gln
Gln Leu Pro Trp Val Phe Phe Ala Trp Gly Gln 100 105 110 Gly Thr Leu
Val Thr Val Ser Ser 115 120 68107PRTArtificial SequenceRA3-VL 68Asp
Ile Gln Met Thr Gln Ser Pro Ser Ser Leu Ser Ala Ser Val Gly 1 5 10
15 Asp Arg Val Thr Ile Thr Cys Gln Ala Ser Gln Asp Ile Ser Asn Tyr
20 25 30 Leu Asn Trp Tyr Gln Gln Lys Pro Gly Lys Ala Pro Lys Leu
Leu Ile 35 40 45 Tyr Asp Ala Ser Thr Leu Gln Ser Gly Val Pro Ser
Arg Phe Ser Gly 50 55 60 Ser Gly Ser Gly Thr Asp Phe Thr Leu Thr
Ile Ser Ser Leu Gln Pro 65 70 75 80 Glu Asp Phe Ala Thr Tyr Tyr Cys
Gln Gln Ser Tyr Ser Ser His Trp 85 90 95 Thr Phe Gly Gln Gly Thr
Lys Val Glu Ile Lys 100 105 69120PRTArtificial SequenceRG1-VH 69Glu
Val Gln Leu Val Gln Ser Gly Ala Glu Val Lys Lys Pro Gly Ser 1 5 10
15 Ser Val Lys Val Ser Cys Lys Ala Ser Gly Gly Thr Phe Ser Arg Tyr
20 25 30 Gly Val His Trp Val Arg Gln Ala Pro Gly Gln Gly Leu Glu
Trp Met 35 40 45 Gly Arg Leu Ile Pro Ile Val Ser Met Thr Asn Tyr
Ala Gln Lys Phe 50 55 60 Gln Asp Arg Val Ser Ile Thr Thr Asp Lys
Ser Thr Gly Thr Ala Tyr 65 70 75 80 Met Glu Leu Arg Ser Leu Thr Ser
Glu Asp Thr Ala Leu Tyr Tyr Cys 85 90 95 Ala Ser Val Gly Gln Gln
Leu Pro Trp Val Phe Phe Ala Trp Gly Gln 100 105 110 Gly Thr Leu Val
Thr Val Ser Ser 115 120 70112PRTArtificial SequenceRG1-VL 70Gln Ser
Val Val Thr Gln Pro Pro Ser Val Ser Gly Ala Pro Gly Gln 1 5 10 15
Arg Val Thr Ile Ser Cys Thr Gly Ser Ser Ser Asn Ile Gly Ala Gly 20
25 30 Tyr Gly Val His Trp Tyr Gln His Leu Pro Gly Ser Ala Pro Lys
Leu 35 40 45 Leu Ile Tyr Gly Asn Ser Asn Arg Pro Ser Gly Val Thr
Asp Arg Ile 50 55 60 Ser Gly Ser Lys Ser Gly Thr Ser Ala Ser Leu
Ala Ile Thr Gly Leu 65 70 75 80 Gln Ala Glu Asp Glu Ala Val Tyr Tyr
Cys Gln Ser Tyr Asp Ser Ser 85 90 95 Leu Ser Thr Ser Val Val Phe
Gly Gly Gly Thr Lys Leu Thr Val Leu 100 105 110 71118PRTArtificial
SequenceRB1-VH 71Gln Met Gln Leu Val Gln Ser Gly Gly Gly Leu Ile
Gln Pro Gly Gly 1 5 10 15 Ser Leu Arg Leu Ser Cys Ala Ala Ser Gly
Phe Thr Phe Ser Ser Tyr 20 25 30 Ala Met His Trp Val Arg Gln Ala
Pro Gly Lys Gly Leu Glu Trp Val 35 40 45 Ala Val Ile Ser Phe Asp
Gly Ser Asn Lys Tyr Tyr Ala Asp Ser Val 50 55 60 Arg Gly Arg Phe
Thr Ile Ser Arg Asp Asn Ser Lys Asn Thr Leu Tyr 65 70 75 80 Leu Gln
Met Asn Ser Leu Arg Thr Glu Asp Thr Ala Val Tyr Tyr Cys 85 90 95
Ala Arg Gly Trp Leu Asp Arg Asp Ile Asp Tyr Trp Gly Gln Gly Thr 100
105 110 Leu Val Thr Val Ser Ser 115 72111PRTArtificial
SequenceRB1-VL 72Gln Ala Gly Leu Thr Gln Pro Ala Ser Val Ser Gly
Ser Pro Gly Gln 1 5 10 15 Ser Ile Thr Ile Ser Cys Thr Gly Thr Ser
Ser Asp Val Gly Gly Tyr 20 25 30 Asn Tyr Val Ser Trp Tyr Gln Gln
His Pro Gly Lys Ala Pro Lys Leu 35 40 45 Met Ile Tyr Asp Val Thr
Lys Arg Pro Ser Gly Val Ser Asn Arg Phe 50 55 60 Ser Gly Ser Lys
Ser Gly Asn Thr Ala Ser Leu Thr Ile Ser Gly Leu 65 70 75 80 Gln Ala
Glu Asp Glu Ala Asn Tyr Tyr Cys Ser Ser Tyr Thr Ser Arg 85 90 95
Ser Thr Ser Val Leu Phe Gly Gly Gly Thr Lys Leu Thr Val Leu 100 105
110 73118PRTArtificial SequenceRG7-VH 73Glu Val Gln Leu Val Glu Ser
Gly Gly Gly Val Val Leu Pro Gly Arg 1 5 10 15 Ser Leu Arg Leu Ser
Cys Ala Ala Ser Gly Phe Thr Phe Ser Ser Tyr 20 25 30 Ala Met His
Trp Val Arg Gln Ala Pro Gly Lys Gly Leu Glu Trp Val 35 40 45 Ala
Val Ile Ser Phe Asp Gly Ser Asn Lys Tyr Tyr Ala Asp Ser Val 50 55
60 Arg Gly Arg Phe Thr Ile Ser Arg Asp Asn Ser Lys Asn Thr Leu Tyr
65 70 75 80 Leu Gln Met Asn Ser Leu Arg Thr Glu Asp Thr Ala Val Tyr
Tyr Cys 85 90 95 Ala Arg Gly Trp Leu Asp Arg Asp Ile Asp Tyr Trp
Gly Gln Gly Thr 100 105 110 Leu Val Thr Val Ser Ser 115
74110PRTArtificial SequenceRG7-VL 74Gln Pro Val Leu Thr Gln Pro Pro
Ser Val Ser Glu Ala Pro Arg Gln 1 5 10 15 Arg Val Thr Ile Ser Cys
Ser Gly Ser Ser Ser Asn Ile Gly His Asn 20 25 30 Ala Val Thr Trp
Tyr Gln Gln Val Pro Gly Lys Ala Pro Lys Leu Leu 35 40 45 Ile Tyr
Tyr Asp Asp Leu Leu Pro Ser Gly Val Ser Asp Arg Phe Ser 50 55 60
Gly Ser Lys Ser Gly Thr Ser Ala Ser Leu Ala Ile Ser Gly Leu Gln 65
70 75 80 Ser Glu Asp Glu Ala Asp Tyr Tyr Cys Ala Ala Trp Asp Asp
Ser Leu 85 90 95 Asn Gly Trp Val Phe Gly Gly Gly Thr Lys Leu Thr
Val Leu 100 105 110 75118PRTArtificial SequenceRA6-VH 75Gln Val Gln
Leu Val Glu Ser Gly Gly Gly Val Val Gln Pro Gly Arg 1 5 10 15 Ser
Leu Arg Leu Ser Cys Ala Ala Ser Gly Phe Thr Phe Ser Ser Tyr 20 25
30 Ala Met His Trp Val Arg Gln Ala Pro Gly Lys Gly Leu Glu Trp Val
35 40 45 Ala Val Ile Ser Phe Asp Gly Ser Asn Lys Tyr Tyr Ala Asp
Ser Val 50 55 60 Arg Gly Arg Phe Thr Ile Ser Arg Asp Asn Ser Lys
Asn Thr Leu Tyr 65 70 75 80 Leu Gln Met Asn Ser Leu Arg Thr Glu Asp
Thr Ala Val Tyr Tyr Cys 85 90 95 Ala Arg Gly Trp Leu Asp Arg Asp
Ile Asp Tyr Trp Gly Gln Gly Thr 100 105 110 Leu Val Thr Val Ser Ser
115 76112PRTArtificial SequenceRA6-VH 76Gln Ala Gly Leu Thr Gln Pro
Ala Ser Val Ser Gly Ser Pro Gly Gln 1 5 10 15 Ser Ile Thr Ile Ser
Cys Thr Gly Thr Ser Ser Asp Val Gly Gly Tyr 20 25 30 Asn Tyr Val
Ser Trp Tyr Gln Gln His Pro Gly Lys Ala Pro Lys Leu 35 40 45 Met
Ile Tyr Asp Val Ser Asn Arg Pro Ser Gly Val Pro Asp Arg Phe 50 55
60 Ser Gly Ser Lys Ser Gly Asn Thr Ala Ser Leu Thr Ile Ser Gly Leu
65 70 75 80 Gln Ala Glu Asp Asp Ala Asp Tyr Tyr Cys Ala Ser Tyr Thr
Ser Thr 85 90 95 Ser Thr Leu Gly Val Val Phe Gly Gly Gly Thr Lys
Leu Thr Val Leu 100 105 110 77118PRTArtificial SequenceRA8-VH 77Gln
Val Gln Leu Val Glu Ser Gly Gly Gly Val Val Gln Pro Gly Arg 1 5 10
15 Ser Leu Arg Leu Ser Cys Ala Ala Ser Gly Phe Thr Phe Ser Ser Tyr
20 25 30 Ala Met His Trp Val Arg Gln Ala Pro Gly Lys Gly Leu Glu
Trp Val 35 40 45 Ala Val Ile Ser Phe Asp Gly Ser Asn Lys Tyr Tyr
Ala Asp Ser Val 50 55 60 Arg Gly Arg Phe Thr Ile
Ser Arg Asp Asn Ser Lys Asn Thr Leu Tyr 65 70 75 80 Leu Gln Met Asn
Ser Leu Arg Thr Glu Asp Thr Ala Val Tyr Tyr Cys 85 90 95 Ala Arg
Gly Trp Leu Asp Arg Asp Ile Asp Tyr Trp Gly Gln Gly Thr 100 105 110
Leu Val Thr Val Ser Ser 115 78111PRTArtificial SequenceRA8-VL 78Gln
Pro Val Leu Thr Gln Pro Ala Ser Val Ser Gly Ser Pro Gly Gln 1 5 10
15 Ser Ile Thr Ile Ser Cys Thr Gly Thr Ser Ser Asp Val Gly Gly Tyr
20 25 30 Asn Tyr Val Ser Trp Tyr Gln His His Pro Gly Lys Ala Pro
Lys Leu 35 40 45 Met Ile Phe Asp Val Asn Lys Arg Pro Ser Gly Val
Ser Asn Arg Phe 50 55 60 Ser Gly Ser Lys Ser Gly Asn Thr Ala Ser
Leu Thr Ile Ser Gly Leu 65 70 75 80 Gln Ala Glu Asp Glu Ala Asp Tyr
Tyr Cys Asn Ser Tyr Thr Thr Ser 85 90 95 Ser Thr Tyr Val Val Phe
Gly Gly Gly Thr Lys Leu Thr Val Leu 100 105 110 79118PRTArtificial
SequenceRA9-VH 79Gln Val Gln Leu Val Glu Ser Gly Gly Gly Val Val
Gln Pro Gly Arg 1 5 10 15 Ser Leu Arg Leu Ser Cys Ala Ala Ser Gly
Phe Thr Phe Ser Ser Tyr 20 25 30 Ala Met His Trp Val Arg Gln Ala
Pro Gly Lys Gly Leu Glu Trp Val 35 40 45 Ala Val Ile Ser Phe Asp
Gly Ser Asn Lys Tyr Tyr Ala Asp Ser Val 50 55 60 Arg Gly Arg Phe
Thr Ile Ser Arg Asp Asn Ser Lys Asn Thr Leu Tyr 65 70 75 80 Leu Gln
Met Asn Ser Leu Arg Thr Glu Asp Thr Ala Val Tyr Tyr Cys 85 90 95
Ala Arg Gly Trp Leu Asp Arg Asp Ile Asp Tyr Trp Gly Gln Gly Thr 100
105 110 Leu Val Thr Val Ser Ser 115 80110PRTArtificial
SequenceRA9-VL 80Gln Ser Val Leu Thr Gln Pro Pro Ser Ala Ser Gly
Thr Pro Gly Gln 1 5 10 15 Arg Val Thr Ile Ser Cys Ser Gly Ser Ser
Ser Asn Ile Gly Ser Asn 20 25 30 Thr Val His Trp Tyr Gln Gln Leu
Pro Gly Thr Ala Pro Lys Val Leu 35 40 45 Ile Tyr Thr Asn Asn Gln
Arg Pro Ser Gly Val Pro Asp Arg Phe Ser 50 55 60 Gly Ser Lys Ser
Gly Thr Ser Ala Ser Leu Ala Ile Ser Gly Leu Gln 65 70 75 80 Ser Glu
Asp Glu Ala Asp Tyr Tyr Cys Ala Ala Trp Asp Gly Arg Leu 85 90 95
Gln Gly Trp Val Phe Gly Gly Gly Thr Lys Leu Thr Val Leu 100 105 110
81118PRTArtificial SequenceRB5-VH 81Gln Val Gln Leu Val Glu Ser Gly
Gly Gly Val Val Gln Pro Gly Arg 1 5 10 15 Ser Leu Arg Leu Ser Cys
Ala Ala Ser Gly Phe Thr Phe Ser Ser Tyr 20 25 30 Ala Met His Trp
Val Arg Gln Ala Pro Gly Lys Gly Leu Glu Trp Val 35 40 45 Ala Val
Ile Ser Phe Asp Gly Ser Asn Lys Tyr Tyr Ala Asp Ser Val 50 55 60
Arg Gly Arg Phe Thr Ile Ser Arg Asp Asn Ser Lys Asn Thr Leu Tyr 65
70 75 80 Leu Gln Met Asn Ser Leu Arg Thr Glu Asp Thr Ala Val Tyr
Tyr Cys 85 90 95 Ala Arg Gly Trp Leu Asp Arg Asp Ile Asp Tyr Trp
Gly Gln Gly Thr 100 105 110 Leu Val Thr Val Ser Ser 115
82110PRTArtificial SequenceRB5-VL 82Gln Ser Val Val Thr Gln Pro Pro
Ser Val Ser Ala Ala Pro Gly Gln 1 5 10 15 Lys Val Thr Ile Ser Cys
Ser Gly Ser Asn Ser Asn Ile Ala Asn Asn 20 25 30 Tyr Val Ser Trp
Tyr Gln Gln Leu Pro Gly Thr Ala Pro Lys Leu Leu 35 40 45 Ile Tyr
Asp Ser Asn Lys Arg Pro Ser Gly Ile Pro Asp Arg Phe Ser 50 55 60
Gly Ser Lys Ser Gly Thr Ser Ala Thr Leu Gly Ile Thr Gly Leu Gln 65
70 75 80 Thr Gly Asp Glu Ala Asp Tyr Tyr Cys Gly Ser Trp Asp Ser
Ser Leu 85 90 95 Ser Val Trp Met Phe Gly Gly Gly Thr Lys Leu Thr
Val Leu 100 105 110 83118PRTArtificial SequenceRB8-VH 83Gln Val Gln
Leu Val Glu Ser Gly Gly Gly Val Val Gln Pro Gly Arg 1 5 10 15 Ser
Leu Arg Leu Ser Cys Ala Ala Ser Gly Phe Thr Phe Ser Ser Tyr 20 25
30 Ala Met His Trp Val Arg Gln Ala Pro Gly Lys Gly Leu Glu Trp Val
35 40 45 Ala Val Ile Ser Phe Asp Gly Ser Asn Lys Tyr Tyr Ala Asp
Ser Val 50 55 60 Arg Gly Arg Phe Thr Ile Ser Arg Asp Asn Ser Lys
Asn Thr Leu Tyr 65 70 75 80 Leu Gln Met Asn Ser Leu Arg Thr Glu Asp
Thr Ala Val Tyr Tyr Cys 85 90 95 Ala Arg Gly Trp Leu Asp Arg Asp
Ile Asp Tyr Trp Gly Gln Gly Thr 100 105 110 Leu Val Thr Val Ser Ser
115 84112PRTArtificial SequenceRB8-VL 84Leu Pro Val Leu Thr Gln Pro
Arg Ser Val Ser Gly Ser Pro Gly Gln 1 5 10 15 Ser Val Thr Ile Ser
Cys Thr Gly Thr Ser Ser Asp Val Gly Gly Tyr 20 25 30 Asn Tyr Val
Ser Trp Tyr Gln Gln His Pro Gly Lys Ala Pro Lys Leu 35 40 45 Met
Ile Tyr Asp Val Thr Lys Arg Pro Ser Gly Val Pro Asp Arg Phe 50 55
60 Ser Gly Ser Lys Ser Gly Asn Thr Ala Ser Leu Thr Ile Ser Gly Leu
65 70 75 80 Gln Ala Glu Asp Glu Ala Asp Tyr Tyr Cys Ser Ser Tyr Thr
Gly Ser 85 90 95 Ser Thr Leu Gly Pro Val Phe Gly Gly Gly Thr Lys
Leu Thr Val Leu 100 105 110 85118PRTArtificial SequenceRC8-VH 85Glu
Val Gln Leu Val Glu Ser Gly Gly Gly Val Val Gln Pro Gly Arg 1 5 10
15 Ser Leu Arg Leu Ser Cys Ala Ala Ser Gly Phe Thr Phe Ser Ser Tyr
20 25 30 Ala Met His Trp Val Arg Gln Ala Pro Gly Lys Gly Leu Glu
Trp Val 35 40 45 Ala Val Ile Ser Phe Asp Gly Ser Asn Lys Tyr Tyr
Ala Asp Ser Val 50 55 60 Arg Gly Arg Phe Thr Ile Ser Arg Asp Asn
Ser Lys Asn Thr Leu Tyr 65 70 75 80 Leu Gln Met Asn Ser Leu Arg Thr
Glu Asp Thr Ala Val Tyr Tyr Cys 85 90 95 Ala Arg Gly Trp Leu Asp
Arg Asp Ile Asp Tyr Trp Gly Gln Gly Thr 100 105 110 Leu Val Thr Val
Ser Ser 115 86110PRTArtificial SequenceRC8-VL 86Gln Ser Val Leu Thr
Gln Pro Pro Ser Val Ser Ala Ala Pro Gly Gln 1 5 10 15 Lys Val Thr
Ile Ser Cys Ser Gly Asn Ser Ser Asn Ile Gly Asn Asn 20 25 30 Tyr
Val Ser Trp Tyr Gln Gln Leu Pro Gly Thr Ala Pro Lys Leu Leu 35 40
45 Ile Tyr Asp Asn Asp Lys Arg Pro Ser Gly Ile Pro Asp Arg Phe Ser
50 55 60 Gly Ser Lys Ser Gly Thr Ser Ala Ser Leu Ala Ile Ser Glu
Leu Arg 65 70 75 80 Phe Glu Asp Glu Ala Asp Tyr Tyr Cys Ala Ala Trp
Asp Asp Thr Leu 85 90 95 Ser Gly His Val Phe Gly Pro Gly Thr Lys
Leu Thr Val Leu 100 105 110 87118PRTArtificial SequenceRC10-VH
87Glu Val Gln Leu Val Glu Ser Gly Gly Gly Val Val Gln Pro Gly Arg 1
5 10 15 Ser Leu Arg Leu Ser Cys Ala Ala Ser Gly Phe Thr Phe Ser Ser
Tyr 20 25 30 Ala Met His Trp Val Arg Gln Ala Pro Gly Lys Gly Leu
Glu Trp Val 35 40 45 Ala Val Ile Ser Phe Asp Gly Ser Asn Lys Tyr
Tyr Ala Asp Ser Val 50 55 60 Arg Gly Arg Phe Thr Ile Ser Arg Asp
Asn Ser Lys Asn Thr Leu Tyr 65 70 75 80 Leu Gln Met Asn Ser Leu Arg
Thr Glu Asp Thr Ala Val Tyr Tyr Cys 85 90 95 Ala Arg Gly Trp Leu
Asp Arg Asp Ile Asp Tyr Trp Gly Gln Gly Thr 100 105 110 Leu Val Thr
Val Ser Ser 115 88108PRTArtificial SequenceRC10-VL 88Ser Tyr Glu
Leu Met Gln Pro Pro Ser Val Ser Val Pro Pro Gly Glu 1 5 10 15 Thr
Ala Arg Ile Thr Cys Gly Gly Asn Asn Ile Gly Asn Lys Asn Val 20 25
30 His Trp Tyr Gln Gln Lys Pro Gly Gln Ala Pro Val Leu Val Val Arg
35 40 45 Glu Asp Ser Ala Arg Pro Ala Gly Ile Pro Glu Arg Phe Ser
Gly Ser 50 55 60 Asn Ser Gly Asn Ser Ala Thr Leu Thr Ile Ser Arg
Val Glu Ala Gly 65 70 75 80 Asp Glu Ala Asp Tyr Tyr Cys Gln Val Trp
Asp Asn Thr Ser Asp His 85 90 95 Val Val Phe Gly Gly Gly Thr Lys
Leu Thr Val Leu 100 105 89118PRTArtificial SequenceRD2-VH 89Gln Val
Gln Leu Val Glu Ser Gly Gly Gly Val Val Gln Pro Gly Arg 1 5 10 15
Ser Leu Arg Leu Ser Cys Ala Ala Ser Gly Phe Thr Phe Ser Ser Tyr 20
25 30 Ala Met His Trp Val Arg Gln Ala Pro Gly Lys Gly Leu Glu Trp
Val 35 40 45 Ala Val Ile Ser Phe Asp Gly Ser Asn Lys Tyr Tyr Ala
Asp Ser Val 50 55 60 Arg Gly Arg Phe Thr Ile Ser Arg Asp Asn Ser
Lys Asn Thr Leu Tyr 65 70 75 80 Leu Gln Met Asn Ser Leu Arg Thr Glu
Asp Thr Ala Val Tyr Tyr Cys 85 90 95 Ala Arg Gly Trp Leu Asp Arg
Asp Ile Asp Tyr Trp Gly Gln Gly Thr 100 105 110 Leu Val Thr Val Ser
Ser 115 90110PRTArtificial SequenceRD2-VL 90Ser Tyr Glu Leu Met Gln
Pro Pro Ser Val Ser Glu Val Pro Gly Gln 1 5 10 15 Arg Val Thr Ile
Ser Cys Ser Gly Ser Ser Ser Asn Ile Gly Asn Asn 20 25 30 Ala Val
Asn Trp Phe Gln Gln Leu Pro Gly Lys Ala Pro Lys Leu Leu 35 40 45
Val Tyr Tyr Asp Asp Trp Val Pro Ser Gly Ile Ser Gly Arg Phe Ser 50
55 60 Ala Ser Lys Ser Gly Thr Ser Ala Ser Leu Ala Ile Ser Gly Leu
Gln 65 70 75 80 Ser Gly Asp Glu Gly Asp Tyr Tyr Cys Ala Val Trp Asp
Asp Arg Leu 85 90 95 Ser Gly Val Val Phe Gly Gly Gly Thr Lys Leu
Thr Val Leu 100 105 110 91118PRTArtificial SequenceRE8-VH 91Gln Val
Gln Leu Val Glu Ser Gly Gly Gly Val Val Gln Pro Gly Arg 1 5 10 15
Ser Leu Arg Leu Ser Cys Ala Ala Ser Gly Phe Thr Phe Ser Ser Tyr 20
25 30 Ala Met His Trp Val Arg Gln Ala Pro Gly Lys Gly Leu Glu Trp
Val 35 40 45 Ala Val Ile Ser Phe Asp Gly Ser Asn Lys Tyr Tyr Ala
Asp Ser Val 50 55 60 Arg Gly Arg Phe Thr Ile Ser Arg Asp Asn Ser
Lys Asn Thr Leu Tyr 65 70 75 80 Leu Gln Met Asn Ser Leu Arg Thr Glu
Asp Thr Ala Val Tyr Tyr Cys 85 90 95 Ala Arg Gly Trp Leu Asp Arg
Asp Ile Asp Tyr Trp Gly Gln Gly Thr 100 105 110 Leu Val Thr Val Ser
Ser 115 92110PRTArtificial SequenceRE8-VL 92Gln Ser Val Val Thr Gln
Pro Pro Ser Val Ser Ala Ala Pro Gly Gln 1 5 10 15 Lys Val Thr Ile
Ser Cys Ser Gly Ser Ser Ser Asn Ile Gly Asn Asn 20 25 30 Tyr Val
Ser Trp Tyr Gln Gln Leu Pro Gly Thr Ala Pro Thr Leu Leu 35 40 45
Ile Tyr Asp Ser Asn Lys Arg Pro Ser Val Ile Pro Asp Arg Phe Ser 50
55 60 Gly Ser Lys Ser Gly Thr Ser Ala Thr Leu Gly Ile Thr Gly Leu
Gln 65 70 75 80 Thr Gly Asp Glu Ala Asp Tyr Tyr Cys Gly Thr Trp Asp
Asp Ser Leu 85 90 95 Asn Gly Trp Val Phe Gly Gly Gly Thr Lys Leu
Thr Val Leu 100 105 110 93118PRTArtificial SequenceRE9-VH 93Glu Val
Gln Leu Val Glu Ser Gly Gly Gly Val Val Gln Pro Gly Arg 1 5 10 15
Ser Leu Arg Leu Ser Cys Ala Ala Ser Gly Phe Thr Phe Ser Ser Tyr 20
25 30 Ala Met His Trp Val Arg Gln Ala Pro Gly Lys Gly Leu Glu Trp
Val 35 40 45 Ala Val Ile Ser Phe Asp Gly Ser Asn Lys Tyr Tyr Ala
Asp Ser Val 50 55 60 Arg Gly Arg Phe Thr Ile Ser Arg Asp Asn Ser
Lys Asn Thr Leu Tyr 65 70 75 80 Leu Gln Met Asn Ser Leu Arg Thr Glu
Asp Thr Ala Val Tyr Tyr Cys 85 90 95 Ala Arg Gly Trp Leu Asp Arg
Asp Ile Asp Tyr Trp Gly Gln Gly Thr 100 105 110 Met Val Thr Val Ser
Ser 115 94111PRTArtificial SequenceRE9-VL 94Gln Ser Ala Leu Thr Gln
Pro Ala Ser Val Ser Gly Ser Pro Gly Gln 1 5 10 15 Ser Ile Thr Ile
Ser Cys Thr Gly Thr Ser Ser Asp Val Gly Gly Tyr 20 25 30 Asn Tyr
Val Ser Trp Tyr Gln Gln His Pro Gly Lys Ala Pro Lys Leu 35 40 45
Met Ile Tyr Asp Val Ser Asn Arg Pro Ser Gly Val Ser Asn Arg Phe 50
55 60 Ser Gly Ser Lys Ser Gly Asn Thr Ala Ser Leu Thr Ile Ser Gly
Leu 65 70 75 80 Gln Ala Glu Asp Glu Ala Asp Tyr Tyr Cys Ser Ser Tyr
Arg Ser Ser 85 90 95 Thr Leu Gly Pro Val Phe Gly Gly Gly Thr Lys
Leu Thr Val Leu 100 105 110 95118PRTArtificial SequenceRG12-VH
95Gln Val Gln Leu Val Glu Ser Gly Gly Gly Val Val Gln Pro Gly Arg 1
5 10 15 Ser Leu Arg Leu Ser Cys Ala Ala Ser Gly Phe Thr Phe Ser Ser
Tyr 20 25 30 Ala Met His Trp Val Arg Gln Ala Pro Gly Lys Gly Leu
Glu Trp Val 35 40 45 Ala Val Ile Ser Phe Asp Gly Ser Asn Lys Tyr
Tyr Ala Asp Ser Val 50 55 60 Arg Gly Arg Phe Thr Ile Ser Arg Asp
Asn Ser Lys Asn Thr Leu Tyr 65 70 75 80 Leu Gln Met Asn Ser Leu Arg
Thr Glu Asp Thr Ala Val Tyr Tyr Cys 85 90 95 Ala Arg Gly Trp Leu
Asp Arg Asp Ile Asp Tyr Trp Gly Gln Gly Thr 100 105 110 Leu Val Thr
Val Ser Ser 115 96111PRTArtificial SequenceRG12-VL 96Gln Ala Gly
Leu Thr Gln Pro Pro Ser Ala Ser Gly Ser Pro Gly Gln 1 5 10 15 Ser
Val Thr Ile Ser Cys Thr Gly Thr Ser Ser Asp Val Gly Gly Tyr 20 25
30 Asn Tyr Val Ser Trp Tyr Gln Gln His Pro Gly Lys Ala Pro Lys Leu
35 40 45 Met Ile Tyr Asp Val Ser Asn Arg Pro Ser Gly Val Pro Asp
Arg Phe 50 55 60 Ser Gly Ser Lys Ser Gly Asn Thr Ala Ser Leu Thr
Ile Ser Gly Leu 65 70 75 80 Gln Ala Glu Asp Glu Ala Asp Tyr Tyr Cys
Ser Ser Tyr Thr Ser Ser 85 90 95 Ser Thr Leu Val
Val Phe Gly Gly Gly Thr Lys Leu Thr Val Leu 100 105 110
97118PRTArtificial SequenceRSA1-VH 97Glu Val Gln Leu Val Gln Ser
Gly Gly Gly Leu Val Gln Pro Gly Gly 1 5 10 15 Ser Leu Arg Leu Ser
Cys Ala Ala Ser Gly Phe Thr Phe Ser Ser Tyr 20 25 30 Ser Met Asn
Trp Val Arg Gln Ala Pro Gly Lys Gly Leu Glu Trp Val 35 40 45 Ser
Tyr Ile Ser Ser Ser Ser Ser Thr Ile Tyr Tyr Ala Asp Ser Val 50 55
60 Lys Gly Arg Phe Thr Ile Ser Arg Asp Asn Ala Lys Asn Ser Leu Tyr
65 70 75 80 Leu Gln Met Asn Ser Leu Arg Asp Glu Asp Thr Ala Val Tyr
Tyr Cys 85 90 95 Ala Arg Gly Asp Tyr Tyr Tyr Gly Met Asp Val Trp
Gly Gln Gly Thr 100 105 110 Thr Val Thr Val Ser Ser 115
98108PRTArtificial SequenceRSA1-VL 98Asn Ile Gln Met Thr Gln Ser
Pro Ser Ser Val Ser Ala Ser Val Gly 1 5 10 15 Asp Arg Val Thr Ile
Thr Cys Arg Ala Ser Gln Asp Ile Ser Arg Trp 20 25 30 Leu Ala Trp
Tyr Gln Gln Lys Pro Gly Lys Ala Pro Lys Leu Leu Ile 35 40 45 Tyr
Ala Ala Ser Ser Leu Gln Ser Gly Val Pro Ser Arg Phe Ser Gly 50 55
60 Ser Gly Ser Gly Thr Asp Phe Ala Leu Thr Ile Ser Ser Leu Gln Pro
65 70 75 80 Glu Asp Phe Ala Thr Tyr Tyr Cys Gln Gln Ala Asp Ser Phe
Phe Ser 85 90 95 Ile Thr Phe Gly Gln Gly Thr Arg Leu Glu Ile Lys
100 105 99118PRTArtificial SequenceR2A7-VH 99Gln Val Gln Leu Val
Gln Ser Gly Ser Glu Val Lys Lys Pro Gly Ala 1 5 10 15 Ser Val Lys
Val Ser Cys Arg Ala Ser Gly Tyr Leu Phe Thr Asn Tyr 20 25 30 Gly
Ile Ser Trp Val Arg Gln Ala Pro Gly Gln Gly Leu Glu Trp Met 35 40
45 Gly Trp Val Ser Ala His Gly Glu Phe Thr Lys Tyr Ala Pro Ser Leu
50 55 60 Gln Asp Arg Val Thr Met Thr Ser Asp Ile Ser Thr Thr Thr
Ala Tyr 65 70 75 80 Met Glu Leu Arg Ser Leu Arg Ser Asp Asp Ala Gly
Val Tyr Tyr Cys 85 90 95 Ala Arg Asp Arg Gly Ala Asp His Phe Asp
Thr Trp Gly Gln Gly Thr 100 105 110 Leu Val Thr Val Ser Ser 115
100107PRTArtificial SequenceR2A7-VL 100Ala Ile Gln Leu Thr Gln Ser
Pro Ala Thr Leu Ser Leu Ser Pro Gly 1 5 10 15 Glu Arg Ala Thr Leu
Ser Cys Arg Ala Ser Gln Ser Val Gly Val Tyr 20 25 30 Leu Ala Trp
Tyr Gln Gln Lys Pro Gly Gln Ser Pro Arg Leu Leu Ile 35 40 45 Tyr
Asp Thr Ser Lys Arg Ala Thr Gly Ile Pro Asp Arg Phe Ser Ala 50 55
60 Ser Gly Ser Gly Thr Asp Phe Thr Leu Thr Ile Ser Arg Leu Glu Pro
65 70 75 80 Glu Asp Phe Ala Val Tyr Tyr Cys His Gln Arg His Ser Trp
Pro Thr 85 90 95 Thr Phe Gly Gln Gly Thr Arg Leu Glu Ile Lys 100
105 101124PRTArtificial SequenceR2B12-VH 101Glu Val Gln Leu Val Gln
Ser Gly Ala Glu Val Lys Lys Pro Gly Ala 1 5 10 15 Ser Val Lys Val
Ser Cys Lys Ala Ser Gly Tyr Thr Phe Thr Ser Tyr 20 25 30 Tyr Met
His Trp Val Arg Gln Ala Pro Gly Gln Gly Leu Glu Trp Met 35 40 45
Gly Met Ile Asn Pro Ser Ser Ala Thr Thr Thr Tyr Thr Gln Lys Phe 50
55 60 Gln Gly Arg Val Ser Met Thr Arg Asp Thr Ser Thr Ser Thr Val
Tyr 65 70 75 80 Met Glu Leu Ser Ser Leu Thr Ser Glu Asp Thr Ala Val
Tyr Tyr Cys 85 90 95 Ala Arg Asp Leu Phe Pro His Ile Tyr Gly Asn
Tyr Tyr Gly Met Asp 100 105 110 Ile Trp Gly Gln Gly Thr Thr Val Thr
Val Ser Ser 115 120 102106PRTArtificial SequenceR2B12-VL 102Asn Ile
Gln Met Thr Gln Ser Pro Ser Ser Leu Ser Ala Ser Val Gly 1 5 10 15
Asp Arg Val Thr Ile Thr Cys Arg Ala Ser Gln Ser Ile Ser Ser Tyr 20
25 30 Leu Asn Trp Tyr Gln Gln Lys Pro Gly Lys Ala Pro Lys Leu Leu
Ile 35 40 45 Tyr Ala Ala Ser Ser Leu Gln Ser Gly Val Pro Ser Arg
Phe Ser Gly 50 55 60 Ser Gly Ser Gly Thr Asp Phe Thr Leu Thr Ile
Ser Ser Leu Gln Pro 65 70 75 80 Glu Asp Phe Ala Thr Tyr Tyr Cys Gln
Gln Ser Tyr Ser Thr Leu Thr 85 90 95 Phe Gly Gly Gly Thr Lys Val
Glu Ile Lys 100 105 103120PRTArtificial SequenceR2C9-VH 103Glu Val
Gln Leu Val Gln Ser Gly Ala Glu Val Lys Lys Pro Gly Ser 1 5 10 15
Ser Val Lys Val Ser Cys Lys Ala Ser Gly Gly Thr Phe Ser Ser His 20
25 30 Val Ile Ser Trp Val Arg Gln Ala Pro Gly Gln Gly Leu Glu Trp
Met 35 40 45 Gly Gly Ile Ile Pro Ile Phe Gly Thr Ala Asn Tyr Ala
Gln Lys Phe 50 55 60 Gln Gly Arg Val Thr Ile Thr Ala Asp Glu Ser
Thr Ser Thr Ala Tyr 65 70 75 80 Met Glu Leu Ser Ser Met Arg Ser Glu
Asp Thr Ala Val Tyr Tyr Cys 85 90 95 Ala Thr Ser Gly Val Val Ala
Ala Thr His Phe Gly Tyr Trp Gly Gln 100 105 110 Gly Thr Leu Val Thr
Val Ser Ser 115 120 104111PRTArtificial SequenceR2C9-VL 104Gln Ser
Val Leu Thr Gln Pro Ala Ser Val Ser Gly Ser Pro Gly Gln 1 5 10 15
Ser Ile Thr Ile Ser Cys Thr Gly Thr Ser Ser Asp Val Gly Asp Tyr 20
25 30 Asn Leu Val Ser Trp Tyr Gln Gln His Pro Gly Lys Ala Pro Lys
Leu 35 40 45 Ile Ile Tyr Glu Val Asn Lys Arg Pro Ser Gly Val Ser
Asn Arg Phe 50 55 60 Ser Gly Ser Lys Ser Gly Asn Thr Ala Ser Leu
Thr Ile Ser Gly Leu 65 70 75 80 Gln Ala Glu Asp Glu Ala Asp Tyr Tyr
Cys Ser Ser Tyr Ala Gly Tyr 85 90 95 Asn Asn Leu Tyr Val Phe Gly
Thr Gly Thr Lys Val Thr Val Leu 100 105 110 105123PRTArtificial
SequenceR2D5-VH 105Gln Val Gln Leu Val Gln Ser Gly Ala Glu Val Lys
Lys Pro Gly Ser 1 5 10 15 Ser Val Lys Val Ser Cys Lys Ala Ser Gly
Gly Thr Phe Ser Ser Tyr 20 25 30 Ala Ile Ser Trp Val Arg Gln Ala
Pro Gly Gln Gly Leu Glu Trp Met 35 40 45 Gly Gly Ile Ile Pro Ile
Phe Gly Thr Ala Asn Tyr Ala Gln Lys Phe 50 55 60 Gln Gly Arg Val
Thr Ile Thr Ala Asp Glu Ser Thr Ser Thr Ala Tyr 65 70 75 80 Met Glu
Leu Ser Ser Leu Arg Ser Glu Asp Thr Ala Val Tyr Tyr Cys 85 90 95
Ala Arg Gly Ala Ser Gly Ser Tyr Phe Ile Thr Thr Tyr Val Asp Tyr 100
105 110 Trp Gly Gln Gly Thr Leu Val Thr Val Ser Ser 115 120
106110PRTArtificial SequenceR2D5-VL 106Gln Ser Ala Leu Thr Gln Pro
Pro Ser Ala Ser Gly Ser Pro Gly Gln 1 5 10 15 Ser Val Thr Ile Ser
Cys Thr Gly Thr Ser Ser Asp Val Gly Gly Tyr 20 25 30 Asn Tyr Val
Ser Trp Tyr Gln Gln His Pro Gly Lys Ala Pro Lys Leu 35 40 45 Ile
Ile Tyr Asp Val Asn Met Arg Pro Ser Gly Val Pro Asp Arg Phe 50 55
60 Ser Gly Ser Lys Ser Gly Asn Thr Ala Ser Leu Thr Ile Ser Gly Leu
65 70 75 80 Gln Ala Glu Asp Glu Ala Asp Tyr Tyr Cys Ser Ser Tyr Ala
Gly Leu 85 90 95 Tyr Phe Pro Leu Phe Gly Gly Gly Thr Gln Leu Thr
Val Leu 100 105 110 107121PRTArtificial SequenceR2D7-VH 107Glu Val
Gln Leu Val Glu Ser Gly Gly Gly Leu Val Gln Pro Gly Gly 1 5 10 15
Pro Leu Arg Leu Ser Cys Ala Ala Ser Gly Phe Thr Leu Ser Ser Tyr 20
25 30 Trp Met Ser Trp Val Arg Gln Ala Pro Gly Lys Gly Leu Glu Trp
Val 35 40 45 Ala Asn Ile Lys Tyr Asp Gly Ser Glu Thr Tyr Tyr Ala
Asp Ser Val 50 55 60 Lys Gly Arg Phe Thr Ile Ser Arg Asp Asn Ala
Lys Asn Ser Leu Tyr 65 70 75 80 Leu Gln Met Asn Arg Leu Arg Leu Glu
Asp Thr Ala Val Tyr Tyr Cys 85 90 95 Ala Arg Glu Val Ser Ser Ala
Ala Thr Ser Pro Leu Asp Arg Trp Gly 100 105 110 Arg Gly Thr Leu Val
Thr Val Ser Ser 115 120 108107PRTArtificial SequenceR2D7-VL 108Asp
Ile Val Met Thr Gln Ser Pro Ser Ser Leu Ser Ala Ser Val Gly 1 5 10
15 Asp Arg Val Thr Ile Thr Cys Arg Ala Ser Gln Ser Ile Ser Ser Tyr
20 25 30 Leu Asn Trp Tyr Gln Gln Lys Pro Gly Lys Ala Pro Lys Leu
Leu Ile 35 40 45 Tyr Ala Ala Ser Ser Leu Gln Ser Gly Val Pro Ser
Arg Phe Ser Gly 50 55 60 Ser Gly Ser Gly Thr Asp Phe Thr Leu Thr
Ile Ser Ser Leu Gln Pro 65 70 75 80 Glu Asp Phe Ala Thr Tyr Tyr Cys
Gln Gln Ser His Ser Ser Arg Tyr 85 90 95 Thr Phe Gly Gln Gly Thr
Lys Leu Glu Ile Lys 100 105 109120PRTArtificial SequenceR2F4-VH
109Glu Val Gln Leu Val Gln Ser Gly Ala Glu Val Lys Lys Pro Gly Ser
1 5 10 15 Ser Val Lys Val Ser Cys Lys Ala Ser Gly Gly Thr Phe Ser
Arg Tyr 20 25 30 Gly Val His Trp Val Arg Gln Ala Pro Gly Gln Gly
Leu Glu Trp Met 35 40 45 Gly Arg Leu Ile Pro Ile Val Ser Met Thr
Asn Tyr Ala Gln Lys Phe 50 55 60 Gln Asp Arg Val Ser Ile Thr Thr
Asp Lys Ser Thr Gly Thr Ala Tyr 65 70 75 80 Met Glu Leu Arg Ser Leu
Thr Ser Glu Asp Thr Ala Leu Tyr Tyr Cys 85 90 95 Ala Ser Val Gly
Gln Gln Leu Pro Trp Val Phe Phe Ala Trp Gly Gln 100 105 110 Gly Thr
Leu Val Thr Val Ser Ser 115 120 110112PRTArtificial SequenceR2F4-VL
110Gln Ser Val Val Thr Gln Pro Pro Ser Val Ser Gly Ala Pro Gly Gln
1 5 10 15 Arg Val Thr Ile Ser Cys Thr Gly Ser Ser Ser Asn Ile Gly
Ala Gly 20 25 30 Tyr Gly Val His Trp Tyr Gln His Leu Pro Gly Ser
Ala Pro Lys Leu 35 40 45 Leu Ile Tyr Gly Asn Ser Asn Arg Pro Ser
Gly Val Thr Asp Arg Ile 50 55 60 Ser Gly Ser Lys Ser Gly Thr Ser
Ala Ser Leu Ala Ile Thr Gly Leu 65 70 75 80 Gln Ala Glu Asp Glu Ala
Val Tyr Tyr Cys Gln Ser Tyr Asp Ser Ser 85 90 95 Leu Ser Thr Ser
Val Val Phe Gly Gly Gly Thr Lys Leu Thr Val Leu 100 105 110
111118PRTArtificial SequenceR2A10-VH 111Glu Val Gln Leu Val Glu Ser
Gly Gly Gly Val Val Gln Pro Gly Gly 1 5 10 15 Ser Leu Arg Leu Ser
Cys Ala Ala Ser Gly Phe Thr Phe Ser Ser Tyr 20 25 30 Ala Met His
Trp Val Arg Gln Ala Pro Gly Lys Gly Leu Glu Trp Val 35 40 45 Ala
Val Ile Ser Phe Asp Gly Ser Asn Lys Tyr Tyr Ala Asp Ser Val 50 55
60 Arg Gly Arg Phe Thr Ile Ser Arg Asp Asn Ser Lys Asn Thr Leu Tyr
65 70 75 80 Leu Gln Met Asn Ser Leu Arg Thr Glu Asp Thr Ala Val Tyr
Tyr Cys 85 90 95 Ala Arg Gly Trp Leu Asp Arg Asp Ile Asp Tyr Trp
Gly Gln Gly Thr 100 105 110 Leu Val Thr Val Ser Ser 115
112110PRTArtificial SequenceR2A10-VL 112Gln Ser Val Leu Thr Gln Pro
Pro Ser Ala Ser Gly Thr Pro Gly Gln 1 5 10 15 Arg Val Thr Ile Ser
Cys Ser Gly Ser Ser Ser Asn Ile Gly Ser Asn 20 25 30 Thr Val His
Trp Tyr Gln Gln Leu Pro Gly Thr Ala Pro Lys Val Leu 35 40 45 Ile
Tyr Thr Asn Asn Gln Arg Pro Ser Gly Val Pro Asp Arg Phe Ser 50 55
60 Gly Ser Lys Ser Gly Thr Ser Ala Ser Leu Ala Ile Ser Gly Leu Gln
65 70 75 80 Ser Glu Asp Glu Ala Asp Tyr Tyr Cys Ala Ala Trp Asp Gly
Arg Leu 85 90 95 Gln Gly Trp Val Phe Gly Gly Gly Thr Gln Leu Thr
Val Leu 100 105 110 113118PRTArtificial SequenceR2E2-VH 113Glu Val
Gln Leu Val Glu Ser Gly Gly Gly Val Val Gln Pro Gly Arg 1 5 10 15
Ser Leu Arg Leu Ser Cys Ala Ala Ser Gly Phe Thr Phe Ser Ser Tyr 20
25 30 Ala Met His Trp Val Arg Gln Ala Pro Gly Lys Gly Leu Glu Trp
Val 35 40 45 Ala Val Ile Ser Phe Asp Gly Ser Asn Lys Tyr Tyr Ala
Asp Ser Val 50 55 60 Arg Gly Arg Phe Thr Ile Ser Arg Asp Asn Ser
Lys Asn Thr Leu Tyr 65 70 75 80 Leu Gln Met Asn Ser Leu Arg Thr Glu
Asp Thr Ala Val Tyr Tyr Cys 85 90 95 Ala Arg Gly Trp Leu Asp Arg
Asp Ile Asp Tyr Trp Gly Gln Gly Thr 100 105 110 Leu Val Thr Val Ser
Ser 115 114110PRTArtificial SequenceR2E2-VL 114Gln Ala Gly Leu Thr
Gln Pro Pro Ser Ala Ser Gly Thr Pro Gly Gln 1 5 10 15 Arg Val Thr
Ile Ser Cys Phe Gly Ser Ser Ser Asp Ile Gly Ser Asn 20 25 30 Thr
Val Asn Trp Tyr Gln Gln Val Ser Gly Arg Ala Pro Lys Leu Leu 35 40
45 Leu Tyr Thr Asn Gly Gln Arg Pro Ser Gly Val Pro Asp Arg Phe Ser
50 55 60 Gly Ser Lys Ser Gly Ser Ser Ala Ser Leu Ala Ile Ser Gly
Leu Gln 65 70 75 80 Ser Glu Asp Glu Ala Asp Tyr Tyr Cys Ala Ser Trp
Asp Asp Ser Leu 85 90 95 Lys Gly Tyr Val Phe Gly Thr Gly Thr Lys
Val Thr Val Leu 100 105 110 115120PRTArtificial SequenceR3B8-VH
115Glu Val Gln Leu Val Gln Ser Gly Ala Glu Val Lys Lys Pro Gly Ser
1 5 10 15 Ser Val Lys Val Ser Cys Lys Ala Ser Gly Gly Thr Phe Ser
Ser Tyr 20 25 30 Ala Ile Ser Trp Val Arg Gln Ala Pro Gly Gln Gly
Leu Glu Trp Met 35 40 45 Gly Arg Ile Ile Pro Ile Leu Gly Ile Ala
Asn Tyr Ala Gln Lys Phe 50 55 60 Gln Gly Arg Val Thr Ile Thr Ala
Asp Lys Ser Thr Ser Thr Ala Tyr 65 70 75 80 Met Glu Leu Ser Ser Leu
Arg Ser Glu Asp Thr Ala Val Tyr Tyr Cys 85 90 95 Ala Arg Val Gly
Gly Gly Ala Gln Thr Pro Phe Asp Tyr Trp Gly Gln 100 105 110 Gly Thr
Leu Val Thr Val Ser Ser
115 120 116109PRTArtificial SequenceR3B8-VL 116Gln Ser Val Leu Thr
Gln Pro Pro Ser Val Ser Ala Ala Pro Gly Gln 1 5 10 15 Lys Val Thr
Ile Ser Cys Ser Gly Ser Ser Ser Asn Ile Gly Asn Ser 20 25 30 Tyr
Val Ser Trp Tyr Gln His Leu Pro Gly Thr Ala Pro Lys Leu Leu 35 40
45 Ile Tyr Asp Asn Asn Lys Arg Pro Ser Gly Ile Pro Asp Arg Phe Ser
50 55 60 Gly Ser Lys Ser Ala Thr Ser Ala Thr Leu Gly Ile Thr Gly
Leu Gln 65 70 75 80 Thr Ala Asp Glu Ala Asp Tyr Tyr Cys Gly Thr Trp
Asp Ser Ser Leu 85 90 95 Gly Val Val Phe Gly Gly Gly Thr Lys Leu
Thr Val Leu 100 105 117124PRTArtificial SequenceR3C3-VH 117Gln Val
Gln Leu Val Gln Ser Gly Ser Glu Val Lys Arg Pro Gly Ala 1 5 10 15
Ser Val Arg Val Ser Cys Lys Ala Ser Gly Tyr Ile Phe Ser Gln Tyr 20
25 30 Thr Ile His Trp Val Arg Gln Ala Pro Gly Glu Arg Leu Glu Trp
Leu 35 40 45 Gly Trp Ile Asn Ala Val Thr Gly Asn Thr Lys Tyr Ala
Gln Lys Phe 50 55 60 Gln Gly Arg Val Thr Ile Thr Met Asp Ser Ser
Ala Ser Thr Ala Phe 65 70 75 80 Met Glu Met Ser Ser Leu Arg Ser Glu
Asp Ala Gly Val Tyr Phe Cys 85 90 95 Ala Arg Asp Met Val Pro Phe
Gly Gly Glu Ile Lys Tyr Gly Phe Asp 100 105 110 Phe Trp Gly Gln Gly
Thr Met Ile Thr Val Ser Ser 115 120 118110PRTArtificial
SequenceR3C3-VL 118Gln Ser Ala Leu Thr Gln Pro Ala Ser Val Ser Gly
Ser Pro Gly Gln 1 5 10 15 Ser Ile Thr Ile Ser Cys Thr Gly Thr Ser
Ser Asp Val Gly Gly Tyr 20 25 30 Asn Tyr Val Ser Trp Tyr Gln Gln
His Pro Gly Lys Ala Pro Lys Leu 35 40 45 Met Ile Tyr Asn Val Ser
Lys Arg Pro Ser Gly Val Ser Asn Arg Phe 50 55 60 Ser Gly Ser Lys
Ser Gly Asn Thr Ala Ser Leu Thr Ile Ser Gly Leu 65 70 75 80 Gln Ala
Glu Asp Glu Ala Asp Tyr Tyr Cys Ser Ser Tyr Thr Ser Ser 85 90 95
Ser Thr Phe Val Phe Gly Thr Gly Thr Lys Val Thr Val Leu 100 105 110
119122PRTArtificial SequenceR3E9-VH 119Gln Val Gln Leu Val Glu Ser
Gly Gly Gly Val Val Gln Pro Gly Arg 1 5 10 15 Ser Leu Arg Leu Ser
Cys Ala Ala Ser Gly Phe Thr Phe Ser Ser Tyr 20 25 30 Gly Met His
Trp Val Arg Gln Ala Pro Gly Lys Gly Leu Glu Trp Val 35 40 45 Ala
Leu Ile Ser Tyr Asp Gly Ser Asn Lys Tyr Tyr Ala Asp Ser Met 50 55
60 Lys Gly Arg Phe Thr Ile Ser Arg Asp Asn Ser Lys Asn Thr Leu Phe
65 70 75 80 Leu Gln Met Asn Ser Leu Arg Ala Glu Asp Thr Ala Val Tyr
Tyr Cys 85 90 95 Ala Lys Thr Leu Met Pro Ala Ser Ile Met Gly Tyr
Phe Thr His Trp 100 105 110 Gly Gln Gly Thr Leu Val Thr Val Ser Ser
115 120 120108PRTArtificial SequenceR3E9-VL 120Ser Tyr Glu Leu Met
Gln Pro Pro Ser Val Ser Val Ala Pro Gly Glu 1 5 10 15 Thr Ala Arg
Ile Thr Cys Gly Gly Asn Asn Ile Gly Ser Lys Ser Val 20 25 30 His
Trp Tyr Gln Gln Lys Pro Gly Gln Ala Pro Ile Leu Val Ile Tyr 35 40
45 Tyr Asp Ser Gly Arg Pro Ser Gly Ile Pro Glu Arg Phe Ser Gly Ser
50 55 60 Asn Ser Gly Asn Thr Ala Thr Leu Thr Ile Ser Arg Ala Glu
Ala Gly 65 70 75 80 Asp Glu Ala Asp Tyr Tyr Cys His Val Trp Asp Ser
Tyr Thr Asp His 85 90 95 Val Val Phe Gly Gly Gly Thr Lys Leu Thr
Val Leu 100 105 121120PRTArtificial SequenceR3E10-VH 121Gln Val Gln
Leu Val Gln Ser Gly Ala Glu Val Lys Lys Pro Gly Ala 1 5 10 15 Ser
Val Lys Val Ser Cys Lys Ala Ser Gly Tyr Thr Phe Thr Ser Tyr 20 25
30 Tyr Met His Trp Val Arg Gln Ala Pro Gly Gln Gly Leu Glu Trp Met
35 40 45 Gly Ile Ile Asn Pro Ser Asp Gly Ser Thr Ser Tyr Ala Gln
Lys Phe 50 55 60 Gln Gly Arg Val Thr Met Thr Arg Asp Thr Ser Thr
Ser Thr Val Tyr 65 70 75 80 Met Glu Leu Ser Ser Leu Arg Ser Glu Asp
Thr Ala Val Tyr Tyr Cys 85 90 95 Ala Arg Gly Tyr Tyr Gly Ser Gly
Ile Ala Met Asp Val Trp Gly Gln 100 105 110 Gly Thr Thr Val Thr Val
Ser Ser 115 120 122108PRTArtificial SequenceR3E10-VL 122Gln Pro Val
Leu Thr Gln Pro Pro Ser Leu Ser Val Ala Pro Gly Lys 1 5 10 15 Thr
Ala Ser Ile Ala Cys Gly Gly Asn Asn Ile Gly Ser Lys Arg Val 20 25
30 His Trp Tyr Gln Gln Lys Pro Gly Gln Ala Pro Val Leu Val Ile Tyr
35 40 45 Tyr Glu Ser Asp Arg Pro Ser Gly Ile Pro Glu Arg Phe Ser
Gly Thr 50 55 60 Ile Ser Gln Asn Thr Ala Thr Leu Ser Ile Ser Arg
Val Glu Ala Gly 65 70 75 80 Asp Glu Ala Asp Tyr Tyr Cys Gln Val Trp
Asp Arg Ser Ser Ala His 85 90 95 Val Val Phe Gly Gly Gly Thr Lys
Val Thr Val Leu 100 105 123118PRTArtificial SequenceR3F7-VH 123Gln
Val Gln Leu Val Gln Ser Gly Ala Glu Val Lys Lys Pro Gly Ser 1 5 10
15 Ser Val Lys Val Ser Cys Lys Ala Ser Gly Gly Thr Phe Ser Ser Tyr
20 25 30 Ala Ile Ser Trp Val Arg Gln Ala Pro Gly Gln Gly Leu Glu
Trp Met 35 40 45 Gly Gly Ile Ile Pro Ile Phe Gly Thr Ala Asn Tyr
Ala Gln Lys Phe 50 55 60 Gln Gly Arg Val Thr Ile Thr Ala Asp Glu
Ser Thr Ser Thr Ala Tyr 65 70 75 80 Met Glu Leu Ser Ser Leu Arg Pro
Glu Asp Thr Ala Val Tyr Tyr Cys 85 90 95 Ala Arg Asp Asn Gly Asp
Leu Gly Phe Asp Tyr Trp Gly Gln Gly Thr 100 105 110 Leu Val Thr Val
Ser Ser 115 124107PRTArtificial SequenceR3F7-VL 124Ala Ile Gln Met
Thr Gln Ser Pro Ser Ser Leu Ser Ala Ser Val Gly 1 5 10 15 Asp Arg
Val Thr Ile Thr Cys Arg Ala Ser Gln Ser Ile Ser Thr Tyr 20 25 30
Leu Asn Trp Tyr Gln Gln Lys Pro Gly Lys Ala Pro Lys Leu Leu Ile 35
40 45 Tyr Ala Ala Ser Ser Leu Gln Asn Gly Val Pro Ser Arg Phe Ser
Gly 50 55 60 Ser Gly Ser Gly Thr Asp Phe Thr Leu Thr Ile Ser Ser
Leu Gln Pro 65 70 75 80 Glu Asp Phe Ala Thr Tyr Tyr Cys Gln Gln Ser
Tyr Ser Thr Pro Arg 85 90 95 Thr Phe Gly Pro Gly Thr Lys Val Asp
Ile Lys 100 105 125118PRTArtificial SequenceR3F10-VH 125Glu Val Gln
Leu Val Glu Ser Gly Gly Gly Leu Ile Gln Pro Gly Gly 1 5 10 15 Ser
Leu Arg Leu Ser Cys Ala Ala Ser Gly Phe Thr Val Ser Ser Asn 20 25
30 Tyr Met Ser Trp Val Arg Gln Ala Pro Gly Lys Gly Leu Glu Trp Val
35 40 45 Ser Val Ile Tyr Ser Gly Gly Thr Ile Tyr Tyr Ala Asp Ser
Val Lys 50 55 60 Gly Arg Phe Thr Ile Ser Arg Asp Ser Ser Lys Asn
Thr Leu Tyr Leu 65 70 75 80 His Met Asn Ser Leu Arg Ala Glu Asp Thr
Gly Val Tyr Tyr Cys Ala 85 90 95 Lys Gly Val Gly Ser Trp Ser Ile
Phe Asp Tyr Trp Gly Gln Gly Thr 100 105 110 Leu Val Thr Val Ser Ser
115 126106PRTArtificial SequenceR3F10-VL 126Asp Ile Gln Met Thr Gln
Ser Pro Ser Ser Leu Ser Ala Ser Val Gly 1 5 10 15 Asp Arg Val Thr
Ile Thr Cys Gln Ala Ser Gln Asp Ile Ser Asn Tyr 20 25 30 Leu Asn
Trp Tyr Gln Gln Lys Pro Gly Lys Ala Pro Lys Leu Leu Ile 35 40 45
Phe Ala Gly Ser Asn Leu Gln Ser Gly Val Pro Ser Arg Phe Ser Gly 50
55 60 Ser Gly Ser Gly Thr Asp Phe Thr Leu Thr Ile Thr Ser Leu Gln
Pro 65 70 75 80 Glu Asp Phe Ala Thr Tyr Tyr Cys Gln Gln Ser Tyr Thr
Thr Pro Thr 85 90 95 Phe Gly Gln Gly Thr Lys Val Glu Ile Lys 100
105 127117PRTArtificial SequenceR4B10-VH 127Glu Val Gln Leu Val Glu
Ser Gly Ala Glu Leu Lys Lys Pro Gly Ser 1 5 10 15 Ser Met Lys Val
Ser Cys Lys Ala Ser Gly Gly Thr Phe Ser Ser Tyr 20 25 30 Ala Ile
Ser Trp Val Arg Gln Ala Pro Gly Gln Gly Leu Glu Tyr Ile 35 40 45
Gly Arg Ile Ile Pro Ile Phe Gly Val Thr Tyr Tyr Ala Gln Lys Phe 50
55 60 Gln Gly Arg Val Thr Ile Ser Ala Asp Lys Ser Thr Ser Thr Val
Tyr 65 70 75 80 Leu Asp Leu Arg Ser Leu Arg Ser Glu Asp Thr Ala Val
Tyr Tyr Cys 85 90 95 Ala Arg Asp Leu Gly Gly Gly Asp Gly Asp Trp
Gly Gln Gly Thr Leu 100 105 110 Val Thr Val Ser Ser 115
128109PRTArtificial SequenceR4B10-VL 128Gln Ser Val Val Thr Gln Pro
Ala Ser Val Ser Gly Ser Pro Gly Gln 1 5 10 15 Ser Ile Thr Ile Ser
Cys Thr Gly Thr Ser Ser Asp Val Gly Ser Tyr 20 25 30 Asn Leu Val
Ser Trp Tyr Gln Gln His Pro Gly Lys Ala Pro Lys Leu 35 40 45 Met
Ile Tyr Glu Gly Ser Lys Arg Pro Ser Gly Val Ser Thr Arg Phe 50 55
60 Ser Gly Ser Lys Ser Gly Asn Thr Ala Ser Leu Thr Ile Ser Gly Leu
65 70 75 80 Gln Ala Glu Asp Glu Ser Asp Tyr Tyr Cys Ser Ser Tyr Thr
Gly Ser 85 90 95 Ala Trp Val Phe Gly Gly Gly Thr Lys Leu Thr Val
Leu 100 105 129114PRTArtificial SequenceR4H1-VH 129Glu Val Gln Leu
Val Gln Ser Gly Ala Glu Val Lys Lys Pro Gly Ser 1 5 10 15 Ser Val
Lys Val Ser Cys Lys Ala Ser Gly Tyr Thr Phe Thr Gly Tyr 20 25 30
Tyr Met His Trp Val Arg Gln Ala Pro Gly Gln Gly Leu Glu Trp Met 35
40 45 Gly Arg Ile Ile Pro Ile Phe Gly Thr Ala Asn Tyr Ala Gln Lys
Phe 50 55 60 Gln Gly Arg Val Thr Ile Thr Ala Asp Glu Ser Thr Ser
Thr Ala Tyr 65 70 75 80 Met Glu Leu Ser Ser Leu Arg Ser Glu Asp Thr
Ala Val Tyr Phe Cys 85 90 95 Val Thr Ser Ala Trp Ser Asp Trp Gly
Gln Gly Thr Leu Val Thr Val 100 105 110 Ser Ser 130110PRTArtificial
SequenceR4H1-VL 130Gln Ser Val Val Thr Gln Pro Pro Ser Val Ser Ala
Thr Pro Gly Gln 1 5 10 15 Lys Val Thr Ile Ser Cys Ser Gly Ser Asp
Ser Asn Ile Gly Asn Asn 20 25 30 Tyr Val Ser Trp Phe Leu Gln Leu
Pro Gly Thr Ala Pro Lys Leu Leu 35 40 45 Ile His Asn Asn Asp Gln
Arg Pro Ser Gly Val Pro Asp Arg Phe Ser 50 55 60 Gly Ser Lys Ser
Gly Thr Ser Ala Ser Leu Ala Ile Thr Gly Leu Gln 65 70 75 80 Ala Glu
Asp Glu Ala Asp Tyr Tyr Cys Gln Ser Phe Asp Asp Ser Leu 85 90 95
Arg Gly Tyr Leu Phe Gly Thr Gly Thr Lys Val Thr Val Leu 100 105 110
131116PRTArtificial SequenceR4A11-VH 131Glu Val Gln Leu Val Glu Ser
Gly Gly Gly Leu Val Gln Pro Gly Gly 1 5 10 15 Ser Leu Arg Leu Ser
Cys Ala Ala Ser Gly Phe Thr Phe Ser Ser Tyr 20 25 30 Trp Met Ser
Trp Val Arg Gln Ala Pro Gly Lys Gly Leu Glu Trp Val 35 40 45 Ala
Asn Ile Lys Gln Asp Gly Ser Glu Lys Tyr Tyr Val Asp Ser Val 50 55
60 Lys Gly Arg Phe Thr Ile Ser Arg Asp Asn Ser Lys Asn Thr Leu Tyr
65 70 75 80 Leu Gln Met Asn Ser Leu Gly Ala Glu Asp Thr Ala Val Tyr
Tyr Cys 85 90 95 Ala Lys Gly Phe Tyr Tyr Pro Asp His Trp Gly Gln
Gly Thr Leu Val 100 105 110 Thr Val Ser Ser 115 132108PRTArtificial
SequenceR4A11-VL 132Gln Ala Val Leu Thr Gln Pro Pro Ser Val Ser Ala
Ala Pro Gly Gln 1 5 10 15 Lys Val Thr Ile Ser Cys Ser Gly Gly Ser
Ser Asn Ile Ala Asn Asn 20 25 30 Tyr Val Ser Trp Tyr Gln His Leu
Pro Gly Thr Ala Pro Lys Leu Leu 35 40 45 Ile Tyr Asp Asp Asn Lys
Arg Pro Ser Gly Ile Pro Asp Arg Phe Ser 50 55 60 Gly Ser Lys Ser
Gly Thr Ser Ala Thr Leu Gly Ile Thr Gly Leu Gln 65 70 75 80 Thr Gly
Asp Gly Ala Asp Tyr Tyr Cys Gly Thr Trp Asp Asn Ser Leu 85 90 95
Asn Ser Asp Trp Val Phe Gly Gly Gly Thr Lys Leu 100 105
133119PRTArtificial SequenceR3D2-VH 133Glu Val Gln Leu Val Glu Ser
Gly Gly Gly Val Val Gln Pro Gly Gly 1 5 10 15 Ser Leu Arg Leu Ser
Cys Glu Val Ser Gly Phe Ile Phe Ser Asp Tyr 20 25 30 Gly Met His
Trp Val Arg Gln Ala Pro Gly Lys Gly Leu Glu Trp Val 35 40 45 Ser
Ser Ile Ser Ser Ser Ser Ser Tyr Ile Tyr Tyr Ala Asp Ser Val 50 55
60 Lys Gly Arg Phe Thr Ile Ser Arg Asp Asn Ala Lys Asn Ser Leu Tyr
65 70 75 80 Leu Gln Met Asn Ser Leu Arg Ala Glu Asp Thr Ala Met Tyr
Tyr Cys 85 90 95 Ala Arg Ser Trp Asn Tyr Gly Arg Phe Phe Asp Tyr
Trp Asp Gln Gly 100 105 110 Thr Leu Val Thr Val Ser Ser 115
134108PRTArtificial SequenceR3D2-VL 134Gln Ser Val Leu Thr Gln Pro
Pro Ser Val Ser Val Ala Pro Gly Lys 1 5 10 15 Thr Ala Arg Ile Thr
Cys Gly Gly Asn Asn Ile Gly Ser Lys Ser Val 20 25 30 His Trp Tyr
Gln Gln Lys Pro Gly Gln Ala Pro Val Leu Val Ile Tyr 35 40 45 Tyr
Asp Ser Asp Arg Pro Ser Gly Ile Pro Glu Arg Phe Ser Gly Ser 50 55
60 Asn Ser Gly Asn Thr Ala Thr Leu Thr Ile Ser Arg Val Glu Ala Gly
65 70 75 80 Asp Glu Ala Asp Tyr Tyr Cys Gln Val Trp Asp Ser Ser Ser
Asp His 85 90 95 Tyr Val Phe Gly Thr Gly Thr Lys Leu Thr Val Leu
100 105 135119PRTArtificial SequenceR5B8-VH 135Glu Val Gln Leu Val
Glu Ser Gly Gly Gly Leu Val Gln Pro Gly Gly 1 5 10 15 Ser Leu Arg
Leu Ser Cys Ala Ala Ser Gly Phe Thr Ser Ser Arg Asn 20
25 30 Trp Met His Trp Val Arg Leu Ala Pro Gly Lys Gly Leu Val Trp
Val 35 40 45 Ser Leu Ile Ala Pro Asp Gly Ser Leu Thr Thr Tyr Ala
Asp Ser Val 50 55 60 Lys Gly Arg Phe Thr Ile Ser Arg Asp Thr Ala
Lys Asn Ser Val Gln 65 70 75 80 Leu Leu Leu Asn Ser Leu Arg Ala Glu
Asp Thr Gly Leu Tyr Phe Cys 85 90 95 Ala Arg Glu Ala Gly Val Ser
Gly Gly Leu Asp Val Trp Gly Gln Gly 100 105 110 Thr Leu Val Thr Val
Ser Ser 115 136107PRTArtificial SequenceR5B8-VL 136Val Ile Trp Met
Thr Gln Ser Pro Ser Ser Leu Ser Ala Ser Val Gly 1 5 10 15 Asp Arg
Val Thr Ile Thr Cys Arg Ala Ser Gln Thr Ile Ser Ser Tyr 20 25 30
Leu Asn Trp Tyr Gln Gln Lys Pro Gly Lys Ala Pro Lys Leu Leu Ile 35
40 45 Tyr Ala Ala Ser Ser Leu Gln Ser Gly Val Pro Ser Arg Phe Ser
Gly 50 55 60 Ser Gly Ser Gly Thr Asp Phe Thr Leu Thr Ile Ser Ser
Leu Gln Pro 65 70 75 80 Glu Asp Phe Ala Thr Tyr Tyr Cys Gln Gln Ala
Asn Ser Phe Pro Leu 85 90 95 Thr Phe Gly Gly Gly Thr Lys Val Glu
Ile Lys 100 105 137123PRTArtificial SequenceSH1A1Q-VH 137Glu Val
Gln Leu Val Gln Ser Gly Ala Glu Val Lys Lys Pro Gly Ser 1 5 10 15
Ser Val Lys Val Ser Cys Lys Ala Ser Gly Gly Thr Phe Ser Ser Tyr 20
25 30 Ala Ile Ser Trp Val Arg Gln Ala Pro Gly Gln Gly Leu Glu Trp
Met 35 40 45 Gly Gly Ile Ile Pro Ile Phe Gly Thr Ala Asn Tyr Ala
Gln Lys Phe 50 55 60 Gln Gly Arg Val Thr Ile Thr Ala Asp Lys Ser
Thr Ser Thr Ala Tyr 65 70 75 80 Met Glu Leu Ser Ser Leu Arg Ser Glu
Asp Thr Ala Val Tyr Tyr Cys 85 90 95 Ala Arg Glu Gly Thr Ile Tyr
Asp Ser Ser Gly Tyr Ser Phe Asp Tyr 100 105 110 Trp Gly Gln Gly Thr
Leu Val Thr Val Ser Ser 115 120 138110PRTArtificial
SequenceSH1A1Q-VL 138Gln Ser Val Leu Thr Gln Pro Pro Ser Val Ser
Ala Ala Pro Gly Gln 1 5 10 15 Lys Val Thr Ile Ser Cys Ser Gly Asn
Asn Ser Asn Ile Ala Asn Asn 20 25 30 Tyr Val Ser Trp Tyr Gln Gln
Leu Pro Gly Thr Ala Pro Lys Leu Leu 35 40 45 Ile Tyr Asp Asn Asn
Tyr Arg Pro Ser Gly Ile Pro Asp Arg Phe Ser 50 55 60 Gly Ser Lys
Ser Gly Thr Ser Ala Thr Leu Asp Ile Thr Gly Leu Gln 65 70 75 80 Thr
Gly Asp Glu Ala Asp Tyr Tyr Cys Gly Val Trp Asp Gly Ser Leu 85 90
95 Thr Thr Gly Val Phe Gly Gly Gly Thr Lys Leu Thr Val Leu 100 105
110 139124PRTArtificial SequenceSH1B7B(K)-VH 139Glu Val Gln Leu Val
Gln Ser Gly Ala Glu Val Lys Lys Pro Gly Ser 1 5 10 15 Ser Val Lys
Val Ser Cys Lys Ala Ser Gly Gly Thr Phe Ser Ser Tyr 20 25 30 Ala
Ile Ser Trp Val Arg Gln Ala Pro Gly Gln Gly Leu Glu Trp Met 35 40
45 Gly Ile Ile Asn Pro Ser Gly Gly Ser Thr Ser Tyr Ala Gln Lys Phe
50 55 60 Gln Gly Arg Val Ser Met Thr Arg Asp Thr Ser Thr Ser Thr
Val Tyr 65 70 75 80 Met Glu Leu Ser Ser Leu Thr Ser Glu Asp Thr Ala
Val Tyr Tyr Cys 85 90 95 Ala Arg Asp Leu Phe Pro His Ile Tyr Gly
Asn Tyr Tyr Gly Met Asp 100 105 110 Ile Trp Gly Gln Gly Thr Thr Val
Thr Val Ser Ser 115 120 140107PRTArtificial SequenceSH1B7B(K)-VL
140Ala Ile Gln Met Thr Gln Ser Pro Ser Ser Leu Ser Ala Ser Val Gly
1 5 10 15 Asp Arg Val Thr Ile Thr Cys Arg Ala Ser Gln Gly Ile Ser
Asn Tyr 20 25 30 Leu Ala Trp Tyr Gln Gln Lys Pro Gly Lys Val Pro
Lys Leu Leu Ile 35 40 45 Tyr Ala Ala Ser Thr Leu Glu Ser Gly Val
Pro Ser Arg Phe Ser Gly 50 55 60 Ser Gly Ser Gly Thr Asp Phe Thr
Leu Thr Ile Ser Ser Leu Gln Pro 65 70 75 80 Glu Asp Leu Ala Thr Tyr
Tyr Cys Gln Gln Leu His Thr Phe Pro Leu 85 90 95 Thr Phe Gly Gly
Gly Thr Lys Val Glu Ile Lys 100 105 141118PRTArtificial
SequenceSH1C1-VH 141Gln Val Gln Leu Val Gln Ser Gly Ala Glu Val Lys
Lys Pro Gly Ser 1 5 10 15 Ser Val Lys Val Ser Cys Lys Ala Ser Gly
Gly Thr Phe Ser Ser Tyr 20 25 30 Ala Ile Ser Trp Val Arg Gln Ala
Pro Gly Gln Gly Leu Glu Trp Met 35 40 45 Gly Gly Ile Ile Pro Ile
Phe Gly Thr Ala Asn Tyr Ala Gln Lys Phe 50 55 60 Gln Gly Arg Val
Thr Ile Thr Ala Asp Lys Ser Thr Ser Thr Ala Tyr 65 70 75 80 Met Glu
Leu Ser Ser Leu Arg Ser Glu Asp Thr Ala Val Tyr Tyr Cys 85 90 95
Ala Arg Leu Ala Val Pro Gly Ala Phe Asp Ile Trp Gly Gln Gly Thr 100
105 110 Met Val Thr Val Ser Ser 115 142111PRTArtificial
SequenceSH1C1-VL 142Gln Pro Val Leu Thr Gln Pro Pro Ser Ala Ser Gly
Ser Pro Gly Gln 1 5 10 15 Ser Val Thr Ile Ser Cys Thr Gly Thr Ser
Ser Asp Val Gly Ala Tyr 20 25 30 Asn Phe Val Ser Trp Tyr Arg Gln
His Pro Gly Lys Ala Pro Lys Leu 35 40 45 Met Ile Tyr Glu Val Asn
Lys Arg Pro Ser Gly Val Pro Asp Arg Phe 50 55 60 Ser Gly Ser Lys
Ser Gly Asn Thr Ala Ser Leu Thr Val Ser Gly Leu 65 70 75 80 Gln Ala
Glu Asp Glu Ala Asp Tyr Tyr Cys Ser Ser Tyr Ala Gly Thr 85 90 95
Asn Ser Leu Gly Ile Phe Gly Thr Gly Thr Lys Leu Thr Val Leu 100 105
110 143119PRTArtificial SequenceSH1C8-VH 143Glu Val Gln Leu Val Glu
Ser Gly Gly Gly Val Val Gln Pro Gly Arg 1 5 10 15 Ser Leu Arg Leu
Ser Cys Ala Ala Ser Gly Phe Thr Phe Ser Ser Tyr 20 25 30 Ala Met
His Trp Val Arg Gln Ala Pro Gly Lys Gly Leu Glu Trp Val 35 40 45
Ala Val Ile Ser Tyr Asp Gly Ser Asn Lys Tyr Tyr Ala Asp Ser Val 50
55 60 Lys Gly Arg Phe Thr Ile Ser Arg Asp Asn Ser Lys Asn Thr Leu
Tyr 65 70 75 80 Leu Gln Met Asn Ser Leu Arg Ala Glu Asp Thr Ala Val
Tyr Tyr Cys 85 90 95 Ala Arg Gly Gln Trp Leu Val Thr Glu Leu Asp
Tyr Trp Gly Gln Gly 100 105 110 Thr Leu Val Thr Val Ser Ser 115
144111PRTArtificial SequenceSH1C8-VL 144Gln Ser Val Val Thr Gln Pro
Pro Ser Val Ser Ala Ala Pro Gly Gln 1 5 10 15 Lys Val Thr Ile Ser
Cys Ser Gly Ser Ser Ser Asp Ile Gly Asn His 20 25 30 Tyr Val Ser
Trp Tyr Gln Gln Leu Pro Gly Thr Ala Pro Lys Leu Leu 35 40 45 Ile
Tyr Asp Asn Asn Gln Arg Pro Ser Gly Ile Pro Asp Arg Phe Ser 50 55
60 Gly Ser Lys Ser Gly Thr Ser Ala Thr Leu Ala Ile Thr Gly Leu Gln
65 70 75 80 Thr Gly Asp Glu Ala Asp Tyr Tyr Cys Gly Thr Trp Asp Asn
Ser Leu 85 90 95 Ser Pro His Leu Leu Phe Gly Gly Gly Thr Lys Leu
Thr Val Leu 100 105 110 145122PRTArtificial SequenceSH1E10-VH
145Glu Val Gln Leu Val Glu Ser Gly Ser Glu Val Glu Lys Pro Gly Ser
1 5 10 15 Ser Val Lys Val Ser Cys Lys Ala Ser Gly Gly Thr Phe Ser
Asp Ser 20 25 30 Gly Ile Ser Trp Val Arg Gln Ala Pro Gly Gln Gly
Leu Glu Trp Met 35 40 45 Gly Gly Ile Ile Pro Met Phe Ala Thr Pro
Tyr Tyr Ala Gln Lys Phe 50 55 60 Gln Asp Arg Val Thr Ile Thr Ala
Asp Glu Ser Thr Ser Thr Val Tyr 65 70 75 80 Met Glu Leu Ser Gly Leu
Arg Ser Asp Asp Thr Ala Val Phe Tyr Cys 85 90 95 Ala Arg Asp Arg
Gly Arg Gly His Leu Pro Trp Tyr Phe Asp Leu Trp 100 105 110 Gly Arg
Gly Thr Leu Val Thr Val Ser Ser 115 120 146110PRTArtificial
SequenceSH1E10-VL 146Gln Ser Val Leu Thr Gln Pro Pro Ser Val Ser
Ala Ala Pro Gly Gln 1 5 10 15 Lys Val Thr Ile Ser Cys Ser Gly Ser
Ser Ser Asn Met Gly Asn Asn 20 25 30 Tyr Val Ser Trp Tyr Lys Gln
Val Pro Gly Thr Ala Pro Lys Leu Leu 35 40 45 Ile Tyr Glu Asn Asp
Lys Arg Pro Ser Gly Ile Pro Asp Arg Phe Ser 50 55 60 Gly Ser Lys
Ser Gly Thr Ser Ala Thr Leu Gly Ile Thr Gly Leu Gln 65 70 75 80 Thr
Gly Asp Glu Ala Asp Tyr Tyr Cys Gly Thr Trp Asp Asn Ser Leu 85 90
95 Ser Gly Phe Val Phe Ala Ser Gly Thr Lys Val Thr Val Leu 100 105
110 147119PRTArtificial SequenceSH1E2-VH 147Glu Val Gln Leu Val Glu
Ser Gly Ala Glu Val Lys Lys Pro Gly Ser 1 5 10 15 Ser Val Lys Val
Ser Cys Lys Ala Ser Gly Gly Thr Phe Ser Ser Tyr 20 25 30 Ala Ile
Ser Trp Val Arg Gln Ala Pro Gly Gln Gly Leu Glu Trp Met 35 40 45
Gly Gly Ile Ile Pro Ile Phe Gly Thr Ala Asn Tyr Ala Gln Lys Phe 50
55 60 Gln Gly Arg Val Thr Ile Thr Ala Asp Glu Ser Thr Ser Thr Ala
Tyr 65 70 75 80 Met Glu Leu Ser Ser Leu Arg Ser Glu Asp Thr Ala Val
Tyr Tyr Cys 85 90 95 Ala Arg Ala Pro Tyr Tyr Tyr Tyr Tyr Met Asp
Val Trp Gly Gln Gly 100 105 110 Thr Thr Val Thr Val Ser Ser 115
148109PRTArtificial SequenceSH1E2-VL 148Gln Ser Ala Leu Thr Gln Pro
Ala Ser Val Ser Gly Ser Leu Gly Gln 1 5 10 15 Ser Val Thr Ile Ser
Cys Thr Gly Ser Ser Ser Asp Val Gly Ser Tyr 20 25 30 Asn Leu Val
Ser Trp Tyr Gln Gln His Pro Gly Lys Ala Pro Asn Leu 35 40 45 Met
Ile Tyr Asp Val Ser Lys Arg Ser Gly Val Ser Asn Arg Phe Ser 50 55
60 Gly Ser Lys Ser Gly Asn Thr Ala Ser Leu Thr Ile Ser Gly Leu Gln
65 70 75 80 Ala Glu Asp Glu Ala Asp Tyr Tyr Cys Ser Ser Tyr Thr Gly
Ile Ser 85 90 95 Thr Val Val Phe Gly Gly Gly Thr Lys Leu Thr Val
Leu 100 105 149124PRTArtificial SequenceSH1A9-VH 149Glu Val Gln Leu
Leu Glu Ser Gly Ala Glu Val Lys Lys Pro Gly Ser 1 5 10 15 Ser Val
Lys Val Ser Cys Lys Ala Ser Gly Gly Thr Leu Ser Arg Tyr 20 25 30
Ala Leu Ser Trp Val Arg Gln Ala Pro Gly Gln Gly Pro Glu Trp Val 35
40 45 Gly Ala Ile Ile Pro Ile Phe Gly Thr Pro His Tyr Ser Lys Lys
Phe 50 55 60 Gln Asp Arg Val Ile Ile Thr Val Asp Thr Ser Thr Asn
Thr Ala Phe 65 70 75 80 Met Glu Leu Ser Ser Leu Arg Phe Glu Asp Thr
Ala Leu Tyr Phe Cys 85 90 95 Ala Arg Gly His Asp Glu Tyr Asp Ile
Ser Gly Tyr His Arg Leu Asp 100 105 110 Tyr Trp Gly Gln Gly Thr Leu
Val Thr Val Ser Ser 115 120 150110PRTArtificial SequenceSH1A9-VL
150Gln Ser Val Leu Thr Gln Pro Ala Ser Val Ser Gly Ser Pro Gly Gln
1 5 10 15 Ser Ile Thr Ile Ser Cys Thr Gly Thr Ser Ser Asp Val Gly
Ser Tyr 20 25 30 Asn Leu Val Ser Trp Tyr Gln Gln His Pro Gly Lys
Ala Pro Lys Leu 35 40 45 Met Ile Tyr Glu Val Ser Lys Arg Pro Ser
Gly Val Ser Asn Arg Phe 50 55 60 Ser Gly Ser Lys Ser Gly Asn Thr
Ala Ser Leu Thr Ile Ser Gly Leu 65 70 75 80 Gln Ala Glu Asp Glu Ala
Asp Tyr Tyr Cys Ser Ser Tyr Gly Gly Phe 85 90 95 Asn Asn Leu Leu
Phe Gly Gly Gly Thr Lys Leu Thr Val Leu 100 105 110
151121PRTArtificial SequenceSH1B11-VH 151Gln Val Gln Leu Val Gln
Ser Gly Ser Glu Leu Lys Lys Pro Gly Ser 1 5 10 15 Ser Val Lys Val
Ser Cys Lys Ala Ser Gly Tyr Ser Phe Ser Gly Tyr 20 25 30 Tyr Ile
His Trp Val Arg Gln Ala Pro Gly Gln Gly Leu Glu Trp Met 35 40 45
Gly Trp Ile Asp Pro Asn Ser Gly Val Thr Asn Tyr Val Arg Arg Phe 50
55 60 Gln Gly Arg Val Thr Met Thr Arg Asp Thr Ser Leu Ser Thr Ala
Tyr 65 70 75 80 Met Glu Leu Ser Gly Leu Thr Ala Asp Asp Thr Ala Val
Tyr Tyr Cys 85 90 95 Ala Arg Asp Glu Asn Leu Trp Gln Phe Gly Tyr
Leu Asp Tyr Trp Gly 100 105 110 Gln Gly Thr Leu Val Thr Val Ser Ser
115 120 152107PRTArtificial SequenceSH1B11-VL 152Asp Ile Val Met
Thr Gln Ser Pro Ser Ser Leu Ser Ala Ser Ile Gly 1 5 10 15 Asp Arg
Val Thr Ile Thr Cys Arg Ala Ser Gln Arg Ile Ser Ala Tyr 20 25 30
Val Asn Trp Tyr Gln Gln Lys Pro Gly Lys Ala Pro Lys Val Leu Ile 35
40 45 Tyr Ala Ala Ser Ser Leu Arg Ser Gly Val Pro Ser Arg Phe Ser
Gly 50 55 60 Ser Gly Ser Gly Thr Asp Phe Thr Leu Thr Ile Ser Ser
Leu Gln Pro 65 70 75 80 Glu Asp Phe Ala Thr Tyr Tyr Cys Gln Gln Thr
Tyr Ser Ser Pro Trp 85 90 95 Thr Phe Gly Gln Gly Thr Lys Val Glu
Ile Lys 100 105 153120PRTArtificial SequenceSH1E4-VH 153Gln Val Gln
Leu Val Gln Ser Gly Ala Glu Val Lys Lys Pro Gly Ser 1 5 10 15 Ser
Val Lys Val Ser Cys Lys Ala Ser Gly Gly Thr Phe Ser Arg Tyr 20 25
30 Gly Val His Trp Val Arg Gln Ala Pro Gly Gln Gly Leu Glu Trp Met
35 40 45 Gly Arg Leu Ile Pro Ile Val Ser Met Thr Asn Tyr Ala Gln
Lys Phe 50 55 60 Gln Asp Arg Val Ser Ile Thr Thr Asp Lys Ser Thr
Gly Thr Ala Tyr 65 70 75 80 Met Glu Leu Arg Ser Leu Thr Ser Glu Asp
Thr Ala Leu Tyr Tyr Cys 85 90 95 Ala Ser Val Gly Gln Gln Leu Pro
Trp Val Phe Phe Ala Trp Gly Gln 100 105 110 Gly Thr Leu Val Thr Val
Ser Ser 115 120 154112PRTArtificial SequenceSH1E4-VL 154Gln Ser Val
Leu Thr Gln Pro Pro Ser Ala Ser Gly Ser Pro Gly Gln 1 5 10 15 Ser
Val Thr Ile Ser Cys Thr Gly Thr Ser Ser Asp Ile Gly Gly Tyr 20
25 30 Asp Ser Val Ser Trp Tyr Gln Gln His Pro Gly Lys Ala Pro Lys
Leu 35 40 45 Met Ile Tyr Asp Val Ser Lys Arg Pro Ser Gly Val Ser
Asn Arg Phe 50 55 60 Ser Gly Ser Lys Ser Gly Asn Thr Ala Ser Leu
Thr Ile Ser Gly Leu 65 70 75 80 Gln Ala Glu Asp Glu Ala Asp Tyr Tyr
Cys Ser Ser Tyr Thr Ser Ser 85 90 95 Ser Ile Phe Phe Tyr Val Phe
Gly Thr Gly Thr Lys Val Thr Val Leu 100 105 110 155118PRTArtificial
SequenceSH1B3-VH 155Gln Val Gln Leu Val Glu Ser Gly Gly Gly Val Val
Gln Pro Gly Arg 1 5 10 15 Ser Leu Arg Leu Ser Cys Ala Ala Ser Gly
Phe Thr Phe Ser Ser Tyr 20 25 30 Ala Met His Trp Val Arg Gln Ala
Pro Gly Lys Gly Leu Glu Trp Val 35 40 45 Ala Val Ile Ser Phe Asp
Gly Ser Asn Lys Tyr Tyr Ala Asp Ser Val 50 55 60 Arg Gly Arg Phe
Thr Ile Ser Arg Asp Asn Ser Lys Asn Thr Leu Tyr 65 70 75 80 Leu Gln
Met Asn Ser Leu Arg Thr Glu Asp Thr Ala Val Tyr Tyr Cys 85 90 95
Ala Arg Gly Trp Leu Asp Arg Asp Ile Asp Tyr Trp Gly Gln Gly Thr 100
105 110 Leu Val Thr Val Ser Ser 115 156110PRTArtificial
SequenceSH1B3-VL 156Leu Pro Val Leu Thr Gln Pro Ala Ser Val Ser Gly
Ser Pro Gly Gln 1 5 10 15 Ser Ile Thr Ile Ser Cys Thr Gly Thr Thr
Ser Asp Ile Gly Gly Tyr 20 25 30 Asp Tyr Val Ser Trp Tyr Gln Gln
His Pro Gly Lys Ala Pro Lys Leu 35 40 45 Met Ile Tyr Asp Val Ser
Lys Arg Pro Ser Gly Val Ser Asn Arg Phe 50 55 60 Ser Gly Ser Lys
Ser Gly Asn Thr Ala Ser Leu Thr Ile Ser Gly Leu 65 70 75 80 Gln Ala
Glu Asp Glu Ala Asp Tyr Tyr Cys Ser Ser Tyr Thr Ser Ser 85 90 95
Ser Thr His Val Phe Gly Thr Gly Thr Lys Leu Thr Val Leu 100 105 110
157118PRTArtificial SequenceSH1D1-VH 157Glu Val Gln Leu Val Glu Ser
Gly Gly Gly Val Val Gln Pro Gly Arg 1 5 10 15 Ser Leu Arg Leu Ser
Cys Ala Ala Ser Gly Phe Thr Phe Ser Ser Tyr 20 25 30 Ala Met His
Trp Val Arg Gln Ala Pro Gly Lys Gly Leu Glu Trp Val 35 40 45 Ala
Val Ile Ser Phe Asp Gly Ser Asn Lys Tyr Tyr Ala Asp Ser Val 50 55
60 Arg Gly Arg Phe Thr Ile Ser Arg Asp Asn Ser Lys Asn Thr Leu Tyr
65 70 75 80 Leu Gln Met Asn Ser Leu Arg Thr Glu Asp Thr Ala Val Tyr
Tyr Cys 85 90 95 Ala Arg Gly Trp Leu Asp Arg Asp Ile Asp Tyr Trp
Gly Gln Gly Thr 100 105 110 Leu Val Thr Val Ser Ser 115
158111PRTArtificial SequenceSH1D1-VL 158Gln Ser Ala Leu Thr Gln Pro
Ala Ser Val Ser Gly Ser Pro Gly Gln 1 5 10 15 Ser Ile Thr Ile Ser
Cys Thr Gly Thr Ser Ser Asp Val Gly Gly Tyr 20 25 30 Asn Tyr Val
Ser Trp Tyr Gln Gln His Pro Gly Lys Ala Pro Lys Leu 35 40 45 Met
Ile Tyr Asp Val Ser Asn Arg Pro Ser Gly Val Ser Asn Arg Phe 50 55
60 Ser Gly Ser Lys Ser Gly Asn Thr Ala Ser Leu Thr Ile Ser Gly Leu
65 70 75 80 Gln Ala Glu Asp Glu Ala Asp Tyr Tyr Cys Ser Ser Tyr Arg
Ser Ser 85 90 95 Thr Leu Gly Pro Val Phe Gly Gly Gly Thr Lys Leu
Thr Val Leu 100 105 110 159118PRTArtificial SequenceSH1D2-VH 159Gln
Val Gln Leu Val Glu Ser Gly Gly Gly Val Val Gln Pro Gly Arg 1 5 10
15 Ser Leu Arg Leu Ser Cys Ala Ala Ser Gly Phe Thr Phe Ser Ser Tyr
20 25 30 Ala Met His Trp Val Arg Gln Ala Pro Gly Lys Gly Leu Glu
Trp Val 35 40 45 Ala Val Ile Ser Phe Asp Gly Ser Asn Lys Tyr Tyr
Ala Asp Ser Val 50 55 60 Arg Gly Arg Phe Thr Ile Ser Arg Asp Asn
Ser Lys Asn Thr Leu Tyr 65 70 75 80 Leu Gln Met Asn Ser Leu Arg Thr
Glu Asp Thr Ala Val Tyr Tyr Cys 85 90 95 Ala Arg Gly Trp Leu Asp
Arg Asp Ile Asp Tyr Trp Gly Gln Gly Thr 100 105 110 Leu Val Thr Val
Ser Ser 115 160110PRTArtificial SequenceSH1D2-VL 160Gln Ala Gly Leu
Thr Gln Pro Pro Ser Val Ser Glu Ala Pro Arg Gln 1 5 10 15 Arg Val
Thr Ile Ser Cys Ser Gly Ser Ser Ser Asn Ile Gly Asn Asn 20 25 30
Ala Val Asn Trp Tyr Gln Gln Leu Pro Gly Lys Ala Pro Lys Leu Leu 35
40 45 Ile Tyr Tyr Asp Asp Leu Leu Pro Ser Gly Val Ser Asp Arg Phe
Ser 50 55 60 Gly Ser Lys Ser Gly Thr Ser Ala Ser Leu Ala Ile Ser
Gly Leu Gln 65 70 75 80 Ser Glu Asp Glu Ala Asp Tyr Tyr Cys Ala Ala
Trp Asp Asp Ser Leu 85 90 95 Asn Gly Tyr Val Phe Gly Thr Gly Thr
Lys Leu Thr Val Leu 100 105 110 161118PRTArtificial
SequenceSH1D12-VH 161Glu Val Gln Leu Val Glu Ser Gly Gly Gly Val
Val Gln Pro Gly Arg 1 5 10 15 Ser Leu Arg Leu Ser Cys Ala Ala Ser
Gly Phe Thr Phe Ser Ser Tyr 20 25 30 Ala Met His Trp Val Arg Gln
Ala Pro Gly Lys Gly Leu Glu Trp Val 35 40 45 Ala Val Ile Ser Phe
Asp Gly Ser Asn Lys Tyr Tyr Ala Asp Ser Val 50 55 60 Arg Gly Arg
Phe Thr Ile Ser Arg Asp Asn Ser Lys Asn Thr Leu Tyr 65 70 75 80 Leu
Gln Met Asn Ser Leu Arg Thr Glu Asp Thr Ala Val Tyr Tyr Cys 85 90
95 Ala Arg Gly Trp Leu Asp Arg Asp Ile Asp Tyr Trp Gly Gln Gly Thr
100 105 110 Leu Val Thr Val Ser Ser 115 162110PRTArtificial
SequenceSH1D12-VL 162Gln Ser Ala Leu Thr Gln Pro Arg Ser Val Ser
Gly Ser Pro Gly Gln 1 5 10 15 Ser Val Thr Ile Ser Cys Thr Gly Thr
Ser Ser Asp Val Gly Gly Tyr 20 25 30 Asn Tyr Val Ser Trp Tyr Gln
Gln His Pro Gly Lys Ala Pro Lys Leu 35 40 45 Met Ile Tyr Asp Val
Ser Lys Arg Pro Ser Gly Val Pro Asp Arg Phe 50 55 60 Ser Gly Ser
Lys Ser Gly Asn Thr Ala Ser Leu Thr Ile Ser Gly Leu 65 70 75 80 Gln
Ala Glu Asp Glu Ala Asp Tyr Tyr Cys Ser Ser Tyr Thr Ser Ser 85 90
95 Thr Thr His Val Phe Gly Thr Gly Thr Lys Val Thr Val Leu 100 105
110 163118PRTArtificial SequenceSH1E1-VH 163Glu Val Gln Leu Val Glu
Ser Gly Gly Gly Val Val Gln Pro Gly Arg 1 5 10 15 Ser Leu Arg Leu
Ser Cys Ala Ala Ser Gly Phe Thr Phe Ser Ser Tyr 20 25 30 Ala Met
His Trp Val Arg Gln Ala Pro Gly Lys Gly Leu Glu Trp Val 35 40 45
Ala Val Ile Ser Phe Asp Gly Ser Asn Lys Tyr Tyr Ala Asp Ser Val 50
55 60 Arg Gly Arg Phe Thr Ile Ser Arg Asp Asn Ser Lys Asn Thr Leu
Tyr 65 70 75 80 Leu Gln Met Asn Ser Leu Arg Thr Glu Asp Thr Ala Val
Tyr Tyr Cys 85 90 95 Ala Arg Gly Trp Leu Asp Arg Asp Ile Asp Tyr
Trp Gly Gln Gly Thr 100 105 110 Leu Val Thr Val Ser Ser 115
164110PRTArtificial SequenceSH1E1-VL 164Gln Ser Val Val Thr Gln Pro
Pro Ser Val Ser Ala Ala Pro Gly Gln 1 5 10 15 Lys Val Thr Ile Ser
Cys Ser Gly Ser Ser Ser Asn Ile Gly Asn Asn 20 25 30 Tyr Val Ser
Trp Tyr Gln Gln Leu Pro Gly Thr Ala Pro Lys Leu Leu 35 40 45 Ile
Tyr Asp Asn Asn Lys Arg Pro Ser Gly Ile Pro Asp Arg Phe Ser 50 55
60 Gly Ser Lys Ser Gly Thr Ser Ala Thr Leu Gly Ile Thr Gly Leu Gln
65 70 75 80 Thr Gly Asp Glu Ala Asp Tyr Tyr Cys Gly Thr Trp Asp Ser
Ser Leu 85 90 95 Ser Val Trp Val Phe Gly Gly Gly Thr Gln Leu Thr
Val Leu 100 105 110 165118PRTArtificial SequenceSH1G9-VH 165Gln Val
Gln Leu Val Glu Ser Gly Gly Gly Val Val Gln Pro Gly Arg 1 5 10 15
Ser Leu Arg Leu Ser Cys Ala Ala Ser Gly Phe Thr Phe Ser Ser Tyr 20
25 30 Ala Met His Trp Val Arg Gln Ala Pro Gly Lys Gly Leu Glu Trp
Val 35 40 45 Ala Val Ile Ser Phe Asp Gly Ser Asn Lys Tyr Tyr Ala
Asp Ser Val 50 55 60 Arg Gly Arg Phe Thr Ile Ser Arg Asp Asn Ser
Lys Asn Thr Leu Tyr 65 70 75 80 Leu Gln Met Asn Ser Leu Arg Thr Glu
Asp Thr Ala Val Tyr Tyr Cys 85 90 95 Ala Arg Gly Trp Leu Asp Arg
Asp Ile Asp Tyr Trp Gly Gln Gly Thr 100 105 110 Leu Val Thr Val Ser
Ser 115 166112PRTArtificial SequenceSH1G9-VL 166Gln Ser Val Leu Thr
Gln Pro Ala Ser Val Ser Gly Ser Pro Gly Gln 1 5 10 15 Ser Ile Thr
Ile Ser Cys Thr Gly Thr Ser Ser Asp Val Gly Gly Tyr 20 25 30 Asn
Tyr Val Ser Trp Tyr Gln Gln His Pro Gly Arg Ala Pro Arg Leu 35 40
45 Met Ile Tyr Asp Val Ser Asn Arg Pro Ser Gly Val Ser Asn Arg Phe
50 55 60 Ser Gly Ser Lys Ser Gly Asn Thr Ala Ser Leu Thr Ile Ser
Gly Leu 65 70 75 80 Gln Ala Glu Asp Glu Gly Asp Tyr Tyr Cys Ser Ser
Tyr Thr Ser Gly 85 90 95 Gly Thr Leu Gly Pro Val Phe Gly Gly Gly
Thr Lys Leu Thr Val Leu 100 105 110 167121PRTArtificial
SequenceSH1A11-VH 167Glu Val Gln Leu Val Gln Ser Gly Gly Gly Leu
Val Gln Pro Gly Gly 1 5 10 15 Ser Leu Arg Leu Ser Cys Ala Ala Ser
Gly Phe Thr Phe Ser Asp Tyr 20 25 30 Gly Met His Trp Val Arg Gln
Pro Pro Gly Lys Gly Leu Glu Trp Leu 35 40 45 Ala Val Ile Ser Tyr
Asp Gly Ser Tyr Lys Ile His Ala Asp Ser Val 50 55 60 Gln Gly Arg
Phe Thr Ile Ser Arg Asp Asn Ala Lys Asn Ser Val Phe 65 70 75 80 Leu
Gln Met Asn Ser Leu Lys Thr Glu Asp Thr Ala Val Tyr Tyr Cys 85 90
95 Thr Thr Asp Arg Lys Trp Leu Ala Trp His Gly Met Asp Val Trp Gly
100 105 110 Gln Gly Thr Thr Val Thr Val Ser Ser 115 120
168110PRTArtificial SequenceSH1A11-VL 168Gln Ala Gly Leu Thr Gln
Pro Pro Ser Ala Ser Gly Thr Pro Gly Gln 1 5 10 15 Arg Val Thr Ile
Ser Cys Ser Gly Ser Ser Ser Asn Ile Gly Ser Asn 20 25 30 Thr Val
Asn Trp Tyr Gln Gln Leu Pro Gly Thr Ala Pro Lys Leu Leu 35 40 45
Ile Tyr Ser Asn Asn Gln Arg Pro Ser Gly Val Pro Asp Arg Phe Ser 50
55 60 Gly Ser Lys Ser Gly Thr Ser Ala Ser Leu Ala Ile Ser Gly Leu
Gln 65 70 75 80 Ser Glu Asp Glu Ala Asp Tyr Tyr Cys Ala Ala Trp Asp
Asp Ser Leu 85 90 95 Asn Gly Trp Val Phe Gly Gly Gly Thr Lys Leu
Thr Val Leu 100 105 110 169118PRTArtificial SequenceSH1C2-VH 169Glu
Val Gln Leu Val Gln Ser Gly Ala Glu Val Lys Lys Pro Gly Ser 1 5 10
15 Ser Val Lys Val Ser Cys Lys Ala Ser Gly Gly Thr Phe Ser Ser Tyr
20 25 30 Ala Ile Ser Trp Val Arg Gln Ala Pro Gly Gln Gly Leu Glu
Trp Met 35 40 45 Gly Gly Ile Ile Pro Ile Phe Gly Thr Ala Asn Tyr
Ala Gln Lys Phe 50 55 60 Gln Gly Arg Val Thr Ile Thr Ala Asp Glu
Ser Thr Ser Thr Ala Tyr 65 70 75 80 Met Glu Leu Ser Ser Leu Arg Ser
Glu Asp Thr Ala Val Tyr Tyr Cys 85 90 95 Ala Arg Asp Gly Ile Val
Ala Asp Phe Gln His Trp Gly Gln Gly Thr 100 105 110 Leu Val Thr Val
Ser Ser 115 170107PRTArtificial SequenceSH1C2-VL 170Ala Ile Arg Met
Thr Gln Ser Pro Ser Ser Leu Ser Ala Ser Val Gly 1 5 10 15 Asp Arg
Val Thr Ile Thr Cys Arg Ala Ser Gln Ser Ile Ser Asn Tyr 20 25 30
Leu Asn Trp Tyr Gln Gln Arg Pro Gly Lys Ala Pro Asn Leu Leu Ile 35
40 45 Tyr Ala Ala Ser Ser Leu Gln Ser Gly Val Pro Ser Arg Phe Ser
Gly 50 55 60 Ser Gly Ser Gly Thr Asp Phe Thr Leu Thr Ile Ser Ser
Leu Gln Pro 65 70 75 80 Glu Asp Phe Ala Thr Tyr Tyr Cys Gln Gln Thr
Tyr Ser Thr Pro Tyr 85 90 95 Thr Phe Gly Gln Gly Thr Lys Leu Glu
Ile Lys 100 105 171121PRTArtificial SequenceSH1G8-VH 171Glu Val Gln
Leu Val Glu Ser Gly Ala Glu Val Lys Lys Pro Gly Ala 1 5 10 15 Ser
Val Lys Val Ser Cys Lys Ala Ser Gly Asp Thr Phe Ser Arg Tyr 20 25
30 Gly Ile Thr Trp Val Arg Gln Ala Pro Gly Arg Gly Leu Glu Trp Met
35 40 45 Gly Asn Ile Val Pro Phe Phe Gly Ala Thr Asn Tyr Ala Gln
Lys Phe 50 55 60 Gln Gly Arg Leu Thr Ile Thr Ala Asp Lys Ser Ser
Tyr Thr Ser Tyr 65 70 75 80 Met Asp Leu Ser Ser Leu Arg Ser Asp Asp
Thr Ala Val Tyr Tyr Cys 85 90 95 Ala Arg Asp His Phe Tyr Gly Ser
Gly Gly Tyr Phe Asp Tyr Trp Gly 100 105 110 Gln Gly Thr Leu Val Thr
Val Ser Ser 115 120 172111PRTArtificial SequenceSH1G8-VL 172Gln Ser
Val Leu Thr Gln Pro Ala Ser Val Ser Gly Ser Pro Gly Gln 1 5 10 15
Ser Ile Thr Ile Ser Cys Thr Gly Thr Ser Ser Asp Val Gly Gly Tyr 20
25 30 Asn Tyr Val Ser Trp Tyr Arg Gln His Pro Gly Lys Ala Pro Lys
Leu 35 40 45 Met Ile Tyr Asp Val Ser Tyr Arg Pro Ser Gly Val Ser
Asn Arg Phe 50 55 60 Ser Gly Ser Lys Ser Gly Asn Thr Ala Ser Leu
Thr Ile Ser Gly Leu 65 70 75 80 Gln Ala Glu Asp Glu Ala Asp Tyr Tyr
Cys Ser Ser Tyr Thr Asp Ser 85 90 95 Ser Thr Arg Tyr Val Phe Gly
Thr Gly Thr Lys Leu Thr Val Leu 100 105 110 173121PRTArtificial
SequenceSH1H2-VH 173Glu Val Gln Leu Leu Glu Ser Gly Ala Glu Val Lys
Lys Pro Gly Ala 1 5 10 15 Ser Val Lys Val Ser Cys Lys Ala Ser Gly
Tyr Thr Phe Asn Ser Tyr 20 25 30 Asp Ile Asn Trp Val Arg Gln Ala
Pro Gly Gln Gly Leu Glu Trp Met 35 40 45 Gly Gly Ile Ile
Pro Val Phe Gly Thr Ala Asn Tyr Ala Glu Ser Phe 50 55 60 Gln Gly
Arg Val Thr Met Thr Ala Asp His Ser Thr Ser Thr Ala Tyr 65 70 75 80
Met Glu Leu Asn Asn Leu Arg Ser Glu Asp Thr Ala Val Tyr Tyr Cys 85
90 95 Ala Arg Asp Arg Trp His Tyr Glu Ser Arg Pro Met Asp Val Trp
Gly 100 105 110 Gln Gly Thr Thr Val Thr Val Ser Ser 115 120
174110PRTArtificial SequenceSH1H2-VL 174Gln Pro Val Leu Thr Gln Pro
Pro Ser Ala Ser Gly Thr Pro Gly Gln 1 5 10 15 Arg Val Ala Ile Ser
Cys Ser Gly Ser Arg Ser Asn Ile Glu Ile Asn 20 25 30 Ser Val Asn
Trp Tyr Gln Gln Leu Pro Gly Thr Ala Pro Lys Leu Leu 35 40 45 Ile
Tyr Asp Asn Asn Lys Arg Pro Ser Gly Ile Pro Asp Arg Phe Ser 50 55
60 Gly Ser Lys Ser Gly Thr Ser Ala Thr Leu Gly Ile Thr Gly Leu Gln
65 70 75 80 Thr Gly Asp Glu Ala Asp Tyr Tyr Cys Gly Ser Trp Asp Ser
Ser Leu 85 90 95 Ser Ala Asp Val Phe Gly Thr Gly Thr Lys Leu Thr
Val Leu 100 105 110 175119PRTArtificial SequenceSH1B10-VH 175Glu
Val Gln Leu Val Glu Ser Gly Gly Gly Leu Val Arg Pro Gly Gly 1 5 10
15 Ser Leu Arg Leu Ala Cys Ala Ala Ser Gly Phe Ser Phe Ser Asp Tyr
20 25 30 Tyr Met Thr Trp Ile Arg Gln Ala Pro Gly Arg Gly Leu Glu
Trp Ile 35 40 45 Ala Tyr Ile Ser Asp Ser Gly Gln Thr Val His Tyr
Ala Asp Ser Val 50 55 60 Lys Gly Arg Phe Thr Ile Ser Arg Asp Asn
Thr Lys Asn Ser Leu Phe 65 70 75 80 Leu Gln Val Asn Thr Leu Arg Ala
Glu Asp Thr Ala Val Tyr Tyr Cys 85 90 95 Ala Arg Glu Asp Leu Leu
Gly Tyr Tyr Leu Gln Ser Trp Gly Gln Gly 100 105 110 Thr Leu Val Thr
Val Ser Ser 115 176110PRTArtificial SequenceSH1B10-VL 176Gln Ser
Val Leu Thr Gln Pro Pro Ser Val Ser Ala Ala Pro Gly Lys 1 5 10 15
Lys Val Thr Ile Ser Cys Ser Gly Ser Ser Ser Asn Ile Gly Asn Asn 20
25 30 Tyr Val Ser Trp Tyr Gln Gln Leu Pro Gly Thr Ala Pro Lys Leu
Leu 35 40 45 Ile Tyr Arg Asn Asn Gln Arg Pro Ser Gly Val Pro Asp
Arg Phe Ser 50 55 60 Gly Ser Lys Ser Gly Thr Ser Ala Ser Leu Ala
Ile Ser Gly Leu Gln 65 70 75 80 Ser Glu Asp Glu Ala Asp Tyr Tyr Cys
Ala Thr Trp Asp Asp Ser Leu 85 90 95 Asn Gly Trp Val Phe Gly Gly
Gly Thr Lys Leu Thr Val Leu 100 105 110 177131PRTArtificial
SequenceSH1B7A(L)-VH 177Gln Val Gln Leu Gln Gln Ser Gly Pro Gly Leu
Val Lys Pro Ser Gln 1 5 10 15 Thr Leu Ser Leu Thr Cys Ala Ile Ser
Gly Asp Ser Val Ser Ser Asn 20 25 30 Ser Ala Ala Trp Asn Trp Ile
Arg Gln Ser Pro Ser Arg Gly Leu Glu 35 40 45 Trp Leu Gly Arg Thr
Tyr Tyr Arg Ser Lys Trp Tyr Asn Asp Tyr Ala 50 55 60 Val Ser Val
Lys Ser Arg Ile Thr Ile Asn Pro Asp Thr Ser Lys Asn 65 70 75 80 Gln
Phe Ser Leu Gln Leu Asn Ser Val Thr Pro Glu Asp Thr Ala Val 85 90
95 Tyr Tyr Cys Ala Arg Asp Glu Pro Arg Ala Val Ala Gly Ser Gln Ala
100 105 110 Tyr Tyr Tyr Tyr Gly Met Asp Val Trp Gly Gln Gly Thr Thr
Val Thr 115 120 125 Val Ser Ser 130 178111PRTArtificial
SequenceSH1B7A(L)-VL 178Gln Ser Val Val Thr Gln Pro Pro Ser Val Ser
Gly Ala Pro Gly Gln 1 5 10 15 Arg Val Thr Ile Ser Cys Thr Gly Ser
Ser Ser Asn Ile Gly Ala Gly 20 25 30 Tyr Asp Val His Trp Tyr Gln
Gln Leu Pro Gly Thr Ala Pro Lys Leu 35 40 45 Leu Ile Tyr Gly Asn
Asn Asn Arg His Ser Gly Val Pro Asp Arg Phe 50 55 60 Ser Gly Ser
Lys Ser Gly Thr Ser Ala Ser Leu Ala Ile Thr Gly Leu 65 70 75 80 Gln
Ala Glu Asp Glu Ala Glu Phe Phe Cys Gly Thr Trp Asp Ser Arg 85 90
95 Leu Thr Thr Tyr Val Phe Gly Ser Gly Thr Lys Leu Thr Val Leu 100
105 110 179120PRTArtificial SequenceSH1E6-VH 179Gln Val Gln Leu Val
Gln Ser Gly Ala Glu Val Lys Lys Pro Gly Ser 1 5 10 15 Ser Val Lys
Val Ser Cys Lys Ala Ser Gly Gly Thr Phe Ser Arg Tyr 20 25 30 Gly
Val His Trp Val Arg Gln Ala Pro Gly Gln Gly Leu Glu Trp Met 35 40
45 Gly Arg Leu Ile Pro Ile Val Ser Met Thr Asn Tyr Ala Gln Lys Phe
50 55 60 Gln Asp Arg Val Ser Ile Thr Thr Asp Lys Ser Thr Gly Thr
Ala Tyr 65 70 75 80 Met Glu Leu Arg Ser Leu Thr Ser Glu Asp Thr Ala
Leu Tyr Tyr Cys 85 90 95 Ala Ser Val Gly Gln Gln Leu Pro Trp Val
Phe Phe Ala Trp Gly Gln 100 105 110 Gly Thr Leu Val Thr Val Ser Ser
115 120 180110PRTArtificial SequenceSH1E6-VL 180Gln Ser Val Val Thr
Gln Pro Pro Ser Val Ser Ala Ala Pro Gly Gln 1 5 10 15 Lys Val Thr
Ile Ser Cys Ser Gly Ser Ser Ser Asn Ile Gly Asn Asn 20 25 30 Tyr
Val Ser Trp Tyr Gln Gln Leu Pro Gly Thr Ala Pro Lys Leu Leu 35 40
45 Ile Tyr Asp Asn Asn Lys Arg Pro Ser Gly Ile Pro Asp Arg Phe Ser
50 55 60 Gly Ser Lys Ser Gly Thr Ser Ala Thr Leu Gly Ile Thr Gly
Leu Gln 65 70 75 80 Thr Gly Asp Glu Ala Asp Tyr Tyr Cys Gly Thr Trp
Asp Ser Ser Leu 85 90 95 Ser Ala Val Val Phe Gly Gly Gly Thr Lys
Leu Thr Val Leu 100 105 110 181124PRTArtificial SequenceSH1C11-VH
181Glu Val Gln Leu Val Gln Ser Gly Ala Glu Val Lys Lys Pro Gly Ala
1 5 10 15 Ser Val Lys Val Ser Cys Lys Ala Ser Gly Tyr Thr Phe Thr
Ser Tyr 20 25 30 Tyr Met His Trp Val Arg Gln Ala Pro Gly Gln Gly
Leu Glu Trp Met 35 40 45 Gly Ile Ile Asn Pro Ser Asp Gly Ser Thr
Ser Tyr Ala Gln Lys Phe 50 55 60 Gln Gly Arg Val Thr Met Thr Arg
Asp Thr Ser Thr Ser Thr Val His 65 70 75 80 Met Glu Leu Ser Ser Leu
Arg Ser Glu Asp Thr Ala Val Tyr Tyr Cys 85 90 95 Ala Arg Asp Leu
Phe Pro His Ile Tyr Gly Asn Tyr Tyr Gly Met Asp 100 105 110 Ile Trp
Gly Gln Gly Thr Thr Val Thr Val Ser Ser 115 120 182107PRTArtificial
SequenceSH1C11-VL 182Val Ile Trp Met Thr Gln Ser Pro Ser Ser Leu
Ser Ala Ser Val Gly 1 5 10 15 Asp Arg Val Thr Ile Thr Cys Arg Ala
Ser Gln Ser Ile Ser Ser Tyr 20 25 30 Leu Asn Trp Tyr Gln Gln Lys
Pro Gly Lys Ala Pro Lys Leu Leu Ile 35 40 45 Tyr Glu Ala Ser Thr
Leu Glu Ser Gly Val Pro Ser Arg Phe Ser Gly 50 55 60 Ser Gly Ser
Gly Thr Glu Phe Thr Leu Thr Ile Ser Ser Leu Gln Pro 65 70 75 80 Glu
Asp Phe Ala Thr Tyr Tyr Cys Gln Gln Ser Tyr Ser Thr Pro Tyr 85 90
95 Thr Phe Gly Gln Gly Thr Lys Leu Glu Ile Lys 100 105
183118PRTArtificial SequenceSH1A2-VH 183Gln Met Gln Leu Val Gln Ser
Gly Gly Gly Val Val Gln Pro Gly Arg 1 5 10 15 Ser Leu Arg Leu Ser
Cys Ala Ala Ser Gly Phe Thr Phe Ser Ser Tyr 20 25 30 Ala Met His
Trp Val Arg Gln Ala Pro Gly Lys Gly Leu Glu Trp Val 35 40 45 Ala
Val Ile Ser Phe Asp Gly Ser Asn Lys Tyr Tyr Ala Asp Ser Val 50 55
60 Arg Gly Arg Phe Thr Ile Ser Arg Asp Asn Ser Lys Asn Thr Leu Tyr
65 70 75 80 Leu Gln Met Asn Ser Leu Arg Thr Glu Asp Thr Ala Val Tyr
Tyr Cys 85 90 95 Ala Arg Gly Trp Leu Asp Arg Asp Ile Asp Tyr Trp
Gly Gln Gly Thr 100 105 110 Leu Val Thr Val Ser Ser 115
184110PRTArtificial SequenceSH1A2-VL 184Gln Ser Val Val Thr Gln Pro
Pro Ser Val Ser Ala Ala Pro Gly Gln 1 5 10 15 Lys Val Thr Ile Ser
Cys Ser Gly Ser Ser Ser Asn Ile Gly Asn Asn 20 25 30 Tyr Val Ser
Trp Tyr Gln Gln Val Pro Gly Thr Ala Pro Lys Leu Leu 35 40 45 Ile
Tyr Asp Asn Asn Lys Arg Pro Ser Gly Ile Pro Asp Arg Phe Ser 50 55
60 Gly Ser Asn Ser Asp Thr Ser Ala Thr Leu Gly Ile Thr Gly Leu Gln
65 70 75 80 Thr Gly Asp Glu Ala Asp Tyr Tyr Cys Gly Thr Trp Asp Ser
Ser Leu 85 90 95 Ser Ala Trp Val Phe Gly Gly Gly Thr Lys Leu Thr
Val Leu 100 105 110 185118PRTArtificial SequenceSH1B1-VH 185Gln Val
Gln Leu Val Gln Ser Gly Gly Gly Val Val Gln Pro Gly Arg 1 5 10 15
Ser Leu Arg Leu Ser Cys Ala Ala Ser Gly Phe Thr Phe Ser Ser Tyr 20
25 30 Ala Met His Trp Val Arg Gln Ala Pro Gly Lys Gly Leu Glu Trp
Val 35 40 45 Ala Val Ile Ser Phe Asp Gly Ser Asn Lys Tyr Tyr Ala
Asp Ser Val 50 55 60 Arg Gly Arg Phe Thr Ile Ser Arg Asp Asn Ser
Lys Asn Thr Leu Tyr 65 70 75 80 Leu Gln Met Asn Ser Leu Arg Thr Glu
Asp Thr Ala Val Tyr Tyr Cys 85 90 95 Ala Arg Gly Trp Leu Asp Arg
Asp Ile Asp Tyr Trp Gly Gln Gly Thr 100 105 110 Leu Val Thr Val Ser
Ser 115 186112PRTArtificial SequenceSH1B1-VL 186Gln Ser Val Val Thr
Gln Pro Pro Ser Val Ser Ala Ala Pro Gly Gln 1 5 10 15 Lys Val Thr
Ile Ser Cys Ser Gly Ser Ser Ser Asn Ile Gly Asn Asn 20 25 30 Tyr
Val Ser Trp Tyr Gln Gln Leu Pro Gly Thr Ala Pro Lys Leu Leu 35 40
45 Ile Tyr Asp Asn Asn Lys Arg Pro Ser Gly Ile Pro Asp Arg Phe Ser
50 55 60 Gly Ser Lys Ser Gly Thr Ser Ala Thr Leu Gly Ile Thr Gly
Leu Gln 65 70 75 80 Thr Gly Asp Glu Ala Asp Tyr Tyr Cys Gly Thr Trp
Asp Ser Ser Leu 85 90 95 Ser Ala Gly Ser Val Val Phe Gly Gly Gly
Thr Lys Leu Thr Val Leu 100 105 110 187118PRTArtificial
SequenceR6B2-VH 187Glu Val Gln Leu Val Gln Ser Gly Ala Glu Val Lys
Lys Pro Gly Ser 1 5 10 15 Ser Val Lys Val Ser Cys Lys Ala Ser Gly
Gly Thr Phe Ser Ser Tyr 20 25 30 Ala Ile Ser Trp Val Arg Gln Ala
Pro Gly Gln Gly Leu Glu Trp Met 35 40 45 Gly Gly Ile Ile Pro Ile
Phe Gly Thr Ala Asn Tyr Ala Gln Lys Phe 50 55 60 Gln Gly Arg Val
Thr Ile Thr Ala Asp Glu Ser Thr Ser Thr Ala Tyr 65 70 75 80 Met Glu
Leu Ser Ser Leu Arg Ser Glu Asp Thr Ala Val Tyr Tyr Cys 85 90 95
Ala Arg Asp Gly Ile Val Ala Asp Phe Gln His Trp Gly Gln Gly Thr 100
105 110 Leu Val Thr Val Ser Ser 115 188110PRTArtificial
SequenceR6B2-VL 188Gln Pro Val Leu Thr Gln Pro Arg Ser Val Ser Gly
Ser Pro Gly Gln 1 5 10 15 Ser Val Thr Ile Ser Cys Thr Gly Thr Ser
Ser Asp Val Gly Gly Tyr 20 25 30 Asn Phe Val Ser Trp Tyr Gln Gln
Asn Pro Gly Lys Ala Pro Lys Leu 35 40 45 Met Ile Tyr Asp Val Ser
Lys Arg Pro Ser Gly Val Pro Asp Arg Phe 50 55 60 Ser Gly Ser Lys
Ser Gly Asn Thr Ala Ser Leu Thr Val Ser Gly Leu 65 70 75 80 Arg Ala
Glu Asp Glu Ala Asp Tyr Tyr Cys Ala Ser Tyr Ala Gly Gly 85 90 95
Arg Thr Phe Val Phe Gly Gly Gly Thr Lys Val Thr Val Leu 100 105 110
189118PRTArtificial SequenceR6B7-VH 189Gln Met Gln Leu Val Gln Ser
Gly Ala Glu Val Lys Lys Pro Gly Ser 1 5 10 15 Ser Val Lys Val Ser
Cys Lys Ala Ser Gly Gly Thr Phe Asn Ser Tyr 20 25 30 Pro Ile Ser
Trp Val Arg Gln Ala Pro Gly Gln Gly Leu Glu Trp Met 35 40 45 Gly
Gly Ile Ile Pro Ile Phe Gly Thr Ala Asn Tyr Ala Gln Lys Phe 50 55
60 Gln Gly Arg Val Thr Ile Thr Ala Asp Glu Ser Thr Ser Thr Ala Tyr
65 70 75 80 Met Glu Leu Ser Ser Leu Arg Ser Glu Asp Thr Ala Met Tyr
Tyr Cys 85 90 95 Ala Lys Asn His Pro Thr Ala Thr Leu Asp Tyr Trp
Gly Gln Gly Thr 100 105 110 Leu Val Thr Val Ser Ser 115
190107PRTArtificial SequenceR6B7-VL 190Gln Ser Val Leu Thr Gln Ser
Pro Ser Ser Phe Ser Ala Ser Thr Gly 1 5 10 15 Asp Arg Val Thr Ile
Thr Cys Arg Ala Ser Gln Gly Ile Ser Ser Tyr 20 25 30 Leu Ala Trp
Tyr Gln Gln Lys Pro Gly Lys Ala Pro Lys Leu Leu Ile 35 40 45 Tyr
Ala Ala Ser Thr Leu Gln Ser Gly Val Pro Ser Arg Phe Ser Gly 50 55
60 Ser Gly Ser Gly Thr Asp Phe Thr Leu Thr Ile Ser Cys Leu Gln Ser
65 70 75 80 Glu Asp Phe Ala Thr Tyr Tyr Cys Gln Gln Tyr Tyr Ser Tyr
Pro Leu 85 90 95 Thr Phe Gly Gly Gly Thr Lys Val Thr Val Leu 100
105 191128PRTArtificial SequenceR6B11-VH 191Gln Val Gln Leu Val Gln
Ser Gly Gly Gly Val Val Gln Pro Gly Arg 1 5 10 15 Ser Leu Arg Leu
Ser Cys Ala Ala Ser Gly Phe Pro Phe Arg Ser Tyr 20 25 30 Asp Met
His Trp Val Arg Gln Ala Pro Gly Glu Gly Leu Glu Trp Val 35 40 45
Ala Leu Ile Ser Ser Asp Gly Ser Asn Lys Tyr Tyr Leu Asp Ser Val 50
55 60 Lys Gly Arg Phe Thr Ile Ser Arg Asp Asn Ser Lys Asn Thr Leu
Tyr 65 70 75 80 Leu Gln Met Asn Ser Leu Arg Ala Glu Asp Thr Ala Val
Tyr Tyr Cys 85 90 95 Ala Lys Asp Leu Leu Pro Tyr Ser Ser Ser Trp
Asp Tyr Tyr Tyr Tyr 100 105 110 Tyr Gly Met Asp Val Trp Gly Gln Gly
Thr Thr Val Thr Val Ser Ser 115 120 125 192110PRTArtificial
SequenceR6B11-VL 192Leu Pro Val Leu Thr Gln Pro Ala Ser Val Ser Ala
Ser Ala Gly Gln 1 5 10 15 Ser Ile Ala Ile Ser Cys Thr Gly Ile Ser
Ser Asp Ile Gly Asp Tyr 20 25 30 Asn Ser Val Ser Trp Tyr Gln Arg
His Pro Gly Lys Ala
Pro Lys Leu 35 40 45 Ile Ile Tyr Asp Val Ser Ser Arg Pro Ser Gly
Val Ala Asp Arg Phe 50 55 60 Ser Gly Ser Lys Ser Gly Ser Thr Ala
Ser Leu Ser Ile Ser Gly Leu 65 70 75 80 Gln Ala Glu Asp Glu Ala Asp
Tyr Tyr Cys Ala Ser Tyr Thr Ala Ser 85 90 95 Asp Asn Pro Val Phe
Gly Gly Gly Thr Lys Leu Thr Val Leu 100 105 110 193120PRTArtificial
SequenceR6D1-VH 193Glu Val Gln Leu Val Glu Ser Gly Gly Gly Leu Val
Gln Pro Gly Gly 1 5 10 15 Ser Leu Arg Leu Ser Cys Ala Ala Ser Gly
Phe Asn Ile Lys Asp Thr 20 25 30 Tyr Ile His Trp Val Arg Gln Ala
Pro Gly Lys Gly Leu Glu Trp Val 35 40 45 Ala Arg Ile Tyr Pro Thr
Asn Gly Tyr Thr Arg Tyr Ala Asp Ser Val 50 55 60 Lys Gly Arg Phe
Thr Ile Ser Ala Asp Thr Ser Lys Asn Thr Ala Tyr 65 70 75 80 Leu Gln
Met Asn Ser Leu Arg Ala Glu Asp Thr Ala Val Tyr Tyr Cys 85 90 95
Ser Arg Trp Gly Gly Asp Gly Phe Tyr Ala Met Asp Tyr Trp Gly Gln 100
105 110 Gly Thr Leu Val Thr Val Ser Ser 115 120 194108PRTArtificial
SequenceR6D1-VL 194Ser Tyr Glu Leu Met Gln Pro Pro Ser Val Ser Val
Ala Pro Gly Lys 1 5 10 15 Thr Ala Thr Ile Ala Cys Gly Gly Glu Asn
Ile Gly Arg Lys Thr Val 20 25 30 His Trp Tyr Gln Gln Lys Pro Gly
Gln Ala Pro Val Leu Val Ile Tyr 35 40 45 Tyr Asp Ser Asp Arg Pro
Ser Gly Ile Pro Glu Arg Phe Ser Gly Ser 50 55 60 Asn Ser Gly Asn
Thr Ala Thr Leu Thr Ile Ser Arg Val Glu Ala Gly 65 70 75 80 Asp Glu
Ala Asp Tyr Tyr Cys Gln Val Trp Asp Ser Ser Ser Asp His 85 90 95
Arg Ile Phe Gly Gly Gly Thr Lys Leu Thr Val Leu 100 105
195116PRTArtificial SequenceR6C8-VH 195Glu Val Gln Leu Val Glu Ser
Gly Gly Gly Leu Val Lys Pro Gly Gly 1 5 10 15 Ser Arg Lys Leu Ser
Cys Ala Ala Ser Gly Phe Thr Phe Ser Asn Tyr 20 25 30 Gly Met His
Trp Val Arg Gln Ala Pro Glu Lys Gly Leu Glu Trp Val 35 40 45 Ala
Tyr Ile Ser Ser Gly Ser Ser Thr Ile Tyr Tyr Ala Asp Thr Val 50 55
60 Lys Gly Arg Phe Thr Ile Ser Arg Asp Asn Ala Lys Asn Thr Leu Phe
65 70 75 80 Leu Gln Met Thr Ser Leu Arg Ser Glu Asp Thr Ala Met Tyr
Tyr Cys 85 90 95 Ala Arg Arg Gly Leu Leu Leu Asp Tyr Trp Gly Gln
Gly Thr Thr Leu 100 105 110 Thr Val Ser Ser 115 196110PRTArtificial
SequenceR6C8-VL 196Gln Ser Val Leu Thr Gln Pro Pro Ser Val Ser Ala
Ala Pro Gly Gln 1 5 10 15 Glu Val Thr Ile Ser Cys Ser Gly Ser Asn
Ser Asn Ile Gly Asn Asn 20 25 30 Tyr Val Ser Trp Tyr Gln Gln Leu
Pro Gly Thr Ala Pro Lys Leu Leu 35 40 45 Ile Tyr Asp Asn Asn Glu
Arg Pro Ser Gly Ile Pro Asp Arg Phe Ser 50 55 60 Gly Ser Lys Ser
Gly Thr Ser Ala Thr Leu Gly Ile Thr Gly Leu Gln 65 70 75 80 Thr Gly
Asp Glu Ala Asp Tyr Tyr Cys Gly Thr Trp Asp Ser Ser Leu 85 90 95
Ser Ala Gly Val Phe Gly Gly Gly Thr Lys Leu Thr Val Leu 100 105 110
197124PRTArtificial SequenceR9G8-VH 197Glu Val Gln Leu Val Gln Ser
Gly Ala Glu Val Lys Lys Pro Gly Ala 1 5 10 15 Ser Val Lys Val Ser
Cys Lys Ala Ser Gly Tyr Thr Phe Thr Ser Tyr 20 25 30 Gly Ile Ser
Trp Val Arg Gln Ala Pro Gly Gln Gly Leu Glu Trp Met 35 40 45 Gly
Trp Ile Ser Ala Tyr Asn Gly Asn Thr Asn Tyr Ala Gln Lys Leu 50 55
60 Gln Gly Arg Val Thr Met Thr Thr Asp Thr Ser Thr Ser Thr Ala Tyr
65 70 75 80 Met Glu Leu Arg Ser Leu Arg Ser Asp Asp Thr Ala Val Tyr
Tyr Cys 85 90 95 Ala Arg Asp Leu Phe Pro Thr Ile Phe Trp Glu Gly
Gly Ala Phe Asp 100 105 110 Ile Trp Gly Gln Gly Thr Met Val Thr Val
Ser Ser 115 120 198110PRTArtificial SequenceR9G8-VL 198Gln Ser Val
Leu Thr Gln Pro Pro Ser Val Ser Ala Ala Pro Gly Gln 1 5 10 15 Glu
Val Thr Ile Ser Cys Ser Gly Ser Asn Ser Asn Ile Gly Asn Asn 20 25
30 Tyr Val Ser Trp Tyr Gln Gln Leu Pro Gly Thr Ala Pro Lys Leu Leu
35 40 45 Ile Tyr Asp Asn Asn Glu Arg Pro Ser Gly Ile Pro Asp Arg
Phe Ser 50 55 60 Gly Ser Lys Ser Gly Thr Ser Ala Thr Leu Gly Ile
Thr Gly Leu Gln 65 70 75 80 Thr Gly Asp Glu Ala Asp Tyr Tyr Cys Gly
Thr Trp Asp Ser Ser Leu 85 90 95 Ser Ala Gly Val Phe Gly Gly Gly
Thr Lys Leu Thr Val Leu 100 105 110 199122PRTArtificial
SequenceR7D1-VH 199Gln Val Gln Leu Val Gln Ser Gly Ser Glu Val Glu
Lys Pro Gly Ser 1 5 10 15 Ser Val Lys Val Ser Cys Lys Ala Ser Gly
Gly Thr Phe Ser Asp Ser 20 25 30 Gly Ile Ser Trp Val Arg Gln Ala
Pro Gly Gln Gly Leu Glu Trp Met 35 40 45 Gly Gly Ile Ile Pro Met
Phe Ala Thr Pro Tyr Tyr Ala Gln Lys Phe 50 55 60 Gln Asp Arg Val
Thr Ile Thr Ala Asp Glu Ser Thr Ser Thr Val Tyr 65 70 75 80 Met Glu
Leu Ser Gly Leu Arg Ser Asp Asp Thr Ala Val Phe Tyr Cys 85 90 95
Ala Arg Asp Arg Gly Arg Gly His Leu Pro Trp Tyr Phe Asp Leu Trp 100
105 110 Gly Arg Gly Thr Leu Val Thr Val Ser Ser 115 120
200110PRTArtificial SequenceR7D1-VL 200Gln Ser Val Leu Thr Gln Pro
Pro Ser Val Ser Ala Ala Pro Gly Gln 1 5 10 15 Glu Val Thr Ile Ser
Cys Ser Gly Ser Asn Ser Asn Ile Gly Asn Asn 20 25 30 Tyr Val Ser
Trp Tyr Gln Gln Leu Pro Gly Thr Ala Pro Lys Leu Leu 35 40 45 Ile
Tyr Asp Asn Asn Glu Arg Pro Ser Gly Ile Pro Asp Arg Phe Ser 50 55
60 Gly Ser Lys Ser Gly Thr Ser Ala Thr Leu Gly Ile Thr Gly Leu Gln
65 70 75 80 Thr Gly Asp Glu Ala Asp Tyr Tyr Cys Gly Thr Trp Asp Ser
Ser Leu 85 90 95 Ser Ala Gly Val Phe Gly Gly Gly Thr Lys Leu Thr
Val Leu 100 105 110 201118PRTArtificial SequenceR7D2-VH 201Gln Val
Gln Leu Val Gln Ser Gly Ala Glu Val Lys Lys Pro Gly Ser 1 5 10 15
Ser Val Lys Val Ser Cys Lys Ala Ser Gly Gly Thr Phe Ser Ser Tyr 20
25 30 Ala Ile Ser Trp Val Arg Gln Ala Pro Gly Gln Gly Leu Glu Trp
Met 35 40 45 Gly Gly Ile Ile Pro Ile Phe Gly Thr Ala Asn Tyr Ala
Gln Lys Phe 50 55 60 Gln Gly Arg Val Thr Ile Thr Ala Asp Glu Ser
Thr Ser Thr Ala Tyr 65 70 75 80 Met Glu Leu Ser Ser Leu Arg Ser Glu
Asp Thr Ala Val Tyr Tyr Cys 85 90 95 Ala Arg Asp Gly Ile Val Ala
Asp Phe Gln His Trp Gly Gln Gly Thr 100 105 110 Leu Val Thr Val Ser
Ser 115 202107PRTArtificial SequenceR7D2-VL 202Ala Ile Arg Met Thr
Gln Ser Pro Ser Ser Leu Ser Ala Ser Val Gly 1 5 10 15 Asp Arg Val
Thr Ile Thr Cys Arg Ala Ser Gln Ser Ile Ser Asn Tyr 20 25 30 Leu
Asn Trp Tyr Gln Gln Arg Pro Gly Lys Ala Pro Asn Leu Leu Ile 35 40
45 Tyr Ala Ala Ser Ser Leu Gln Ser Gly Val Pro Ser Arg Phe Ser Gly
50 55 60 Ser Gly Ser Gly Thr Asp Phe Thr Leu Thr Ile Ser Ser Leu
Gln Pro 65 70 75 80 Glu Asp Phe Ala Thr Tyr Tyr Cys Gln Gln Thr Tyr
Ser Thr Pro Tyr 85 90 95 Thr Phe Gly Gln Gly Thr Lys Leu Glu Ile
Lys 100 105 203121PRTArtificial SequenceR7E7-VH 203Glu Val Gln Leu
Leu Glu Ser Gly Ala Glu Val Lys Lys Pro Gly Ser 1 5 10 15 Ser Val
Lys Val Ser Cys Lys Ala Ser Gly Gly Thr Phe Ser Ser Tyr 20 25 30
Ala Ile Ser Trp Val Arg Gln Ala Pro Gly Gln Gly Leu Glu Trp Met 35
40 45 Gly Arg Ile Ile Pro Ile Leu Gly Ile Ala Asp Tyr Ala Gln Lys
Phe 50 55 60 Gln Gly Arg Val Thr Ile Thr Ala Asp Lys Phe Thr Ser
Thr Ala Tyr 65 70 75 80 Met Glu Leu Ser Ser Leu Arg Ser Glu Asp Thr
Ala Val Tyr Tyr Cys 85 90 95 Ala Thr Val Glu Gly Trp Gly Ala Val
Thr Thr Phe Asp Tyr Trp Gly 100 105 110 Gln Gly Thr Leu Val Thr Val
Ser Ser 115 120 204110PRTArtificial SequenceR7E7-VL 204Gln Ser Val
Leu Thr Gln Pro Pro Ser Val Ser Ala Ala Pro Gly Gln 1 5 10 15 Glu
Val Thr Ile Ser Cys Ser Gly Ser Asn Ser Asn Ile Gly Asn Asn 20 25
30 Tyr Val Ser Trp Tyr Gln Gln Leu Pro Gly Thr Ala Pro Lys Leu Leu
35 40 45 Ile Tyr Asp Asn Asn Glu Arg Pro Ser Gly Ile Pro Asp Arg
Phe Ser 50 55 60 Gly Ser Lys Ser Gly Thr Ser Ala Thr Leu Gly Ile
Thr Gly Leu Gln 65 70 75 80 Thr Gly Asp Glu Ala Asp Tyr Tyr Cys Gly
Thr Trp Asp Ser Ser Leu 85 90 95 Ser Ala Gly Val Phe Gly Gly Gly
Thr Lys Leu Thr Val Leu 100 105 110 205122PRTArtificial
SequenceR7F2-VH 205Gln Val Gln Leu Val Gln Ser Gly Ala Glu Val Lys
Lys Pro Gly Ser 1 5 10 15 Ser Val Lys Val Ser Cys Lys Ala Ser Gly
Gly Thr Leu Ser Ser Tyr 20 25 30 Ala Ile Ser Trp Val Arg Gln Val
Pro Gly His Gly Leu Glu Trp Met 35 40 45 Gly Arg Ile Ile Ser Met
Leu Gly Val Ser Asn Tyr Ala Gln Asn Phe 50 55 60 Gln Gly Arg Val
Thr Ile Thr Ala Asp Lys Ser Thr Ser Thr Ala Tyr 65 70 75 80 Met Glu
Leu Arg Ser Leu Thr Ser Asp Asp Thr Ala Val Tyr Tyr Cys 85 90 95
Ala Thr Val Thr Ile Phe Asp Gly Asp Tyr Tyr Ala Met Asp Val Trp 100
105 110 Gly Gln Gly Thr Thr Val Thr Val Ser Ser 115 120
206111PRTArtificial SequenceR7F2-VL 206Gln Ser Val Leu Thr Gln Pro
Pro Ser Val Ser Gly Ala Pro Gly Gln 1 5 10 15 Arg Val Thr Ile Ser
Cys Thr Gly Ser Ser Ser Asn Ile Gly Ala Gly 20 25 30 Tyr Asp Val
Tyr Trp Tyr Gln His Leu Leu Gly Lys Ala Pro Lys Leu 35 40 45 Leu
Ile Tyr Gly Asn Ser Asn Arg Pro Ser Gly Val Ser Asp Arg Phe 50 55
60 Ser Ala Ser Lys Ser Gly Thr Ser Val Ser Leu Ala Ile Thr Gly Leu
65 70 75 80 Gln Ala Glu Asp Glu Ala Asp Tyr Tyr Cys Gln Ser Tyr Asp
Ser Ser 85 90 95 Leu Ser Gly Tyr Val Phe Gly Thr Gly Thr Lys Leu
Thr Val Leu 100 105 110 207118PRTArtificial SequenceR7F7-VH 207Glu
Val Gln Leu Val Gln Ser Gly Ala Glu Val Lys Lys Pro Gly Ser 1 5 10
15 Ser Val Lys Val Ser Cys Lys Ala Ser Gly Gly Thr Phe Ser Ser His
20 25 30 Val Ile Ser Trp Val Arg Gln Ala Pro Gly Gln Gly Leu Glu
Trp Met 35 40 45 Gly Ile Ile Leu Pro Ser Phe Gly Lys Thr Asn Tyr
Ala Gln Lys Phe 50 55 60 Gln Gly Arg Val Thr Met Thr Gly Asp Thr
Ser Thr Ser Thr Val Tyr 65 70 75 80 Met Glu Leu Ser Ser Leu Thr Ser
Glu Asp Thr Ala Val Tyr Tyr Cys 85 90 95 Val Arg Glu Phe Ser Gly
Gly Tyr Phe Asp Tyr Trp Gly Gln Gly Thr 100 105 110 Leu Val Thr Val
Ser Ser 115 208110PRTArtificial SequenceR7F7-VL 208Gln Pro Val Leu
Thr Gln Pro Ala Ser Val Ser Gly Ser Pro Gly Gln 1 5 10 15 Ser Ile
Thr Ile Ser Cys Thr Gly Thr Ser Ser Asp Val Gly Ser Tyr 20 25 30
Asn Leu Val Ser Trp Tyr Gln Gln His Pro Gly Lys Ala Pro Lys Leu 35
40 45 Met Ile Tyr Glu Val Ser Lys Arg Pro Ser Gly Val Ser Asn Arg
Phe 50 55 60 Ser Gly Ser Lys Ser Gly Asn Thr Ala Ser Leu Thr Ile
Ser Gly Leu 65 70 75 80 Gln Ala Glu Asp Glu Ala Asp Tyr Tyr Cys Asn
Thr Tyr Thr Ser Ser 85 90 95 Gly Thr Tyr Val Ile Gly Thr Gly Thr
Lys Val Thr Val Leu 100 105 110 209120PRTArtificial SequenceR9H2-VH
209Gln Val Gln Leu Val Gln Ser Gly Ala Glu Val Lys Lys Pro Gly Ala
1 5 10 15 Ser Val Lys Val Ser Cys Lys Ala Ser Gly Tyr Thr Phe Thr
Ser Tyr 20 25 30 Val Ile His Trp Val Arg Gln Ala Pro Gly Gln Arg
Leu Glu Trp Met 35 40 45 Gly Trp Ile His Ala Gly Asn Gly His Thr
Lys Tyr Ala Gln Asn Phe 50 55 60 Gln Gly Arg Val Thr Ile Thr Arg
Asp Thr Ser Ala Thr Thr Ala Tyr 65 70 75 80 Val Glu Val Ser Ser Leu
Gly Ser Glu Asp Thr Ala Leu Tyr Tyr Cys 85 90 95 Ala Arg Glu Gly
Ser Asp Ile Gly Leu Asp Leu His Tyr Trp Gly Gln 100 105 110 Gly Thr
Leu Val Thr Val Ser Ser 115 120 210110PRTArtificial SequenceR9H2-VL
210Gln Pro Val Leu Thr Gln Pro Ala Ser Val Ser Gly Ser Pro Gly Gln
1 5 10 15 Ser Ile Thr Ile Ser Cys Thr Gly Thr Ser Ser Asp Ile Gly
Arg Tyr 20 25 30 Asn Tyr Val Ser Trp Tyr Gln Gln His Pro Gly Lys
Ala Pro Lys Val 35 40 45 Met Ile Tyr Asp Val Ser Asn Arg Pro Ser
Gly Val Ser Asn Arg Phe 50 55 60 Ser Gly Ser Lys Ser Gly Asn Thr
Ala Ser Leu Thr Ile Ser Gly Leu 65 70 75 80 Gln Ala Glu Asp Glu Ala
Asp Tyr Tyr Cys Ser Ser Tyr Thr Ser Ser 85 90 95 Ser Thr Trp Val
Phe Gly Gly Gly Thr Lys Leu Thr Val Leu 100 105 110
211121PRTArtificial SequenceR9H6-VH 211Glu Val Gln Leu Val Gln Ser
Gly Gly Gly Val Val Gln Pro Gly Arg 1 5 10 15 Ser Leu Arg Leu Ser
Cys Glu Ala Ser Gly Phe Thr Phe Arg Asn Phe 20 25 30 Ala Met His
Trp Val Arg Gln Ala Pro Gly Lys Gly Leu Glu Trp Ala 35 40 45 Ala
Val Ile Ser
Val Asp Gly Ser Arg Glu His Tyr Ala Asp Ser Val 50 55 60 Lys Gly
Arg Phe Thr Ile Ser Arg Asp Asn Ser Gln Asn Thr Val Tyr 65 70 75 80
Leu Gln Met Asn Gly Leu Arg Pro Glu Asp Thr Ala Glu Tyr Tyr Cys 85
90 95 Ala Arg Glu Gly Glu Gly Ser Thr Trp Ser Ser Phe Asp Tyr Trp
Gly 100 105 110 Gln Gly Thr Leu Val Thr Val Ser Ser 115 120
212110PRTArtificial SequenceR9H6-VL 212Gln Ser Val Val Thr Gln Pro
Pro Ser Val Ser Ala Ala Pro Gly Gln 1 5 10 15 Lys Val Thr Ile Ser
Cys Ser Gly Ser Ser Ser Asn Ile Gly Asn Asn 20 25 30 Tyr Val Ser
Trp Tyr Gln Gln Leu Pro Gly Thr Ala Pro Lys Ile Leu 35 40 45 Ile
Tyr Asp Asn Asp Lys Arg Pro Ser Gly Ile Pro Asp Arg Phe Ser 50 55
60 Gly Ser Lys Ser Gly Thr Ser Ala Thr Leu Gly Ile Thr Gly Leu Gln
65 70 75 80 Thr Gly Asp Glu Ala Asp Tyr Tyr Cys Gly Thr Trp Asp Arg
Ser Leu 85 90 95 Ser Gly Tyr Val Phe Gly Thr Gly Thr Lys Val Thr
Val Leu 100 105 110 213121PRTArtificial SequenceH6B1L-VH 213Gln Met
Gln Leu Val Gln Ser Gly Ala Glu Val Lys Lys Pro Gly Ser 1 5 10 15
Ser Val Lys Val Ser Cys Lys Ala Ser Gly Gly Thr Phe Ser Ser Tyr 20
25 30 Ala Tyr Ser Trp Val Arg Gln Ala Pro Gly Gln Gly Leu Glu Trp
Met 35 40 45 Gly Gly Ile Ile Pro Ser Phe Gly Thr Ala Asn Tyr Ala
Gln Lys Phe 50 55 60 Gln Gly Arg Val Thr Ile Thr Ala Asp Glu Ser
Thr Ser Thr Ala Tyr 65 70 75 80 Met Glu Leu Ser Ser Leu Arg Ser Glu
Asp Thr Ala Val Tyr Tyr Cys 85 90 95 Ala Arg Gly Pro Ile Val Ala
Thr Ile Thr Pro Leu Asp Tyr Trp Gly 100 105 110 Gln Gly Thr Leu Val
Thr Val Ser Ser 115 120 214108PRTArtificial SequenceH6B1L-VL 214Ser
Tyr Glu Leu Met Gln Pro Pro Ser Val Ser Val Ala Pro Gly Lys 1 5 10
15 Thr Ala Thr Ile Ala Cys Gly Gly Glu Asn Ile Gly Arg Lys Thr Val
20 25 30 His Trp Tyr Gln Gln Lys Pro Gly Gln Ala Pro Val Leu Val
Ile Tyr 35 40 45 Tyr Asp Ser Asp Arg Pro Ser Gly Ile Pro Glu Arg
Phe Ser Gly Ser 50 55 60 Asn Ser Gly Asn Thr Ala Thr Leu Thr Ile
Ser Arg Val Glu Ala Gly 65 70 75 80 Asp Glu Ala Asp Tyr Tyr Cys Leu
Val Trp Asp Ser Ser Ser Asp His 85 90 95 Arg Ile Phe Gly Gly Gly
Thr Lys Leu Thr Val Leu 100 105 215121PRTArtificial SequenceH6A1-VH
215Gln Met Gln Leu Val Gln Ser Gly Ala Glu Val Lys Lys Pro Gly Ser
1 5 10 15 Ser Val Lys Val Ser Cys Lys Ala Ser Gly Gly Thr Phe Ser
Ser Tyr 20 25 30 Ala Tyr Ser Trp Val Arg Gln Ala Pro Gly Gln Gly
Leu Glu Trp Met 35 40 45 Gly Gly Ile Ile Pro Ile Phe Gly Thr Ala
Asn Tyr Ala Gln Lys Phe 50 55 60 Gln Gly Arg Val Thr Ile Thr Ala
Asp Glu Ser Thr Ser Thr Ala Tyr 65 70 75 80 Met Glu Leu Ser Ser Leu
Arg Ser Glu Asp Thr Ala Val Tyr Tyr Cys 85 90 95 Ala Arg Gly Pro
Ile Val Ala Thr Ile Thr Pro Leu Asp Tyr Trp Gly 100 105 110 Gln Gly
Thr Leu Val Thr Val Ser Ser 115 120 216108PRTArtificial
SequenceH6A1-VL 216Ser Tyr Glu Leu Met Gln Pro Pro Ser Val Ser Val
Ala Pro Gly Lys 1 5 10 15 Thr Ala Thr Ile Ala Cys Gly Gly Glu Asn
Ile Gly Arg Lys Thr Val 20 25 30 His Trp Tyr Gln Gln Lys Pro Gly
Gln Ala Pro Val Leu Val Ile Tyr 35 40 45 Tyr Asp Ser Asp Arg Pro
Ser Gly Ile Pro Glu Arg Phe Ser Gly Ser 50 55 60 Asn Ser Gly Asn
Thr Ala Thr Leu Thr Ile Ser Arg Val Glu Ala Gly 65 70 75 80 Asp Glu
Ala Asp Tyr Tyr Cys Gln Val Trp Asp Ser Ser Ser Asp His 85 90 95
Arg Ile Phe Gly Gly Gly Thr Lys Leu Thr Val Leu 100 105
217121PRTArtificial SequenceH6B1-VH 217Gln Met Gln Leu Val Gln Ser
Gly Ala Glu Val Lys Lys Pro Gly Ser 1 5 10 15 Ser Val Lys Val Ser
Cys Lys Ala Ser Gly Gly Thr Phe Ser Ser Tyr 20 25 30 Ala Tyr Ser
Trp Val Arg Gln Ala Pro Gly Gln Gly Leu Glu Trp Met 35 40 45 Gly
Gly Ile Ile Pro Ser Phe Gly Thr Ala Asn Tyr Ala Gln Lys Phe 50 55
60 Gln Gly Arg Val Thr Ile Thr Ala Asp Glu Ser Thr Ser Thr Ala Tyr
65 70 75 80 Met Glu Leu Ser Ser Leu Arg Ser Glu Asp Thr Ala Val Tyr
Tyr Cys 85 90 95 Ala Arg Gly Pro Ile Val Ala Thr Ile Thr Pro Leu
Asp Tyr Trp Gly 100 105 110 Gln Gly Thr Leu Val Thr Val Ser Ser 115
120 218108PRTArtificial SequenceH6B1-VL 218Ser Tyr Glu Leu Met Gln
Pro Pro Ser Val Ser Val Ala Pro Gly Lys 1 5 10 15 Thr Ala Thr Ile
Ala Cys Gly Gly Glu Asn Ile Gly Arg Lys Thr Val 20 25 30 His Trp
Tyr Gln Gln Lys Pro Gly Gln Ala Pro Val Leu Val Ile Tyr 35 40 45
Tyr Asp Ser Asp Arg Pro Ser Gly Ile Pro Glu Arg Phe Ser Gly Ser 50
55 60 Asn Ser Gly Asn Thr Ala Thr Leu Thr Ile Ser Arg Val Glu Ala
Gly 65 70 75 80 Asp Glu Ala Asp Tyr Tyr Cys Gln Val Trp Asp Ser Ser
Ser Asp His 85 90 95 Arg Ile Phe Gly Gly Gly Thr Lys Leu Thr Val
Leu 100 105 219121PRTArtificial SequenceH6B2-VH 219Gln Met Gln Leu
Val Gln Ser Gly Ala Glu Val Lys Lys Pro Gly Ser 1 5 10 15 Ser Val
Lys Val Ser Cys Lys Ala Ser Gly Gly Thr Phe Ser Ser Tyr 20 25 30
Ala Ile Ser Trp Val Arg Gln Ala Pro Gly Gln Gly Leu Glu Trp Met 35
40 45 Gly Gly Ile Ile Pro Ala Phe Gly Thr Ala Asn Tyr Ala Gln Lys
Phe 50 55 60 Gln Gly Arg Val Thr Ile Thr Ala Asp Glu Ser Thr Ser
Thr Ala Tyr 65 70 75 80 Met Glu Leu Ser Ser Leu Arg Ser Glu Asp Thr
Ala Val Tyr Tyr Cys 85 90 95 Ala Arg Gly Pro Ile Val Ala Thr Ile
Thr Pro Leu Asp Tyr Trp Gly 100 105 110 Gln Gly Thr Leu Val Thr Val
Ser Ser 115 120 220108PRTArtificial SequenceH6B2-VL 220Ser Tyr Glu
Leu Met Gln Pro Pro Ser Val Ser Val Ala Pro Gly Lys 1 5 10 15 Thr
Ala Thr Ile Ala Cys Gly Gly Glu Asn Ile Gly Arg Lys Thr Val 20 25
30 His Trp Tyr Gln Gln Lys Pro Gly Gln Ala Pro Val Leu Val Ile Tyr
35 40 45 Tyr Asp Ser Asp Arg Pro Ser Gly Ile Pro Glu Arg Phe Ser
Gly Ser 50 55 60 Asn Ser Gly Asn Thr Ala Thr Leu Thr Ile Ser Arg
Val Glu Ala Gly 65 70 75 80 Asp Glu Ala Asp Tyr Tyr Cys Gln Val Trp
Asp Ser Ser Ser Asp His 85 90 95 Arg Ile Phe Gly Gly Gly Thr Lys
Leu Thr Val Leu 100 105 221124PRTArtificial SequenceH19C-VH 221Gln
Val Gln Leu Val Gln Ser Gly Ala Glu Val Lys Lys Pro Gly Ala 1 5 10
15 Ser Val Lys Val Ser Cys Lys Thr Ser Gly Asn Thr Phe Thr Asn Tyr
20 25 30 Ala Leu His Trp Val Arg Gln Ala Pro Gly Gln Gly Leu Glu
Trp Met 35 40 45 Gly Gly Met Lys Pro Ser Gly Gly Ser Thr Ser Ile
Ala Gln Lys Phe 50 55 60 Gln Gly Arg Val Thr Met Thr Arg Asp Lys
Ser Thr Ser Thr Val Tyr 65 70 75 80 Met Glu Leu Ser Ser Leu Thr Ser
Glu Asp Thr Ala Val Tyr Tyr Cys 85 90 95 Ala Arg Asp Leu Phe Pro
His Ile Phe Gly Asn Tyr Tyr Gly Met Asp 100 105 110 Ile Trp Gly Gln
Gly Thr Thr Val Thr Val Ser Ser 115 120 222107PRTArtificial
SequenceH19C-VL 222Asp Ile Val Met Thr Gln Ser Pro Pro Ser Leu Ser
Ala Ser Val Gly 1 5 10 15 Asp Arg Val Thr Ile Thr Cys Arg Ala Ser
Gln Ser Ile Ser Ser Tyr 20 25 30 Leu Asn Trp Tyr Gln Gln Lys Pro
Gly Lys Ala Pro Lys Leu Leu Ile 35 40 45 Tyr Ala Thr Ser Ser Leu
Gln Tyr Gly Val Pro Ser Arg Phe Ser Gly 50 55 60 Ser Gly Ser Gly
Thr Asp Phe Thr Leu Thr Ile Ser Ser Leu Gln Pro 65 70 75 80 Glu Asp
Phe Ala Thr Tyr Tyr Cys Gln Gly Ser Tyr Ser Thr Pro Tyr 85 90 95
Thr Phe Gly Gln Gly Thr Lys Val Glu Ile Lys 100 105
223124PRTArtificial SequenceH110D-VH 223Gln Val Gln Leu Val Gln Ser
Gly Ala Glu Val Lys Lys Pro Gly Ala 1 5 10 15 Ser Val Lys Val Ser
Cys Lys Thr Ser Gly Asn Thr Phe Thr Asn Tyr 20 25 30 Tyr Met His
Trp Val Arg Gln Ala Pro Gly Gln Gly Leu Glu Trp Met 35 40 45 Gly
Ser Met Gln Pro Ser Gly Gly Ser Thr Ser Leu Ala Gln Lys Phe 50 55
60 Gln Gly Arg Val Thr Met Thr Arg Asp Lys Ser Thr Ser Thr Val Tyr
65 70 75 80 Met Glu Leu Ser Ser Leu Thr Ser Glu Asp Thr Ala Val Tyr
Tyr Cys 85 90 95 Ala Arg Asp Leu Phe Pro His Ile Leu Gly Asn Tyr
Tyr Gly Met Asp 100 105 110 Ile Trp Gly Gln Gly Thr Thr Val Thr Val
Ser Ser 115 120 224107PRTArtificial SequenceH110D-VL 224Asp Ile Val
Met Thr Gln Ser Pro Pro Ser Leu Ser Ala Ser Val Gly 1 5 10 15 Asp
Arg Val Thr Ile Thr Cys Arg Ala Ser Gln Ser Ile Ser Ser Tyr 20 25
30 Leu Asn Trp Tyr Gln Gln Lys Pro Gly Lys Ala Pro Lys Leu Leu Ile
35 40 45 Tyr Ala Ala Ser Ser Leu Gln Ser Gly Val Pro Ser Arg Phe
Ser Gly 50 55 60 Ser Gly Ser Gly Thr Asp Phe Thr Leu Thr Ile Ser
Ser Leu Gln Pro 65 70 75 80 Glu Asp Phe Ala Thr Tyr Tyr Cys Gln Gly
Ser Tyr Ser Thr Pro Tyr 85 90 95 Thr Phe Gly Gln Gly Thr Lys Val
Glu Ile Lys 100 105 225124PRTArtificial SequenceH11F-VH 225Gln Val
Gln Leu Val Gln Ser Gly Ala Glu Val Lys Lys Pro Gly Ala 1 5 10 15
Ser Val Lys Val Ser Cys Lys Thr Ser Gly Asn Thr Phe Thr Asn Tyr 20
25 30 Pro Met His Trp Val Arg Gln Ala Pro Gly Gln Gly Leu Glu Trp
Met 35 40 45 Gly Ser Met Lys Pro Ser Gly Gly Ser Thr Ser Leu Ala
Pro Lys Phe 50 55 60 Gln Gly Arg Val Thr Met Thr Arg Asp Lys Ser
Thr Ser Thr Val Tyr 65 70 75 80 Met Glu Leu Ser Ser Leu Thr Ser Glu
Asp Thr Ala Val Tyr Tyr Cys 85 90 95 Ala Arg Asp Leu Phe Pro His
Ile Ile Gly Asn Tyr Tyr Gly Met Asp 100 105 110 Ile Trp Gly Gln Gly
Thr Thr Val Thr Val Ser Ser 115 120 226107PRTArtificial
SequenceH11F-VL 226Asp Ile Val Met Thr Gln Ser Pro Pro Ser Leu Ser
Ala Ser Val Gly 1 5 10 15 Asp Arg Val Thr Ile Thr Cys Arg Ala Ser
Gln Ser Ile Ser Ser Tyr 20 25 30 Leu Asn Trp Tyr Gln Gln Lys Pro
Gly Lys Ala Pro Lys Leu Leu Ile 35 40 45 Tyr Ala Ala Ser Ser Leu
Gln Tyr Gly Val Pro Ser Arg Phe Ser Gly 50 55 60 Ser Gly Ser Gly
Thr Asp Phe Thr Leu Thr Ile Ser Ser Leu Gln Pro 65 70 75 80 Glu Asp
Phe Ala Thr Tyr Tyr Cys Gln Gly Ser Tyr Ser Thr Pro Tyr 85 90 95
Thr Phe Gly Gln Gly Thr Lys Val Glu Ile Lys 100 105
227124PRTArtificial SequenceH1C1-VH 227Gln Val Gln Leu Val Gln Ser
Gly Ala Glu Val Lys Lys Pro Gly Ala 1 5 10 15 Ser Val Lys Val Ser
Cys Lys Thr Ser Gly Asn Thr Phe Thr Asn Tyr 20 25 30 Ser Met His
Trp Val Arg Gln Ala Pro Gly Gln Gly Leu Glu Trp Met 35 40 45 Gly
Ile Met Asn Pro Ser Gly Gly Ser Thr Ser Tyr Ala Gln Lys Phe 50 55
60 Gln Gly Arg Val Thr Met Thr Arg Asp Lys Ser Thr Ser Thr Val Tyr
65 70 75 80 Met Glu Leu Ser Ser Leu Thr Ser Glu Asp Thr Ala Val Tyr
Tyr Cys 85 90 95 Ala Arg Asp Leu Phe Pro His Ile Tyr Gly Asn Tyr
Tyr Gly Met Asp 100 105 110 Ile Trp Gly Gln Gly Thr Thr Val Thr Val
Ser Ser 115 120 228107PRTArtificial SequenceH1C1-VL 228Asp Ile Val
Met Thr Gln Ser Pro Pro Ser Leu Ser Ala Ser Val Gly 1 5 10 15 Asp
Arg Val Thr Ile Thr Cys Arg Ala Ser Gln Ser Ile Ser Ser Tyr 20 25
30 Leu Asn Trp Tyr Gln Gln Lys Pro Gly Lys Ala Pro Lys Leu Leu Ile
35 40 45 Tyr Ala Ala Ser Ser Leu Gln Ser Gly Val Pro Ser Arg Phe
Ser Gly 50 55 60 Ser Gly Ser Gly Thr Asp Phe Thr Leu Thr Ile Ser
Ser Leu Gln Pro 65 70 75 80 Glu Asp Phe Ala Thr Tyr Tyr Cys Gln Gln
Ser Tyr Ser Thr Pro Tyr 85 90 95 Thr Phe Gly Gln Gly Thr Lys Val
Glu Ile Lys 100 105 229118PRTArtificial SequenceGPG1A2-VH 229Glu
Val Gln Leu Val Gln Ser Gly Ala Glu Val Lys Lys Pro Gly Ala 1 5 10
15 Ser Val Lys Val Ser Cys Lys Ala Ser Gly Tyr Thr Phe Thr Gly Tyr
20 25 30 Tyr Met His Trp Val Arg Gln Ala Pro Gly Gln Gly Leu Glu
Trp Met 35 40 45 Gly Trp Ile Asn Pro Asn Ser Asp Asn Thr Gly Ser
Ala Gln Lys Phe 50 55 60 Gln Gly Arg Val Phe Met Thr Lys Thr Thr
Ser Leu Asn Thr Ala Tyr 65 70 75 80 Met Glu Leu Ser Gly Leu Arg Ser
Glu Asp Thr Ala Ile Tyr Tyr Cys 85 90 95 Ala Arg Glu Arg Ser Ser
Gly Tyr Phe Asp Phe Trp Gly Gln Gly Thr 100 105 110 Leu Val Thr Val
Ser Ser 115 230107PRTArtificial SequenceGPG1A2-VL 230Asp Ile Val
Met Thr Gln Ser Pro Ser Ser Leu Ser Ala Ser Val Gly 1 5 10 15 Asp
Arg Val Thr Ile Thr Cys Arg Ala Ser Gln Ser Ile Ser Ser Phe 20 25
30 Leu Asn Trp Tyr Gln Gln Lys Pro Gly Lys Ala Pro Lys Leu Leu Ile
35 40 45 Tyr Ala Ala Ser Ser Leu Gln Ser Gly Val Pro Ser Arg Phe
Ser Gly 50
55 60 Ser Gly Ser Gly Thr Asp Phe Thr Leu Thr Ile Ser Ser Leu Gln
Pro 65 70 75 80 Glu Asp Phe Ala Thr Tyr Tyr Cys Gln Gln Ser Tyr Ser
Thr Pro Ile 85 90 95 Thr Phe Gly Gln Gly Thr Lys Val Glu Ile Lys
100 105 231118PRTArtificial SequenceGPGG8-VH 231Gln Val Gln Leu Val
Gln Ser Gly Ala Glu Val Lys Lys Leu Gly Ala 1 5 10 15 Ser Val Lys
Val Ser Cys Lys Ala Ser Gly Tyr Pro Phe Thr Gly Tyr 20 25 30 Tyr
Met His Trp Val Arg Gln Ala Pro Gly Gln Gly Leu Glu Trp Met 35 40
45 Gly Trp Ile Asn Pro Asn Gly Asp Asn Thr Gly Leu Ala Gln Lys Phe
50 55 60 Gln Gly Arg Val Phe Met Thr Lys Thr Thr Ser Leu Asn Thr
Ala Tyr 65 70 75 80 Met Glu Leu Ser Gly Leu Arg Ser Glu Asp Thr Ala
Ile Tyr Tyr Cys 85 90 95 Ala Arg Glu Arg Ser Ser Gly Tyr Phe Asp
Phe Trp Gly Gln Gly Thr 100 105 110 Leu Val Thr Val Ser Ser 115
232107PRTArtificial SequenceGPGG8-VL 232Asp Ile Val Met Thr Gln Ser
Pro Ser Ser Leu Ser Ala Ser Val Gly 1 5 10 15 Asp Arg Val Thr Ile
Thr Cys Arg Ala Thr Pro Ser Thr Ser Ser Tyr 20 25 30 Leu Asn Trp
Tyr Gln Gln Lys Pro Gly Lys Ala Pro Lys Leu Leu Ile 35 40 45 Tyr
Ala Ala Ser Ser Leu Gln Ser Gly Val Pro Ser Arg Phe Ser Gly 50 55
60 Ser Gly Ser Gly Thr Asp Phe Thr Leu Thr Ile Ser Ser Leu Gln Pro
65 70 75 80 Glu Asp Phe Ala Thr Tyr Tyr Cys Gln Gln Ser Tyr Ser Thr
Pro Ile 85 90 95 Thr Phe Gly Gln Gly Thr Lys Leu Glu Ile Lys 100
105 233118PRTArtificial SequenceGPGG10-VH 233Gln Val Gln Leu Val
Gln Ser Gly Ala Glu Val Lys Lys Pro Gly Ala 1 5 10 15 Ser Val Lys
Val Ser Cys Lys Thr Ser Gly Tyr Pro Phe Thr Gly Tyr 20 25 30 Tyr
Met His Trp Val Arg Gln Ala Pro Gly Gln Gly Leu Glu Trp Met 35 40
45 Gly Trp Ile Asn Pro Leu Ser Asp Thr Thr Gly Ser Ala Gln Lys Phe
50 55 60 Gln Gly Arg Val Phe Met Thr Lys Thr Thr Ser Leu Asn Thr
Ala Tyr 65 70 75 80 Met Glu Leu Ser Gly Leu Arg Ser Glu Asp Thr Ala
Ile Tyr Tyr Cys 85 90 95 Ala Arg Glu Arg Ser Ser Gly Tyr Phe Asp
Phe Trp Gly Gln Gly Thr 100 105 110 Leu Val Thr Val Ser Ser 115
234107PRTArtificial SequenceGPGG10-VL 234Asp Ile Val Met Thr Gln
Ser Pro Ser Ser Leu Ser Ala Ser Val Gly 1 5 10 15 Asp Arg Val Thr
Ile Thr Cys Arg Ala Ser Gln Ser Ile Ser Ser Tyr 20 25 30 Leu Asn
Trp Tyr Gln Gln Lys Pro Gly Lys Ala Pro Lys Leu Leu Ile 35 40 45
Tyr Ala Ala Ser Ser Leu Gln Ser Gly Val Pro Ser Arg Phe Ser Gly 50
55 60 Ser Gly Ser Gly Thr Asp Phe Thr Leu Thr Ile Ser Ser Leu Gln
Pro 65 70 75 80 Glu Asp Phe Ala Thr Tyr Tyr Cys Gln Gln Ser Tyr Ser
Thr Pro Ile 85 90 95 Thr Phe Gly Gln Gly Thr Lys Leu Glu Ile Lys
100 105 235118PRTArtificial SequenceGPGH7-VH 235Gln Val Gln Leu Val
Gln Ser Gly Ala Glu Val Lys Lys Pro Gly Ala 1 5 10 15 Ser Val Lys
Val Ser Cys Lys Ala Ser Gly Tyr Thr Phe Thr Gly Tyr 20 25 30 Tyr
Met His Trp Val Arg Gln Ala Pro Gly Gln Gly Leu Glu Trp Met 35 40
45 Gly Trp Ile Asn Pro Leu Ser Asp Asn Thr Gly Ser Ala Gln Lys Phe
50 55 60 Gln Gly Arg Val Phe Met Thr Lys Thr Thr Ser Leu Asn Thr
Ala Tyr 65 70 75 80 Met Glu Leu Ser Gly Leu Arg Ser Glu Asp Thr Ala
Ile Tyr Tyr Cys 85 90 95 Ala Arg Glu Arg Ser Ser Gly Tyr Phe Asp
Phe Trp Gly Gln Gly Thr 100 105 110 Leu Val Thr Val Ser Ser 115
236107PRTArtificial SequenceGPGH7-VL 236Asp Ile Val Met Thr Gln Ser
Pro Ser Ser Leu Ser Ala Ser Val Gly 1 5 10 15 Asp Arg Val Thr Ile
Thr Cys Arg Ala Ser Gln Ser Ile Ser Ser Phe 20 25 30 Leu Asn Trp
Tyr Gln Gln Lys Pro Gly Lys Ala Pro Lys Leu Leu Ile 35 40 45 Tyr
Leu Ala Ser Ser Leu Gln Ser Gly Val Pro Ser Arg Phe Ser Gly 50 55
60 Ser Gly Ser Gly Thr Asp Phe Thr Leu Thr Ile Ser Ser Leu Gln Pro
65 70 75 80 Glu Asp Phe Ala Thr Tyr Tyr Cys Gln Gln Ser Tyr Ser Thr
Pro Ile 85 90 95 Thr Phe Gly Gln Gly Thr Lys Val Glu Ile Lys 100
105 237118PRTArtificial SequenceGPGH10-VH 237Gln Val Gln Leu Val
Gln Ser Gly Ala Glu Val Lys Lys Pro Gly Ala 1 5 10 15 Ser Val Lys
Val Ser Cys Lys Thr Ser Gly Tyr Thr Phe Thr Gly Tyr 20 25 30 Tyr
Met His Trp Val Arg Gln Ala Pro Gly Gln Gly Leu Glu Trp Met 35 40
45 Gly Trp Ile Asn Pro Asn Ser Asp Asn Thr Gly Tyr Ala Gln Lys Phe
50 55 60 Gln Gly Arg Val Phe Met Thr Lys Thr Thr Ser Leu Asn Thr
Ala Tyr 65 70 75 80 Met Glu Leu Ser Gly Leu Arg Ser Glu Asp Thr Ala
Ile Tyr Tyr Cys 85 90 95 Ala Arg Glu Arg Ser Ser Gly Tyr Phe Asp
Phe Trp Gly Gln Gly Thr 100 105 110 Leu Val Thr Val Ser Ser 115
238107PRTArtificial SequenceGPGH10-VL 238Asp Ile Val Met Thr Gln
Ser Pro Ser Ser Leu Ser Ala Ser Val Gly 1 5 10 15 Asp Arg Val Thr
Ile Thr Cys Arg Ala Ser Gln Ser Ile Ser Ser Phe 20 25 30 Leu Asn
Trp Tyr Gln Gln Lys Pro Gly Lys Ala Pro Lys Leu Leu Ile 35 40 45
Tyr Ala Ala Ser Ser Leu Gln Ser Gly Val Pro Ser Arg Phe Ser Gly 50
55 60 Ser Gly Ser Gly Thr Asp Phe Thr Leu Thr Ile Ser Ser Leu Gln
Pro 65 70 75 80 Glu Asp Phe Ala Thr Tyr Tyr Cys Gln Gln Ala Tyr Ser
Thr Pro Ile 85 90 95 Thr Phe Gly Gln Gly Thr Lys Val Glu Ile Lys
100 105 239118PRTArtificial SequenceGPGH11-VH 239Gln Val Gln Leu
Val Gln Ser Gly Ala Glu Val Lys Lys Pro Gly Ala 1 5 10 15 Ser Val
Lys Val Ser Cys Lys Ala Ser Gly Tyr Pro Phe Thr Gly Tyr 20 25 30
Tyr Met His Trp Val Arg Gln Ala Pro Gly Gln Gly Leu Glu Trp Met 35
40 45 Gly Trp Ile Asn Pro Leu Ser Asp Ser Thr Gly Ser Ala Gln Lys
Phe 50 55 60 Gln Gly Arg Val Phe Met Thr Lys Thr Thr Ser Leu Asn
Thr Ala Tyr 65 70 75 80 Met Glu Leu Ser Gly Leu Arg Ser Glu Asp Thr
Ala Ile Tyr Tyr Cys 85 90 95 Ala Arg Glu Arg Ser Ser Gly Tyr Phe
Asp Phe Trp Gly Gln Gly Thr 100 105 110 Leu Val Thr Val Ser Ser 115
240107PRTArtificial SequenceGPGH11-VL 240Asp Ile Val Met Thr Gln
Ser Pro Ser Ser Leu Ser Ala Ser Val Gly 1 5 10 15 Asp Arg Val Thr
Ile Thr Cys Arg Ala Ser Gln Ser Ile Ser Ser Tyr 20 25 30 Leu Asn
Trp Tyr Gln Gln Lys Pro Gly Lys Ala Pro Lys Leu Leu Ile 35 40 45
Tyr Ala Ala Ser Ser Leu Gln Ser Gly Val Pro Ser Arg Phe Ser Gly 50
55 60 Ser Gly Ser Gly Thr Asp Phe Thr Leu Thr Ile Ser Ser Leu Gln
Pro 65 70 75 80 Glu Asp Phe Ala Thr Tyr Tyr Cys Gln Gln Ser Tyr Ser
Thr Pro Ile 85 90 95 Thr Phe Gly Gln Gly Thr Lys Leu Glu Ile Lys
100 105 241118PRTArtificial SequenceGPGH10P-VH 241Gln Val Gln Leu
Val Gln Ser Gly Ala Glu Val Lys Lys Pro Gly Ala 1 5 10 15 Ser Val
Lys Val Ser Cys Lys Thr Ser Gly Tyr Thr Phe Thr Gly Tyr 20 25 30
Tyr Met His Trp Val Arg Gln Ala Pro Gly Gln Gly Leu Glu Trp Met 35
40 45 Gly Trp Ile Asn Pro Asn Ser Asp Asn Thr Gly Tyr Ala Gln Lys
Phe 50 55 60 Gln Gly Arg Val Phe Met Thr Lys Thr Thr Ser Leu Asn
Thr Ala Tyr 65 70 75 80 Met Glu Leu Ser Gly Leu Arg Ser Glu Asp Thr
Ala Ile Tyr Tyr Cys 85 90 95 Ala Arg Glu Arg Ser Ser Gly Tyr Phe
Asp Phe Trp Gly Gln Gly Thr 100 105 110 Leu Val Thr Val Ser Ser 115
242107PRTArtificial SequenceGPGH10P-VL 242Asp Ile Val Met Thr Gln
Ser Pro Ser Ser Leu Ser Ala Ser Val Gly 1 5 10 15 Asp Arg Val Thr
Ile Thr Cys Arg Ala Ser Gln Ser Ile Ser Ser Phe 20 25 30 Leu Asn
Trp Tyr Gln Gln Lys Pro Gly Lys Ala Pro Lys Leu Leu Ile 35 40 45
Tyr Ala Ala Ser Ser Leu Gln Ser Gly Val Pro Ser Arg Phe Ser Gly 50
55 60 Ser Gly Ser Gly Thr Asp Phe Thr Leu Thr Ile Ser Ser Leu Gln
Pro 65 70 75 80 Glu Asp Phe Ala Thr Tyr Tyr Cys Gln Gln Pro Tyr Ser
Thr Pro Ile 85 90 95 Thr Phe Gly Gln Gly Thr Lys Val Glu Ile Lys
100 105
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References