RU2795232C2 - Combined medicinal products targeting pd-1, tim-3 and lag-3 - Google Patents

Abstract

FIELD: biotechnology.

SUBSTANCE: variants of a method for enhancing immunity in a human patient that is in need of immunity enhancing are proposed. The methods include administering an anti-TIM-3 antibody and an anti-PD-1 antibody to a patient. Also a pharmaceutical composition for enhancing immunity and treating cancer, containing an antibody to TIM-3 or an antigen-binding portion thereof and an antibody to PD-1 or an antigen-binding portion thereof are provided.

EFFECT: invention provides enhanced immunity with significantly increased efficiency and can be used in cancer therapy.

19 cl, 13 dwg, 9 tbl, 12 ex

Description

Link to Related Application

[0001] The present application claims priority under U.S. Provisional Application 62/481,973, filed Apr. 5, 2017, the disclosure of which is incorporated herein by reference in its entirety.

Sequence list

[0002] This application contains a Sequence Listing that has been electronically submitted in ASCII format and is incorporated herein by reference in its entirety. The electronic copy of the sequence listing created on March 23, 2018 is named 022675_WO058_SL.txt and has a size of 232360 bits.

State of the art invention

[0003] PD-1, also known as programmed cell death protein 1 and CD279, is a 268 amino acid cell surface receptor that belongs to the immunoglobulin superfamily. PD-1 is a member of the CD28 family of T cell regulators and is expressed on T cells, B cells, and macrophages. It binds the PD-L1 (also known as the B7 homologue) and PD-L2 (also known as B7-DC) ligands. PD-1 is a type I membrane protein whose structure contains an IgV extracellular domain, a transmembrane region, and an intracellular tail containing two phosphorylation sites. Known as the immune checkpoint protein, PD-1 functions as an inducible immunomodulatory receptor involved, for example, in downregulating T cell responses to antigen challenge.

[0004] PD-L1 is the main ligand for PD-1. Binding of PD-L1 to PD-1 inhibits T cell activity, decreasing cytokine production and inhibiting T cell proliferation. Cancer cells that express PD-L1 are able to use this mechanism to inactivate the antitumor activity of T cells by binding PD-L1 to the PD-1 receptor. Because of its immune response regulating properties, PD-1 has been investigated as a potential target for immunotherapy, including the treatment of cancer and autoimmune diseases. Two anti-PD-1 antibodies, pembrolizumab and nivolumab, have been approved for the treatment of certain cancers in the US and Europe.

[0005] Other immune checkpoint proteins include TIM-3 (protein 3 containing T-cell immunoglobulin and mucin domain) and LAG-3 (lymphocyte activation gene 3). TIM-3, also known as HAVCR2 (hepatitis A virus cell receptor 2) or CD366, is a member of a family of proteins containing T-cell immunoglobulin and a mucin domain. In humans, TIM-3 is encoded by the Havcr2 gene and is a 33 kDa type I glycoprotein with an IgV membrane distal domain and a mucin membrane proximal domain. It contains a conserved region of five Tyr residues in the intracellular domain, which are phosphorylated upon ligand binding. TIM-3 is expressed by a number of different cells derived from both adaptive and innate branches of the immune system, including T cells, dendritic cells, macrophages, and natural killer (NK) cells. TIM-3 expression is low on naïve T cells, but is highly elevated when T cells are activated. Unlike T cells, innate cells such as dendritic cells, NK cells, and monocytes have a high basal expression of TIM-3. TIM-3 is associated with several, mainly promiscuous, ligands, including galectin-9, phosphatidylserine, CEACAM-1, and HMGB-1, but the exact role of these ligands is currently unknown.

[0006] Although it has been proposed that TIM-3 is a checkpoint inhibitor, there is little evidence to support the idea that TIM-3 directly mediates suppression of T cell activation or cytokine secretion in a manner similar to, for example, PD-1. Furthermore, unlike PD-1, TIM-3 appears to be important for the regulation of cells of the innate system and, in particular, dendritic cells. Most of the functional data relating to TIM-3 and its role in tumor immunology comes from in vivo studies using various antibodies. In most of these studies, due to poor screening of antibodies, it is not clear whether the action of anti-TIM-3 antibodies is mediated by inhibition of ligand binding or by agonist action on the target. Because of its immune response regulatory properties, TIM-3 has been investigated as a potential target for immunotherapy, including cancer and autoimmune diseases. One anti-TIM-3 antibody is currently in clinical development, but there are currently no approved anti-TIM-3 antibodies.

[0007] LAG-3, also known as CD223, is an immunoglobulin superfamily protein that functions as an immune checkpoint receptor. The mature protein is a 503 amino acid type I transmembrane protein with four extracellular Ig-like domains. It is expressed on various cell types, including activated T cells, T regulatory (Treg) cells, natural killer cells, B cells, and plasmacytoid dendritic cells. Information about sequence data, exon/intron organization, and chromosomal localization of LAG-3 indicates that it is closely associated with CD4. Like CD4, LAG-3 binds MHC class II molecules, albeit with higher affinity and in a separate site than CD4.

[0008] LAG-3 is a co-inhibitory receptor that is believed to regulate T cell proliferation, activation, and homeostasis in a manner similar to CTLA-4 and PD-1. Upon binding of the ligand to the extracellular domain, LAG-3 exerts its effect through subsequent signaling through the cytoplasmic domain. The best characterized ligand for LAG-3 is MHC class II (MHCII), but other LAG-3 ligands have been described, including LSECtin. LAG-3 does not have the classic ITIM or ITSM motifs, but has a conserved KIEELE motif (SEQ ID NO: 397) thought to be required for its inhibitory effect on T cell activity. The exact mechanism by which LAG-3 influences T cell activity is poorly understood. LAG-3 inhibits T cell expansion by blocking the entry of activated T cells into the growth phase of the cell cycle, leading to accumulation of cells in the S phase. It is also believed that LAG-3 is important for enhancing the inhibitory activity of regulatory T cells and for modulating dendritic cell function. Cancer cells have the ability to upregulate the expression of MHCII, which binds LAG-3 to effector T cells, thereby inhibiting their activity and causing the tumor to elude the immune response.

[0009] In view of the critical role of PD-1, LAG-3 and TIM-3 as immunomodulators, there is a need for new and improved combination drugs that target these receptors for the treatment of cancer and certain disorders of the immune system.

The essence of the invention

[0010] The present invention is based on the discovery that the immunity-enhancing efficacy of an anti-PD-1 antibody, such as described herein, is significantly enhanced when the antibody is used in combination with an anti-TIM-3 antibody and/or an anti-LAG-3 antibody. The present inventors have found that the combination drugs of the present invention are particularly effective in treating cancer in a human patient by activating the patient's own anti-cancer immunity. Compared to currently available cancer therapies, including antibody treatments, it is expected that the combination drugs of the invention can provide an excellent clinical response.

[0011] Accordingly, the present invention provides a method for enhancing immunity in a human patient in need, such as a cancer patient, by administering to the patient (1) an anti-PD-1 antibody, or an antigen-binding portion thereof, that competes with an antibody selected from the group consisting of from 12819.15384, 12748.15381, 12748.16124, 12865.15377, 12892.15378, 12796.15376, 12777.15382, 12760.15375 and 13112.15380, for linking to human PD-1 or binds to the same human PD-1 epitope as it; and (2) antibodies against TIM-3 or an antigen-binding portion thereof and/or antibodies against LAG-3 or an antigen-binding portion thereof. In some embodiments, the method includes administering an anti-PD-1 antibody or antigen-binding portion thereof, an anti-TIM-3 antibody or antigen-binding portion thereof, and an anti-LAG-3 antibody or antigen-binding portion thereof.

[0012] In some embodiments, an anti-PD-1 antibody binds to a human PD-1 epitope comprising:

a) residues V64, L128, P130, K131 and A132 SEQ ID NO: 388;

b) residues V44 and T145 SEQ ID NO: 388;

c) residues K131 and E136 SEQ ID NO: 388; or

d) residues V44 and T145 of SEQ ID NO: 388.

[0013] In some embodiments, an anti-PD-1 antibody binds to a human PD-1 epitope comprising:

a) residues 56-64, 69-90 and 122-140 of SEQ ID NO: 388;

b) residues 69-90 and 122-140 of SEQ ID NO: 388;

c) residues 69-75 of SEQ ID NO: 388;

d) residues 136-140 of SEQ ID NO: 388; or

e) residues 69-75 and 136-140 of SEQ ID NO: 388.

[0014] In some embodiments, an anti-PD-1 antibody has at least one of the following properties:

a) binds to human PD-1 with a KD of 750 pM or less;

b) binds to cynomolgus monkey PD-1 with a KD of 7 nM or less;

c) binds to mouse PD-1 with a KD of 1 nM or less;

d) does not bind to rat PD-1;

e) increases IL-2 secretion in a staphylococcal enterotoxin B (SEB) stimulated whole blood assay;

f) increases IFN-γ secretion in a mixed lymphocyte culture unidirectional reaction assay;

g) inhibits the interaction of PD-1 with PD-L1 by at least 60% at a concentration of 10 μg/ml in a competitive analysis by flow cytometry;

h) blocks the binding of PD-L1 and PD-L2 to PD-1 by at least 90% at a concentration of 10 μg/ml as determined by biolayer interferometry analysis; And

i) inhibits tumor growth in vivo.

In some embodiments, the implementation of the antibody against PD-1 has all of these properties.

[0015] In some embodiments, the heavy chain complementarity determining regions 1-3 (H-CDRs) and the light chain complementarity determining regions 1-3 (L-CDRs) of an anti-PD-1 antibody comprise the amino acid sequences of:

a) SEQ ID NO: 228-233, respectively;

b) SEQ ID NO: 238-243, respectively;

c) SEQ ID NO: 248-253, respectively;

d) SEQ ID NOs: 258-263, respectively;

e) SEQ ID NO: 268-273, respectively;

f) SEQ ID NO: 278-283, respectively;

g) SEQ ID NO: 288-293, respectively; or

h) SEQ ID NO: 298-303, respectively.

[0016] In some embodiments, the heavy and light chain variable domains of an anti-PD-1 antibody comprise amino acid sequences from:

a) SEQ ID NOs: 226 and 227, respectively;

b) SEQ ID NOs: 236 and 237, respectively;

c) SEQ ID NOs: 236 and 392, respectively;

d) SEQ ID NOs: 246 and 247, respectively;

e) SEQ ID NOs: 256 and 257, respectively;

f) SEQ ID NOs: 266 and 267, respectively;

g) SEQ ID NOs: 276 and 277, respectively;

h) SEQ ID NOs: 286 and 287, respectively; or

i) SEQ ID NOs: 296 and 297, respectively.

[0017] In some embodiments, the anti-PD-1 antibody comprises:

a) a heavy chain (HC) containing the amino acid sequence of SEQ ID NO: 226 and the amino acid sequence of SEQ ID NO: 375, and a light chain (LC) containing the amino acid sequence of SEQ ID NO: 227 and the amino acid sequence of SEQ ID NO: 379;

b) HC containing the amino acid sequence of SEQ ID NO: 236 and the amino acid sequence of SEQ ID NO: 375, and LC containing the amino acid sequence of SEQ ID NO: 237 and the amino acid sequence of SEQ ID NO: 379;

c) HC containing the amino acid sequence of SEQ ID NO: 236 and the amino acid sequence of SEQ ID NO: 375, and LC containing the amino acid sequence of SEQ ID NO: 392 and the amino acid sequence of SEQ ID NO: 379;

d) HC containing the amino acid sequence of SEQ ID NO: 246 and the amino acid sequence of SEQ ID NO: 375, and LC containing the amino acid sequence of SEQ ID NO: 247 and the amino acid sequence of SEQ ID NO: 379;

e) HC containing the amino acid sequence of SEQ ID NO: 256 and the amino acid sequence of SEQ ID NO: 375, and LC containing the amino acid sequence of SEQ ID NO: 257 and the amino acid sequence of SEQ ID NO: 379;

f) HC containing the amino acid sequence of SEQ ID NO: 266 and the amino acid sequence of SEQ ID NO: 375, and LC containing the amino acid sequence of SEQ ID NO: 267 and the amino acid sequence of SEQ ID NO: 379;

g) HC containing the amino acid sequence of SEQ ID NO: 276 and the amino acid sequence of SEQ ID NO: 375, and LC containing the amino acid sequence of SEQ ID NO: 277 and the amino acid sequence of SEQ ID NO: 379;

h) HC containing the amino acid sequence of SEQ ID NO: 286 and the amino acid sequence of SEQ ID NO: 375, and LC containing the amino acid sequence of SEQ ID NO: 287 and the amino acid sequence of SEQ ID NO: 379; or

i) HC containing the amino acid sequence of SEQ ID NO: 296 and the amino acid sequence of SEQ ID NO: 375, and LC containing the amino acid sequence of SEQ ID NO: 297 and the amino acid sequence of SEQ ID NO: 379.

[0018] In some embodiments, an anti-TIM-3 antibody competes for binding to human TIM-3 or binds to the same human TIM-3 epitope as an antibody selected from the group consisting of 15086.17145, 15086.15086, 15086.16837, 15086.17144, 20131, 20293, 15105, 15107, 15109, 15174, 15175, 15260, 15284, 15299, 15353, 15354, 17244, 17245, 19324, 19416, 19568, 20 185, 20300, 20362 and 20621.

[0019] In some embodiments, an anti-TIM-3 antibody binds to a human TIM-3 epitope comprising:

a) residues P50, V60, F61, E62, G64, R69, I117, M118 and D120 SEQ ID NO: 389;

b) residues F61, R69 and I117 of SEQ ID NO: 389; or

c) residues P50, F61, E62, I117, M118 and D120 SEQ ID NO: 389.

[0020] In some embodiments, an anti-TIM-3 antibody binds to a human TIM-3 epitope comprising:

a) residues 62-67 of SEQ ID NO: 389; or

b) residues 114-117 of SEQ ID NO: 389.

[0021] In some embodiments, the anti-TIM-3 antibody has at least one of the following properties:

a) binds to human TIM-3 with a KD of 23 nM or less as measured by surface plasmon resonance;

b) binds to cynomolgus TIM-3 with a KD of 22 nM or less as measured by surface plasmon resonance;

c) binds to human TIM-3 with an EC50 of 1.2 nM or less as measured by ELISA;

d) binds to cynomolgus TIM-3 with an EC50 of 46 nM or less as measured by ELISA;

e) increases IFN-γ secretion in a mixed lymphocyte culture unidirectional reaction assay;

f) increases IFN-γ secretion in a bidirectional mixed lymphocyte culture assay;

g) increases TNF-α secretion in a mixed lymphocyte culture unidirectional reaction assay;

h) increases the secretion of TNF-α from dendritic cells; And

i) inhibits the interaction of TIM-3 with phosphatidylserine.

In some embodiments, the anti-TIM-3 antibody has at least the properties a), c), d), e), g), h) and i).

[0022] In some embodiments, the H-CDR1-3 and L-CDR1-3 anti-TIM-3 antibodies comprise amino acid sequences from:

a) SEQ ID NO: 8-13, respectively;

b) SEQ ID NO: 18-23, respectively;

c) SEQ ID NO: 28-33, respectively;

d) SEQ ID NO: 38-43, respectively;

e) SEQ ID NO: 48-53, respectively;

f) SEQ ID NO: 58-63, respectively;

g) SEQ ID NO: 68-73, respectively;

h) SEQ ID NO: 78-83, respectively;

i) SEQ ID NO: 88-93, respectively;

j) SEQ ID NO: 98-103, respectively;

k) SEQ ID NOs: 108-113, respectively;

l) SEQ ID NO: 118-123, respectively;

m) SEQ ID NO: 128-133, respectively;

n) SEQ ID NO: 138-143, respectively;

o) SEQ ID NO: 148-153, respectively;

p) SEQ ID NOs: 158-163, respectively;

q) SEQ ID NO: 168-173, respectively;

r) SEQ ID NOs: 178-183, respectively;

s) SEQ ID NO: 188-193, respectively;

t) SEQ ID NO: 198-203, respectively;

u) SEQ ID NOs: 208-213, respectively; or

v) SEQ ID NO: 218-223, respectively.

[0023] In some embodiments, the heavy and light chain variable domains of an anti-TIM-3 antibody comprise amino acid sequences from:

a) SEQ ID NO: 7 and 4, respectively;

b) SEQ ID NO: 3 and 4, respectively;

c) SEQ ID NOs: 16 and 17, respectively;

d) SEQ ID NOs: 26 and 27, respectively;

e) SEQ ID NOs: 36 and 37, respectively;

f) SEQ ID NOs: 46 and 47, respectively;

g) SEQ ID NOs: 56 and 57, respectively;

h) SEQ ID NOs: 66 and 67, respectively;

i) SEQ ID NOs: 76 and 77, respectively;

j) SEQ ID NOs: 86 and 87, respectively;

k) SEQ ID NOs: 96 and 97, respectively;

l) SEQ ID NOs: 106 and 107, respectively;

m) SEQ ID NOs: 116 and 117, respectively;

n) SEQ ID NOs: 126 and 127, respectively;

o) SEQ ID NOs: 136 and 137, respectively;

p) SEQ ID NOs: 146 and 147, respectively;

q) SEQ ID NOs: 156 and 157, respectively;

r) SEQ ID NOs: 166 and 167, respectively;

s) SEQ ID NOs: 176 and 177, respectively;

t) SEQ ID NOs: 186 and 187, respectively;

u) SEQ ID NOs: 196 and 197, respectively;

v) SEQ ID NOs: 206 and 207, respectively; or

w) SEQ ID NOs: 216 and 217, respectively.

[0024] In some embodiments, the anti-TIM-3 antibody comprises:

a) HC containing the amino acid sequence of SEQ ID NO: 7 and the amino acid sequence of SEQ ID NO: 374, 375, 376 or 377, and LC containing the amino acid sequence of SEQ ID NO: 4 and the amino acid sequence of SEQ ID NO: 378;

b) HC containing the amino acid sequence of SEQ ID NO: 3 and the amino acid sequence of SEQ ID NO: 374, 375, 376 or 377, and LC containing the amino acid sequence of SEQ ID NO: 4 and the amino acid sequence of SEQ ID NO: 378;

c) HC containing the amino acid sequence of SEQ ID NO: 16 and the amino acid sequence of SEQ ID NO: 374, 375, 376 or 377, and LC containing the amino acid sequence of SEQ ID NO: 17 and the amino acid sequence of SEQ ID NO: 378;

d) HC containing the amino acid sequence of SEQ ID NO: 26 and the amino acid sequence of SEQ ID NO: 374, 375, 376 or 377, and LC containing the amino acid sequence of SEQ ID NO: 27 and the amino acid sequence of SEQ ID NO: 378;

e) HC containing the amino acid sequence of SEQ ID NO: 36 and the amino acid sequence of SEQ ID NO: 374, 375, 376 or 377, and LC containing the amino acid sequence of SEQ ID NO: 37 and the amino acid sequence of SEQ ID NO: 378;

f) HC containing the amino acid sequence of SEQ ID NO: 46 and the amino acid sequence of SEQ ID NO: 374, 375, 376 or 377, and LC containing the amino acid sequence of SEQ ID NO: 47 and the amino acid sequence of SEQ ID NO: 378;

g) HC containing the amino acid sequence of SEQ ID NO: 56 and the amino acid sequence of SEQ ID NO: 374, 375, 376 or 377, and LC containing the amino acid sequence of SEQ ID NO: 57 and the amino acid sequence of SEQ ID NO: 378;

h) HC containing the amino acid sequence of SEQ ID NO: 66 and the amino acid sequence of SEQ ID NO: 374, 375, 376 or 377, and LC containing the amino acid sequence of SEQ ID NO: 67 and the amino acid sequence of SEQ ID NO: 378;

i) HC containing the amino acid sequence of SEQ ID NO: 76 and the amino acid sequence of SEQ ID NO: 374, 375, 376 or 377, and LC containing the amino acid sequence of SEQ ID NO: 77 and the amino acid sequence of SEQ ID NO: 378;

j) HC containing the amino acid sequence of SEQ ID NO: 86 and the amino acid sequence of SEQ ID NO: 374, 375, 376 or 377, and LC containing the amino acid sequence of SEQ ID NO: 87 and the amino acid sequence of SEQ ID NO: 378;

k) HC containing the amino acid sequence of SEQ ID NO: 96 and the amino acid sequence of SEQ ID NO: 374, 375, 376 or 377, and LC containing the amino acid sequence of SEQ ID NO: 97 and the amino acid sequence of SEQ ID NO: 378;

l) HC containing the amino acid sequence of SEQ ID NO: 106 and the amino acid sequence of SEQ ID NO: 374, 375, 376 or 377, and LC containing the amino acid sequence of SEQ ID NO: 107 and the amino acid sequence of SEQ ID NO: 378;

m) HC containing the amino acid sequence of SEQ ID NO: 116 and the amino acid sequence of SEQ ID NO: 374, 375, 376 or 377, and LC containing the amino acid sequence of SEQ ID NO: 117 and the amino acid sequence of SEQ ID NO: 378;

n) HC containing the amino acid sequence of SEQ ID NO: 126 and the amino acid sequence of SEQ ID NO: 374, 375, 376 or 377, and LC containing the amino acid sequence of SEQ ID NO: 127 and the amino acid sequence of SEQ ID NO: 378;

o) HC containing the amino acid sequence of SEQ ID NO: 136 and the amino acid sequence of SEQ ID NO: 374, 375, 376 or 377, and LC containing the amino acid sequence of SEQ ID NO: 137 and the amino acid sequence of SEQ ID NO: 378;

p) HC containing the amino acid sequence of SEQ ID NO: 146 and the amino acid sequence of SEQ ID NO: 374, 375, 376 or 377, and LC containing the amino acid sequence of SEQ ID NO: 147 and the amino acid sequence of SEQ ID NO: 378;

q) HC containing the amino acid sequence of SEQ ID NO: 156 and the amino acid sequence of SEQ ID NO: 374, 375, 376 or 377, and LC containing the amino acid sequence of SEQ ID NO: 157 and the amino acid sequence of SEQ ID NO: 378;

r) HC containing the amino acid sequence of SEQ ID NO: 166 and the amino acid sequence of SEQ ID NO: 374, 375, 376 or 377, and LC containing the amino acid sequence of SEQ ID NO: 167 and the amino acid sequence of SEQ ID NO: 378;

s) HC containing the amino acid sequence of SEQ ID NO: 176 and the amino acid sequence of SEQ ID NO: 374, 375, 376 or 377, and LC containing the amino acid sequence of SEQ ID NO: 177 and the amino acid sequence of SEQ ID NO: 378;

t) HC containing the amino acid sequence of SEQ ID NO: 186 and the amino acid sequence of SEQ ID NO: 374, 375, 376 or 377, and LC containing the amino acid sequence of SEQ ID NO: 187 and the amino acid sequence of SEQ ID NO: 378;

u) HC containing the amino acid sequence of SEQ ID NO: 196 and the amino acid sequence of SEQ ID NO: 374, 375, 376 or 377, and LC containing the amino acid sequence of SEQ ID NO: 197 and the amino acid sequence of SEQ ID NO: 378;

v) HC containing the amino acid sequence of SEQ ID NO: 206 and the amino acid sequence of SEQ ID NO: 374, 375, 376 or 377, and LC containing the amino acid sequence of SEQ ID NO: 207 and the amino acid sequence of SEQ ID NO: 378; or

w) HC containing the amino acid sequence of SEQ ID NO: 216 and the amino acid sequence of SEQ ID NO: 374, 375, 376 or 377, and LC containing the amino acid sequence of SEQ ID NO: 217 and the amino acid sequence of SEQ ID NO: 378.

[0025] In some embodiments, an anti-LAG-3 antibody competes with an antibody selected from the group consisting of 15532, 15646, 15723, 15595, 15431, 15572, and 15011 for binding to human LAG-3 or binds to the same epitope LAG-3 man, which is it.

[0026] In some embodiments, an anti-LAG-3 antibody binds to a human LAG-3 epitope comprising:

a) residues H85, P86, A87, P89, S91, W92 and G93 SEQ ID NO: 68;

b) residues A40, Q41, P43, P46, P49, D52, T62, Q64, H65, Q66, P67, D68, G93, P94, P96, R98, Y99, T100, V101, P106, G107, R119, E124, R129 , G130, D131, S133, R137, P138, D143, R148 and R163 SEQ ID NO: 68;

c) residues A40, Q41, P43, P46, P49, D52, T62, Q64, H65, Q66, P67, D68, P96, Y99, T100, V101, P106, G107, R119, E124, R129, G130, D131, S133 , R137, P138, D143, R148 and R163 SEQ ID NO: 68; or

d) residues G107, L109, R110 and S111 of SEQ ID NO: 68.

[0027] In some embodiments, an anti-LAG-3 antibody binds to a human LAG-3 epitope comprising:

a) residues 98-105 of SEQ ID NO: 68;

b) residues 78-105 and 123-131 of SEQ ID NO: 68;

c) residues 23-30, 40-66, 88-105, 123-137 and 148-152 of SEQ ID NO: 68; or

d) residues 23-30, 40-66, 98-105, 118-137 and 148-161 of SEQ ID NO: 68.

[0028] In some embodiments, an anti-LAG-3 antibody has at least one of the following properties:

a) at a concentration of 20 μg/ml, it reduces the binding of human LAG-3 to human class II MHC in A375 cells by more than 85% compared to a negative control antibody, as determined by competitive analysis by flow cytometry;

b) at a concentration of 20 μg/ml reduces the binding of human LAG-3 to human class II MHC in A375 cells by up to 35%-85% compared to a negative control antibody, as determined by competitive analysis by flow cytometry;

c) blocks binding between human LAG-3 expressed in Jurkat cells and human class II MHC expressed in Raji cells;

d) binds to human LAG-3 with an EC50 of 0.1 nM or less as measured by flow cytometry;

e) binds to cynomolgus monkey LAG-3 with an EC50 of 0.3 nM or less as measured by flow cytometry;

f) binds to human LAG-3 with a KD of 3.0 x 10 ^-8 or less as measured by surface plasmon resonance;

g) binds to cynomolgus monkey LAG-3 with a KD of 1.5 x 10 ^-7 or less as measured by surface plasmon resonance;

h) binds to mouse LAG-3 with a KD of 3.5 x 10 ^-8 or less as measured by surface plasmon resonance;

i) stimulates IL-2 production in staphylococcal enterotoxin B (SEB) treated human peripheral blood mononuclear cells (PBMC);

j) reduces cellular levels of LAG-3 in human T cells;

k) reduces soluble levels of LAG-3 in cultured human T cells;

l) induces regression of tumor growth in vivo;

m) inhibits tumor growth in vivo; And

n) does not bind to the same human LAG-3 epitope as the 25F7-Lag3.5 antibody.

In some embodiments, an anti-LAG-3 antibody has at least the properties a), c), d), e), f), g), i), j), k), m) and n).

[0029] In some embodiments, the H-CDR1-3 and L-CDR1-3 anti-LAG-3 antibodies comprise amino acid sequences from:

a) SEQ ID NO: 318-323, respectively;

b) SEQ ID NO: 308-313, respectively;

c) SEQ ID NO: 328-333, respectively;

d) SEQ ID NO: 338-343, respectively;

e) SEQ ID NO: 348-353, respectively;

f) SEQ ID NO: 358-363, respectively; or

g) SEQ ID NO: 368-373, respectively.

[0030] In some embodiments, the heavy and light chain variable domains of an anti-LAG-3 antibody comprise amino acid sequences from:

a) SEQ ID NOs: 316 and 317, respectively;

b) SEQ ID NOs: 306 and 307, respectively;

c) SEQ ID NOs: 326 and 327, respectively;

d) SEQ ID NOs: 336 and 337, respectively;

e) SEQ ID NOs: 346 and 347, respectively;

f) SEQ ID NOs: 356 and 357, respectively; or

g) SEQ ID NOs: 366 and 367, respectively.

[0031] In some embodiments, the anti-LAG-3 antibody comprises:

a) HC containing the amino acid sequence of SEQ ID NO: 316 and the amino acid sequence of SEQ ID NO: 375, and LC containing the amino acid sequence of SEQ ID NO: 317 and the amino acid sequence of SEQ ID NO: 378;

b) HC containing the amino acid sequence of SEQ ID NO: 306 and the amino acid sequence of SEQ ID NO: 375, and LC containing the amino acid sequence of SEQ ID NO: 307 and the amino acid sequence of SEQ ID NO: 378;

c) HC containing the amino acid sequence of SEQ ID NO: 326 and the amino acid sequence of SEQ ID NO: 375, and LC containing the amino acid sequence of SEQ ID NO: 327 and the amino acid sequence of SEQ ID NO: 378;

d) HC containing the amino acid sequence of SEQ ID NO: 336 and the amino acid sequence of SEQ ID NO: 375, and LC containing the amino acid sequence of SEQ ID NO: 337 and the amino acid sequence of SEQ ID NO: 378;

e) HC containing the amino acid sequence of SEQ ID NO: 346 and the amino acid sequence of SEQ ID NO: 375, and LC containing the amino acid sequence of SEQ ID NO: 347 and the amino acid sequence of SEQ ID NO: 378;

f) HC containing the amino acid sequence of SEQ ID NO: 356 and the amino acid sequence of SEQ ID NO: 375, and LC containing the amino acid sequence of SEQ ID NO: 357 and the amino acid sequence of SEQ ID NO: 378; or

g) HC containing the amino acid sequence of SEQ ID NO: 366 and the amino acid sequence of SEQ ID NO: 375, and LC containing the amino acid sequence of SEQ ID NO: 367 and the amino acid sequence of SEQ ID NO: 379.

[0032] In some embodiments, the method includes administering to the patient:

a) antibodies against PD-1, H-CDR1-3 and L-CDR1-3 which contain the amino acid sequence of SEQ ID NO: 228-233, respectively; and antibodies against TIM-3, H-CDR1-3 and L-CDR1-3 which contain the amino acid sequence of SEQ ID NO: 8-13, respectively;

b) antibodies against PD-1, VH and VL which contain the amino acid sequence of SEQ ID NO: 226 and 227, respectively; and antibodies against TIM-3, VH and VL which contain the amino acid sequence of SEQ ID NO: 7 and 4, respectively; or

c) an anti-PD-1 antibody containing an HC which contains the amino acid sequences of SEQ ID NOs: 226 and 375 and an LC which contains the amino acid sequences of SEQ ID NOs: 227 and 379; and an anti-TIM-3 antibody containing an HC that contains the amino acid sequences of SEQ ID NOs: 7 and 377, and an LC that contains the amino acid sequences of SEQ ID NOs: 4 and 378.

[0033] In some embodiments, the method includes administering to the patient:

a) antibodies against PD-1, H-CDR1-3 and L-CDR1-3 which contain the amino acid sequence of SEQ ID NO: 228-233, respectively; and antibodies against LAG-3, H-CDR1-3 and L-CDR1-3 which contain the amino acid sequence of SEQ ID NO: 318-323, respectively;

b) antibodies against PD-1, VH and VL which contain the amino acid sequence of SEQ ID NO: 226 and 227, respectively; and antibodies against LAG-3, VH and VL which contain the amino acid sequence of SEQ ID NO: 316 and 317, respectively; or

c) an anti-PD-1 antibody containing an HC which contains the amino acid sequences of SEQ ID NOs: 226 and 375 and an LC which contains the amino acid sequences of SEQ ID NOs: 227 and 379; and an anti-LAG-3 antibody containing an HC that contains the amino acid sequences of SEQ ID NOs: 316 and 375, and an LC that contains the amino acid sequences of SEQ ID NOs: 317 and 378.

[0034] In some embodiments, the method includes administering to the patient:

a) antibodies against PD-1, H-CDR1-3 and L-CDR1-3 which contain the amino acid sequence of SEQ ID NO: 228-233, respectively; antibodies against TIM-3, H-CDR1-3 and L-CDR1-3 which contain the amino acid sequence of SEQ ID NO: 8-13, respectively; and antibodies against LAG-3, H-CDR1-3 and L-CDR1-3 which contain the amino acid sequence of SEQ ID NO: 318-323, respectively;

b) antibodies against PD-1, VH and VL which contain the amino acid sequence of SEQ ID NO: 226 and 227, respectively; antibodies against TIM-3, VH and VL which contain the amino acid sequence of SEQ ID NO: 7 and 4, respectively; and antibodies against LAG-3, VH and VL which contain the amino acid sequence of SEQ ID NO: 316 and 317, respectively; or

c) an anti-PD-1 antibody containing an HC which contains the amino acid sequences of SEQ ID NOs: 226 and 375 and an LC which contains the amino acid sequences of SEQ ID NOs: 227 and 379; antibodies against TIM-3 containing HC, which contains the amino acid sequences of SEQ ID NO: 7 and 377, and LC, which contains the amino acid sequence of SEQ ID NO: 4 and 378; and an anti-LAG-3 antibody containing an HC that contains the amino acid sequences of SEQ ID NOs: 316 and 375, and an LC that contains the amino acid sequences of SEQ ID NOs: 317 and 378.

[0035] Antibodies or antigen-binding portions can be administered to a patient simultaneously (eg, in a single pharmaceutical composition) or sequentially.

[0036] The medicaments of the present invention are useful in treating a patient who has a cancer, such as a hematologic malignancy (eg, leukemia, Hodgkin's lymphoma, or non-Hodgkin's lymphoma) or a solid tumor. In some embodiments, the patient may have melanoma, non-small cell lung cancer, bladder cancer, head and neck squamous cell carcinoma, ovarian cancer, colon cancer, renal cell carcinoma, Merkel cell carcinoma, fibrosarcoma, gliosarcoma, or glioblastoma. Further, the medicaments of the present invention may include radiation or at least one of a chemotherapeutic agent, an antitumor agent, and an antiangiogenic agent.

[0037] Also provided herein is a polyspecific (eg, bispecific or trispecific) antibody that specifically binds to: a) human PD-1 and human TIM-3; b) human PD-1 and human LAG-3; or c) human PD-1, human TIM-3, and human LAG-3. In some embodiments, a polyspecific antibody comprises an antigen-binding portion of an anti-PD-1 antibody as described herein, an antigen-binding portion of an anti-TIM-3 antibody as described herein, and/or an antigen-binding portion of an anti-LAG-3 antibody as described herein. document.

[0038] Also provided herein is a pharmaceutical composition comprising (1) an anti-PD-1 antibody or antigen-binding portion thereof as described herein, (2) an anti-TIM-3 antibody or antigen-binding portion thereof and/or an anti-LAG- 3 or an antigen-binding portion thereof; and (3) a pharmaceutically acceptable adjuvant. The anti-TIM-3 antibody and the anti-LAG-3 antibody can be selected from those described herein.

[0039] In some embodiments, the implementation of the pharmaceutical composition contains:

a) an antibody against PD-1, H-CDR1-3 and L-CDR1-3 which contain the amino acid sequence of SEQ ID NO: 228-233, respectively; antibody against TIM-3, H-CDR1-3 and L-CDR1-3 which contain the amino acid sequence of SEQ ID NO: 8-13, respectively; and an antibody against LAG-3, H-CDR1-3 and L-CDR1-3 which contain the amino acid sequence of SEQ ID NO: 318-323, respectively;

b) an anti-PD-1 antibody whose VH and VL comprise the amino acid sequences of SEQ ID NOs: 226 and 227, respectively; an antibody against TIM-3, VH and VL which contain the amino acid sequence of SEQ ID NO: 7 and 4, respectively; and an anti-LAG-3 antibody whose VH and VL comprise the amino acid sequences of SEQ ID NOs: 316 and 317, respectively; or

c) an anti-PD-1 antibody comprising a HC which contains the amino acid sequences of SEQ ID NOs: 226 and 375 and an LC which contains the amino acid sequences of SEQ ID NOs: 227 and 379; an antibody against TIM-3 containing HC, which contains the amino acid sequences of SEQ ID NO: 7 and 377, and LC, which contains the amino acid sequence of SEQ ID NO: 4 and 378; and an anti-LAG-3 antibody containing an HC that contains the amino acid sequences of SEQ ID NOS: 316 and 375 and an LC that contains the amino acid sequences of SEQ ID NOS: 317 and 378.

[0040] Antibodies in the composition can be provided in equal amounts. In some embodiments, the pharmaceutical composition is for use in the treatment of a human patient in the method described herein. In certain embodiments, the pharmaceutical composition is for use in enhancing immunity in a human patient in need, such as in the treatment of cancer.

[0041] The present invention also provides an anti-PD-1 antibody, or an antigen-binding portion thereof, as described herein, for use in the method of treatment described herein, for example, to enhance immunity and/or treat cancer in a patient in need thereof. -human in combination with an anti-TIM-3 antibody or antigen-binding portion thereof and/or an anti-LAG-3 antibody or antigen-binding portion thereof. The anti-TIM-3 antibody and the anti-LAG-3 antibody can be selected from those described herein.

[0042] The present invention also provides an anti-PD-1 antibody, or an antigen-binding portion thereof, as described herein, for use in treating a human patient in the method described herein.

[0043] The present invention also provides the use of an anti-PD-1 antibody, or an antigen-binding portion thereof, as described herein, for the preparation of a medicament for enhancing immunity and/or treating cancer in a patient (e.g., a human patient) in need thereof in combinations with an anti-TIM-3 antibody or antigen-binding portion thereof and/or an anti-LAG-3 antibody or antigen-binding portion thereof. In some embodiments, the present invention provides the use of an anti-PD-1 antibody, or antigen-binding portion thereof, as described herein, and an anti-TIM-3 antibody, or antigen-binding portion thereof, and/or an anti-LAG-3 antibody, or antigen-binding portion thereof, to obtain a drug for enhancing immunity in a human patient in need thereof, for example for the treatment of cancer. The anti-TIM-3 antibody and the anti-LAG-3 antibody can be selected from those described herein.

[0044] The present invention also provides the use of an anti-PD-1 antibody, or an antigen-binding portion thereof, as described herein, for the preparation of a medicament for the treatment of a human patient in the method described herein.

[0045] The present invention further provides an article of manufacture comprising an anti-PD-1 antibody, or antigen-binding portion thereof, as described herein, in combination with an anti-TIM-3 antibody, or antigen-binding portion thereof, and/or an anti-LAG-3 antibody, or an antigen-binding portion thereof. antigen-binding part, and the specified finished product is suitable for enhancing immunity and/or treating cancer in a patient (such as a human patient), for example, in the method of treatment described herein. The anti-TIM-3 antibody and the anti-LAG-3 antibody can be selected from those described herein.

Brief description of drawings

[0046] FIG. 1 is a set of graphs showing the percentage increase in IFN-γ levels in three donor pairs (Panels A-C) after treatment with 10 μg/ml control antibody (LALA or IgG2 IgG1), anti-PD-1 antibody 12819, anti-TIM-3.17145 antibody 15086, or combination antibodies 12819 and 15086.17145 in a 1:1 ratio after 5 days of culture in a unidirectional MLR (Mixed Lymphocyte Culture Reaction) assay. Each point on the graph represents a double value, and the average value is shown as a horizontal bar.

[0047] FIG. 2 is a set of graphs showing the percentage increase in IFN-γ levels in three pairs of donors (Panels A-C) after treatment with 10 μg/ml control antibody (LALA IgG1 or IgG2), anti-PD-1 antibody 12819, anti-TIM-3.17145 antibody 15086, or combination antibodies 12819 and 15086.17145 in a 1:1 ratio after 5 days of culture in a bidirectional MLR assay. Each point on the graph represents a double value, and the average value is shown as a horizontal bar.

[0048] FIG. 3 is a pair of graphs showing the effect of anti-TIM-3.17145 antibody 15086 versus positive control anti-PD-1 antibody 12819 on T cell proliferation in a unidirectional MLR assay. Antibodies were added to a final concentration of 25 μg/ml and incubated with or without soluble anti-CD3 antibodies (Panel B) or without (Panel A) for 5 days before adding 1 μCi/well of 3H-thymidine for a further 18 hours. 3H-thymidine incorporation into harvested cells was determined using a liquid scintillation counter.

[0049] FIG. 4 is a graph showing the effect of anti-TIM-3.17145 antibody 15086 on IL-12p40 secretion from monocyte-derived dendritic cells incubated for 5 days with 10 μg/ml of antibody. The levels of IL-12p40 in cell supernatants were determined using ELISA.

[0050] FIG. 5 is a pair of graphs showing expression levels of selected activation markers in monocyte-derived dendritic cells after treatment with 25 μg/ml of anti-TIM-3.17145 antibody 15086 for 24 hours. Panel A shows gene expression analysis of several activation markers and co-stimulatory molecules. Panel B shows confirmation of elevated CD80 and Cd86 levels using FACS. The histogram overlays shown represent CD11c+ dendritic cells and the numbers next to the histograms indicate MFI (Mean Fluorescence Intensity) values.

[0051] FIG. 6 is a graph showing the effect of TIM-3 targeting on tumor growth in a CD34+ humanized NSG-SGM3 mouse model implanted with a Human Patient Lung (PDX)-derived LG1306 xenograft model. Mice were treated with anti-TIM-3 antibody 15086.17145 at an initial dose of 10 mg/kg followed by 5 mg/kg 5x Q5D. The gray area indicates the treatment period. Data are presented as means ± SEM. **p<0.01.

[0052] In FIG. 7 is a pair of graphs showing the enhanced effect on IL-2 levels of combining anti-PD-1 antibody 12819 with anti-LAG-3 antibody 15532 and/or anti-TIM-3 antibody 15086.17145 in the SEB (staphylococcal enterotoxin B) + PBMC (peripheral mononuclear cells) assay. blood) for two pairs of donors (Panels A and B). The bars show the secretion of IL-2 from PBMC treated with 10 μg/ml of the indicated antibodies or mixtures of antibodies and SEB for 48 hours. The symbols above the bars indicate a single treatment that is significantly different (p<0.05) from the control antibody (*), or a mixture of two antibodies that is significantly different from the treatment with the constituent single antibodies (#).

[0053] FIG. 8 is a pair of graphs showing the effect on tumor growth of 10 mg/kg anti-PD-1 antibody 12819, anti-LAG-3 antibody C9B7W (which is capable of reacting with mouse LAG-3), or a combination of anti-PD-1 and anti-LAG-3 antibodies, or neutral base treatment in two syngeneic mouse tumor models: MC38 (colon cancer, Panel A) and ASB-XIV (lung cancer, Panel B). The gray area indicates the treatment period. Data are presented as means ± SEM (standard error of the mean). **p<0.01, ***p<0.001, ****p<0.0001.

[0054] FIG. 9 is a graph showing the effect on tumor growth of 10 mg/kg anti-PD-1 antibody 12819, anti-LAG-3 antibody 15011, or a combination of anti-PD-1 and anti-LAG-3 antibodies, or neutral base treatment, in ASB-XIV syngeneic mouse tumor models. The gray area indicates the treatment period. Data are presented as means ± SEM. *p<0.05, ****p<0.0001.

[0055] FIG. 10 is a pair of graphs showing the effect on tumor growth of anti-PD-1 antibody 12819, anti-TIM-3 antibody 5D12, or a combination of anti-PD-1 and anti-TIM-3 antibodies, or the effect of neutral base treatment on tumor growth in two syngeneic mouse tumor models: ASB-XIV (lung cancer, Panel A) and Sa1N (fibrosarcoma, Panel B). Antibody treatment in mice with ASB-XIV tumors was performed at a dose of 10 mg/kg/target. Mice with Sa1N tumors were injected with anti-PD-1 and anti-TIM-3 antibodies at a dose of 1 mg/kg and 10 mg/kg, respectively. The gray area indicates the treatment period. Data are presented as means ± SEM. **p<0.01, ***p<0.001, and ****p<0.0001.

[0056] FIG. 11 is a set of graphs showing the effect on tumor growth of 10 mg/kg anti-PD-1 antibody 12819, anti-TIM-3 antibody 15086, or a combination of anti-PD-1 and anti-TIM-3 antibodies, or treatment with a neutral base in a human xenograft tumor model, where mice with reconstituted human PBMCs were implanted with the A375 human melanoma cell line. A single human PBMC donor was used in each experiment, and three different donors are shown in the three graphs (Panels A-C). The gray area indicates the treatment period. Data are presented as means ± SEM. *p<0.05 and **p<0.01.

[0057] FIG. 12 is a set of graphs showing the effect of single and dual targeting of PD-1 and TIM-3 on percentage survival (Panel A) and tumor growth (Panel BE) in NOD-scid mice implanted with a mixture of human PBMC and A375 melanoma cells. Mice were treated with anti-PD-1 antibody 12819, anti-TIM-3 antibody 15086.17145, or a combination of anti-PD-1 and anti-TIM-3 antibodies. Antibody treatment was performed at a dose of 10 mg/kg three times a week for each antibody. The gray area indicates the treatment period. Data in panel A are presented as the percentage of mice with tumor size <400 mm ³ in each treatment group over time.

[0058] FIG. 13 is a set of graphs showing the effect of single, dual and triple targeting of PD-1, LAG-3 and TIM-3 on percent survival (Panel A) and tumor growth (Panels B-H) in a syngeneic ASB-XIV tumor model using antibody 12819 anti-PD-1, anti-LAG-3 antibody C9B7W, anti-TIM-3 antibody 5D12, combination of anti-PD1 and anti-LAG3 antibodies, combination of anti-PD1 and anti-TIM-3 antibodies or “triple combination” (which refers to the combination of anti-PD1 and anti-LAG3 antibodies). 1, against LAG-3 and against TIM-3). Antibody treatment was performed at a dose of 10 mg/kg for each antibody. The gray area indicates the treatment period.

Detailed Description of the Invention

[0059] The present invention provides novel combination drugs and compositions that target human PD-1, human TIM-3, and/or human LAG-3 through the use of antibodies that bind these targets. Drugs and compositions can be used to enhance the immune system in a human patient, such as a cancer patient. For the purposes of the present invention, unless otherwise indicated, "PD-1" refers to human PD-1. The human PD-1 polypeptide sequence is available under Uniprot Accession Q15116, shown herein as SEQ ID NO: 388. As used herein, unless otherwise indicated, "TIM-3" refers to human TIM-3. The human TIM-3 polypeptide sequence is available under Uniprot Accession Q8TDQ0, shown herein as SEQ ID NO: 389. As used herein, unless otherwise indicated, "LAG-3" refers to human LAG-3. The human LAG-3 polypeptide sequence is available under Uniprot Accession P18627, shown herein as SEQ ID NO: 390.

[0060] The term "antibody" (Ab) or "immunoglobulin" (Ig), in the context of the present invention, refers to a tetramer containing two heavy (H) chains (approximately 50-70 kDa) and two light (L) chains (approximately 25 kDa) linked by disulfide bonds. Each heavy chain is composed of a heavy chain variable domain (VH) and a heavy chain constant region (CH). Each light chain is composed of a light chain variable domain (VL) and a light chain constant region (CL). The VH and VL domains can be further subdivided into regions of hypervariability called "complementarity determining regions" (CDRs) interspersed with regions that are more conserved, called "framework regions" (FRs). Each VH and VL consists of three CDRs (H-CDR herein denotes the heavy chain CDR; and L-CDR herein denotes the light chain CDR) and four FRs arranged from amino to carboxyl in the following order: FR1, CDR1, FR2, CDR2, FR3, CDR3, FR4. Assignment of amino acid numbers in the heavy or light chain can be according to the definitions of IMGT® (Lefranc et al. Dev Comp Immunol 27(1):55-77 (2003)); or the definitions of Kabat, Sequences of Proteins of Immunological Interest (National Institutes of Health, Bethesda, MD (1987 and 1991)); Chothia & Lesk, J. Mol. Biol. 196:901-917 (1987); or Chothia et al. Nature 342:878-883 (1989). Unless otherwise indicated, all amino acid residue numbers of antibodies referred to in this disclosure are numbers according to the IMGT® numbering scheme.

[0061] The term "recombinant antibody" refers to an antibody that is expressed from a cell or cell line containing a nucleotide sequence(s) that encode an antibody, said nucleotide sequence(s) not naturally associated with the cell.

[0062] The term "isolated protein", "isolated polypeptide" or "isolated antibody" refers to a protein, polypeptide or antibody that, due to its origin or source of production (1), is not associated with naturally associated components that accompany it in native condition, (2) do not contain other proteins of the same species, (3) are expressed by a cell of a different species, and/or (4) do not occur naturally. Thus, a polypeptide that is chemically synthesized or synthesized in a cellular system other than the cell from which it naturally originates will be "isolated" from its naturally associated components. The protein can also be made substantially free of naturally associated components by isolation using protein purification techniques well known in the art.

[0063] The term "affinity" refers to a measure of attraction between an antigen and an antibody. The inherent strength of attraction of an antibody to an antigen is usually expressed as the binding affinity equilibrium constant (KD) of a particular antibody-antigen interaction. An antibody is said to specifically bind to an antigen when the KD is ≤ 1 mM, preferably ≤ 100 nM. The binding affinity constant KD can be measured, for example, using surface plasmon resonance (SPR) (BIAcoreTM) or biolayer interferometry, for example, using the IBIS MX96 SPR system from IBIS Technologies, the ProteOnTM XPR36 SPR system from Bio-Rad, or the OctetTM system from ForteBio.

[0064] The term "koff" refers to the dissociation rate constant of a particular antibody-antigen interaction. The dissociation rate constant koff can be measured, for example, using biolayer interferometry, for example using one of the systems listed above.

[0065] The term "epitope" in the context of the present invention refers to a site (determinant) of an antigen that specifically binds to an antibody or associated molecule, such as a bespecifically binding molecule. Epitopic determinants usually consist of chemically active surface groups of molecules, such as amino acid or carbohydrate or sugar side chains, and usually have specific three-dimensional structural characteristics as well as specific charge characteristics. An epitope may be "linear" or "conformational". In a linear epitope, all points of interaction between a protein (eg, an antigen) and an interacting molecule (such as an antibody) are located linearly along the protein's primary amino acid sequence. In a conformational epitope, interaction points are located across amino acid residues on a protein that are separated from each other in the primary amino acid sequence. Once a desired epitope has been determined on an antigen, antibodies to that epitope can be generated using techniques well known in the art. For example, an antibody to a linear epitope can be obtained, for example, by immunizing an animal with a peptide having the amino acid residues of the linear epitope. An antibody to a conformational epitope can be obtained, for example, by immunizing an animal with a mini-domain containing the corresponding amino acid residues of the conformational epitope. An antibody to a particular epitope can also be generated, for example, by immunizing an animal with the target molecule of interest, or an appropriate portion thereof, then screening for epitope binding.

[0066] Whether an antibody binds to or competes for binding to the same epitope as an antibody as described herein can be determined using methods known in the art, including, but not limited to, competition assays, epitope -specific sorting and alanine scanning. In some embodiments, a test antibody and an antibody as described herein bind to at least one common residue (e.g., at least two, three, four, five, six, seven, eight, or nine residues) on a protein targets (i.e. TIM-3, PD-1 or LAG-3). In additional embodiments, contact residues in the target protein are completely identical between the antibody being tested and the antibody as described herein. In one embodiment, an antibody as described herein is provided to bind to a target protein under saturation conditions, and then the ability of the test antibody to bind to the target protein is measured. If the test antibody is able to bind to the target protein at the same time as the reference antibody, then the test antibody binds to a different epitope than the reference antibody. However, if the test antibody is unable to simultaneously bind to the target protein, then the test antibody binds to the same epitope, an overlapping epitope, or an epitope that is in close proximity to an epitope bound by an antibody as described herein. This experiment can be performed using, for example, ELISA, RIA, BIACORETM, SPR, biolayer interferometry or flow cytometry. To test whether an antibody competes with another antibody, the bidirectional competition method described above can be applied, i.e. determining whether a known antibody blocks a test antibody and vice versa. Such cross-competition experiments can be performed using, for example, the IBIS MX96 SPR instrument or the OctetTM system.

[0067] The term "chimeric antibody" in the broadest sense refers to an antibody that contains one or more regions from one antibody and one or more regions from one or more other antibodies, usually an antibody that is part human and part non-human origin, i.e. derived in part from a non-human animal, such as a mouse, rat, or other rodent or bird, such as a chicken. Chimeric antibodies are preferred over non-human antibodies to reduce the risk of an antibody response in humans, such as a human anti-mouse antibody response in the case of a mouse antibody. An example of a conventional chimeric antibody is one in which the variable domain sequences are murine while the constant region sequences are human. In the case of a chimeric antibody, the non-human portions may be further altered to humanize the antibody. The chimeric antibodies described herein have chicken variable domain sequences and human constant region sequences.

[0068] The term "humanize" refers to the fact that when an antibody is wholly or partly non-human in origin (e.g., a mouse or chicken antibody obtained by immunizing mice or chickens, respectively, with an antigen of interest, or a chimeric antibody based on such a mouse or chicken antibody), it is possible to replace some amino acids, in particular in the framework regions and constant regions of the heavy and light chains, in order to avoid or minimize the immune response in humans. Although it is not possible to accurately predict the immunogenicity, and hence the antibody response, in humans to a particular antibody, non-human antibodies tend to be more immunogenic in humans than human antibodies. It has been shown that chimeric antibodies where foreign constant regions (eg, rodents or birds) have been replaced with human-derived sequences are generally less immunogenic than fully foreign-derived antibodies, and there is a trend towards humanized or fully human antibodies in therapeutic antibodies. Thus, to reduce the risk of an antibody response in humans, chimeric antibodies or other non-human antibodies can be humanized.

[0069] For chimeric antibodies, humanization typically involves modifying the framework regions of the variable domain sequences. Due to humanization, amino acid residues that are part of the complementarity-determining regions (CDRs) should most often not be changed, although in some cases it may be necessary to change individual CDR amino acid residues, for example, to remove a glycosylation site, a deamidation site, an aspartate isomerization site, or an unnecessary cysteine or methionine residue. N-linked glycosylation occurs by attaching an oligosaccharide chain to an asparagine residue in the tripeptide sequence Asn-X-Ser or Asn-X-Thr, where X can be any amino acid except Pro. Removal of the N-glycosylation site can be achieved by mutating either the Asn or Ser/Thr residue with another residue, preferably by conservative substitution. Deamidation of asparagine and glutamine residues can occur depending on factors such as pH and surface exposure. Asparagine residues are particularly sensitive to deamidation, primarily when they are present in the Asn-Gly sequence, and to a lesser extent in other dipeptide sequences such as Asn-Ala. When such a deamidation site, in particular Asn-Gly, is present in the CDR sequence, it may therefore be desirable to remove the site, usually by conservative substitution, to remove one of the residues involved.

[0070] Many methods are known in the art for humanizing an antibody sequence; see, for example, a review by Almagro & Fransson, Front Biosci. 13:1619-1633 (2008). One commonly used method is CDR transplantation, which, for example, for a chimeric mouse-derived antibody, involves identifying human germline analogs from mouse variable domain genes and transplanting mouse CDR sequences into this framework. The specificity of the interaction of an antibody with a target antigen lies mainly in the amino acid residues located in the six CDRs of the heavy and light chains. Therefore, the amino acid sequences within the CDR are much more variable between individual antibodies than those outside the CDR. Because CDR sequences are responsible for most antibody-antigen interactions, it is possible to express recombinant antibodies that mimic the properties of a specific naturally occurring antibody, or more generally any specific antibody with a given amino acid sequence, for example, by constructing expression vectors that express the CDR sequences. from a particular antibody, transplanted into framework sequences from another antibody. As a result, it is possible to "humanize" a non-human antibody and still substantially retain the binding specificity and affinity of the original antibody. CDR transplantation may be based on Kabat's CDR definitions, although a later publication (Magdelaine-Beuzelin et al., Crit Rev. Oncol Hematol. 64: 210-225 (2007)) suggested that the IMGT® (International Information System®) definition ImMunoGeneTics, www.imgt.org) can improve humanization outcome (see Lefranc et al., Dev. Comp Immunol. 27: 55-77 (2003)).

[0071] In some cases, CDR transplantation can reduce the binding specificity and affinity, and therefore the biological activity, of the CDR-grafted non-human antibody compared to the parent antibody from which the CDRs are derived. To restore the specificity and binding affinity of the parent antibody, backmutations (sometimes referred to as "frame repair") can be introduced into selected positions of the CDR-grafted antibody, usually in the framework regions. Positions for possible backmutations can be identified using information available in the literature and antibody databases. Amino acid residues that are candidates for backmutation are usually those that are on the surface of the antibody molecule, while residues that are on the inside or that have low exposure to the surface will usually not be changed.

[0072] An alternative humanization technique for CDR grafting and backmutation is surface alteration, in which non-human residues that are not exposed on the surface are retained, while residues on the surface are changed to human residues.

[0073] In some cases, to improve the binding affinity for the target epitope, it may be necessary to change one or more amino acid residues of the CDR. This is known as "affinity maturation". Various methods of affinity maturation are known in the art, for example, the in vitro scanning saturation mutagenesis method described by Burks et al. Proc Natl Acad Sci USA, 94:412-417 (1997), and the stepwise in vitro affinity maturation method of Wu et al. Proc Natl Acad Sci USA 95:6037-6042 (1998).

[0074] The term "human antibody" refers to an antibody in which the variable domain and constant region sequences are derived from human sequences. The term encompasses antibodies with sequences that are derived from human genes but have been modified, for example, to reduce immunogenicity, increase affinity, and/or increase stability. In addition, the term encompasses antibodies produced recombinantly using human-derived sequences in non-human cells that can transmit glycosylation not characteristic of human cells. The term also encompasses antibodies produced in transgenic non-human organisms with human antibody genes (eg, OmniRat® rats).

[0075] As used herein, the term "antigen-binding portion" of an antibody (or simply "antibody portion") refers to one or more regions or fragments of an antibody that retain the ability to specifically bind to an antigen (e.g., human TIM-3, PD-1 human or human LAG-3 or parts thereof). It has been shown that some fragments of a full-length antibody can perform the antigen-binding function of the antibody. Examples of binding fragments encompassed by the term "antigen binding portion" include (i) a Fab fragment: a monovalent fragment consisting of the VL, VH, CL, and CH1 domains; (ii) an F(ab')2 fragment: a bivalent fragment containing two Fab fragments linked by a disulfide bridge in the hinge region; (iii) an Fd fragment consisting of VH and CH1 domains; (iv) an Fv fragment consisting of the VL and VH domains of one antibody arm, (v) a dAb fragment which consists of a VH domain; and (vi) an isolated complementarity determining region (CDR) capable of specifically binding to an antigen. In addition, although the two fragment domains Fv, VL and VH are encoded by separate genes, they can be combined using recombinant methods with a synthetic linker that allows them to form a single protein chain in which the pair of VL and VH domains form monovalent molecules (known as single chain Fv (scFv)). Also within the scope of the invention are antigen-binding molecules containing VH and/or VL. In the case of a VH, the molecule may also contain one or more of a CH1, hinge, CH2, or CH3 region. Such single chain antibodies are also intended to be encompassed by the term "antigen-binding portion" of an antibody. Other forms of single chain antibodies, such as diabodies, are also covered. Diabodies are bivalent, bispecific antibodies in which the VH and VL domains are expressed on the same polypeptide chain, but using a linker that is too short to allow pairing between two domains on the same chain, thereby forcing the domains to pair with complementary domains of another chain and creating two antigen-binding sites.

[0076] Parts of antibodies, such as fragments of Fab and F(ab')2, can be obtained from whole antibodies using conventional methods, such as cleavage of whole antibodies with papain or pepsin. Additionally, antibodies, antibody moieties, and immunoadhesion molecules can be generated using standard recombinant DNA techniques, such as those described herein.

[0077] The class (isotype) and subclass of the antibodies described herein can be determined by any method known in the art. Typically, the class and subclass of an antibody can be determined using antibodies that are specific to a particular class and subclass of the antibody. Such antibodies are commercially available. Class and subclass can be determined using ELISA and Western blotting, among other methods. Alternatively, the class and subclass can be determined by sequencing all or part of the constant regions of heavy and/or light chains of antibodies, comparing their amino acid sequences with known amino acid sequences of various classes and subclasses of immunoglobulins, and determining the class and subclass of antibodies. The preferred isotype according to the present invention is the IgG isotype.

[0078] When referring to specific amino acid residues at a given position in an antibody sequence, an indication of, for example, "35S" refers to position and residue, i.e. in this case indicates the presence of a serine (S) residue at position 35 of the sequence. Similarly, an indication, for example, "13Q+35S" refers to two residues in the respective positions. Unless otherwise indicated, all antibody amino acid residue numbers referred to in this specification correspond to numbers in the IMGT® numbering scheme.

Antibodies against PD-1

[0079] In some embodiments, the anti-PD-1 antibodies disclosed herein may be chimeric, with chicken-derived variable domains and human constant regions, or may be humanized.

[0080] Anti-PD-1 antibodies disclosed herein may be designated by either a 5-digit number, such as "12819" or a 10-digit number, such as "12819.15384". Within the scope of the present invention, a 5-digit number refers to all antibodies having the heavy and light chain CDR1-3 sequences shown for that number, while the use of a 10-digit number refers to a specific humanized variant. For example, 12819.15384 is a specific humanized variant having the CDR sequences of antibody 12819. The 5-digit number covers, for example, 10-digit variants that are identical except for some changes in FR (for example, the absence of SY residues at the N-terminus of the mature light chain or the presence of residues SS instead of SY). These modifications do not change the functional (eg, antigen-binding) properties of the antibodies.

[0081] In some embodiments, the combination drug or composition comprises an anti-PD-1 antibody or antigen-binding portion thereof, wherein the anti-PD-1 antibody is an antibody referred to herein as antibody 12819.15384, 12748.15381, 12748.16124, 12865.15377, 12892.15378, 12796.15376; 12777.15382; changes, which may be, for example, in the frame regions) without loss of antigen-binding specificity of the antibody.

[0082] In some embodiments, the anti-PD-1 antibody competes with any of the antibodies 12819.15384, 12748.15381, 12748.16124, 12865.15377, 12892.15378, 12796.15376, 12777.15382, 12760. 15375 and 13112.15380 for binding to human PD-1 or binds to the same epitope of PD- 1 person that they are.

[0083] In some embodiments, any of the anti-PD-1 antibodies or antigen-binding portions described herein can compete or cross-compete with antibodies 12865, 12892, and 12777 (e.g., antibodies 12865.15377, 12892.15378, and 12777.15382) for binding to PD- 1. In some embodiments, any of the anti-PD-1 antibodies or antigen-binding portions described herein can compete or cross-compete with antibody 12819 (eg, antibody 12819.15384) for binding to PD-1. In some embodiments, any of the anti-PD-1 antibodies or antigen-binding portions described herein can compete or cross-compete with antibodies 12760 and 13112 (e.g., antibodies 12760.15375 and 13112.15380) for binding to PD-1. In some embodiments, the antibody is in IgG1 or IgG2 format. In some embodiments, the antibody is in IgG1 format.

[0084] In some embodiments, the anti-PD-1 antibody competes or cross-competes with an antibody whose heavy chain (H) CDR1-3 and light chain (L) CDR1-3 comprise, respectively, SEQ ID NOS: 228-233, 238 -243, 248-253, 258-263, 268-273, 278-283, 288-293, or 298-303, for binding to human PD-1, or binds to the same human PD-1 epitope as it .

[0085] In some embodiments, the anti-PD-1 antibody comprises an H-CDR3 comprising the amino acid sequence of H-CDR3 SEQ ID NO: 230, 240, 250, 260, 270, 280, 290, or 300.

[0086] In some embodiments, the anti-PD-1 antibody comprises H-CDR1-3 comprising the amino acid sequences of H-CDR1-3, respectively, from SEQ ID NOs: 228-230, 238-240, 248-250, 258-260 , 268-270, 278-280, 288-290 or 298-300.

[0087] In some embodiments, the anti-PD-1 antibody has a VH whose amino acid sequence is at least 90% (e.g., at least 92%, at least 95%, at least 96%, at least at least 97%, at least 98%, or at least 99%) identical to SEQ ID NO: 226, 236, 246, 256, 266, 276, 286, or 296.

[0088] In some embodiments, the anti-PD-1 antibody has a VH that contains SEQ ID NOs: 226, 236, 246, 256, 266, 276, 286, or 296.

[0089] In some embodiments, the anti-PD-1 antibody has a VH whose sequence is at least 90% (e.g., at least 92%, at least 95%, at least 96%, at least 97%, at least 98%, or at least 99%) identical to SEQ ID NO: 226, 236, 246, 256, 266, 276, 286, or 296; and CH, the sequence of which is at least 90% (for example, at least 92%, at least 95%, at least 96%, at least 97%, at least 98%, or at least 99%) identical to SEQ ID NO: 375.

[0090] In some embodiments, the anti-PD-1 antibody has a HC that contains the VH amino acid sequence of SEQ ID NO: 226, 236, 246, 256, 266, 276, 286, or 296 and the CH amino acid sequence of SEQ ID NO: 375.

[0091] In some embodiments, the anti-PD-1 antibody has an L-CDR3 comprising the amino acid sequence of L-CDR3 of SEQ ID NO: 233, 243, 253, 263, 273, 283, 293, or 303.

[0092] In some embodiments, the anti-PD-1 antibody comprises L-CDR1-3 containing the amino acid sequences of L-CDR1-3, respectively, SEQ ID NOs: 231-233, 241-243, 251-253, 261-263, 271-273, 281-283, 291-293 or 301-303.

[0093] In some embodiments, the anti-PD-1 antibody has a VL whose sequence is at least 90% (e.g., at least 92%, at least 95%, at least 96%, at least 97%, at least 98%, or at least 99%) identical to the amino acid sequence of VL SEQ ID NO: 227, 237, 247, 257, 267, 277, 287, 297, or 392.

[0094] In some embodiments, the anti-PD-1 antibody has a VL that contains the VL amino acid sequence of SEQ ID NO: 227, 237, 247, 257, 267, 277, 287, 297, or 392.

[0095] In some embodiments, the anti-PD-1 antibody has a VL whose sequence is at least 90% (e.g., at least 92%, at least 95%, at least 96%, at least 97%, at least 98%, or at least 99%) identical to the amino acid sequence of VL SEQ ID NO: 227, 237, 247, 257, 267, 277, 287, 297, or 392; and CL, the sequence of which is at least 90% (for example, at least 92%, at least 95%, at least 96%, at least 97%, at least 98%, or at least 99%) identical to SEQ ID NO: 379.

[0096] In some embodiments, the anti-PD-1 antibody has an LC that contains the VL amino acid sequence of SEQ ID NO: 227, 237, 247, 257, 267, 277, 287, 297, or 392 and the CL amino acid sequence of SEQ ID NO: 379 .

[0097] In some embodiments, the anti-PD-1 antibody comprises any of the above heavy chain sequences and any of the above light chain sequences.

[0098] In some embodiments, the anti-PD-1 antibody comprises H-CDR3 and L-CDR3 comprising the amino acid sequences of H-CDR3 and L-CDR3, respectively, from SEQ ID NOs: 230 and 233, 240 and 243, 250 and 253 , 260 and 263, 270 and 273, 280 and 283, 290 and 293 or 300 and 303.

[0099] In some embodiments, the anti-PD-1 antibody comprises H-CDR1-3 and L-CDR1-3 containing the sequences H-CDR1-3 and L-CDR1-3, respectively, from SEQ ID NOs: 228-233, 238-243, 248-253, 258-263, 268-273, 278-283, 288-293 or 298-303.

[0100] In some embodiments, the anti-PD-1 antibody comprises a VH whose sequence is at least 90% (e.g., at least 92%, at least 95%, at least 96%, at least 97%, at least 98%, or at least 99%) identical to the amino acid sequence of SEQ ID NO: 226, 236, 246, 256, 266, 276, 286 or 296, and VL, the sequence of which is at least 90% (e.g., at least 92%, at least 95%, at least 96%, at least 97%, at least 98%, or at least 99%) amino acid sequence identical SEQ ID NO: 227, 237, 247, 257, 267, 277, 287, 297 or 392.

[0101] In some embodiments, the anti-PD-1 antibody has a VH that contains the amino acid sequence of SEQ ID NO: 226, 236, 246, 256, 266, 276, 286, or 296 and a VL that contains the amino acid sequence of SEQ ID NO: 227, 237, 247, 257, 267, 277, 287, 297 or 392.

[0102] In some embodiments, the anti-PD-1 antibody has an HC that comprises the amino acid sequence of SEQ ID NO: 226, 236, 246, 256, 266, 276, 286, or 296 and the amino acid sequence of SEQ ID NO: 375; and an LC that contains the amino acid sequence of SEQ ID NO: 227, 237, 247, 257, 267, 277, 287, 297, or 392 and the amino acid sequence of SEQ ID NO: 379.

[0103] In some embodiments, the anti-PD-1 antibody comprises the amino acid sequences H-CDR1-3 and L-CDR1-3 from:

a) SEQ ID NO: 228-233, respectively;

b) SEQ ID NO: 238-243, respectively;

c) SEQ ID NO: 248-253, respectively;

d) SEQ ID NOs: 258-263, respectively;

e) SEQ ID NO: 268-273, respectively;

f) SEQ ID NO: 278-283, respectively;

g) SEQ ID NO: 288-293, respectively; or

h) SEQ ID NO: 298-303, respectively.

[0104] In some embodiments, the anti-PD-1 antibody comprises VH and VL having the amino acid sequences of:

a) SEQ ID NOs: 226 and 227, respectively;

b) SEQ ID NOs: 236 and 237, respectively;

c) SEQ ID NOs: 236 and 392, respectively;

d) SEQ ID NOs: 246 and 247, respectively;

e) SEQ ID NOs: 256 and 257, respectively;

f) SEQ ID NOs: 266 and 267, respectively;

g) SEQ ID NOs: 276 and 277, respectively;

h) SEQ ID NOs: 286 and 287, respectively; or

i) SEQ ID NOs: 296 and 297, respectively.

[0105] In some embodiments, the anti-PD-1 antibody comprises:

a) HC containing the amino acid sequence of SEQ ID NO: 226 and the amino acid sequence of SEQ ID NO: 375, and LC containing the amino acid sequence of SEQ ID NO: 227 and the amino acid sequence of SEQ ID NO: 379;

b) HC containing the amino acid sequence of SEQ ID NO: 236 and the amino acid sequence of SEQ ID NO: 375, and LC containing the amino acid sequence of SEQ ID NO: 237 and the amino acid sequence of SEQ ID NO: 379;

c) HC containing the amino acid sequence of SEQ ID NO: 236 and the amino acid sequence of SEQ ID NO: 375, and LC containing the amino acid sequence of SEQ ID NO: 392 and the amino acid sequence of SEQ ID NO: 379;

d) HC containing the amino acid sequence of SEQ ID NO: 246 and the amino acid sequence of SEQ ID NO: 375, and LC containing the amino acid sequence of SEQ ID NO: 247 and the amino acid sequence of SEQ ID NO: 379;

e) HC containing the amino acid sequence of SEQ ID NO: 256 and the amino acid sequence of SEQ ID NO: 375, and LC containing the amino acid sequence of SEQ ID NO: 257 and the amino acid sequence of SEQ ID NO: 379;

f) HC containing the amino acid sequence of SEQ ID NO: 266 and the amino acid sequence of SEQ ID NO: 375, and LC containing the amino acid sequence of SEQ ID NO: 267 and the amino acid sequence of SEQ ID NO: 379;

g) HC containing the amino acid sequence of SEQ ID NO: 276 and the amino acid sequence of SEQ ID NO: 375, and LC containing the amino acid sequence of SEQ ID NO: 277 and the amino acid sequence of SEQ ID NO: 379;

h) HC containing the amino acid sequence of SEQ ID NO: 286 and the amino acid sequence of SEQ ID NO: 375, and LC containing the amino acid sequence of SEQ ID NO: 287 and the amino acid sequence of SEQ ID NO: 379; or

i) HC containing the amino acid sequence of SEQ ID NO: 296 and the amino acid sequence of SEQ ID NO: 375, and LC containing the amino acid sequence of SEQ ID NO: 297 and the amino acid sequence of SEQ ID NO: 379.

[0106] In some embodiments, the anti-PD-1 antibody is selected from the group consisting of:

a) antibodies, H-CDR1-3 which contain the amino acid sequence of SEQ ID NO: 228-230, respectively;

b) an antibody whose VH sequence is at least 90% identical to the amino acid sequence of SEQ ID NO: 226;

c) an antibody whose VH contains the amino acid sequence of SEQ ID NO: 226;

d) an antibody whose HC contains the amino acid sequences of SEQ ID NOs: 226 and 375;

e) antibodies, L-CDR1-3 which contain the amino acid sequence of SEQ ID NO: 231-233, respectively;

f) an antibody whose VL sequence is at least 90% identical to the amino acid sequence of SEQ ID NO: 227;

g) an antibody whose VL contains the amino acid sequence of SEQ ID NO: 227;

h) an antibody whose LC contains the amino acid sequences of SEQ ID NOs: 227 and 379;

i) antibodies, H-CDR1-3 and L-CDR1-3 which contain the amino acid sequence of SEQ ID NO: 228-233, respectively;

j) an antibody whose VH sequence is at least 90% identical to the amino acid sequence of SEQ ID NO: 226 and whose VL sequence is at least 90% identical to the amino acid sequence of SEQ ID NO: 227;

k) an antibody whose VH contains the amino acid sequence of SEQ ID NO: 226 and whose VL contains the amino acid sequence of SEQ ID NO: 227; And

l) an antibody whose HC contains the amino acid sequence of SEQ ID NO: 226 and the amino acid sequence of SEQ ID NO: 375; and the LC of which contains the amino acid sequences of SEQ ID NOs: 227 and 379.

[0107] In some embodiments, the anti-PD-1 antibody is selected from the group consisting of:

a) antibodies, H-CDR1-3 which contain the amino acid sequence of SEQ ID NO: 238-240, respectively;

b) an antibody whose VH sequence is at least 90% identical to the amino acid sequence of SEQ ID NO: 236;

c) an antibody whose VH contains the amino acid sequence of SEQ ID NO: 236;

d) an antibody whose HC contains the amino acid sequences of SEQ ID NOs: 236 and 375;

e) antibodies, L-CDR1-3 which contain the amino acid sequence of SEQ ID NO: 241-243, respectively;

f) an antibody whose VL sequence is at least 90% identical to the amino acid sequence of SEQ ID NO: 237;

g) an antibody whose VL contains the amino acid sequence of SEQ ID NO: 237;

h) an antibody whose LC contains the amino acid sequences of SEQ ID NOs: 237 and 379;

i) antibodies, H-CDR1-3 and L-CDR1-3 which contain the amino acid sequence of SEQ ID NO: 238-243, respectively;

j) an antibody whose VH sequence is at least 90% identical to the amino acid sequence of SEQ ID NO: 236 and whose VL sequence is at least 90% identical to the amino acid sequence of SEQ ID NO: 237;

k) an antibody whose VH contains the amino acid sequence of SEQ ID NO: 236 and the VL of which contains the amino acid sequence of SEQ ID NO: 237; And

l) an antibody whose HC contains the amino acid sequence of SEQ ID NO: 236 and the amino acid sequence of SEQ ID NO: 375; and the LC of which contains the amino acid sequences of SEQ ID NOs: 237 and 379.

[0108] In some embodiments, the anti-PD-1 antibody is selected from the group consisting of:

a) antibodies, H-CDR1-3 which contain the amino acid sequence of SEQ ID NO: 238-240, respectively;

b) an antibody whose VH sequence is at least 90% identical to the amino acid sequence of SEQ ID NO: 236;

c) an antibody whose VH contains the amino acid sequence of SEQ ID NO: 236;

d) an antibody whose HC contains the amino acid sequences of SEQ ID NOs: 236 and 375;

e) antibodies, L-CDR1-3 which contain the amino acid sequence of SEQ ID NO: 241-243, respectively;

f) an antibody whose VL sequence is at least 90% identical to the amino acid sequence of SEQ ID NO: 392;

g) an antibody whose VL contains the amino acid sequence of SEQ ID NO: 392;

h) an antibody whose LC contains the amino acid sequences of SEQ ID NOs: 392 and 379;

i) antibodies, H-CDR1-3 and L-CDR1-3 which contain the amino acid sequence of SEQ ID NO: 238-243, respectively;

j) an antibody whose VH sequence is at least 90% identical to the amino acid sequence of SEQ ID NO: 236 and whose VL sequence is at least 90% identical to the amino acid sequence of SEQ ID NO: 392;

k) an antibody whose VH contains the amino acid sequence of SEQ ID NO: 236 and the VL of which contains the amino acid sequence of SEQ ID NO: 392; And

l) an antibody whose HC contains the amino acid sequence of SEQ ID NO: 236 and the amino acid sequence of SEQ ID NO: 375; and the LC of which contains the amino acid sequences of SEQ ID NOs: 392 and 379.

[0109] In some embodiments, the anti-PD-1 antibody is selected from the group consisting of:

a) antibodies, H-CDR1-3 which contain the amino acid sequence of SEQ ID NO: 248-250, respectively;

b) an antibody whose VH sequence is at least 90% identical to the amino acid sequence of SEQ ID NO: 246;

c) an antibody whose VH contains the amino acid sequence of SEQ ID NO: 246;

d) an antibody whose HC contains the amino acid sequences of SEQ ID NOs: 246 and 375;

e) antibodies, L-CDR1-3 which contain the amino acid sequence of SEQ ID NO: 251-253, respectively;

f) an antibody whose VL sequence is at least 90% identical to the amino acid sequence of SEQ ID NO: 247;

g) an antibody whose VL contains the amino acid sequence of SEQ ID NO: 247;

h) an antibody whose LC contains the amino acid sequences of SEQ ID NOs: 247 and 379;

i) antibodies, H-CDR1-3 and L-CDR1-3 which contain the amino acid sequence of SEQ ID NO: 248-253, respectively;

j) an antibody whose VH sequence is at least 90% identical to the amino acid sequence of SEQ ID NO: 246 and whose VL sequence is at least 90% identical to the amino acid sequence of SEQ ID NO: 247;

k) an antibody whose VH contains the amino acid sequence of SEQ ID NO: 246 and whose VL contains the amino acid sequence of SEQ ID NO: 247; And

l) an antibody whose HC contains the amino acid sequence of SEQ ID NO: 246 and the amino acid sequence of SEQ ID NO: 375; and the LC of which contains the amino acid sequences of SEQ ID NOs: 247 and 379.

[0110] In some embodiments, the anti-PD-1 antibody is selected from the group consisting of:

a) antibodies, H-CDR1-3 which contain the amino acid sequence of SEQ ID NO: 258-260, respectively;

b) an antibody whose VH sequence is at least 90% identical to the amino acid sequence of SEQ ID NO: 256;

c) an antibody whose VH contains the amino acid sequence of SEQ ID NO: 256;

d) an antibody whose HC contains the amino acid sequences of SEQ ID NOs: 256 and 375;

e) antibodies, L-CDR1-3 which contain the amino acid sequence of SEQ ID NO: 261-263, respectively;

f) an antibody whose VL sequence is at least 90% identical to the amino acid sequence of SEQ ID NO: 257;

g) an antibody whose VL contains the amino acid sequence of SEQ ID NO: 257;

h) an antibody whose LC contains the amino acid sequences of SEQ ID NOs: 257 and 379;

i) antibodies, H-CDR1-3 and L-CDR1-3 which contain the amino acid sequence of SEQ ID NO: 258-263, respectively;

j) an antibody whose VH sequence is at least 90% identical to the amino acid sequence of SEQ ID NO: 256 and whose VL sequence is at least 90% identical to the amino acid sequence of SEQ ID NO: 257;

k) an antibody whose VH contains the amino acid sequence of SEQ ID NO: 256 and whose VL contains the amino acid sequence of SEQ ID NO: 257; And

l) an antibody whose HC contains the amino acid sequence of SEQ ID NO: 256 and the amino acid sequence of SEQ ID NO: 375; and the LC of which contains the amino acid sequences of SEQ ID NOs: 257 and 379.

[0111] In some embodiments, the anti-PD-1 antibody is selected from the group consisting of:

a) antibodies, H-CDR1-3 which contain the amino acid sequence of SEQ ID NO: 268-270, respectively;

b) an antibody whose VH sequence is at least 90% identical to the amino acid sequence of SEQ ID NO: 266;

c) an antibody whose VH contains the amino acid sequence of SEQ ID NO: 266;

d) an antibody whose HC contains the amino acid sequences of SEQ ID NOs: 266 and 375;

e) antibodies, L-CDR1-3 which contain the amino acid sequence of SEQ ID NO: 271-273, respectively;

f) an antibody whose VL sequence is at least 90% identical to the amino acid sequence of SEQ ID NO: 267;

g) an antibody whose VL contains the amino acid sequence of SEQ ID NO: 267;

h) an antibody whose LC contains the amino acid sequences of SEQ ID NOs: 267 and 379;

i) antibodies, H-CDR1-3 and L-CDR1-3 which contain the amino acid sequence of SEQ ID NO: 268-273, respectively;

j) an antibody whose VH sequence is at least 90% identical to the amino acid sequence of SEQ ID NO: 266 and whose VL sequence is at least 90% identical to the amino acid sequence of SEQ ID NO: 267;

k) an antibody whose VH contains the amino acid sequence of SEQ ID NO: 266 and whose VL contains the amino acid sequence of SEQ ID NO: 267; And

l) an antibody whose HC contains the amino acid sequence of SEQ ID NO: 266 and the amino acid sequence of SEQ ID NO: 375; and the LC of which contains the amino acid sequences of SEQ ID NOs: 267 and 379.

[0112] In some embodiments, the anti-PD-1 antibody is selected from the group consisting of:

a) antibodies, H-CDR1-3 which contain the amino acid sequence of SEQ ID NO: 278-280, respectively;

b) an antibody whose VH sequence is at least 90% identical to the amino acid sequence of SEQ ID NO: 276;

c) an antibody whose VH contains the amino acid sequence of SEQ ID NO: 276;

d) an antibody whose HC contains the amino acid sequences of SEQ ID NOs: 276 and 375;

e) antibodies, L-CDR1-3 which contain the amino acid sequence of SEQ ID NO: 281-283, respectively;

f) an antibody whose VL sequence is at least 90% identical to the amino acid sequence of SEQ ID NO: 277;

g) an antibody whose VL contains the amino acid sequence of SEQ ID NO: 277;

h) an antibody whose LC contains the amino acid sequences of SEQ ID NOs: 277 and 379;

i) antibodies, H-CDR1-3 and L-CDR1-3 which contain the amino acid sequence of SEQ ID NO: 278-283, respectively;

j) an antibody whose VH sequence is at least 90% identical to the amino acid sequence of SEQ ID NO: 276 and whose VL sequence is at least 90% identical to the amino acid sequence of SEQ ID NO: 277;

k) an antibody whose VH contains the amino acid sequence of SEQ ID NO: 276 and the VL of which contains the amino acid sequence of SEQ ID NO: 277; And

l) an antibody whose HC contains the amino acid sequence of SEQ ID NO: 276 and the amino acid sequence of SEQ ID NO: 375; and the LC of which contains the amino acid sequences of SEQ ID NOs: 277 and 379.

[0113] In some embodiments, the anti-PD-1 antibody is selected from the group consisting of:

a) antibodies, H-CDR1-3 which contain the amino acid sequence of SEQ ID NO: 288-290, respectively;

b) an antibody whose VH sequence is at least 90% identical to the amino acid sequence of SEQ ID NO: 286;

c) an antibody whose VH contains the amino acid sequence of SEQ ID NO: 286;

d) an antibody whose HC contains the amino acid sequences of SEQ ID NOs: 286 and 375;

e) antibodies, L-CDR1-3 which contain the amino acid sequence of SEQ ID NO: 291-293, respectively;

f) an antibody whose VL sequence is at least 90% identical to the amino acid sequence of SEQ ID NO: 287;

g) an antibody whose VL contains the amino acid sequence of SEQ ID NO: 287;

h) an antibody whose LC contains the amino acid sequences of SEQ ID NOs: 287 and 379;

i) antibodies, H-CDR1-3 and L-CDR1-3 which contain the amino acid sequence of SEQ ID NO: 288-293, respectively;

j) an antibody whose VH sequence is at least 90% identical to the amino acid sequence of SEQ ID NO: 286 and whose VL sequence is at least 90% identical to the amino acid sequence of SEQ ID NO: 287;

k) an antibody whose VH contains the amino acid sequence of SEQ ID NO: 286 and the VL of which contains the amino acid sequence of SEQ ID NO: 287; And

l) an antibody whose HC contains the amino acid sequence of SEQ ID NO: 286 and the amino acid sequence of SEQ ID NO: 375; and the LC of which contains the amino acid sequences of SEQ ID NOs: 287 and 379.

[0114] In some embodiments, the anti-PD-1 antibody is selected from the group consisting of:

a) antibodies, H-CDR1-3 which contain the amino acid sequence of SEQ ID NO: 298-300, respectively;

b) an antibody whose VH sequence is at least 90% identical to the amino acid sequence of SEQ ID NO: 296;

c) an antibody whose VH contains the amino acid sequence of SEQ ID NO: 296;

d) an antibody whose HC contains the amino acid sequences of SEQ ID NOs: 296 and 375;

e) antibodies, L-CDR1-3 which contain the amino acid sequence of SEQ ID NO: 301-303, respectively;

f) an antibody whose VL sequence is at least 90% identical to the amino acid sequence of SEQ ID NO: 297;

g) an antibody whose VL contains the amino acid sequence of SEQ ID NO: 297;

h) an antibody whose LC contains the amino acid sequences of SEQ ID NOs: 297 and 379;

i) antibodies, H-CDR1-3 and L-CDR1-3 which contain the amino acid sequence of SEQ ID NO: 298-303, respectively;

j) an antibody whose VH sequence is at least 90% identical to the amino acid sequence of SEQ ID NO: 296 and whose VL sequence is at least 90% identical to the amino acid sequence of SEQ ID NO: 297;

k) an antibody whose VH contains the amino acid sequence of SEQ ID NO: 296 and the VL of which contains the amino acid sequence of SEQ ID NO: 297; And

l) an antibody whose HC contains the amino acid sequence of SEQ ID NO: 296 and the amino acid sequence of SEQ ID NO: 375; and the LC of which contains the amino acid sequences of SEQ ID NOs: 297 and 379.

[0115] In some embodiments, any of the anti-PD-1 antibodies or antigen-binding portions described herein can bind to human PD-1 with a KD of at least 900, at least 850, at least 800, at least 750, at least 700, at least 650, at least 600, at least 550, at least 500, at least 450, at least 400, at least 350, at least 300, at least 250, at least 200, at least 150, at least 100, at least 50, at least 40, at least 30, or at least 20 pM. In some embodiments, KD is determined using surface plasmon resonance. In certain embodiments, anti-PD-1 antibodies or antigen-binding portions bind to human PD-1 with higher affinity than nivolumab, pembrolizumab, or both.

[0116] In some embodiments, any of the anti-PD-1 antibodies or antigen-binding portions described herein can bind to cynomolgus monkey PD-1 with a KD of at least 9000, at least 8000, at least 7000, at least at least 6000, at least 5000, at least 4000, at least 3000, at least 2500, at least 2000, at least 1500, at least 1000, at least 900, at least 800, at least at least 700, at least 600, at least 500, at least 400, at least 300, at least 200, at least 100, at least 75, at least 50, at least 25, at least at least 20, at least 15, at least 10 or at least 5 pM. In some embodiments, KD is determined using surface plasmon resonance.

[0117] In some embodiments, any of the anti-PD-1 antibodies or antigen-binding portions described herein can bind to mouse PD-1 with a KD of at least 1000, at least 950, at least 900, or at least 850 pM. In some embodiments, KD is determined using surface plasmon resonance.

[0118] In some embodiments, any of the anti-PD-1 antibodies or antigen-binding portions described herein can inhibit the interaction of PD-1 with PD-L1 by at least 60%, at least 65%, at least 70%, at least 75%, at least 80%, at least 81%, at least 82%, at least 83%, at least 84%, at least 85%, at least 86%, at least 87%, at least 88%, at least 89%, at least 90%, at least 91%, at least 92 %, at least 93%, at least 94%, at least 95%, at least 96%, at least 97%, at least 98%, at least 99% or 100% at 10 µg/mL in a competitive flow cytometry assay. In some embodiments, anti-PD-1 antibodies or antigen-binding portions can inhibit the interaction of PD-1 with PD-L1 by at least 83%.

[0119] In some embodiments, any of the anti-PD-1 antibodies or antigen-binding portions described herein can block PD-L1 and PD-L2 from binding to PD-1 by at least 20%, at least 30%. at least 40%, at least 50%, at least 60%, at least 70%, at least 80%, at least 85%, at least 90%, at least 91%, at least 92%, at least 93%, at least 94%, at least 95%, at least 96%, at least 97%, at least 98%, at least 99%, or 100% at a concentration of 10 μg/ml as determined by biolayer interferometry analysis. In some embodiments, the anti-PD-1 antibodies or antigen-binding portions block the binding of PD-L1 and PD-L2 to PD-1 by at least 90%.

[0120] In some embodiments, an anti-PD-1 antibody or antigen-binding portion described herein has at least one of the following properties:

a) binds to human PD-1 with a KD of 750 pM or less;

b) binds to cynomolgus monkey PD-1 with a KD of 7 nM or less;

c) binds to mouse PD-1 with a KD of 1 nM or less;

d) does not bind to rat PD-1;

e) increases IL-2 secretion in the SEB stimulated whole blood assay;

f) increases IFN-γ secretion in a mixed lymphocyte culture unidirectional reaction assay;

g) inhibits the interaction of PD-1 with PD-L1 by at least 60% at a concentration of 10 μg/ml in a competitive analysis by flow cytometry;

h) blocks the binding of PD-L1 and PD-L2 to PD-1 by at least 90% at a concentration of 10 μg/ml as determined by biolayer interferometry analysis; And

i) inhibits tumor growth in vivo.

Examples of such an antibody include, without limitation, antibody 12819 (having properties a-i); antibodies 12748, 12892 and 12777 (having at least properties a, b and e-h); antibodies 12865 and 12796 (having at least properties a, b, e, f and h); and antibodies 12760 and 13112 (having at least properties a, b, e and f). In some embodiments, the anti-PD-1 antibody or antigen-binding portion has all of these properties. In some embodiments, the anti-PD-1 antibody or antigen-binding portion has at least properties a, b, and e-h. In some embodiments, the anti-PD-1 antibody or antigen-binding portion has at least properties a, b, e, f, and h. In some embodiments, the anti-PD-1 antibody or antigen-binding portion has at least properties a, b, e, and f.

[0121] In some embodiments, an anti-PD-1 antibody or antigen-binding portion thereof, as described herein, binds to a PD-1 epitope that contains at least one (e.g., at least one, at least two, at least three, at least four or at least five) of the following residues of SEQ ID NO: 388: V44, V64, L128, P130, K131, A132, E136 and T145. In some embodiments, the antibody or antigen-binding portion binds to a PD-1 epitope that contains residues V64, L128, P130, K131, and A132 of SEQ ID NO: 388 (e.g., antibody 12819, e.g., antibody 12819.15384). In some embodiments, the antibody or antigen-binding portion binds to a PD-1 epitope that contains residues K131 and E136 of SEQ ID NO: 388 (eg, antibody 12865, eg, antibody 12865.15377). In some embodiments, the antibody or antigen-binding portion binds to a PD-1 epitope that contains residues V44 and T145 of SEQ ID NO: 388 (eg, antibody 13112, eg, antibody 13112.15380).

[0122] In some embodiments, the combination drug or composition comprises an anti-PD-1 antibody, or an antigen-binding portion thereof, that binds to a PD-1 epitope containing amino acid residue K131 of SEQ ID NO: 388 (e.g., antibody 12819 or 12865). In some embodiments, the epitope further comprises amino acid residues P130 and A132, and may further comprise amino acid residues V64 and L128 (eg, antibody 12819). In some embodiments, the implementation of the epitope further contains the amino acid residue E136 (eg, antibody 12865).

[0123] In some embodiments, an anti-PD-1 antibody, or antigen-binding portion thereof, as described herein, binds to a PD-1 epitope that contains residues 56-64, 69-90, and/or 122-140 of SEQ ID NO: 388. In some embodiments, the antibody or antigen-binding portion binds to a PD-1 epitope that contains residues 69-90 and 122-140 of SEQ ID NO: 388 (e.g., antibodies 12819 and 12865, e.g., antibodies 12819.15384 and 12865.15377). In some embodiments, the antibody or antigen-binding portion binds to a PD-1 epitope that contains residues 56-64, 69-90, and 122-140 of SEQ ID NO: 388 (eg, antibody 12819). In some embodiments, the antibody or antigen-binding portion binds to a PD-1 epitope that contains residues 69-90 and 122-140 of SEQ ID NO: 388 (eg, antibody 12865). In some embodiments, the antibody, or portion thereof, binds to residues 69-75 (or fragments thereof, e.g., a fragment of one, two, three, four, five, or six residues), SEQ ID NO: 388 (e.g., antibodies 12819 and 12865, for example, antibodies 12819.15384 and 12865.15377). In some embodiments, an antibody or portion thereof binds to residues 136-140 (or fragments thereof, e.g., a fragment of one, two, three, or four residues) of SEQ ID NO: 388 (e.g., antibodies 12819 and 12865, e.g., antibodies 12819.15384 and 12865.15377). In some embodiments, the antibody or portion thereof binds to residues 69-75 (or fragments thereof) and residues 136-140 (or fragments thereof) of SEQ ID NO: 388, (e.g. antibodies 12819 and 12865, e.g. antibodies 12819.15384 and 12865.15377) . An epitope with any combination of the above residues is also provided.

[0124] In some embodiments, an anti-PD-1 antibody or antigen-binding portion thereof as described herein is an anti-PD-1 antibody or antigen-binding portion as described in PCT Patent Publication WO 2017/055547 or PCT Patent Application PCT/EP 2017/079615, which are incorporated herein by reference in their entirety.

Antibodies against TIM-3

[0125] In a separate embodiment, the anti-TIM-3 antibodies disclosed herein are human antibodies derived from transgenic rats that are capable of generating antibodies with human idiotypes.

[0126] Anti-TIM-3 antibodies disclosed herein may be designated by either a 5-digit number, such as "20131" or a 10-digit number, such as "15086.16837". 10-digit numbers with the same first five digits are derived from the same parent antibody, as in the case of antibodies 15086.15086, 15086.16837, 15086.17145, 15086.17144. Those antibodies that have the same six CDRs are expected to have the same or substantially the same target binding properties. As will be understood from the protein and DNA sequences provided herein, variants 15086.16837, 15086.17145, and 15086.17144 have only one amino acid difference in the VH sequence compared to the parent antibody 15086 (“15086.15086”), namely E, not Q, at position 6 while the VL amino acid sequences are identical. It should also be clear that these variants differ primarily in their antibody format/subclass, i.e.:

15086.15086: IgG1

15086.16837: IgG1 LALA

15086.17145: IgG2

15086.17144: IgG4

The VH sequence of the IgG2 and IgG4 subclass antibodies is the same as that of the IgG1 LALA variant. The VL sequence is the same for all four antibody subclasses.

[0127] In some embodiments, the combination drug or composition comprises an anti-TIM-3 antibody or an antigen-binding portion thereof, wherein the anti-TIM-3 antibody is an antibody referred to herein as antibody 15086.17145, 15086.15086, 15086.16837, 15086.17144, 20131, 20293 , 15105 15107 15109 15174 15175 15260 15284 15299 15353 15354 17244 17245 19324 19416 19568 20185 20300 20362 or 20621 or a variant of any of them, and the variant may, for example, contain some minimal amino acid change relative to said antibody (e.g., 1, 2, 3, 4, 5, 6, 7, 8, 9, or 10 amino acid changes, which may be, for example, in framework regions) without loss of antigen-binding specificity of the antibody.

[0128] In some embodiments, the TIM-3 antibody competes or cross-competes with IgG1 format antibody 15086.15086, LALA IgG1 format antibody 15086.16837, IgG2 format antibody 15086.17145, or IgG4 format antibody 15086.17144 for binding with human TIM-3 or binds to the same human TIM-3 epitope as they do. In some embodiments, the antibody is in IgG1 or IgG2 format. In some embodiments, the antibody is in IgG2 format.

[0129] In some embodiments, the anti-TIM-3 antibody competes or cross-competes with antibody 20131, 20293, 15105, 15107, 15109, 15174, 15175, 15260, 15284, 15299, 15353, 15354, 17244, 1 7245, 19324, 19416, 19568, 20185, 20300, 20362, or 20621 for binding to human TIM-3 or binding to the same human TIM-3 epitope as they do. In some embodiments, the antibody is in IgG1 or IgG2 format. In some embodiments, the antibody is in IgG2 format.

[0130] In some embodiments, the anti-TIM-3 antibody competes or cross-competes with an antibody whose heavy chain (H) CDR1-3 and light chain (L) CDR1-3 comprise, respectively, SEQ ID NOS: 8-13, 18 -23, 28-33, 38-43, 48-53, 58-63, 68-73, 78-83, 88-93, 98-103, 108-113, 118-123, 128-133, 138-143 , 148-153, 158-163, 168-173, 178-183, 188-193, 198-203, 208-213, or 218-223, for binding to human TIM-3 or binding to the same TIM-3 epitope person, which is it.

[0131] In some embodiments, the anti-TIM-3 antibody comprises an H-CDR3 comprising the amino acid sequence of H-CDR3 SEQ ID NOs: 10, 20, 30, 40, 50, 60, 70, 80, 90, 100, 110, 120 , 130, 140, 150, 160, 170, 180, 190, 200, 210 or 220.

[0132] In some embodiments, the anti-TIM-3 antibody comprises H-CDR1-3 containing the amino acid sequences of H-CDR1-3, respectively, from SEQ ID NOs: 8-10, 18-20, 28-30, 38-40 , 48-50 58-60 68-70 78-80 88-90 98-100 108-110 118-120 128-130 138-140 148-150 158-160 168 -170, 178-180, 188-190, 198-200, 208-210 or 218-220.

[0133] In some embodiments, the anti-TIM-3 antibody has a VH whose amino acid sequence is at least 90% (e.g., at least 92%, at least 95%, at least 96%, at least at least 97%, at least 98%, or at least 99%) identical to SEQ ID NOs: 3, 7, 16, 26, 36, 46, 56, 66, 76, 86, 96, 106, 116, 126, 136, 146, 156, 166, 176, 186, 196, 206 or 216.

[0134] In some embodiments, the anti-TIM-3 antibody has a VH that contains SEQ ID NOs: 3, 7, 16, 26, 36, 46, 56, 66, 76, 86, 96, 106, 116, 126, 136 , 146, 156, 166, 176, 186, 196, 206 or 216.

[0135] In some embodiments, the anti-TIM-3 antibody has a VH whose sequence is at least 90% (e.g., at least 92%, at least 95%, at least 96%, at least 97%, at least 98%, or at least 99%) identical to SEQ ID NOs: 3, 16, 26, 36, 46, 56, 66, 76, 86, 96, 106, 116, 126, 136 , 146, 156, 166, 176, 186, 196, 206 or 216; and CH, the sequence of which is at least 90% (for example, at least 92%, at least 95%, at least 96%, at least 97%, at least 98%, or at least 99%) identical to SEQ ID NO: 374.

[0136] In some embodiments, the anti-TIM-3 antibody has a HC that contains the amino acid sequence VH SEQ ID NOs: 3, 16, 26, 36, 46, 56, 66, 76, 86, 96, 106, 116, 126, 136, 146, 156, 166, 176, 186, 196, 206 or 216 and the amino acid sequence of CH SEQ ID NO: 374.

[0137] In some embodiments, the anti-TIM-3 antibody has a VH whose sequence is at least 90% (e.g., at least 92%, at least 95%, at least 96%, at least 97%, at least 98%, or at least 99%) identical to SEQ ID NOs: 7, 16, 26, 36, 46, 56, 66, 76, 86, 96, 106, 116, 126, 136 , 146, 156, 166, 176, 186, 196, 206 or 216; and CH, the sequence of which is at least 90% (for example, at least 92%, at least 95%, at least 96%, at least 97%, at least 98%, or at least 99%) identical to SEQ ID NO: 375, 376 or 377.

[0138] In some embodiments, the anti-TIM-3 antibody has a HC that contains the amino acid sequence VH SEQ ID NOs: 7, 16, 26, 36, 46, 56, 66, 76, 86, 96, 106, 116, 126, 136, 146, 156, 166, 176, 186, 196, 206, or 216 and the CH amino acid sequence of SEQ ID NO: 375, 376, or 377. In some embodiments, the CH amino acid sequence is SEQ ID NO: 377.

[0139] In some embodiments, the anti-TIM-3 antibody comprises an L-CDR3 comprising the amino acid sequence of L-CDR3 SEQ ID NOs: 13, 23, 33, 43, 53, 63, 73, 83, 93, 103, 113, 123 , 133, 143, 153, 163, 173, 183, 193, 203, 213 or 223.

[0140] In some embodiments, the anti-TIM-3 antibody comprises L-CDR1-3 containing the amino acid sequences of L-CDR1-3, respectively, SEQ ID NOs: 11-13, 21-23, 31-33, 41-43, 51-53, 61-63, 71-73, 81-83, 91-93, 101-103, 111-113, 121-123, 131-133, 141-143, 151-153, 161-163, 171- 173, 181-183, 191-193, 201-203, 211-213 or 221-223.

[0141] In some embodiments, the anti-TIM-3 antibody has a VL whose sequence is at least 90% (e.g., at least 92%, at least 95%, at least 96%, at least 97%, at least 98%, or at least 99%) identical to the amino acid sequence of VL SEQ ID NO: 4, 17, 27, 37, 47, 57, 67, 77, 87, 97, 107, 117, 127, 137, 147, 157, 167, 177, 187, 197, 207 or 217.

[0142] In some embodiments, the anti-TIM-3 antibody has a VL that contains the amino acid sequence of VL SEQ ID NOs: 4, 17, 27, 37, 47, 57, 67, 77, 87, 97, 107, 117, 127, 137, 147, 157, 167, 177, 187, 197, 207 or 217.

[0143] In some embodiments, the anti-TIM-3 antibody has a VL whose sequence is at least 90% (e.g., at least 92%, at least 95%, at least 96%, at least 97%, at least 98%, or at least 99%) identical to the amino acid sequence of VL SEQ ID NO: 4, 17, 27, 37, 47, 57, 67, 77, 87, 97, 107, 117, 127, 137, 147, 157, 167, 177, 187, 197, 207 or 217; and CL, the sequence of which is at least 90% (for example, at least 92%, at least 95%, at least 96%, at least 97%, at least 98%, or at least 99%) identical to SEQ ID NO: 378.

[0144] In some embodiments, the anti-TIM-3 antibody has an LC that contains the amino acid sequence VL of SEQ ID NOs: 4, 17, 27, 37, 47, 57, 67, 77, 87, 97, 107, 117, 127, 137, 147, 157, 167, 177, 187, 197, 207 or 217 and the amino acid sequence of CL SEQ ID NO: 378.

[0145] In some embodiments, the anti-TIM-3 antibody comprises any of the above heavy chain sequences and any of the above light chain sequences.

[0146] In some embodiments, the anti-TIM-3 antibody comprises H-CDR3 and L-CDR3 comprising the amino acid sequences of H-CDR3 and L-CDR3, respectively, from SEQ ID NOs: 10 and 13, 20 and 23, 30 and 33 , 40 and 43, 50 and 53, 60 and 63, 70 and 73, 80 and 83, 90 and 93, 100 and 103, 110 and 113, 120 and 123, 130 and 133, 140 and 143, 150 and 153, 160 and 163, 170 and 173, 180 and 183, 190 and 193, 200 and 203, 210 and 213 or 220 and 223.

[0147] In some embodiments, the anti-TIM-3 antibody comprises H-CDR1-3 and L-CDR1-3 containing the sequences H-CDR1-3 and L-CDR1-3, respectively, from SEQ ID NOs: 8-13, 18-23, 28-33, 38-43, 48-53, 58-63, 68-73, 78-83, 88-93, 98-103, 108-113, 118-123, 128-133, 138- 143, 148-153, 158-163, 168-173, 178-183, 188-193, 198-203, 208-213 or 218-223.

[0148] In some embodiments, the anti-TIM-3 antibody has a VH whose sequence is at least 90% (e.g., at least 92%, at least 95%, at least 96%, at least 97%, at least 98%, or at least 99%) identical to the amino acid sequence of SEQ ID NO: 3, 7, 16, 26, 36, 46, 56, 66, 76, 86, 96, 106, 116 , 126, 136, 146, 156, 166, 176, 186, 196, 206 or 216, and VL, the sequence of which is at least 90% (for example, at least 92%, at least 95%, according to at least 96%, at least 97%, at least 98%, or at least 99%) identical to the amino acid sequence of SEQ ID NO: 4, 17, 27, 37, 47, 57, 67, 77, 87, 97, 107, 117, 127, 137, 147, 157, 167, 177, 187, 197, 207 or 217.

[0149] In some embodiments, the anti-TIM-3 antibody has a VH that contains the amino acid sequence of SEQ ID NOs: 3, 7, 16, 26, 36, 46, 56, 66, 76, 86, 96, 106, 116, 126 , 136, 146, 156, 166, 176, 186, 196, 206 or 216, and VL which contains the amino acid sequence of SEQ ID NO: 4, 17, 27, 37, 47, 57, 67, 77, 87, 97, 107, 117, 127, 137, 147, 157, 167, 177, 187, 197, 207 or 217.

[0150] In some embodiments, the anti-TIM-3 antibody has an HC that contains the amino acid sequence of SEQ ID NOs: 3, 7, 16, 26, 36, 46, 56, 66, 76, 86, 96, 106, 116, 126 , 136, 146, 156, 166, 176, 186, 196, 206 or 216 and the amino acid sequence of SEQ ID NO: 378; and LC which contains the amino acid sequence of SEQ ID NO: 4, 17, 27, 37, 47, 57, 67, 77, 87, 97, 107, 117, 127, 137, 147, 157, 167, 177, 187, 197 , 207 or 217 and the amino acid sequence of SEQ ID NO: 374, 375, 376 or 377.

[0151] In some embodiments, the anti-TIM-3 antibody comprises the amino acid sequences H-CDR1-3 and L-CDR1-3 from:

a) SEQ ID NO: 8-13, respectively;

b) SEQ ID NO: 18-23, respectively;

c) SEQ ID NO: 28-33, respectively;

d) SEQ ID NO: 38-43, respectively;

e) SEQ ID NO: 48-53, respectively;

f) SEQ ID NO: 58-63, respectively;

g) SEQ ID NO: 68-73, respectively;

h) SEQ ID NO: 78-83, respectively;

i) SEQ ID NO: 88-93, respectively;

j) SEQ ID NO: 98-103, respectively;

k) SEQ ID NOs: 108-113, respectively;

l) SEQ ID NO: 118-123, respectively;

m) SEQ ID NO: 128-133, respectively;

n) SEQ ID NO: 138-143, respectively;

o) SEQ ID NO: 148-153, respectively;

p) SEQ ID NOs: 158-163, respectively;

q) SEQ ID NO: 168-173, respectively;

r) SEQ ID NOs: 178-183, respectively;

s) SEQ ID NO: 188-193, respectively;

t) SEQ ID NO: 198-203, respectively;

u) SEQ ID NOs: 208-213, respectively; or

v) SEQ ID NO: 218-223, respectively.

[0152] In some embodiments, the anti-TIM-3 antibody comprises a heavy chain variable domain and a light chain variable domain having the amino acid sequences of:

a) SEQ ID NO: 7 and 4, respectively;

b) SEQ ID NO: 3 and 4, respectively;

c) SEQ ID NOs: 16 and 17, respectively;

d) SEQ ID NOs: 26 and 27, respectively;

e) SEQ ID NOs: 36 and 37, respectively;

f) SEQ ID NOs: 46 and 47, respectively;

g) SEQ ID NOs: 56 and 57, respectively;

h) SEQ ID NOs: 66 and 67, respectively;

i) SEQ ID NOs: 76 and 77, respectively;

j) SEQ ID NOs: 86 and 87, respectively;

k) SEQ ID NOs: 96 and 97, respectively;

l) SEQ ID NOs: 106 and 107, respectively;

m) SEQ ID NOs: 116 and 117, respectively;

n) SEQ ID NOs: 126 and 127, respectively;

o) SEQ ID NOs: 136 and 137, respectively;

p) SEQ ID NOs: 146 and 147, respectively;

q) SEQ ID NOs: 156 and 157, respectively;

r) SEQ ID NOs: 166 and 167, respectively;

s) SEQ ID NOs: 176 and 177, respectively;

t) SEQ ID NOs: 186 and 187, respectively;

u) SEQ ID NOs: 196 and 197, respectively;

v) SEQ ID NOs: 206 and 207, respectively; or

w) SEQ ID NOs: 216 and 217, respectively.

[0153] In some embodiments, the anti-TIM-3 antibody comprises:

a) HC containing the amino acid sequence of SEQ ID NO: 7 and the amino acid sequence of SEQ ID NO: 374, 375, 376 or 377, and LC containing the amino acid sequence of SEQ ID NO: 4 and the amino acid sequence of SEQ ID NO: 378;

b) HC containing the amino acid sequence of SEQ ID NO: 3 and the amino acid sequence of SEQ ID NO: 374, 375, 376 or 377, and LC containing the amino acid sequence of SEQ ID NO: 4 and the amino acid sequence of SEQ ID NO: 378;

c) HC containing the amino acid sequence of SEQ ID NO: 16 and the amino acid sequence of SEQ ID NO: 374, 375, 376 or 377, and LC containing the amino acid sequence of SEQ ID NO: 17 and the amino acid sequence of SEQ ID NO: 378;

d) HC containing the amino acid sequence of SEQ ID NO: 26 and the amino acid sequence of SEQ ID NO: 374, 375, 376 or 377, and LC containing the amino acid sequence of SEQ ID NO: 27 and the amino acid sequence of SEQ ID NO: 378;

e) HC containing the amino acid sequence of SEQ ID NO: 36 and the amino acid sequence of SEQ ID NO: 374, 375, 376 or 377, and LC containing the amino acid sequence of SEQ ID NO: 37 and the amino acid sequence of SEQ ID NO: 378;

f) HC containing the amino acid sequence of SEQ ID NO: 46 and the amino acid sequence of SEQ ID NO: 374, 375, 376 or 377, and LC containing the amino acid sequence of SEQ ID NO: 47 and the amino acid sequence of SEQ ID NO: 378;

g) HC containing the amino acid sequence of SEQ ID NO: 56 and the amino acid sequence of SEQ ID NO: 374, 375, 376 or 377, and LC containing the amino acid sequence of SEQ ID NO: 57 and the amino acid sequence of SEQ ID NO: 378;

h) HC containing the amino acid sequence of SEQ ID NO: 66 and the amino acid sequence of SEQ ID NO: 374, 375, 376 or 377, and LC containing the amino acid sequence of SEQ ID NO: 67 and the amino acid sequence of SEQ ID NO: 378;

i) HC containing the amino acid sequence of SEQ ID NO: 76 and the amino acid sequence of SEQ ID NO: 374, 375, 376 or 377, and LC containing the amino acid sequence of SEQ ID NO: 77 and the amino acid sequence of SEQ ID NO: 378;

j) HC containing the amino acid sequence of SEQ ID NO: 86 and the amino acid sequence of SEQ ID NO: 374, 375, 376 or 377, and LC containing the amino acid sequence of SEQ ID NO: 87 and the amino acid sequence of SEQ ID NO: 378;

k) HC containing the amino acid sequence of SEQ ID NO: 96 and the amino acid sequence of SEQ ID NO: 374, 375, 376 or 377, and LC containing the amino acid sequence of SEQ ID NO: 97 and the amino acid sequence of SEQ ID NO: 378;

l) HC containing the amino acid sequence of SEQ ID NO: 106 and the amino acid sequence of SEQ ID NO: 374, 375, 376 or 377, and LC containing the amino acid sequence of SEQ ID NO: 107 and the amino acid sequence of SEQ ID NO: 378;

m) HC containing the amino acid sequence of SEQ ID NO: 116 and the amino acid sequence of SEQ ID NO: 374, 375, 376 or 377, and LC containing the amino acid sequence of SEQ ID NO: 117 and the amino acid sequence of SEQ ID NO: 378;

n) HC containing the amino acid sequence of SEQ ID NO: 126 and the amino acid sequence of SEQ ID NO: 374, 375, 376 or 377, and LC containing the amino acid sequence of SEQ ID NO: 127 and the amino acid sequence of SEQ ID NO: 378;

o) HC containing the amino acid sequence of SEQ ID NO: 136 and the amino acid sequence of SEQ ID NO: 374, 375, 376 or 377, and LC containing the amino acid sequence of SEQ ID NO: 137 and the amino acid sequence of SEQ ID NO: 378;

p) HC containing the amino acid sequence of SEQ ID NO: 146 and the amino acid sequence of SEQ ID NO: 374, 375, 376 or 377, and LC containing the amino acid sequence of SEQ ID NO: 147 and the amino acid sequence of SEQ ID NO: 378;

q) HC containing the amino acid sequence of SEQ ID NO: 156 and the amino acid sequence of SEQ ID NO: 374, 375, 376 or 377, and LC containing the amino acid sequence of SEQ ID NO: 157 and the amino acid sequence of SEQ ID NO: 378;

r) HC containing the amino acid sequence of SEQ ID NO: 166 and the amino acid sequence of SEQ ID NO: 374, 375, 376 or 377, and LC containing the amino acid sequence of SEQ ID NO: 167 and the amino acid sequence of SEQ ID NO: 378;

s) HC containing the amino acid sequence of SEQ ID NO: 176 and the amino acid sequence of SEQ ID NO: 374, 375, 376 or 377, and LC containing the amino acid sequence of SEQ ID NO: 177 and the amino acid sequence of SEQ ID NO: 378;

t) HC containing the amino acid sequence of SEQ ID NO: 186 and the amino acid sequence of SEQ ID NO: 374, 375, 376 or 377, and LC containing the amino acid sequence of SEQ ID NO: 187 and the amino acid sequence of SEQ ID NO: 378;

u) HC containing the amino acid sequence of SEQ ID NO: 196 and the amino acid sequence of SEQ ID NO: 374, 375, 376 or 377, and LC containing the amino acid sequence of SEQ ID NO: 197 and the amino acid sequence of SEQ ID NO: 378;

v) HC containing the amino acid sequence of SEQ ID NO: 206 and the amino acid sequence of SEQ ID NO: 374, 375, 376 or 377, and LC containing the amino acid sequence of SEQ ID NO: 207 and the amino acid sequence of SEQ ID NO: 378; or

w) HC containing the amino acid sequence of SEQ ID NO: 216 and the amino acid sequence of SEQ ID NO: 374, 375, 376 or 377, and LC containing the amino acid sequence of SEQ ID NO: 217 and the amino acid sequence of SEQ ID NO: 378.

[0154] In some embodiments, the anti-TIM-3 antibody is selected from the group consisting of:

a) antibodies, H-CDR1-3 which contain the amino acid sequence of SEQ ID NO: 8-10, respectively;

b) an antibody whose VH sequence is at least 90% identical to the amino acid sequence of SEQ ID NO: 3 or 7;

c) an antibody whose VH contains the amino acid sequence of SEQ ID NO: 3 or 7;

d) an antibody whose HC contains the amino acid sequences of SEQ ID NO: 3 and 374 or the amino acid sequence of SEQ ID NO: 7 and the amino acid sequence of SEQ ID NO: 375, 376 or 377;

e) antibodies, L-CDR1-3 which contain the amino acid sequence of SEQ ID NO: 11-13, respectively;

f) an antibody whose VL sequence is at least 90% identical to the amino acid sequence of SEQ ID NO: 4;

g) an antibody whose VL contains the amino acid sequence of SEQ ID NO: 4;

h) an antibody whose LC contains the amino acid sequences of SEQ ID NOs: 4 and 378;

i) antibodies, H-CDR1-3 and L-CDR1-3 which contain the amino acid sequence of SEQ ID NO: 8-13, respectively;

j) an antibody whose VH sequence is at least 90% identical to the amino acid sequence of SEQ ID NO: 3 or 7 and whose VL sequence is at least 90% identical to the amino acid sequence of SEQ ID NO: 4;

k) an antibody whose VH contains the amino acid sequence of SEQ ID NO: 3 or 15 and whose VL contains the amino acid sequence of SEQ ID NO: 4; And

l) an antibody whose HC contains the amino acid sequences of SEQ ID NO: 3 and 374 or the amino acid sequence of SEQ ID NO: 7 and the amino acid sequence of SEQ ID NO: 375, 376 or 377; and the LC of which contains the amino acid sequences of SEQ ID NOs: 4 and 378.

[0155] In some embodiments, the anti-TIM-3 antibody is selected from the group consisting of:

a) antibodies, H-CDR1-3 which contain the amino acid sequence of SEQ ID NO: 18-20, respectively;

b) an antibody whose VH sequence is at least 90% identical to the amino acid sequence of SEQ ID NO: 16;

c) an antibody whose VH contains the amino acid sequence of SEQ ID NO: 16;

d) an antibody whose HC contains the amino acid sequences of SEQ ID NO: 16 and SEQ ID NO: 374, 375, 376 or 377;

e) antibodies, L-CDR1-3 which contain the amino acid sequence of SEQ ID NO: 21-23, respectively;

f) an antibody whose VL sequence is at least 90% identical to the amino acid sequence of SEQ ID NO: 17;

g) an antibody whose VL contains the amino acid sequence of SEQ ID NO: 17;

h) an antibody whose LC contains the amino acid sequences of SEQ ID NOs: 17 and 378;

i) antibodies, H-CDR1-3 and L-CDR1-3 which contain the amino acid sequence of SEQ ID NO: 18-23, respectively;

j) an antibody whose VH sequence is at least 90% identical to the amino acid sequence of SEQ ID NO: 16 and whose VL sequence is at least 90% identical to the amino acid sequence of SEQ ID NO: 17;

k) an antibody whose VH contains the amino acid sequence of SEQ ID NO: 16 and whose VL contains the amino acid sequence of SEQ ID NO: 17; And

l) an antibody whose HC contains the amino acid sequence of SEQ ID NO: 16 and the amino acid sequence of SEQ ID NO: 374, 375, 376 or 377; and the LC of which contains the amino acid sequences of SEQ ID NOs: 17 and 378.

[0156] In some embodiments, the anti-TIM-3 antibody is selected from the group consisting of:

a) antibodies, H-CDR1-3 which contain the amino acid sequence of SEQ ID NO: 28-30, respectively;

b) an antibody whose VH sequence is at least 90% identical to the amino acid sequence of SEQ ID NO: 26;

c) an antibody whose VH contains the amino acid sequence of SEQ ID NO: 26;

d) an antibody whose HC contains the amino acid sequences of SEQ ID NO: 26 and SEQ ID NO: 374, 375, 376 or 377;

e) antibodies, L-CDR1-3 which contain the amino acid sequence of SEQ ID NO: 31-33, respectively;

f) an antibody whose VL sequence is at least 90% identical to the amino acid sequence of SEQ ID NO: 27;

g) an antibody whose VL contains the amino acid sequence of SEQ ID NO: 27;

h) an antibody whose LC contains the amino acid sequences of SEQ ID NOs: 27 and 378;

i) antibodies, H-CDR1-3 and L-CDR1-3 which contain the amino acid sequence of SEQ ID NO: 28-33, respectively;

j) an antibody whose VH sequence is at least 90% identical to the amino acid sequence of SEQ ID NO: 26 and whose VL sequence is at least 90% identical to the amino acid sequence of SEQ ID NO: 27;

k) an antibody whose VH contains the amino acid sequence of SEQ ID NO: 26 and whose VL contains the amino acid sequence of SEQ ID NO: 27; And

l) an antibody whose HC contains the amino acid sequence of SEQ ID NO: 26 and the amino acid sequence of SEQ ID NO: 374, 375, 376 or 377; and the LC of which contains the amino acid sequences of SEQ ID NOs: 27 and 378.

[0157] In some embodiments, the anti-TIM-3 antibody is selected from the group consisting of:

a) antibodies, H-CDR1-3 which contain the amino acid sequence of SEQ ID NO: 38-40, respectively;

b) an antibody whose VH sequence is at least 90% identical to the amino acid sequence of SEQ ID NO: 36;

c) an antibody whose VH contains the amino acid sequence of SEQ ID NO: 36;

d) an antibody whose HC contains the amino acid sequences of SEQ ID NO: 36 and SEQ ID NO: 374, 375, 376 or 377;

e) antibodies, L-CDR1-3 which contain the amino acid sequence of SEQ ID NO: 41-43, respectively;

f) an antibody whose VL sequence is at least 90% identical to the amino acid sequence of SEQ ID NO: 37;

g) an antibody whose VL contains the amino acid sequence of SEQ ID NO: 37;

h) an antibody whose LC contains the amino acid sequences of SEQ ID NOs: 37 and 378;

i) antibodies, H-CDR1-3 and L-CDR1-3 which contain the amino acid sequence of SEQ ID NO: 38-43, respectively;

j) an antibody whose VH sequence is at least 90% identical to the amino acid sequence of SEQ ID NO: 36 and whose VL sequence is at least 90% identical to the amino acid sequence of SEQ ID NO: 37;

k) an antibody whose VH contains the amino acid sequence of SEQ ID NO: 36 and whose VL contains the amino acid sequence of SEQ ID NO: 37; And

l) an antibody whose HC contains the amino acid sequence of SEQ ID NO: 36 and the amino acid sequence of SEQ ID NO: 374, 375, 376 or 377; and the LC of which contains the amino acid sequences of SEQ ID NOs: 37 and 378.

[0158] In some embodiments, the anti-TIM-3 antibody is selected from the group consisting of:

a) antibodies, H-CDR1-3 which contain the amino acid sequence of SEQ ID NO: 48-50, respectively;

b) an antibody whose VH sequence is at least 90% identical to the amino acid sequence of SEQ ID NO: 46;

c) an antibody whose VH contains the amino acid sequence of SEQ ID NO: 46;

d) an antibody whose HC contains the amino acid sequences of SEQ ID NO: 46 and SEQ ID NO: 374, 375, 376 or 377;

e) antibodies, L-CDR1-3 which contain the amino acid sequence of SEQ ID NO: 51-53, respectively;

f) an antibody whose VL sequence is at least 90% identical to the amino acid sequence of SEQ ID NO: 47;

g) an antibody whose VL contains the amino acid sequence of SEQ ID NO: 47;

h) an antibody whose LC contains the amino acid sequences of SEQ ID NOs: 47 and 378;

i) antibodies, H-CDR1-3 and L-CDR1-3 which contain the amino acid sequence of SEQ ID NO: 48-53, respectively;

j) an antibody whose VH sequence is at least 90% identical to the amino acid sequence of SEQ ID NO: 46 and whose VL sequence is at least 90% identical to the amino acid sequence of SEQ ID NO: 47;

k) an antibody whose VH contains the amino acid sequence of SEQ ID NO: 46 and the VL of which contains the amino acid sequence of SEQ ID NO: 47; And

l) an antibody whose HC contains the amino acid sequence of SEQ ID NO: 46 and the amino acid sequence of SEQ ID NO: 374, 375, 376 or 377; and the LC of which contains the amino acid sequences of SEQ ID NOs: 47 and 378.

[0159] In some embodiments, the anti-TIM-3 antibody is selected from the group consisting of:

a) antibodies, H-CDR1-3 which contain the amino acid sequence of SEQ ID NO: 58-60, respectively;

b) an antibody whose VH sequence is at least 90% identical to the amino acid sequence of SEQ ID NO: 56;

c) an antibody whose VH contains the amino acid sequence of SEQ ID NO: 56;

d) an antibody whose HC contains the amino acid sequences of SEQ ID NO: 56 and SEQ ID NO: 374, 375, 376 or 377;

e) antibodies, L-CDR1-3 which contain the amino acid sequence of SEQ ID NO: 61-63, respectively;

f) an antibody whose VL sequence is at least 90% identical to the amino acid sequence of SEQ ID NO: 57;

g) an antibody whose VL contains the amino acid sequence of SEQ ID NO: 57;

h) an antibody whose LC contains the amino acid sequences of SEQ ID NOs: 57 and 378;

i) antibodies, H-CDR1-3 and L-CDR1-3 which contain the amino acid sequence of SEQ ID NO: 58-63, respectively;

j) an antibody whose VH sequence is at least 90% identical to the amino acid sequence of SEQ ID NO: 56 and whose VL sequence is at least 90% identical to the amino acid sequence of SEQ ID NO: 57;

k) an antibody whose VH contains the amino acid sequence of SEQ ID NO: 56 and the VL of which contains the amino acid sequence of SEQ ID NO: 57; And

l) an antibody whose HC contains the amino acid sequence of SEQ ID NO: 56 and the amino acid sequence of SEQ ID NO: 374, 375, 376 or 377; and the LC of which contains the amino acid sequences of SEQ ID NOs: 57 and 378.

[0160] In some embodiments, the anti-TIM-3 antibody is selected from the group consisting of:

a) antibodies, H-CDR1-3 which contain the amino acid sequence of SEQ ID NO: 68-70, respectively;

b) an antibody whose VH sequence is at least 90% identical to the amino acid sequence of SEQ ID NO: 66;

c) an antibody whose VH contains the amino acid sequence of SEQ ID NO: 66;

d) an antibody whose HC contains the amino acid sequences of SEQ ID NO: 66 and SEQ ID NO: 374, 375, 376 or 377;

e) antibodies, L-CDR1-3 which contain the amino acid sequence of SEQ ID NO: 71-73, respectively;

f) an antibody whose VL sequence is at least 90% identical to the amino acid sequence of SEQ ID NO: 67;

g) an antibody whose VL contains the amino acid sequence of SEQ ID NO: 67;

h) an antibody whose LC contains the amino acid sequences of SEQ ID NOs: 67 and 378;

i) antibodies, H-CDR1-3 and L-CDR1-3 which contain the amino acid sequence of SEQ ID NO: 68-73, respectively;

j) an antibody whose VH sequence is at least 90% identical to the amino acid sequence of SEQ ID NO: 66 and whose VL sequence is at least 90% identical to the amino acid sequence of SEQ ID NO: 67;

k) an antibody whose VH contains the amino acid sequence of SEQ ID NO: 66 and whose VL contains the amino acid sequence of SEQ ID NO: 67; And

l) an antibody whose HC contains the amino acid sequence of SEQ ID NO: 66 and the amino acid sequence of SEQ ID NO: 374, 375, 376 or 377; and the LC of which contains the amino acid sequences of SEQ ID NOs: 67 and 378.

[0161] In some embodiments, the anti-TIM-3 antibody is selected from the group consisting of:

a) antibodies, H-CDR1-3 which contain the amino acid sequence of SEQ ID NO: 78-80, respectively;

b) an antibody whose VH sequence is at least 90% identical to the amino acid sequence of SEQ ID NO: 76;

c) an antibody whose VH contains the amino acid sequence of SEQ ID NO: 76;

d) an antibody whose HC contains the amino acid sequences of SEQ ID NO: 76 and SEQ ID NO: 374, 375, 376 or 377;

e) antibodies, L-CDR1-3 which contain the amino acid sequence of SEQ ID NO: 81-83, respectively;

f) an antibody whose VL sequence is at least 90% identical to the amino acid sequence of SEQ ID NO: 77;

g) an antibody whose VL contains the amino acid sequence of SEQ ID NO: 77;

h) an antibody whose LC contains the amino acid sequences of SEQ ID NOs: 77 and 378;

i) antibodies, H-CDR1-3 and L-CDR1-3 which contain the amino acid sequence of SEQ ID NO: 78-83, respectively;

j) an antibody whose VH sequence is at least 90% identical to the amino acid sequence of SEQ ID NO: 76 and whose VL sequence is at least 90% identical to the amino acid sequence of SEQ ID NO: 77;

k) an antibody whose VH contains the amino acid sequence of SEQ ID NO: 76 and whose VL contains the amino acid sequence of SEQ ID NO: 77; And

l) an antibody whose HC contains the amino acid sequence of SEQ ID NO: 76 and the amino acid sequence of SEQ ID NO: 374, 375, 376 or 377; and the LC of which contains the amino acid sequences of SEQ ID NOs: 77 and 378.

[0162] In some embodiments, the anti-TIM-3 antibody is selected from the group consisting of:

a) antibodies, H-CDR1-3 which contain the amino acid sequence of SEQ ID NO: 88-90, respectively;

b) an antibody whose VH sequence is at least 90% identical to the amino acid sequence of SEQ ID NO: 86;

c) an antibody whose VH contains the amino acid sequence of SEQ ID NO: 86;

d) an antibody whose HC contains the amino acid sequences of SEQ ID NO: 86 and SEQ ID NO: 374, 375, 376 or 377;

e) antibodies, L-CDR1-3 which contain the amino acid sequence of SEQ ID NO: 91-93, respectively;

f) an antibody whose VL sequence is at least 90% identical to the amino acid sequence of SEQ ID NO: 87;

g) an antibody whose VL contains the amino acid sequence of SEQ ID NO: 87;

h) an antibody whose LC contains the amino acid sequences of SEQ ID NOs: 87 and 378;

i) antibodies, H-CDR1-3 and L-CDR1-3 which contain the amino acid sequence of SEQ ID NO: 88-93, respectively;

j) an antibody whose VH sequence is at least 90% identical to the amino acid sequence of SEQ ID NO: 86 and whose VL sequence is at least 90% identical to the amino acid sequence of SEQ ID NO: 87;

k) an antibody whose VH contains the amino acid sequence of SEQ ID NO: 86 and the VL of which contains the amino acid sequence of SEQ ID NO: 87; And

l) an antibody whose HC contains the amino acid sequence of SEQ ID NO: 86 and the amino acid sequence of SEQ ID NO: 374, 375, 376 or 377; and the LC of which contains the amino acid sequences of SEQ ID NOs: 87 and 378.

[0163] In some embodiments, the anti-TIM-3 antibody is selected from the group consisting of:

a) antibodies, H-CDR1-3 which contain the amino acid sequence of SEQ ID NO: 98-100, respectively;

b) an antibody whose VH sequence is at least 90% identical to the amino acid sequence of SEQ ID NO: 96;

c) an antibody whose VH contains the amino acid sequence of SEQ ID NO: 96;

d) an antibody whose HC contains the amino acid sequences of SEQ ID NO: 96 and SEQ ID NO: 374, 375, 376 or 377;

e) antibodies, L-CDR1-3 which contain the amino acid sequence of SEQ ID NO: 101-103, respectively;

f) an antibody whose VL sequence is at least 90% identical to the amino acid sequence of SEQ ID NO: 97;

g) an antibody whose VL contains the amino acid sequence of SEQ ID NO: 97;

h) an antibody whose LC contains the amino acid sequences of SEQ ID NOs: 97 and 378;

i) antibodies, H-CDR1-3 and L-CDR1-3 which contain the amino acid sequence of SEQ ID NO: 98-103, respectively;

j) an antibody whose VH sequence is at least 90% identical to the amino acid sequence of SEQ ID NO: 96 and whose VL sequence is at least 90% identical to the amino acid sequence of SEQ ID NO: 97;

k) an antibody whose VH contains the amino acid sequence of SEQ ID NO: 96 and the VL of which contains the amino acid sequence of SEQ ID NO: 97; And

l) an antibody whose HC contains the amino acid sequence of SEQ ID NO: 96 and the amino acid sequence of SEQ ID NO: 374, 375, 376 or 377; and the LC of which contains the amino acid sequences of SEQ ID NOs: 97 and 378.

[0164] In some embodiments, the anti-TIM-3 antibody is selected from the group consisting of:

a) antibodies, H-CDR1-3 which contain the amino acid sequence of SEQ ID NO: 108-110, respectively;

b) an antibody whose VH sequence is at least 90% identical to the amino acid sequence of SEQ ID NO: 106;

c) an antibody whose VH contains the amino acid sequence of SEQ ID NO: 106;

d) an antibody whose HC contains the amino acid sequences of SEQ ID NO: 106 and SEQ ID NO: 374, 375, 376 or 377;

e) antibodies, L-CDR1-3 which contain the amino acid sequence of SEQ ID NO: 111-113, respectively;

f) an antibody whose VL sequence is at least 90% identical to the amino acid sequence of SEQ ID NO: 107;

g) an antibody whose VL contains the amino acid sequence of SEQ ID NO: 107;

h) an antibody whose LC contains the amino acid sequences of SEQ ID NOs: 107 and 378;

i) antibodies, H-CDR1-3 and L-CDR1-3 which contain the amino acid sequence of SEQ ID NO: 108-113, respectively;

j) an antibody whose VH sequence is at least 90% identical to the amino acid sequence of SEQ ID NO: 106 and whose VL sequence is at least 90% identical to the amino acid sequence of SEQ ID NO: 107;

k) an antibody whose VH contains the amino acid sequence of SEQ ID NO: 106 and the VL of which contains the amino acid sequence of SEQ ID NO: 107; And

l) an antibody whose HC contains the amino acid sequence of SEQ ID NO: 106 and the amino acid sequence of SEQ ID NO: 374, 375, 376 or 377; and the LC of which contains the amino acid sequences of SEQ ID NOs: 107 and 378.

[0165] In some embodiments, the anti-TIM-3 antibody is selected from the group consisting of:

a) antibodies, H-CDR1-3 which contain the amino acid sequence of SEQ ID NO: 118-120, respectively;

b) an antibody whose VH sequence is at least 90% identical to the amino acid sequence of SEQ ID NO: 116;

c) an antibody whose VH contains the amino acid sequence of SEQ ID NO: 116;

d) an antibody whose HC contains the amino acid sequences of SEQ ID NO: 116 and SEQ ID NO: 374, 375, 376 or 377;

e) antibodies, L-CDR1-3 which contain the amino acid sequence of SEQ ID NO: 121-123, respectively;

f) an antibody whose VL sequence is at least 90% identical to the amino acid sequence of SEQ ID NO: 117;

g) an antibody whose VL contains the amino acid sequence of SEQ ID NO: 117;

h) an antibody whose LC contains the amino acid sequences of SEQ ID NOs: 117 and 378;

i) antibodies, H-CDR1-3 and L-CDR1-3 which contain the amino acid sequence of SEQ ID NO: 118-123, respectively;

j) an antibody whose VH sequence is at least 90% identical to the amino acid sequence of SEQ ID NO: 116 and whose VL sequence is at least 90% identical to the amino acid sequence of SEQ ID NO: 117;

k) an antibody whose VH contains the amino acid sequence of SEQ ID NO: 116 and the VL of which contains the amino acid sequence of SEQ ID NO: 117; And

l) an antibody whose HC contains the amino acid sequence of SEQ ID NO: 116 and the amino acid sequence of SEQ ID NO: 374, 375, 376 or 377; and the LC of which contains the amino acid sequences of SEQ ID NOs: 117 and 378.

[0166] In some embodiments, the anti-TIM-3 antibody is selected from the group consisting of:

a) antibodies, H-CDR1-3 which contain the amino acid sequence of SEQ ID NO: 128-130, respectively;

b) an antibody whose VH sequence is at least 90% identical to the amino acid sequence of SEQ ID NO: 126;

c) an antibody whose VH contains the amino acid sequence of SEQ ID NO: 126;

d) an antibody whose HC contains the amino acid sequences of SEQ ID NO: 126 and SEQ ID NO: 374, 375, 376 or 377;

e) antibodies, L-CDR1-3 which contain the amino acid sequence of SEQ ID NO: 131-133, respectively;

f) an antibody whose VL sequence is at least 90% identical to the amino acid sequence of SEQ ID NO: 127;

g) an antibody whose VL contains the amino acid sequence of SEQ ID NO: 127;

h) an antibody whose LC contains the amino acid sequences of SEQ ID NOs: 127 and 378;

i) antibodies, H-CDR1-3 and L-CDR1-3 which contain the amino acid sequence of SEQ ID NO: 128-133, respectively;

j) an antibody whose VH sequence is at least 90% identical to the amino acid sequence of SEQ ID NO: 126 and whose VL sequence is at least 90% identical to the amino acid sequence of SEQ ID NO: 127;

k) an antibody whose VH contains the amino acid sequence of SEQ ID NO: 126 and the VL of which contains the amino acid sequence of SEQ ID NO: 127; And

l) an antibody whose HC contains the amino acid sequence of SEQ ID NO: 126 and the amino acid sequence of SEQ ID NO: 374, 375, 376 or 377; and the LC of which contains the amino acid sequences of SEQ ID NOs: 127 and 378.

[0167] In some embodiments, the anti-TIM-3 antibody is selected from the group consisting of:

a) antibodies, H-CDR1-3 which contain the amino acid sequence of SEQ ID NO: 138-140, respectively;

b) an antibody whose VH sequence is at least 90% identical to the amino acid sequence of SEQ ID NO: 136;

c) an antibody whose VH contains the amino acid sequence of SEQ ID NO: 136;

d) an antibody whose HC contains the amino acid sequences of SEQ ID NO: 136 and SEQ ID NO: 374, 375, 376 or 377;

e) antibodies, L-CDR1-3 which contain the amino acid sequence of SEQ ID NO: 141-143, respectively;

f) an antibody whose VL sequence is at least 90% identical to the amino acid sequence of SEQ ID NO: 137;

g) an antibody whose VL contains the amino acid sequence of SEQ ID NO: 137;

h) an antibody whose LC contains the amino acid sequences of SEQ ID NOs: 137 and 378;

i) antibodies, H-CDR1-3 and L-CDR1-3 which contain the amino acid sequence of SEQ ID NO: 138-143, respectively;

j) an antibody whose VH sequence is at least 90% identical to the amino acid sequence of SEQ ID NO: 136 and whose VL sequence is at least 90% identical to the amino acid sequence of SEQ ID NO: 137;

k) an antibody whose VH contains the amino acid sequence of SEQ ID NO: 136 and the VL of which contains the amino acid sequence of SEQ ID NO: 137; And

l) an antibody whose HC contains the amino acid sequence of SEQ ID NO: 136 and the amino acid sequence of SEQ ID NO: 374, 375, 376 or 377; and the LC of which contains the amino acid sequences of SEQ ID NOs: 137 and 378.

[0168] In some embodiments, the anti-TIM-3 antibody is selected from the group consisting of:

a) antibodies, H-CDR1-3 which contain the amino acid sequence of SEQ ID NO: 148-150, respectively;

b) an antibody whose VH sequence is at least 90% identical to the amino acid sequence of SEQ ID NO: 146;

c) an antibody whose VH contains the amino acid sequence of SEQ ID NO: 146;

d) an antibody whose HC contains the amino acid sequences of SEQ ID NO: 146 and SEQ ID NO: 374, 375, 376 or 377;

e) antibodies, L-CDR1-3 which contain the amino acid sequence of SEQ ID NO: 151-153, respectively;

f) an antibody whose VL sequence is at least 90% identical to the amino acid sequence of SEQ ID NO: 147;

g) an antibody whose VL contains the amino acid sequence of SEQ ID NO: 147;

h) an antibody whose LC contains the amino acid sequences of SEQ ID NOs: 147 and 378;

i) antibodies, H-CDR1-3 and L-CDR1-3 which contain the amino acid sequence of SEQ ID NO: 148-53, respectively;

j) an antibody whose VH sequence is at least 90% identical to the amino acid sequence of SEQ ID NO: 146 and whose VL sequence is at least 90% identical to the amino acid sequence of SEQ ID NO: 147;

k) an antibody whose VH contains the amino acid sequence of SEQ ID NO: 146 and the VL of which contains the amino acid sequence of SEQ ID NO: 147; And

l) an antibody whose HC contains the amino acid sequence of SEQ ID NO: 146 and the amino acid sequence of SEQ ID NO: 374, 375, 376 or 377; and the LC of which contains the amino acid sequences of SEQ ID NOs: 147 and 378.

[0169] In some embodiments, the anti-TIM-3 antibody is selected from the group consisting of:

a) antibodies, H-CDR1-3 which contain the amino acid sequence of SEQ ID NO: 158-160, respectively;

b) an antibody whose VH sequence is at least 90% identical to the amino acid sequence of SEQ ID NO: 156;

c) an antibody whose VH contains the amino acid sequence of SEQ ID NO: 156;

d) an antibody whose HC contains the amino acid sequences of SEQ ID NO: 156 and SEQ ID NO: 374, 375, 376 or 377;

e) antibodies, L-CDR1-3 which contain the amino acid sequence of SEQ ID NO: 161-163, respectively;

f) an antibody whose VL sequence is at least 90% identical to the amino acid sequence of SEQ ID NO: 157;

g) an antibody whose VL contains the amino acid sequence of SEQ ID NO: 157;

h) an antibody whose LC contains the amino acid sequences of SEQ ID NOs: 157 and 378;

i) antibodies, H-CDR1-3 and L-CDR1-3 which contain the amino acid sequence of SEQ ID NO: 158-163, respectively;

j) an antibody whose VH sequence is at least 90% identical to the amino acid sequence of SEQ ID NO: 156 and whose VL sequence is at least 90% identical to the amino acid sequence of SEQ ID NO: 157;

k) an antibody whose VH contains the amino acid sequence of SEQ ID NO: 156 and whose VL contains the amino acid sequence of SEQ ID NO: 157; And

l) an antibody whose HC contains the amino acid sequence of SEQ ID NO: 156 and the amino acid sequence of SEQ ID NO: 374, 375, 376 or 377; and the LC of which contains the amino acid sequences of SEQ ID NOs: 157 and 378.

[0170] In some embodiments, the anti-TIM-3 antibody is selected from the group consisting of:

a) antibodies, H-CDR1-3 which contain the amino acid sequence of SEQ ID NO: 168-170, respectively;

b) an antibody whose VH sequence is at least 90% identical to the amino acid sequence of SEQ ID NO: 166;

c) an antibody whose VH contains the amino acid sequence of SEQ ID NO: 166;

d) an antibody whose HC contains the amino acid sequences of SEQ ID NO: 166 and SEQ ID NO: 374, 375, 376 or 377;

e) antibodies, L-CDR1-3 which contain the amino acid sequence of SEQ ID NO: 171-173, respectively;

f) an antibody whose VL sequence is at least 90% identical to the amino acid sequence of SEQ ID NO: 167;

g) an antibody whose VL contains the amino acid sequence of SEQ ID NO: 167;

h) an antibody whose LC contains the amino acid sequences of SEQ ID NOs: 167 and 378;

i) antibodies, H-CDR1-3 and L-CDR1-3 which contain the amino acid sequence of SEQ ID NO: 168-173, respectively;

j) an antibody whose VH sequence is at least 90% identical to the amino acid sequence of SEQ ID NO: 166 and whose VL sequence is at least 90% identical to the amino acid sequence of SEQ ID NO: 167;

k) an antibody whose VH contains the amino acid sequence of SEQ ID NO: 166 and the VL of which contains the amino acid sequence of SEQ ID NO: 167; And

l) an antibody whose HC contains the amino acid sequence of SEQ ID NO: 166 and the amino acid sequence of SEQ ID NO: 374, 375, 376 or 377; and the LC of which contains the amino acid sequences of SEQ ID NOs: 167 and 378.

[0171] In some embodiments, the anti-TIM-3 antibody is selected from the group consisting of:

a) antibodies, H-CDR1-3 which contain the amino acid sequence of SEQ ID NO: 178-80, respectively;

b) an antibody whose VH sequence is at least 90% identical to the amino acid sequence of SEQ ID NO: 176;

c) an antibody whose VH contains the amino acid sequence of SEQ ID NO: 176;

d) an antibody whose HC contains the amino acid sequences of SEQ ID NO: 176 and SEQ ID NO: 374, 375, 376 or 377;

e) antibodies, L-CDR1-3 which contain the amino acid sequence of SEQ ID NO: 181-183, respectively;

f) an antibody whose VL sequence is at least 90% identical to the amino acid sequence of SEQ ID NO: 177;

g) an antibody whose VL contains the amino acid sequence of SEQ ID NO: 177;

h) an antibody whose LC contains the amino acid sequences of SEQ ID NOs: 177 and 378;

i) antibodies, H-CDR1-3 and L-CDR1-3 which contain the amino acid sequence of SEQ ID NO: 178-183, respectively;

j) an antibody whose VH sequence is at least 90% identical to the amino acid sequence of SEQ ID NO: 176 and whose VL sequence is at least 90% identical to the amino acid sequence of SEQ ID NO: 177;

k) an antibody whose VH contains the amino acid sequence of SEQ ID NO: 176 and the VL of which contains the amino acid sequence of SEQ ID NO: 177; And

l) an antibody whose HC contains the amino acid sequence of SEQ ID NO: 176 and the amino acid sequence of SEQ ID NO: 374, 375, 376 or 377; and the LC of which contains the amino acid sequences of SEQ ID NOs: 177 and 378.

[0172] In some embodiments, the anti-TIM-3 antibody is selected from the group consisting of:

a) antibodies, H-CDR1-3 which contain the amino acid sequence of SEQ ID NO: 188-190, respectively;

b) an antibody whose VH sequence is at least 90% identical to the amino acid sequence of SEQ ID NO: 186;

c) an antibody whose VH contains the amino acid sequence of SEQ ID NO: 186;

d) an antibody whose HC contains the amino acid sequences of SEQ ID NO: 186 and SEQ ID NO: 374, 375, 376 or 377;

e) antibodies, L-CDR1-3 which contain the amino acid sequence of SEQ ID NO: 191-193, respectively;

f) an antibody whose VL sequence is at least 90% identical to the amino acid sequence of SEQ ID NO: 187;

g) an antibody whose VL contains the amino acid sequence of SEQ ID NO: 187;

h) an antibody whose LC contains the amino acid sequences of SEQ ID NOs: 187 and 378;

i) antibodies, H-CDR1-3 and L-CDR1-3 which contain the amino acid sequence of SEQ ID NO: 188-193, respectively;

j) an antibody whose VH sequence is at least 90% identical to the amino acid sequence of SEQ ID NO: 186 and whose VL sequence is at least 90% identical to the amino acid sequence of SEQ ID NO: 187;

k) an antibody whose VH contains the amino acid sequence of SEQ ID NO: 186 and the VL of which contains the amino acid sequence of SEQ ID NO: 187; And

l) an antibody whose HC contains the amino acid sequence of SEQ ID NO: 186 and the amino acid sequence of SEQ ID NO: 374, 375, 376 or 377; and the LC of which contains the amino acid sequences of SEQ ID NOs: 187 and 378.

[0173] In some embodiments, the anti-TIM-3 antibody is selected from the group consisting of:

a) antibodies, H-CDR1-3 which contain the amino acid sequence of SEQ ID NO: 198-200, respectively;

b) an antibody whose VH sequence is at least 90% identical to the amino acid sequence of SEQ ID NO: 196;

c) an antibody whose VH contains the amino acid sequence of SEQ ID NO: 196;

d) an antibody whose HC contains the amino acid sequences of SEQ ID NO: 196 and SEQ ID NO: 374, 375, 376 or 377;

e) antibodies, L-CDR1-3 which contain the amino acid sequence of SEQ ID NO: 201-203, respectively;

f) an antibody whose VL sequence is at least 90% identical to the amino acid sequence of SEQ ID NO: 197;

g) an antibody whose VL contains the amino acid sequence of SEQ ID NO: 197;

h) an antibody whose LC contains the amino acid sequences of SEQ ID NOs: 197 and 378;

i) antibodies, H-CDR1-3 and L-CDR1-3 which contain the amino acid sequence of SEQ ID NO: 198-203, respectively;

j) an antibody whose VH sequence is at least 90% identical to the amino acid sequence of SEQ ID NO: 196 and whose VL sequence is at least 90% identical to the amino acid sequence of SEQ ID NO: 197;

k) an antibody whose VH contains the amino acid sequence of SEQ ID NO: 196 and the VL of which contains the amino acid sequence of SEQ ID NO: 197; And

l) an antibody whose HC contains the amino acid sequence of SEQ ID NO: 196 and the amino acid sequence of SEQ ID NO: 374, 375, 376 or 377; and the LC of which contains the amino acid sequences of SEQ ID NOs: 197 and 378.

[0174] In some embodiments, the anti-TIM-3 antibody is selected from the group consisting of:

a) antibodies, H-CDR1-3 which contain the amino acid sequence of SEQ ID NO: 208-210, respectively;

b) an antibody whose VH sequence is at least 90% identical to the amino acid sequence of SEQ ID NO: 206;

c) an antibody whose VH contains the amino acid sequence of SEQ ID NO: 206;

d) an antibody whose HC contains the amino acid sequences of SEQ ID NO: 206 and SEQ ID NO: 374, 375, 376 or 377;

e) antibodies, L-CDR1-3 which contain the amino acid sequence of SEQ ID NO: 211-213, respectively;

f) an antibody whose VL sequence is at least 90% identical to the amino acid sequence of SEQ ID NO: 207;

g) an antibody whose VL contains the amino acid sequence of SEQ ID NO: 207;

h) an antibody whose LC contains the amino acid sequences of SEQ ID NOs: 207 and 378;

i) antibodies, H-CDR1-3 and L-CDR1-3 which contain the amino acid sequence of SEQ ID NO: 208-213, respectively;

j) an antibody whose VH sequence is at least 90% identical to the amino acid sequence of SEQ ID NO: 206 and whose VL sequence is at least 90% identical to the amino acid sequence of SEQ ID NO: 207;

k) an antibody whose VH contains the amino acid sequence of SEQ ID NO: 206 and whose VL contains the amino acid sequence of SEQ ID NO: 207; And

l) an antibody whose HC contains the amino acid sequence of SEQ ID NO: 206 and the amino acid sequence of SEQ ID NO: 374, 375, 376 or 377; and the LC of which contains the amino acid sequences of SEQ ID NOs: 207 and 378.

[0175] In some embodiments, the anti-TIM-3 antibody is selected from the group consisting of:

a) antibodies, H-CDR1-3 which contain the amino acid sequence of SEQ ID NO: 218-220, respectively;

b) an antibody whose VH sequence is at least 90% identical to the amino acid sequence of SEQ ID NO: 216;

c) an antibody whose VH contains the amino acid sequence of SEQ ID NO: 216;

d) an antibody whose HC contains the amino acid sequences of SEQ ID NO: 216 and SEQ ID NO: 374, 375, 376 or 377;

e) antibodies, L-CDR1-3 which contain the amino acid sequence of SEQ ID NO: 221-223, respectively;

f) an antibody whose VL sequence is at least 90% identical to the amino acid sequence of SEQ ID NO: 217;

g) an antibody whose VL contains the amino acid sequence of SEQ ID NO: 217;

h) an antibody whose LC contains the amino acid sequences of SEQ ID NOs: 217 and 378;

i) antibodies, H-CDR1-3 and L-CDR1-3 which contain the amino acid sequence of SEQ ID NO: 218-223, respectively;

j) an antibody whose VH sequence is at least 90% identical to the amino acid sequence of SEQ ID NO: 216 and whose VL sequence is at least 90% identical to the amino acid sequence of SEQ ID NO: 217;

k) an antibody whose VH contains the amino acid sequence of SEQ ID NO: 216 and whose VL contains the amino acid sequence of SEQ ID NO: 217; And

l) an antibody whose HC contains the amino acid sequence of SEQ ID NO: 216 and the amino acid sequence of SEQ ID NO: 374, 375, 376 or 377; and the LC of which contains the amino acid sequences of SEQ ID NOs: 217 and 378.

[0176] In some embodiments, any of the anti-TIM-3 antibodies or antigen-binding portions described herein can inhibit TIM-3 binding of ligands such as galectin-9, CEACAM1, HMGB-1, and phosphatidylserine.

[0177] In some embodiments, any of the anti-TIM-3 antibodies or antigen-binding portions described herein can increase NK cell activity. In some embodiments, this activity may mediate ADCC.

[0178] In some embodiments, administration of an anti-TIM-3 antibody, or antigen-binding portion thereof, as described herein, can activate dendritic cells, causing them to mature and hence their ability to stimulate T cells. Without wishing to be bound by any particular theory, it is believed that the anti-TIM-3 antibodies described herein function as activators of TIM-3 expressing dendritic cells, whereby their effect on dendritic cells serves to stimulate T- cells. Thus, in tumor-associated conditions, anti-TIM-3 antibodies will induce the maturation and activation of tumor-associated dendritic cells, leading to the activation of tumor-specific T cells.

[0179] In some embodiments, administration of an anti-TIM-3 antibody, or antigen-binding portion thereof, as described herein, can directly activate T cells.

[0180] In some embodiments, the anti-TIM-3 antibody or antigen-binding portion described herein has at least one of the following properties:

a) binds to human TIM-3 with a KD of 23 nM or less as measured by surface plasmon resonance;

b) binds to cynomolgus TIM-3 with a KD of 22 nM or less as measured by surface plasmon resonance;

c) binds to human TIM-3 with an EC50 of 1.2 nM or less as measured by ELISA;

d) binds to cynomolgus TIM-3 with an EC50 of 46 nM or less as measured by ELISA;

e) increases IFN-γ secretion in a mixed lymphocyte culture unidirectional reaction assay;

f) increases IFN-γ secretion in a bidirectional mixed lymphocyte culture assay;

g) increases TNF-α secretion in a mixed lymphocyte culture unidirectional reaction assay;

h) increases the secretion of TNF-α from dendritic cells; And

i) inhibits the interaction of TIM-3 with phosphatidylserine.

Examples of such an antibody include, without limitation, antibody 15086.15086 (having at least properties a, c, d, e, g, and h); antibody 15086.17145 (having at least properties a, c, d, e, g, h and i), antibody 15086.16837 or 15086.17144 (having at least properties a, c and d), antibody 20293 or 20131 (having at least properties a, b, c, d, e, f, and h), antibody 20362 (having at least properties c, e, f, and h) and antibody 19324, 19416, 19568, 20185, 20300, or 20621 (having at least properties c, d, e, f and h). In some embodiments, the anti-TIM-3 antibody or antigen-binding portion has all of these properties. In some embodiments, the anti-TIM-3 antibody or antigen-binding portion has at least properties a, c, d, e, g, and h. In some embodiments, the anti-TIM-3 antibody or antigen-binding portion has at least properties a, c, d, e, g, h, and i. In some embodiments, the anti-TIM-3 antibody or antigen-binding portion has at least properties a, c, and d. In some embodiments, the anti-TIM-3 antibody or antigen-binding portion has at least properties a, b, c, d, e, f, and h. In some embodiments, the anti-TIM-3 antibody or antigen-binding portion has at least properties c, e, f, and h. In some embodiments, the anti-TIM-3 antibody or antigen-binding portion has at least properties c, d, e, f, and h.

[0181] In some embodiments, an anti-TIM-3 antibody, or antigen-binding portion thereof, as described herein, binds to a TIM-3 epitope that contains at least one (e.g., at least two, at least three, at least four, at least five, at least six, at least seven, at least eight, or at least nine) of the following residues of SEQ ID NO: 389: P50, V60, F61, E62, G64, R69, I117 , M118 and D120. In some embodiments, the antibody or antigen-binding portion binds to a TIM-3 epitope that contains residues P50, V60, F61, E62, G64, R69, I117, M118, and D120 of SEQ ID NO: 389 (e.g., antibody 15086.15086, 15086.16837, 15086.17145 or 15086.17144). In some embodiments, the antibody or antigen-binding portion binds to a TIM-3 epitope that contains residues F61, R69, and I117 of SEQ ID NO: 389 (eg, antibody 20293). In some embodiments, the antibody or antigen-binding portion binds to a TIM-3 epitope that contains residues P50, F61, E62, I117, M118, and D120 of SEQ ID NO: 389 (eg, antibody 20131).

[0182] In some embodiments, an anti-TIM-3 antibody, or an antigen-binding portion thereof, binds to a TIM-3 epitope containing the amino acid residues F61 and I117 of SEQ ID NO: 389 (e.g., antibody 15086.15086, 15086.16837, 15086.17145, 15086.17144, 20293, or 20131) . In some embodiments, the epitope further comprises the amino acid residue R69 (eg, antibody 15086.15086, 15086.16837, 15086.17145, 15086.17144, or 20293). In some embodiments, the epitope further comprises P50, E62, M118, and D120 (e.g., antibody 15086.15086, 15086.16837, 15086.17145, 15086.17144, or 20131) and may further contain amino acid residues V60 and G64 (e.g., antibody 15086.15086, 15086.16837, 15086.17145 or 15086.17144).

[0183] In some embodiments, an anti-TIM-3 antibody, or an antigen-binding portion thereof, as described herein, binds to a TIM-3 epitope that contains at least one (e.g., at least one, at least two, at least three, at least four, at least five, at least six, at least seven, at least eight, or at least nine) of the following residues of SEQ ID NO: 236: P50, V60, F61, E62, G64, R69, I117, M118 and D120. An epitope with any combination of the above residues is contemplated.

[0184] In some embodiments, an anti-TIM-3 antibody or antigen-binding portion thereof, as described herein, binds to a TIM-3 epitope that contains residues 62-67 and/or 114-117 of SEQ ID NO: 389. In some embodiments, the antibody or portion thereof binds to residues 62-67 (or fragments thereof, e.g., a fragment of one, two, three, four, or five residues) of SEQ ID NO: 389 (e.g., antibodies 15086.15086, 15086.16837, 15086.17145, 15086.17144 and 20293 ). In some embodiments, the antibody, or portion thereof, binds to residues 114-117 (or fragments thereof, eg, a fragment of one, two, or three residues) of SEQ ID NO: 389 (eg, antibody 20131). An epitope with any combination of the above residues is also provided.

[0185] In some embodiments, the anti-TIM-3 antibody or antigen-binding portion thereof does not compete with ABTIM3 (from PCT patent publication WO 2015/117002) and/or mAb15 (from PCT patent publication WO 2016/111947) for binding to TIM-3 . In some embodiments, the anti-TIM-3 antibody or antigen-binding portion does not bind to the same epitope as ABTIM3 and/or mAB15; for example, the antibody or portion thereof binds to one or more residues on TIM-3 that are not bound by ABTIM3 and/or mAb15.

[0186] In some embodiments, an anti-TIM-3 antibody or antigen-binding portion thereof as described herein is an anti-TIM-3 antibody or antigen-binding portion as described in PCT Patent Publication WO 2017/178493, which is hereby incorporated by reference in its entirety. document.

Antibodies against LAG-3

[0187] In some embodiments, the anti-LAG-3 antibodies disclosed herein are human antibodies derived from transgenic rats that are capable of generating human idiotype antibodies. In another embodiment, the antibodies are chicken-derived chimeric antibodies comprising chicken CDR sequences and human framework regions, wherein the framework regions have been humanized.

[0058] One advantage of the novel anti-LAG-3 antibodies described herein is that they are able to enhance T cell activity as measured by increased production of IL-2. Without wishing to be bound by any particular theory, it is believed that anti-LAG-3 antibodies are capable of blocking the interaction of LAG-3 with its putative ligands such as MHCII and LSECtin. Antibodies can do this directly by blocking the ligand binding site or by promoting LAG-3 internalization. Another potential advantage of the anti-LAG-3 antibodies described herein is the low level of secondary effector functions in antibodies having "LALA" (L234A/L235A) mutations that prevent the antibody from meaningfully binding to human FcgR (Fc receptors gamma) and hence the depletion of effector T cells.

[0188] In some embodiments, the combination drug or composition comprises an anti-LAG-3 antibody or an antigen-binding portion thereof, wherein the anti-LAG-3 antibody is an antibody referred to herein as antibody 15646, 15532, 15723, 15595, 15431, 15572 or 15011 or a variant of any of them, and the variant may, for example, contain some minimal amino acid changes relative to the specified antibody (for example, 1, 2, 3, 4, 5, 6, 7, 8, 9 or 10 amino acid changes, which can be , for example, in framework regions) without losing the antigen-binding specificity of the antibody.

[0189] In some embodiments, the anti-LAG-3 antibody, or antigen-binding portion thereof, competes or cross-competes with antibody 15646, 15532, 15723, 15595, 15431, 15572, or 15011 for binding to human LAG-3 or binds to the same LAG epitope -3 people, which is it. In some embodiments, the antibody is in IgG1 or IgG2 format. In some embodiments, the antibody is in IgG2 format.

[0190] In some embodiments, an anti-LAG-3 antibody competes or cross-competes with an antibody whose heavy chain (H) CDR1-3 and light chain (L) CDR1-3 comprise, respectively, SEQ ID NOS: 308-313, 318 -323, 328-333, 338-343, 348-353, 358-363, or 368-373, for binding to human LAG-3 or binding to the same human LAG-3 epitope as it.

[0191] In some embodiments, the anti-LAG-3 antibody comprises an H-CDR3 comprising the amino acid sequence of H-CDR3 SEQ ID NO: 310, 320, 330, 340, 350, 360, or 370.

[0192] In some embodiments, the anti-LAG-3 antibody comprises H-CDR1-3 containing the amino acid sequences of H-CDR1-3, respectively, from SEQ ID NOs: 308-310, 318-320, 328-330, 338-340 , 348-350, 358-360 or 368-370.

[0193] In some embodiments, an anti-LAG-3 antibody has a VH whose amino acid sequence is at least 90% (e.g., at least 92%, at least 95%, at least 96%, at least at least 97%, at least 98%, or at least 99%) identical to SEQ ID NO: 306, 316, 326, 336, 346, 356, or 366.

[0194] In some embodiments, the anti-LAG-3 antibody has a VH that contains SEQ ID NOs: 306, 316, 326, 336, 346, 356, or 366.

[0195] In some embodiments, an anti-LAG-3 antibody has a VH whose sequence is at least 90% (e.g., at least 92%, at least 95%, at least 96%, at least 97%, at least 98%, or at least 99%) identical to SEQ ID NO: 306, 316, 326, 336, 346, 356, or 366; and CH, the sequence of which is at least 90% (for example, at least 92%, at least 95%, at least 96%, at least 97%, at least 98%, or at least 99%) identical to SEQ ID NO: 375.

[0196] In some embodiments, the anti-LAG-3 antibody has a HC that contains the VH amino acid sequence of SEQ ID NO: 306, 316, 326, 336, 346, 356, or 366 and the CH amino acid sequence of SEQ ID NO: 375.

[0197] In some embodiments, the anti-LAG-3 antibody comprises an L-CDR3 comprising the amino acid sequence of L-CDR3 of SEQ ID NO: 313, 323, 333, 343, 353, 363, or 373.

[0198] In some embodiments, the anti-LAG-3 antibody comprises L-CDR1-3 containing the amino acid sequences of L-CDR1-3, respectively, SEQ ID NOs: 311-313, 321-323, 331-333, 341-343, 351-353, 361-363 or 371-373.

[0199] In some embodiments, an anti-LAG-3 antibody has a VL whose sequence is at least 90% (e.g., at least 92%, at least 95%, at least 96%, at least 97%, at least 98%, or at least 99%) identical to the amino acid sequence of VL SEQ ID NO: 307, 317, 327, 337, 347, 357, or 367.

[0200] In some embodiments, the anti-LAG-3 antibody has a VL that contains the VL amino acid sequence of SEQ ID NO: 307, 317, 327, 337, 347, 357, or 367.

[0201] In some embodiments, an anti-LAG-3 antibody has a VL whose sequence is at least 90% (e.g., at least 92%, at least 95%, at least 96%, at least 97%, at least 98%, or at least 99%) identical to the amino acid sequence of VL SEQ ID NO: 307, 317, 327, 337, 347, or 357; and CL, the sequence of which is at least 90% (for example, at least 92%, at least 95%, at least 96%, at least 97%, at least 98%, or at least 99%) identical to SEQ ID NO: 378.

[0202] In some embodiments, an anti-LAG-3 antibody has an LC that contains the VL amino acid sequence of SEQ ID NO: 307, 317, 327, 337, 347, or 357 and the CL amino acid sequence of SEQ ID NO: 378. In some embodiments, the antibody against LAG-3 has an LC that contains the VL amino acid sequence of SEQ ID NO: 367 and the CL amino acid sequence of SEQ ID NO: 379.

[0203] In some embodiments, the anti-LAG-3 antibody comprises any of the above heavy chain sequences and any of the above light chain sequences.

[0204] In some embodiments, the anti-LAG-3 antibody comprises H-CDR3 and L-CDR3 comprising the amino acid sequences of H-CDR3 and L-CDR3, respectively, from SEQ ID NOs: 310 and 313, 320 and 323, 330 and 333 , 340 and 343, 350 and 353, 360 and 363 or 370 and 373.

[0205] In some embodiments, the anti-LAG-3 antibody comprises H-CDR1-3 and L-CDR1-3 containing the sequences H-CDR1-3 and L-CDR1-3, respectively, from SEQ ID NOs: 308-313, 318-323, 328-333, 338-343, 348-353, 358-363 or 368-373.

[0206] In some embodiments, an anti-LAG-3 antibody has a VH whose sequence is at least 90% (e.g., at least 92%, at least 95%, at least 98%, or at least 99%) identical to the amino acid sequence of SEQ ID NO: 306, 316, 326, 336, 346, 356 or 366, and VL, the sequence of which is at least 90% (for example, at least 92%, at least 95%, at least 98%, or at least 99%) identical to the amino acid sequence of SEQ ID NO: 307, 317, 327, 337, 347, 357, or 367.

[0207] In some embodiments, the anti-LAG-3 antibody has a VH that contains the amino acid sequence of SEQ ID NO: 306, 316, 326, 336, 346, 356, or 366, and a VL that contains the amino acid sequence of SEQ ID NO: 307, 317, 327, 337, 347, 357 or 367.

[0208] In some embodiments, the anti-LAG-3 antibody has a HC that comprises the amino acid sequence of SEQ ID NO: 306, 316, 326, 336, 346, 356, or 366 and the amino acid sequence of SEQ ID NO: 375; and an LC that contains the amino acid sequence of SEQ ID NO: 307, 317, 327, 337, 347, or 357 and the amino acid sequence of SEQ ID NO: 378.

[0209] In some embodiments, the implementation of the antibody against LAG-3 has a HC that contains the amino acid sequence of SEQ ID NO: 306, 316, 326, 336, 346, 356 or 366 and the amino acid sequence of SEQ ID NO: 375; and LC, which contains the amino acid sequence of SEQ ID NO: 367 and the amino acid sequence of SEQ ID NO: 379.

[0210] In some embodiments, the anti-LAG-3 antibody comprises the amino acid sequences H-CDR1-3 and L-CDR1-3 from:

a) SEQ ID NO: 308-313, respectively;

b) SEQ ID NOs: 318-323, respectively;

c) SEQ ID NO: 328-333, respectively;

d) SEQ ID NO: 338-343, respectively;

e) SEQ ID NO: 348-353, respectively;

f) SEQ ID NO: 358-363, respectively; or

g) SEQ ID NO: 368-373, respectively.

[0211] In some embodiments, an anti-LAG-3 antibody comprises a heavy chain variable domain and a light chain variable domain having the amino acid sequences of:

a) SEQ ID NOs: 306 and 307, respectively;

b) SEQ ID NOs: 316 and 317, respectively;

c) SEQ ID NOs: 326 and 327, respectively;

d) SEQ ID NOs: 336 and 337, respectively;

e) SEQ ID NOs: 346 and 347, respectively;

f) SEQ ID NOs: 356 and 357, respectively; or

g) SEQ ID NOs: 366 and 367, respectively.

[0212] In some embodiments, the anti-LAG-3 antibody comprises:

a) HC containing the amino acid sequence of SEQ ID NO: 306 and the amino acid sequence of SEQ ID NO: 375, and LC containing the amino acid sequence of SEQ ID NO: 307 and the amino acid sequence of SEQ ID NO: 378;

b) HC containing the amino acid sequence of SEQ ID NO: 316 and the amino acid sequence of SEQ ID NO: 375, and LC containing the amino acid sequence of SEQ ID NO: 317 and the amino acid sequence of SEQ ID NO: 378;

c) HC containing the amino acid sequence of SEQ ID NO: 326 and the amino acid sequence of SEQ ID NO: 375, and LC containing the amino acid sequence of SEQ ID NO: 327 and the amino acid sequence of SEQ ID NO: 378;

d) HC containing the amino acid sequence of SEQ ID NO: 336 and the amino acid sequence of SEQ ID NO: 375, and LC containing the amino acid sequence of SEQ ID NO: 337 and the amino acid sequence of SEQ ID NO: 378;

e) HC containing the amino acid sequence of SEQ ID NO: 346 and the amino acid sequence of SEQ ID NO: 375, and LC containing the amino acid sequence of SEQ ID NO: 347 and the amino acid sequence of SEQ ID NO: 378;

f) HC containing the amino acid sequence of SEQ ID NO: 356 and the amino acid sequence of SEQ ID NO: 375, and LC containing the amino acid sequence of SEQ ID NO: 357 and the amino acid sequence of SEQ ID NO: 378; or

g) HC containing the amino acid sequence of SEQ ID NO: 366 and the amino acid sequence of SEQ ID NO: 375, and LC containing the amino acid sequence of SEQ ID NO: 367 and the amino acid sequence of SEQ ID NO: 379.

[0213] In some embodiments, the anti-LAG-3 antibody is selected from the group consisting of:

a) antibodies, H-CDR1-3 which contain the amino acid sequence of SEQ ID NO: 308-310, respectively;

b) an antibody whose VH sequence is at least 90% identical to the amino acid sequence of SEQ ID NO: 306;

c) an antibody whose VH contains the amino acid sequence of SEQ ID NO: 306;

d) an antibody whose HC contains the amino acid sequences of SEQ ID NOs: 306 and 375;

e) antibodies, L-CDR1-3 which contain the amino acid sequence of SEQ ID NO: 311-313, respectively;

f) an antibody whose VL sequence is at least 90% identical to the amino acid sequence of SEQ ID NO: 307;

g) an antibody whose VL contains the amino acid sequence of SEQ ID NO: 307;

h) an antibody whose LC contains the amino acid sequences of SEQ ID NOs: 307 and 378;

i) antibodies, H-CDR1-3 and L-CDR1-3 which contain the amino acid sequence of SEQ ID NO: 308-313, respectively;

j) an antibody whose VH sequence is at least 90% identical to the amino acid sequence of SEQ ID NO: 306 and whose VL sequence is at least 90% identical to the amino acid sequence of SEQ ID NO: 307;

k) an antibody whose VH contains the amino acid sequence of SEQ ID NO: 306 and the VL of which contains the amino acid sequence of SEQ ID NO: 307; And

l) an antibody whose HC contains the amino acid sequences of SEQ ID NOs: 306 and 375; and the LC of which contains the amino acid sequences of SEQ ID NOs: 307 and 378.

[0214] In some embodiments, the anti-LAG-3 antibody is selected from the group consisting of:

a) antibodies, H-CDR1-3 which contain the amino acid sequence of SEQ ID NO: 318-320, respectively;

b) an antibody whose VH sequence is at least 90% identical to the amino acid sequence of SEQ ID NO: 316;

c) an antibody whose VH contains the amino acid sequence of SEQ ID NO: 316;

d) an antibody whose HC contains the amino acid sequences of SEQ ID NOs: 316 and 375;

e) antibodies, L-CDR1-3 which contain the amino acid sequence of SEQ ID NO: 321-323, respectively;

f) an antibody whose VL sequence is at least 90% identical to the amino acid sequence of SEQ ID NO: 317;

g) an antibody whose VL contains the amino acid sequence of SEQ ID NO: 317;

h) an antibody whose LC contains the amino acid sequences of SEQ ID NOs: 317 and 378;

i) antibodies, H-CDR1-3 and L-CDR1-3 which contain the amino acid sequence of SEQ ID NO: 318-323, respectively;

j) an antibody whose VH sequence is at least 90% identical to the amino acid sequence of SEQ ID NO: 316 and whose VL sequence is at least 90% identical to the amino acid sequence of SEQ ID NO: 317;

k) an antibody whose VH contains the amino acid sequence of SEQ ID NO: 316 and whose VL contains the amino acid sequence of SEQ ID NO: 317; And

l) an antibody whose HC contains the amino acid sequences of SEQ ID NOs: 316 and 375; and the LC of which contains the amino acid sequences of SEQ ID NOs: 317 and 378.

[0215] In some embodiments, the anti-LAG-3 antibody is selected from the group consisting of:

a) antibodies, H-CDR1-3 which contain the amino acid sequence of SEQ ID NO: 328-330, respectively;

b) an antibody whose VH sequence is at least 90% identical to the amino acid sequence of SEQ ID NO: 326;

c) an antibody whose VH contains the amino acid sequence of SEQ ID NO: 326;

d) an antibody whose HC contains the amino acid sequences of SEQ ID NOs: 326 and 375;

e) antibodies, L-CDR1-3 which contain the amino acid sequence of SEQ ID NO: 331-333, respectively;

f) an antibody whose VL sequence is at least 90% identical to the amino acid sequence of SEQ ID NO: 327;

g) an antibody whose VL contains the amino acid sequence of SEQ ID NO: 327;

h) an antibody whose LC contains the amino acid sequences of SEQ ID NOs: 327 and 378;

i) antibodies, H-CDR1-3 and L-CDR1-3 which contain the amino acid sequence of SEQ ID NO: 328-333, respectively;

j) an antibody whose VH sequence is at least 90% identical to the amino acid sequence of SEQ ID NO: 326 and whose VL sequence is at least 90% identical to the amino acid sequence of SEQ ID NO: 327;

k) an antibody whose VH contains the amino acid sequence of SEQ ID NO: 326 and the VL of which contains the amino acid sequence of SEQ ID NO: 327; And

l) an antibody whose HC contains the amino acid sequences of SEQ ID NOs: 326 and 375; and the LC of which contains the amino acid sequences of SEQ ID NOs: 327 and 378.

[0216] In some embodiments, the anti-LAG-3 antibody is selected from the group consisting of:

a) antibodies, H-CDR1-3 which contain the amino acid sequence of SEQ ID NO: 338-340, respectively;

b) an antibody whose VH sequence is at least 90% identical to the amino acid sequence of SEQ ID NO: 336;

c) an antibody whose VH contains the amino acid sequence of SEQ ID NO: 336;

d) an antibody whose HC contains the amino acid sequences of SEQ ID NOs: 336 and 375;

e) antibodies, L-CDR1-3 which contain the amino acid sequence of SEQ ID NO: 341-343, respectively;

f) an antibody whose VL sequence is at least 90% identical to the amino acid sequence of SEQ ID NO: 337;

g) an antibody whose VL contains the amino acid sequence of SEQ ID NO: 337;

h) an antibody whose LC contains the amino acid sequences of SEQ ID NOs: 337 and 378;

i) antibodies, H-CDR1-3 and L-CDR1-3 which contain the amino acid sequence of SEQ ID NO: 338-343, respectively;

j) an antibody whose VH sequence is at least 90% identical to the amino acid sequence of SEQ ID NO: 336 and whose VL sequence is at least 90% identical to the amino acid sequence of SEQ ID NO: 337;

k) an antibody whose VH contains the amino acid sequence of SEQ ID NO: 336 and the VL of which contains the amino acid sequence of SEQ ID NO: 337; And

l) an antibody whose HC contains the amino acid sequences of SEQ ID NOs: 336 and 375; and the LC of which contains the amino acid sequences of SEQ ID NOs: 337 and 378.

[0217] In some embodiments, the anti-LAG-3 antibody is selected from the group consisting of:

a) antibodies, H-CDR1-3 which contain the amino acid sequence of SEQ ID NO: 348-350, respectively;

b) an antibody whose VH sequence is at least 90% identical to the amino acid sequence of SEQ ID NO: 346;

c) an antibody whose VH contains the amino acid sequence of SEQ ID NO: 346;

d) an antibody whose HC contains the amino acid sequences of SEQ ID NOs: 346 and 375;

e) antibodies, L-CDR1-3 which contain the amino acid sequence of SEQ ID NO: 351-353, respectively;

f) an antibody whose VL sequence is at least 90% identical to the amino acid sequence of SEQ ID NO: 347;

g) an antibody whose VL contains the amino acid sequence of SEQ ID NO: 347;

h) an antibody whose LC contains the amino acid sequences of SEQ ID NOs: 347 and 378;

i) antibodies, H-CDR1-3 and L-CDR1-3 which contain the amino acid sequence of SEQ ID NO: 348-353, respectively;

j) an antibody whose VH sequence is at least 90% identical to the amino acid sequence of SEQ ID NO: 346 and whose VL sequence is at least 90% identical to the amino acid sequence of SEQ ID NO: 347;

k) an antibody whose VH contains the amino acid sequence of SEQ ID NO: 346 and the VL of which contains the amino acid sequence of SEQ ID NO: 347; And

l) an antibody whose HC contains the amino acid sequences of SEQ ID NOs: 346 and 375; and the LC of which contains the amino acid sequences of SEQ ID NOs: 347 and 378.

[0218] In some embodiments, the anti-LAG-3 antibody is selected from the group consisting of:

a) antibodies, H-CDR1-3 which contain the amino acid sequence of SEQ ID NO: 358-360, respectively;

b) an antibody whose VH sequence is at least 90% identical to the amino acid sequence of SEQ ID NO: 356;

c) an antibody whose VH contains the amino acid sequence of SEQ ID NO: 356;

d) an antibody whose HC contains the amino acid sequences of SEQ ID NOs: 356 and 375;

e) antibodies, L-CDR1-3 which contain the amino acid sequence of SEQ ID NO: 361-363, respectively;

f) an antibody whose VL sequence is at least 90% identical to the amino acid sequence of SEQ ID NO: 357;

g) an antibody whose VL contains the amino acid sequence of SEQ ID NO: 357;

h) an antibody whose LC contains the amino acid sequences of SEQ ID NOs: 357 and 378;

i) antibodies, H-CDR1-3 and L-CDR1-3 which contain the amino acid sequence of SEQ ID NO: 358-363, respectively;

j) an antibody whose VH sequence is at least 90% identical to the amino acid sequence of SEQ ID NO: 356 and whose VL sequence is at least 90% identical to the amino acid sequence of SEQ ID NO: 357;

k) an antibody whose VH contains the amino acid sequence of SEQ ID NO: 356 and the VL of which contains the amino acid sequence of SEQ ID NO: 357; And

l) an antibody whose HC contains the amino acid sequences of SEQ ID NOs: 356 and 375; and the LC of which contains the amino acid sequences of SEQ ID NOs: 357 and 378.

[0219] In some embodiments, the anti-LAG-3 antibody is selected from the group consisting of:

a) antibodies, H-CDR1-3 which contain the amino acid sequence of SEQ ID NO: 368-370, respectively;

b) an antibody whose VH sequence is at least 90% identical to the amino acid sequence of SEQ ID NO: 366;

c) an antibody whose VH contains the amino acid sequence of SEQ ID NO: 366;

d) an antibody whose HC contains the amino acid sequences of SEQ ID NOs: 366 and 375;

e) antibodies, L-CDR1-3 which contain the amino acid sequence of SEQ ID NO: 371-373, respectively;

f) an antibody whose VL sequence is at least 90% identical to the amino acid sequence of SEQ ID NO: 367;

g) an antibody whose VL contains the amino acid sequence of SEQ ID NO: 367;

h) an antibody whose LC contains the amino acid sequences of SEQ ID NOs: 367 and 379;

i) antibodies, H-CDR1-3 and L-CDR1-3 which contain the amino acid sequence of SEQ ID NO: 368-373, respectively;

j) an antibody whose VH sequence is at least 90% identical to the amino acid sequence of SEQ ID NO: 366 and whose VL sequence is at least 90% identical to the amino acid sequence of SEQ ID NO: 367;

k) an antibody whose VH contains the amino acid sequence of SEQ ID NO: 366 and the VL of which contains the amino acid sequence of SEQ ID NO: 367; And

l) an antibody whose HC contains the amino acid sequences of SEQ ID NOs: 366 and 375; and the LC of which contains the amino acid sequences of SEQ ID NOs: 367 and 379.

[0220] In some embodiments, any of the anti-LAG-3 antibodies or antigen-binding portions described herein can bind to human LAG-3 with an EC50, e.g., 0.2 nM or less, 0.15 nM or less, 0 .1 nM or less, 0.09 nM or less, 0.08 nM or less, 0.07 nM or less, 0.06 nM or less, 0.05 nM or less, or 0.04 nM or less. In some embodiments, any of the anti-LAG-3 antibodies or antigen-binding portions described herein can bind to cynomolgus monkey LAG-3, for example, with an EC50 of 0.4 nM or less, 0.3 nM or less, 0.2 nM or less, 0.1 nM or less, 0.09 nM or less, 0.08 nM or less, 0.07 nM or less, 0.06 nM or less, 0.05 nM or less, 0.04 nM or less, or 0.03 nM or less. In certain embodiments, any of the anti-LAG-3 antibodies or antigen-binding portions described herein can bind to human LAG-3, e.g., an EC50 of 0.1 nM or less, and cynomolgus LAG-3, e.g., an EC50 of 0 .3 nM or less.

[0221] In some embodiments, any of the anti-LAG-3 antibodies or antigen-binding portions described herein can bind to human LAG-3 with an EC50 of, for example, 0.1 nM or less. In some embodiments, any of the anti-LAG-3 antibodies or antigen-binding portions described herein can bind to cynomolgus monkey LAG-3, for example, with an EC50 of 0.3 nM or less. In certain embodiments, any of the anti-LAG-3 antibodies or antigen-binding portions described herein can bind to human LAG-3, e.g., an EC50 of 0.1 nM or less, and cynomolgus LAG-3, e.g., an EC50 of 0 .3 nM or less.

[0222] In some embodiments, any of the anti-LAG-3 antibodies or antigen-binding portions described herein can inhibit the binding of ligands such as MHC class II (MHCII) or LSECtin to LAG-3. For example, at 20 µg/mL, an anti-LAG-3 antibody or antigen-binding portion can reduce LAG-3 binding to MHCII by at least 35%, at least 40%, at least 45%, at least 50% at least 55%, at least 60%, at least 65%, at least 70%, at least 75%, at least 80%, at least 85%, at least 89%, at least 90%, at least 91%, at least 92%, at least 93%, at least 94%, at least 95%, at least 96%, at least 97%, at least 98%, at least 99%, or 100% compared to binding in the presence of a negative control antibody. In one embodiment, an anti-LAG-3 antibody or antigen-binding protein can reduce the binding of LAG-3 to MHCII by more than 85% compared to a negative control. In one embodiment, the anti-LAG-3 antibody or antigen binding protein can reduce the binding of LAG-3 to MHCII by about 25%-95%, 30%-90%, or 35%-85% compared to a negative control.

[0223] In some embodiments, any of the anti-LAG-3 antibodies or antigen-binding portions described herein can block binding between LAG-3 and MHC class II, e.g., human LAG-3 expressed in Jurkat cells and MHC II human class expressed in Raji cells (e.g. at 0.1 µg/mL, 0.5 µg/mL, 1 µg/mL, 5 µg/mL, 10 µg/mL, 20 µg/mL, 30 µg/mL , 40 µg/ml or 50 µg/ml).

[0224] In some embodiments, any of the anti-LAG-3 antibodies or antigen-binding portions described herein can bind to human LAG-3 with a KD of 5.0 x 10 ^-8 or less, 4.0 x 10 ^-8 or less than, 3.0× ^10–8 or less, 2.0× ^10–8 or less, 1.0× ^10–8 or less, 9.0× ^10–9 or less, 8.0× ^10–9 or less than, 7.0× ^10–9 or less, 6.0× ^10–9 or less, 5.0× ^10–9 or less, 4.0× ^10–9 or less, 3.0× ^10–9 or less, 2.0×10 ^-9 or less, or 1.0×10 ^-9 or less, as measured by surface plasmon resonance.

[0225] In some embodiments, any of the anti-LAG-3 antibodies or antigen-binding portions described herein can bind to cynomolgus monkey LAG-3 with a KD of 1.5 x 10 ^-7 or less, 1.0 x 10 ^-7 or less, 9.0× ^10–8 or less, 8.0× ^10–8 or less, 7.0× ^10–8 or less, 6.0× ^10–8 or less, 5.0× ^10–8 or less, 4.0× ^10–8 or less, 3.0× ^10–8 or less, 2.0× ^10–8 or less, or 1.0× ^10–8 or less, as measured by surface plasmon resonance .

[0226] In some embodiments, any of the anti-LAG-3 antibodies or antigen-binding portions described herein can bind to mouse LAG-3 with a KD of 5.0 x 10 ^-8 or less, 4.5 x 10 ^-8 or less than, 4.0×10 ^-8 or less, 3.5×10 ^-8 or less, or 3.0×10 ^-8 or less, as measured by surface plasmon resonance.

[0227] In some embodiments, any of the anti-LAG-3 antibodies or antigen-binding portions described herein can stimulate the production of IL-2, for example, from stimulated SEB PBMCs.

[0228] In some embodiments, any of the anti-LAG-3 antibodies or antigen-binding portions described herein can reduce cellular and/or soluble levels of LAG-3, for example, in a human T cell line (such as a T cell line human overexpressing LAG-3).

[0229] In some embodiments, any of the anti-LAG-3 antibodies or antigen-binding portions described herein can induce regression of tumor growth and/or delay tumor growth in vivo.

[0230] In some embodiments, any of the anti-LAG-3 antibodies or antigen-binding portions described herein can bind to a different human LAG-3 epitope than the 25F7-Lag3.5 antibody.

[0231] In some embodiments, any of the anti-LAG-3 antibodies or antigen-binding portions described herein can activate T cells, causing enhanced antitumor activity.

[0232] In some embodiments, an anti-LAG-3 antibody or antigen-binding portion described herein has at least one of the following properties:

a) at a concentration of 20 μg/ml, it reduces the binding of human LAG-3 to human class II MHC in A375 cells by more than 85% compared to a negative control antibody, as determined by competitive analysis by flow cytometry;

b) at a concentration of 20 μg/ml reduces the binding of human LAG-3 to human class II MHC in A375 cells by up to 35%-85% compared to a negative control antibody, as determined by competitive analysis by flow cytometry;

c) blocks binding between human LAG-3 expressed in Jurkat cells and human class II MHC expressed in Raji cells;

d) binds to human LAG-3 with an EC50 of 0.1 nM or less as measured by flow cytometry;

e) binds to cynomolgus monkey LAG-3 with an EC50 of 0.3 nM or less as measured by flow cytometry;

f) binds to human LAG-3 with a KD of 3.0 x 10 ^-8 or less as measured by surface plasmon resonance;

g) binds to cynomolgus monkey LAG-3 with a KD of 1.5 x 10 ^-7 or less as measured by surface plasmon resonance;

h) binds to mouse LAG-3 with a KD of 3.5 x 10 ^-8 or less as measured by surface plasmon resonance;

i) stimulates IL-2 production in staphylococcal enterotoxin B (SEB) treated human peripheral blood mononuclear cells (PBMC);

j) reduces cellular levels of LAG-3 in human T cells;

k) reduces soluble levels of LAG-3 in cultured human T cells;

l) induces regression of tumor growth in vivo;

m) inhibits tumor growth in vivo; And

n) does not bind to the same human LAG-3 epitope as the 25F7-Lag3.5 antibody.

Examples of such an antibody include, without limitation, antibody 15646 (having at least properties b, c, d, e, i, and n), antibody 15532 (having at least properties a, c, d, e, f, g , i, j, k, m and n), antibody 15723 (having at least properties b, c, d, e, i and n), antibody 15595 (having at least properties a, c, d, e, i and n), antibody 15431 (having at least properties a, c, d, e, f, g, i and n), antibody 15572 (having at least properties b, c, d, e, f, g, i and n), and antibody 15011 (having at least properties a, c, d, e, f, g, h, i, j, k, l, m, and n). In some embodiments, an anti-TIM-3 antibody or antigen-binding portion of the invention has at least 13, 12, 11, 10, 9, 8, 7, 6, 5, 4, 3, 2, or 1 of these properties. In some embodiments, an anti-TIM-3 antibody or antigen-binding portion of the invention has at least properties b, c, d, e, i, and n; at least properties a, c, d, e, f, g, i, j, k, m, and n; at least properties a, c, d, e, i and n; at least properties a, c, d, e, f, g, i, and n; at least properties b, c, d, e, f, g, i and n; or at least properties a, c, d, e, f, g, h, i, j, k, l, m, and n.

[0233] In some embodiments, an anti-LAG-3 antibody or antigen-binding portion of the invention competes with antibody 15011, 15572, and/or 15431 for binding to human LAG-3.

[0234] In some embodiments, an anti-LAG-3 antibody or antigen-binding portion of the invention binds to a human LAG-3 epitope having:

a) amino acid residues H85, P86, A87, P89, S91, W92 and G93 SEQ ID NO: 68;

b) amino acid residues A40, Q41, P43, P46, P49, D52, T62, Q64, H65, Q66, P67, D68, G93, P94, P96, R98, Y99, T100, V101, P106, G107, R119, E124, R129, G130, D131, S133, R137, P138, D143, R148 and R163 SEQ ID NO: 68;

c) amino acid residues A40, Q41, P43, P46, P49, D52, T62, Q64, H65, Q66, P67, D68, P96, Y99, T100, V101, P106, G107, R119, E124, R129, G130, D131, S133, R137, P138, D143, R148 and R163 SEQ ID NO: 68; or

d) amino acid residues G107, L109, R110 and S111 of SEQ ID NO: 68.

[0235] In some embodiments, an anti-LAG-3 antibody or antigen-binding portion of the invention binds to an epitope having amino acid residues 98-105 of SEQ ID NO: 68. Examples of such an antibody include, without limitation, antibodies 15532, 15431, 15572, and 15011.

[0236] In some embodiments, an anti-LAG-3 antibody or antigen-binding portion of the invention binds to an epitope having:

a) amino acid residues 78-105 and 123-131 of SEQ ID NO: 68;

b) amino acid residues 23-30, 40-66, 88-105, 123-137 and 148-152 of SEQ ID NO: 68; or

c) amino acid residues 23-30, 40-66, 98-105, 118-137 and 148-161 SEQ ID NO: 68

[0237] In some embodiments, an anti-LAG-3 antibody or antigen-binding portion thereof as described herein is an anti-LAG-3 antibody or antigen-binding portion as described in PCT Patent Application PCT/EP 2017/076188, which is incorporated herein in its entirety. document through a link.

[0238] The class of the antibody described herein can be changed or switched to another class or subclass. In one aspect, a nucleic acid molecule encoding VL or VH is isolated using methods well known in the art such that it does not contain nucleic acid sequences encoding CL or CH. The nucleic acid molecules encoding VL or VH are then operably linked to a nucleic acid sequence encoding CL or CH, respectively, from a different class of immunoglobulin molecule. This can be achieved using a vector or nucleic acid molecule that contains the CL or CH chain as described above. For example, an antibody that was originally IgM can be switched to the IgG class. In addition, class switching can be used to convert one IgG subclass to another, for example from IgG1 to IgG2. The light chain constant region κ can be changed to, for example, the light chain constant region λ. A preferred method for producing an antibody as described herein with the desired Ig isotype comprises the steps of isolating a nucleic acid molecule encoding an antibody heavy chain and a nucleic acid molecule encoding an antibody light chain, obtaining a heavy chain variable domain, ligating the heavy chain variable domain to a constant region of the heavy chain of the desired isotype, expression of the light chain and ligated heavy chain in the cell, and collection of antibodies with the desired isotype.

[0239] An antibody described herein may be an IgG, IgM, IgE, IgA, or IgD molecule, but is usually of an IgG isotype, such as an IgG subclass of IgG1, IgG2a or IgG2b, IgG3, or IgG4. In one embodiment, the antibody is IgG1. In another embodiment, the antibody is IgG2.

[0240] In one embodiment, the antibody may contain at least one mutation in the Fc region. a number of different Fc mutations are known, where these mutations provide an altered effector function. For example, in many cases it will be necessary to reduce or eliminate effector function, such as when ligand/receptor interactions are undesirable or in the case of antibody-drug conjugates.

[0241] In one embodiment, the antibody contains at least one mutation in the Fc region that reduces effector function. Amino acid positions of the Fc region that may preferably be mutated to reduce effector function include one or more of positions 228, 233, 234 and 235, where the amino acid positions are numbered according to the IMGT® numbering scheme.

[0242] In some embodiments, one or both of the amino acid residues at positions 234 and 235 can be mutated, for example, from Leu to Ala (L234A/L235A). These mutations reduce the effector function of the Fc region of IgG1 antibodies. Additionally or alternatively, the amino acid residue at position 228 can be mutated, for example in Pro. In some embodiments, the amino acid residue at position 233 may be mutated, for example, to Pro, the amino acid residue at position 234 may be mutated, for example, to Val, and/or the amino acid residue at position 235 may be mutated, for example, to Ala. Amino acid positions are numbered according to the IMGT® numbering scheme.

[0243] In some embodiments, where the antibody is of the IgG4 subclass, it may contain the S228P mutation, i. e. have a proline at position 228, where the amino acid position is numbered according to the Eu IMGT® numbering scheme. This mutation is known to reduce unwanted Fab exchange (Angal et al. Mol Immunol. 30:105-8 (1993)).

[0244] In some embodiments, an antibody or antigen-binding portion thereof, as described herein, may be part of a larger immunoadhesion molecule formed by covalent or non-covalent association of the antibody or antibody portion with one or more other proteins or peptides. Examples of such an immunoadhesion molecule include the use of the streptavidin core region to obtain a tetramer scFv molecule (Kipriyanov et al. Human Antibodies and Hybridomas 6:93-101 (1995)) and the use of a cysteine residue, a marker peptide, and a C-terminal polyhistidine tag to obtain a bivalent and a biotinylated scFv molecule (Kipriyanov et al. Mol. Immunol. 31:1047-1058 (1994)). Other examples include when one or more CDRs from an antibody are either covalently or non-covalently incorporated into the molecule to make it an immunoadhesin that specifically binds to the antigen of interest. In such embodiments, the CDR may be inserted as part of a larger polypeptide chain, may be covalently linked to another polypeptide chain, or may be inserted non-covalently.

[0245] In another embodiment, a fusion antibody or immunoadhesin can be prepared that contains all or part of an antibody described herein linked to another polypeptide. In some embodiments, only the variable domains of an antibody are bound to a polypeptide. In some embodiments, the VH domain of an antibody is linked to a first polypeptide, while the VL domain of an antibody is linked to a second polypeptide, which is linked to the first polypeptide such that the VH and VL domains can interact with each other to form an antigen binding site. In another preferred embodiment, the VH domain is separated from the VL domain by a linker so that the VH and VL domains can interact with each other (eg single chain antibodies). The VH-linker-VL antibody is then linked to the polypeptide of interest. In addition, fusion antibodies can be generated in which two (or more) single chain antibodies are linked to each other. This is useful if you want to get a bivalent or polyvalent antibody on a single polypeptide chain, or if you want to get a bispecific antibody.

[0246] To obtain a single chain antibody (scFv), the VH and VL encoding DNA fragments are operably linked to another flexible linker encoding fragment, for example, encoding the amino acid sequence (Gly4-Ser)3 (SEQ ID NO: 396), thus so that the VH and VL sequences can be expressed as a continuous single chain protein, with the VL and VH domains linked by a flexible linker. See, for example, Bird et al. Science 242:423426 (1988); Huston et al. Proc. Natl. Acad. sci. USA 85:5879-5883 (1988); and McCafferty et al. Nature 348:552-554 (1990). A single chain antibody may be monovalent if only one VH and VL is used; bivalent if two VH and VL are used; or polyvalent if more than two VH and VL are used. You can get bispecific or polyvalent antibodies that specifically bind to, for example, human PD-1, TIM-3 or LAG-3 and another molecule. In some embodiments, the bispecific or polyvalent antibodies can bind to PD-1 and TIM-3, PD-1 and LAG-3, TIM-3 and LAG-3, or PD-1, TIM-3 and LAG-3.

[0247] In other embodiments, other modified antibodies can be generated using antibody-encoding nucleic acid molecules. For example, "body kappa" (Ill et al. Protein Eng. 10:949-57 (1997)), "minibody" (Martin et al. EMBO J. 13:5303-9 (1994)), "diabody" (Holliger et al. Proc. Natl. Acad. Sci. USA 90:6444-6448 (1993)) or "Janusins" (Traunecker et al. EMBO J. 10:3655-3659 (1991) and Trauneck

er et al. Int. J. Cancer (Suppl.) 7:51-52 (1992)) can be obtained using standard molecular biological technologies, following the directions of the description.

[0248] An antibody or antigen-binding portion as described herein can be derivatized or linked to another molecule (eg, another peptide or protein). Generally, antibodies or portions thereof are derivatized such that derivatization or labeling does not adversely affect antigen binding. Accordingly, the antibodies and antibody portions that can be used in combination drugs and compositions according to the invention are intended to include both intact and modified forms of the antibodies described herein. For example, an antibody or antibody portion thereof as described herein can be operably linked (by chemical bonding, genetic fusion, non-covalent bonding, or otherwise) to one or more other molecular entities, such as another antibody (e.g., a bispecific antibody or a diabody). ), a detecting agent, a pharmaceutical agent, and/or a protein or peptide that can mediate the binding of an antibody or antibody portion to another molecule (such as a streptavidin core or polyhistidine tag).

[0249] One type of derivatized antibody is obtained by cross-linking two or more antibodies (same type or different types, for example, to obtain bispecific antibodies). Suitable crosslinking agents include agents that are heterobifunctional, having two distinctly reactive groups separated by a suitable spacer (eg, m-maleimidobenzoyl-N-hydroxysuccinimide ester) or homobifunctional (eg, disuccinimidyl suberate). Such linkers are available, for example, from Pierce Chemical Company, Rockford, Il.

[0250] An antibody can also be derivatized with a chemical group such as polyethylene glycol (PEG), a methyl or ethyl group, or a carbohydrate group. These groups may be useful for improving the biological characteristics of an antibody, for example, to increase the serum half-life.

[0251] An antibody as described herein can also be labelled. Within the scope of the present invention, the terms "label" or "label" refer to the incorporation of another molecule into an antibody. In one embodiment, the label is a detectable marker, such as incorporating a radiolabeled amino acid or attaching biotinyl fragments to the polypeptide, which can be detected using labeled avidin (for example, streptavidin containing a fluorescent marker, or an enzymatic activity that can be detected using optical or colorimetric methods). In another embodiment, the label or marker may be therapeutic, such as a drug conjugate or a toxin. You can use various methods of labeling polypeptides and glycoproteins known in this field. Examples of labels for polypeptides include, but are not limited to, radioisotopes or radionuclides (eg 3H, 14C, 15N, 35S, 90Y, 99Tc, 111In, 125I, 131I), fluorescent labels (eg FITC, rhodamine, lanthanide phosphors) , enzymatic labels (eg, horseradish peroxidase, β-galactosidase, luciferase, alkaline phosphatase), chemiluminescent markers, biotinyl groups, target polypeptide epitopes recognized by the secondary reporter (eg, leucine zipper pair sequences, binding sites for secondary antibodies, metal-binding domains, epitope tags ), magnetic agents such as gadolinium chelates, toxins such as pertussis toxin, taxol, cytochalasin B, gramicidin D, ethidium bromide, emetine, mitomycin, etoposide, tenoposide, vincristine, vinblastine, colchicine, doxorubicin, daunorubicin, dihydroxyanthracindione, mitoxantrone, mithramycin, actinomycin D, 1-dehydrotestosterone, glucocorticoids, procaine, tetracaine, lidocaine, propranolol and puromycin, and analogues or homologues thereof. In some embodiments, marks of various lengths are attached to the spacer legs to reduce potential steric hindrance.

[0252] In some embodiments, the antibodies described herein can be presented in neutral form (including zwitterionic forms) or as positively or negatively charged particles. In some embodiments, the antibodies may complex with the counterion to form a pharmaceutically acceptable salt.

[0253] The term "pharmaceutically acceptable salt" refers to a complex containing one or more antibodies and one or more counterions, the counterions being derived from pharmaceutically acceptable inorganic and organic acids and bases.

Combined medicines

[0254] The present invention provides a combination drug (e.g., composition) that contains any (e.g., any one) of the anti-PD-1 antibodies or antigen-binding portions thereof described herein and any (e.g., any one) of antibodies against TIM-3, or antigen-binding portions thereof, as described herein. In some embodiments, the combination drug comprises any (e.g., any one) of the anti-PD-1 antibodies or antigen-binding portions described herein and any (e.g., any one) of the anti-LAG-3 antibodies or antigen-binding portions thereof, described in this document. In some embodiments, the combination drug comprises any (e.g., any one) of the anti-TIM-3 antibodies or antigen-binding portions thereof described herein and any (e.g., any one) of the anti-LAG-3 antibodies or antigen-binding portions thereof, described in this document. In certain embodiments, the combination drug comprises any (e.g., any one) of the anti-PD-1 antibodies or antigen-binding portions thereof described herein, any (e.g., any one) of the anti-TIM-3 antibodies or antigen-binding portions thereof described herein, and any (eg, any one) of the anti-LAG-3 antibodies or antigen-binding portions described herein. The combination drug may take the form, for example, of a drug using said antibodies or antigen-binding moieties or a pharmaceutical composition containing said antibodies or antigen-binding moieties.

[0255] In some embodiments, the combination drug or composition of the invention comprises anti-PD-1 antibody 12819 and anti-TIM-3 antibody 15086.17145. In some embodiments, the combination drug or composition of the invention comprises an anti-PD-1 antibody 12819 and an anti-LAG-3 antibody 15532. In some embodiments, the combination drug or composition of the invention comprises anti-PD-1 antibody 12819, anti-TIM-3 antibody 15086.17145, and anti-LAG-3 antibody 15532.

[0256] In some embodiments, the implementation of the combination drug or composition according to the invention contains:

- an antibody against PD-1 or its antigennegative part, containing the amino acid sequences H-CDR1-3 and L-CDR1-3 SEQ ID NO: 228-233, respectively; and an anti-TIM-3 antibody, or an antigen-binding portion thereof, comprising the amino acid sequences H-CDR1-3 and L-CDR1-3 of SEQ ID NOs: 8-13, respectively;

- antibody against PD-1 or its antigennegative part, containing VH and amino acid sequence VL SEQ ID NO: 226 and 227, respectively; and an anti-TIM-3 antibody, or an antigen-binding portion thereof, comprising the VH and VL amino acid sequences of SEQ ID NOs: 7 and 4, respectively; or

- an antibody against PD-1 containing HC, which contains the amino acid sequences of SEQ ID NOs: 226 and 375, and LC, which contains the amino acid sequences of SEQ ID NOs: 227 and 379; and an anti-TIM-3 antibody comprising a HC which contains the amino acid sequences of SEQ ID NOs: 7 and 377 and an LC which contains the amino acid sequences of SEQ ID NOs: 4 and 378.

[0257] In some embodiments, the implementation of the combination drug or composition according to the invention contains:

- an antibody against PD-1 or its antigennegative part, containing the amino acid sequences H-CDR1-3 and L-CDR1-3 SEQ ID NO: 228-233, respectively; and an anti-LAG-3 antibody, or an antigen-binding portion thereof, comprising the amino acid sequences H-CDR1-3 and L-CDR1-3 of SEQ ID NOs: 318-323, respectively;

- antibody against PD-1 or its antigennegative part, containing VH and amino acid sequence VL SEQ ID NO: 226 and 227, respectively; and an anti-LAG-3 antibody, or an antigen-binding portion thereof, comprising the VH and VL amino acid sequences of SEQ ID NOs: 316 and 317, respectively; or

- an antibody against PD-1 containing HC, which contains the amino acid sequences of SEQ ID NOs: 226 and 375, and LC, which contains the amino acid sequences of SEQ ID NOs: 227 and 379; and an anti-LAG-3 antibody containing an HC that contains the amino acid sequences of SEQ ID NOS: 316 and 375 and an LC that contains the amino acid sequences of SEQ ID NOS: 317 and 378.

[0258] In some embodiments, the implementation of the combination drug or composition according to the invention contains:

an anti-TIM-3 antibody, or an antigen-binding portion thereof, comprising the amino acid sequences H-CDR1-3 and L-CDR1-3 of SEQ ID NOs: 8-13, respectively; and an anti-LAG-3 antibody, or an antigen-binding portion thereof, comprising the amino acid sequences H-CDR1-3 and L-CDR1-3 of SEQ ID NOs: 318-323, respectively;

- antibody against TIM-3 or its antigennegative part, containing VH and amino acid sequence VL SEQ ID NO: 7 and 4, respectively; and an anti-LAG-3 antibody, or an antigen-binding portion thereof, comprising the VH and VL amino acid sequences of SEQ ID NOs: 316 and 317, respectively; or

- antibody against TIM-3 containing HC, which contains the amino acid sequences of SEQ ID NO: 7 and 377, and LC, which contains the amino acid sequence of SEQ ID NO: 4 and 378; and an anti-LAG-3 antibody containing HC, which contains the amino acid sequences of SEQ ID NOS: 316 and 375, and LC, which contains the amino acid sequences of SEQ ID NOS: 317 and 378.

[0259] In some embodiments, the implementation of the combination drug or composition according to the invention contains:

- an antibody against PD-1 or its antigennegative part, containing the amino acid sequences H-CDR1-3 and L-CDR1-3 SEQ ID NO: 228-233, respectively; an anti-TIM-3 antibody, or an antigen-binding portion thereof, comprising the amino acid sequences H-CDR1-3 and L-CDR1-3 of SEQ ID NOs: 8-13, respectively; and an anti-TIM-3 antibody, or antigen-binding portion thereof, comprising the amino acid sequences H-CDR1-3 and L-CDR1-3 of SEQ ID NOs: 318-323, respectively;

- antibody against PD-1 or its antigennegative part, containing VH and amino acid sequence VL SEQ ID NO: 226 and 227, respectively; an anti-TIM-3 antibody, or an antigen-binding portion thereof, comprising the VH and VL amino acid sequences of SEQ ID NOs: 7 and 4, respectively; and an anti-LAG-3 antibody, or an antigen-binding portion thereof, comprising the VH and VL amino acid sequences of SEQ ID NOs: 316 and 317, respectively; or

- an antibody against PD-1 containing HC, which contains the amino acid sequences of SEQ ID NOs: 226 and 375, and LC, which contains the amino acid sequences of SEQ ID NOs: 227 and 379; an antibody against TIM-3 containing HC, which contains the amino acid sequences of SEQ ID NO: 7 and 377, and LC, which contains the amino acid sequence of SEQ ID NO: 4 and 378; and an anti-LAG-3 antibody containing HC, which contains the amino acid sequences of SEQ ID NOS: 316 and 375, and LC, which contains the amino acid sequences of SEQ ID NOS: 317 and 378.

[0260] In some embodiments, any or all of the antibodies in the combination drug or composition may be IgG, such as IgG1 or IgG2.

Polyspecific Binding Molecules

[0261] In a further aspect, the invention provides a polyspecific binding molecule having a binding specificity (e.g., containing antigen-binding moieties, such as antigen-binding moieties containing six CDRs):

- antibodies against PD-1, which is described herein, and antibodies against TIM-3, which is described herein;

- antibodies against PD-1, which is described herein, and antibodies against LAG-3, which is described herein; or

- antibodies against TIM-3, which is described herein, and antibodies against LAG-3, which is described herein.

In some embodiments, the anti-PD-1 antibody, anti-TIM-3 antibody, and/or anti-LAG-3 antibody is selected from the antibodies described herein. In some embodiments, the multispecific binding molecule has the binding specificity of an anti-PD-1 antibody described herein, an anti-TIM-3 antibody described herein, and an anti-LAG-3 antibody described herein. Multispecific binding molecules are known in the art, and examples of various types of multispecific binding molecules are provided elsewhere herein. Combination drugs according to the invention cover such polyspecific (eg, bispecific or trispecific) binding molecules.

[0262] In a further aspect, the invention provides a combination drug with two or more of a PD-1 targeting bispecific binding molecule, a TIM-3 targeting bispecific molecule, and a LAG-3 targeting bispecific binding molecule. A bispecific binding molecule that targets PD-1, TIM-3, or LAG-3 may have the binding specificity of an antibody that targets said antigen, as described herein, and the binding specificity of another antibody that targets the same antigen (e.g., another an antibody as described herein) or an antibody that targets another protein, such as another immune checkpoint protein, cancer antigen, or other cell surface molecule whose activity mediates a disease state such as cancer. Such bispecific binding molecules are known in the art, and examples of various types of bispecific binding molecules are provided elsewhere herein.

Nucleic acid molecules and Vectors

[0263] Also described are nucleic acid molecules and sequences encoding anti-PD-1, anti-TIM-3, and/or anti-LAG-3 antibodies, or antigen-binding portions thereof, as described herein. In some embodiments, different nucleic acid molecules encode the heavy chain and light chain amino acid sequences of an anti-PD-1 antibody or antigen-binding portion thereof, an anti-TIM-3 antibody or antigen-binding portion thereof, or an anti-LAG-3 antibody or antigen-binding portion thereof. In other embodiments, the same nucleic acid molecule encodes the heavy chain and light chain amino acid sequences of an anti-PD-1 antibody or antigen-binding portion thereof, an anti-TIM-3 antibody or antigen-binding portion thereof, or an anti-LAG-3 antibody or antigen-binding portion thereof.

[0264] Unless otherwise indicated, reference to a nucleotide sequence encompasses its complement. Thus, reference to a nucleic acid having a particular sequence is to be understood as encompassing its complementary strand with its complementary sequence. The term "polynucleotide" in the context of the present invention means a polymeric form of nucleotides of at least 10 bases in length, either ribonucleotides or deoxynucleotides, or a modified form of a nucleotide of any type. The term includes single and double stranded forms.

[0265] In some embodiments, the nucleotide sequences are at least 70%, 75%, 80%, 85%, 90%, 95%, 97%, 98%, or 99% identical to one or more of the nucleotide sequences listed herein. , for example, a nucleotide sequence encoding an amino acid sequence selected from the group consisting of SEQ ID NO: 1, 2, 5, 6, 14, 15, 24, 25, 34, 35, 44, 45, 54, 55, 64, 65 , 74, 75, 84, 85, 94, 95, 104, 105, 114, 115, 124, 125, 134, 135, 144, 145, 154, 155, 164, 165, 174, 175, 184, 185, 194 , 195, 204, 205, 214, 215, 224, 225, 234, 235, 244, 245, 254, 255, 264, 265, 274, 275, 284, 285, 294, 295, 304, 305, 314, 315 , 324, 325, 334, 335, 344, 345, 354, 355, 364, 365, or 391. The term "percent sequence identity" in the context of nucleic acid sequences refers to residues in two sequences that are the same when aligned for maximum match. The length of the sequence identity comparison can be at least about nine nucleotides, typically at least about 18 nucleotides, more preferably at least about 24 nucleotides, typically at least about 28 nucleotides, more typically at least about 32 nucleotides, and preferably at least about 32 nucleotides. at least about 36, 48 or more nucleotides. A number of different algorithms are known in the art that can be used to measure nucleotide sequence identity. For example, polynucleotide sequences can be compared using FASTA, Gap, or Bestfit, which are programs in Wisconsin Package Version 10.0, Genetics Computer Group (GCG), Madison, Wisconsin. FASTA, which includes, for example, the programs FASTA2 and FASTA3, provides alignments and percent identity of best overlap region sequences between query and search sequences (see, for example, Pearson, Methods Enzymol. 183:63-98 (1990); Pearson, Methods Mol Biol 132:185-219 (2000), Pearson, Methods Enzymol 266:227-258 (1996), and Pearson, J Mol Biol 276:71-84 (1998), incorporated herein via link). Unless otherwise specified, the default settings for a particular program or algorithm are used. For example, percent sequence identity between nucleic acid sequences can be determined using FASTA with its default parameters (word size 6 and NOPAM factor for the scoring matrix) or using Gap with its default parameters as provided in GCG version 6.1 included herein. document through a link.

[0266] In some embodiments, the implementation of the nucleic acid molecule contains one or more nucleotide sequences selected from the group consisting of SEQ ID NO: 1, 2, 5, 6, 14, 15, 24, 25, 34, 35, 44, 45 , 54, 55, 64, 65, 74, 75, 84, 85, 94, 95, 104, 105, 114, 115, 124, 125, 134, 135, 144, 145, 154, 155, 164, 165, 174 , 175, 184, 185, 194, 195, 204, 205, 214, 215, 224, 225, 234, 235, 244, 245, 254, 255, 264, 265, 274, 275, 284, 285, 294, 295 , 304, 305, 314, 315, 324, 325, 334, 335, 344, 345, 354, 355, 364, 365 or 391.

[0267] In any of the above embodiments, nucleic acid molecules can be isolated. The nucleic acid molecule encoding the heavy and/or light chain of an antibody or antigen-binding portion described herein can be isolated from any source that produces such an antibody or portion thereof. In various embodiments, nucleic acid molecules are isolated from B cells that express an antibody isolated from an animal immunized with a PD-1, TIM-3, or LAG-3 antigen, or from an immortalized cell derived from such a B cell. Methods for isolating nucleic acids encoding antibodies are well known in the art. For use in polymerase chain reaction (PCR) or cDNA cloning of antibody genes, the mRNA can be isolated and used to generate cDNA. In some embodiments, a nucleic acid molecule as described herein can be synthesized rather than isolated.

[0268] In some embodiments, a nucleic acid molecule as described herein may comprise a nucleotide sequence encoding a VH domain from an antibody or antigen-binding portion described herein fused in frame to a nucleotide sequence encoding a heavy chain constant region from any source. Similarly, a nucleic acid molecule as described herein may comprise a nucleotide sequence encoding a VL domain from an antibody or antigen-binding portion described herein fused in frame to a nucleotide sequence encoding a light chain constant region from any source.

[0269] In a further aspect, nucleic acid molecules encoding a heavy (VH) and/or light (VL) chain variable domain can be "translated" into full length antibody genes. In one embodiment, nucleic acid molecules encoding VH or VL domains are converted into full-length antibody genes by insertion into an expression vector already encoding heavy chain (CH) or light chain (CL) constant regions, respectively, so as to be operably linked within vector, a VH segment with a CH segment(s) and/or operably link, within the vector, a VL segment with a CL segment. In another embodiment, nucleic acid molecules encoding the VH or VL domains are converted into full-length antibody genes by linking, e.g., ligating, a nucleic acid molecule encoding the VH or VL domains to a nucleic acid molecule encoding a CH and/or CL region, with using standard molecular biological technologies. Nucleic acid molecules encoding full-length heavy and/or light chains can then be expressed from the cell into which they have been introduced and the antibody isolated.

[0270] nucleic acid molecules can be used for recombinant expression of large amounts of antibodies. Nucleic acid molecules can also be used to generate chimeric antibodies, bispecific antibodies, single chain antibodies, immunoadhesins, diabodies, mutant antibodies, and antibody derivatives as described herein.

[0271] Also described herein is a vector suitable for expressing one or both chains of an anti-PD-1 antibody or antigen-binding portion thereof, an anti-TIM-3 antibody or antigen-binding portion thereof, and/or an anti-LAG-3 antibody or antigen-binding portion thereof, which described in this document. The term "vector" in the context of the present invention means a nucleic acid molecule capable of transporting another nucleic acid to which it has been linked. In some embodiments, the implementation of the vector is a plasmid, i. a circular double-stranded piece of DNA into which additional DNA segments can be ligated. In some embodiments, the vector is a viral vector in which additional DNA segments can be ligated into the viral genome. In some embodiments, the vectors are capable of autonomous replication in the host cell into which they are introduced (eg, bacterial vectors having a bacterial origin of replication and mammalian episomal vectors). In other embodiments, the vectors (eg, non-episomal mammalian vectors) can be integrated into the genome of a host cell when introduced into the host cell and hence replicate along with the host genome. In addition, some vectors are capable of directing the expression of genes to which they are operatively linked. Such vectors are referred to herein as "recombinant expression vectors" (or simply, "expression vectors").

[0272] In some embodiments, the vectors contain nucleic acid molecules that encode the heavy chain, light chain, or both the heavy and light chains of an antibody described herein or an antigen-binding portion thereof. In some embodiments, the vectors contain nucleic acid molecules encoding fusion proteins, modified antibodies, antibody fragments, and their probes.

[0273] In some embodiments, anti-PD-1, anti-TIM-3, or anti-LAG-3 antibodies, or antigen-binding portions thereof, are expressed by inserting DNA encoding partial or full-length light and heavy chains prepared as described above into expression vectors such as so that the genes are operably linked to the necessary expression control sequences, such as transcription and translation control sequences. Expression vectors include plasmids, retroviruses, adenoviruses, adeno-associated viruses (AAVs), plant viruses such as cauliflower mosaic virus, tobacco mosaic virus, cosmids, YACs derived from EBV episomes, and the like. An antibody coding sequence can be ligated into a vector such that the transcription and translation control sequences within the vector perform their intended function of regulating transcription and translation of the antibody coding sequence. The expression vector and expression control sequences can be chosen to be compatible with the expression host cell used. The antibody light chain coding sequence and the antibody heavy chain coding sequence can be inserted into separate vectors and can be operably linked to the same or different expression control sequences (eg, promoters). In one embodiment, both coding sequences are inserted into the same expression vector and can be operably linked to the same expression control sequences (e.g., a common promoter) to separate identical expression control sequences (e.g., promoters), or to different control sequences. expression (eg, promoters). The antibody coding sequences can be introduced into the expression vector by standard methods (eg, ligation of complementary restriction sites on the antibody gene fragment and vector, or blunt end ligation if no restriction sites are present).

[0274] A suitable vector is a vector that encodes an operably completed human CH or CL immunoglobulin sequence with appropriate restriction sites, constructed such that any VH or VL sequence can be easily inserted and expressed as described above. The genes encoding HC and LC in such vectors may contain intron sequences that will increase the overall protein yield of the antibody by stabilizing the bound mRNA. The intron sequences are flanked by splice donor and splice acceptor sites that determine where the RNA will splice. When multiple introns are used, the location of the intron sequences can be either in the variable or constant regions of the antibody chains, or in both the variable and constant regions. Polyadenylation and transcriptional termination can occur at native chromosomal sites downstream of coding regions. the recombinant expression vector can also encode a signal peptide that facilitates secretion of the antibody chain from the host cell. The antibody chain gene can be cloned into a vector such that the in-frame signal peptide is linked to the amino terminus of the immunoglobulin chain. The signal peptide can be an immunoglobulin signal peptide or a heterologous signal peptide (ie, a signal peptide from a non-immunoglobulin protein).

[0275] In addition to the antibody chain genes, recombinant expression vectors may carry regulatory sequences that control the expression of the antibody chain genes in the host cell. Those skilled in the art will appreciate that the design of the expression vector, including the choice of regulatory sequences, may depend on factors such as the choice of the host cell to be transformed, the desired level of protein expression, and so on. Preferred regulatory sequences for mammalian host cell expression include viral elements that direct high levels of protein expression in mammalian cells, such as promoters and/or enhancers derived from retroviral LTRs, cytomegalovirus (CMV) (e.g., CMV promoter/enhancer), virus monkey 40 (SV40) (eg, SV40 promoter/enhancer), adenovirus (eg, adenovirus major late promoter (AdMLP)), polyoma, and strong mammalian promoters, eg, native immunoglobulin and actin promoters. For further description of viral regulatory elements and their sequences, see, for example, US Pat. See, for example, US Pat. No. 6,517,529. Methods for expressing polypeptides in bacterial or fungal cells, such as yeast cells, are also well known in the art.

[0276] In addition to antibody chain genes and regulatory sequences, recombinant expression vectors may carry additional sequences, such as sequences that regulate the vector's replication in host cells (eg, origin of replication) and selectable marker genes. The selectable marker gene facilitates the selection of host cells into which the vector has been introduced (see, for example, US Pat. For example, a commonly selectable marker gene confers resistance to drugs such as G418, hygromycin, or methotrexate in the host cell into which the vector has been introduced. For example, selectable marker genes include the dihydrofolate reductase (DHFR) gene (for use in dhfr host cells with methotrexate selection/amplification), the neo gene (for G418 selection), and the glutamate synthetase gene.

[0277] In the framework of the present invention, the term "expression control sequence" means polynucleotide sequences that are necessary for the implementation of the expression and processing of the coding sequences into which they are ligated. Expression control sequences include appropriate initiation, termination, promoter, and transcriptional enhancer sequences; efficient RNA processing signals such as splicing and polyadenylation signals; sequences that stabilize cytoplasmic mRNA; sequences that increase the efficiency of translation (ie the Kozak consensus sequence); sequences that enhance protein stability; and, optionally, sequences that enhance protein secretion. The nature of such control sequences varies depending on the host organism; in prokaryotes, such control sequences typically include a promoter, a ribosome binding site, and a transcription termination sequence; in eukaryotes, such control sequences typically include promoters and a transcription termination sequence. The term "control sequences" is intended to cover at least all components whose presence is essential for expression and processing, and may also cover additional components whose presence is preferred, such as leader sequences and fusion partner sequences.

Host Cells and Methods for Producing Antibodies and Antibody Compositions

[0278] Also described are methods for preparing combination drugs (eg, compositions) according to the invention. One embodiment relates to a method for producing antibodies as described herein, comprising providing recombinant host cells capable of expressing antibodies, culturing said host cells under conditions suitable for antibody expression, and isolating the resulting antibodies. Antibodies resulting from such expression in such recombinant host cells are referred to herein as "recombinant antibodies". Progeny cells of such host cells and the antibodies they produce are also described.

[0279] As used herein, the term "recombinant host cell" (or simply "host cell") means a cell into which a recombinant expression vector has been introduced. The host cell may contain, for example, one or more of the vectors described herein. The host cells may contain, for example, a nucleotide sequence encoding a heavy chain or an antigen-binding portion thereof, a nucleotide sequence encoding a light chain or an antigen-binding portion thereof, or an anti-PD-1, anti-TIM-3 and/or anti-LAG-3 antibody or their antigen-binding portions, which are described herein. It should be understood that "recombinant host cell" and "host cell" mean not only the specific claimed cell, but also the progeny of such a cell. Because certain modifications may occur in subsequent generations due to mutation or environmental influences, such progeny may not actually be identical to the parent cell, but are still included within the scope of the term "host cell" within the scope of the present invention.

[0280] Nucleic acid molecules encoding anti-PD-1, anti-TIM-3, and/or anti-LAG-3 antibodies, or antigen-binding portions thereof, and vectors containing these nucleic acid molecules, can be used to transfect a host cell of a suitable mammal, plant , bacteria or yeast. Transformation can be carried out by any known method of introducing polynucleotides into the host cell. Methods for introducing heterologous polynucleotides into mammalian cells are well known in the art and include dextran-mediated transfection, calcium phosphate precipitation, polybren-mediated transfection, protoplast fusion, electroporation, encapsulation of polynucleotide(s) into liposomes, and direct DNA microinjection into nuclei. In addition, nucleic acid molecules can be introduced into mammalian cells by viral vectors. Methods for transforming cells are well known in the art. See, for example, US Pat. Nos. 4,399,216; 4,912,040; Methods for transforming bacterial and yeast cells are also well known in the art.

[0281] Mammalian cell lines available as hosts for expression are well known in the art and include many immortalized cell lines available from the American Type Culture Collection (ATCC). These include, but are not limited to, Chinese Hamster Ovary (CHO) cells, NS0 cells, SP2 cells, HEK-293T cells, 293 Freestyle cells (Invitrogen), NIH-3T3 cells, HeLa cells, Newborn Hamster Kidney (BHK) cells, African green monkey (COS) kidneys, human hepatocellular carcinoma cells (eg, Hep G2), A549 cells, and a number of other cell lines. Particularly preferred cell lines are selected by determining which cell lines have high levels of expression. Other cell lines that can be used are insect cell lines such as Sf9 or Sf21 cells. When recombinant expression vectors encoding antibody genes are introduced into mammalian host cells, antibodies are obtained by culturing the host cells for a period of time sufficient to allow expression of the antibody in the host cells or, more preferably, secretion of the antibody in a culture medium in which grow host cells. Antibodies can be isolated from the culture medium using standard protein purification methods. Plant host cells include, for example, Nicotiana, Arabidopsis, duckweed, corn, wheat, potato, and the like. Bacterial host cells include E. coli and Streptomyces species. Yeast host cells include Schizosaccharomyces pombe, Saccharomyces cerevisiae and Pichia pastoris.

[0282] In addition, expression of antibodies or antigen-binding portions thereof, as described herein, from derived cell lines can be improved using a number of known techniques. For example, the glutamine synthetase gene expression system (GS system) is a common approach to enhance expression under certain conditions. The GS system is discussed in whole or in part in connection with EP 0216846, 0256055, 0323997 and 0338841.

[0283] It is likely that antibodies expressed by different cell lines or in transgenic animals will have different glycosylation patterns from each other. However, all antibodies encoded by the nucleic acid molecules provided herein, or containing the amino acid sequences provided herein, are part of the present invention, regardless of the glycosylation state of the antibodies, and, more generally, regardless of the presence or absence of post-translational modification ( modifications).

[0284] In some embodiments, the invention provides a method for preparing an antibody composition comprising an anti-PD-1 antibody and an anti-TIM-3 antibody, the method comprising:

- providing first and second host cells, wherein the first host cell is capable of expressing an anti-PD-1 antibody as described herein and the second host cell is capable of expressing an anti-TIM-3 antibody as described herein,

- culturing the first and second host cells under conditions suitable for expression of the anti-PD-1 antibody and the anti-TIM-3 antibody, and

- isolation of the resulting antibodies.

[0285] In some embodiments, the invention provides a method for preparing an antibody composition comprising an anti-PD-1 antibody and an anti-LAG-3 antibody, the method comprising:

- providing first and second host cells, wherein the first host cell is capable of expressing an anti-PD-1 antibody as described herein and the second host cell is capable of expressing an anti-LAG-3 antibody as described herein,

- culturing the first and second host cells under conditions suitable for expression of the anti-PD-1 antibody and the anti-LAG-3 antibody, and

- isolation of the resulting antibodies.

[0286] In some embodiments, the invention provides a method for preparing an antibody composition comprising an anti-TIM-3 antibody and an anti-LAG-3 antibody, the method comprising:

- providing first and second host cells, wherein the first host cell is capable of expressing an anti-TIM-3 antibody as described herein and the second host cell is capable of expressing an anti-LAG-3 antibody as described herein,

- culturing the first and second host cells under conditions suitable for expression of the anti-TIM-3 antibody and the anti-LAG-3 antibody, and

- isolation of the resulting antibodies.

[0287] In some embodiments, the invention provides a method for preparing an antibody composition comprising an anti-PD-1 antibody, an anti-TIM-3 antibody, and an anti-LAG-3 antibody, the method comprising:

- providing first, second and third host cells, wherein the first host cell is capable of expressing an anti-PD-1 antibody as described herein, the second host cell is capable of expressing an anti-TIM-3 antibody as described herein, and the third the host cell is capable of expressing an anti-LAG-3 antibody as described herein,

- culturing the first, second and third host cells under conditions suitable for expression of anti-PD-1 antibody, anti-TIM-3 antibody and anti-LAG-3 antibody, and

- isolation of the resulting antibodies.

[0288] To obtain an antibody composition according to the invention, antibodies directed to different targets can be obtained separately, i.e. each antibody is produced in a separate bioreactor, or the individual antibodies can be produced together in a single bioreactor. If an antibody composition is produced in more than one bioreactor, a purified antibody composition can be obtained by pooling antibodies obtained from separately purified supernatants from each bioreactor. PCT publication WO 2009/129814 describes various approaches for preparing a polyclonal antibody composition in many bioreactors where cell line or antibody preparations are pooled at the last moment before or before or during post-treatment.

[0289] In the case of obtaining individual antibodies in one bioreactor, this can be done, for example, as described in PCT publication WO 2004/061104 or WO 2008/145133. The method described in WO 2004/061104 is based on site-specific integration of an antibody coding sequence into the genome of individual host cells, while the method of WO 2008/145133 includes an alternative approach using random integration to produce antibodies in a single bioreactor.

[0290] Additional information regarding methods suitable for preparing antibody compositions of the invention can be found in PCT publications WO 2012/059857 and WO 2013/164689.

[0291] The present invention also provides a polyclonal cell line that produces:

at least one anti-PD-1 antibody, or antigen-binding portion thereof, as described herein, and at least one anti-TIM-3 antibody, or antigen-binding portion thereof, as described herein;

at least one anti-PD-1 antibody, or antigen-binding portion thereof, as described herein, and at least one anti-LAG-3 antibody, or antigen-binding portion thereof, as described herein;

at least one anti-TIM-3 antibody or antigen-binding portion thereof, as described herein, and at least one anti-LAG-3 antibody, or antigen-binding portion thereof, as described herein; or

at least one anti-PD-1 antibody or antigen-binding portion thereof as described herein, at least one anti-TIM-3 antibody or antigen-binding portion thereof as described herein, and at least one anti-LAG antibody; 3 or an antigen-binding portion thereof, as described herein.

[0292] The present invention also provides a method for producing a polyclonal cell line as described above, comprising providing host cells each containing a nucleotide sequence that encodes a heavy chain, or an antigen-binding portion thereof, and a nucleotide sequence that encodes a light chain, or an antigen-binding portion thereof. at least one of the antibodies or parts produced by the polyclonal cell line.

[0293] The present invention also provides host cells containing:

- a nucleotide sequence that encodes the heavy chain, or an antigen-binding portion thereof, a nucleotide sequence that encodes the light chain, or an antigen-binding portion thereof, or both, of an anti-PD-1 antibody as described herein, and a nucleotide sequence that encodes a heavy a chain, or an antigen-binding portion thereof, a nucleotide sequence that encodes a light chain, or an antigen-binding portion thereof, or both, of an anti-TIM-3 antibody as described herein;

- a nucleotide sequence that encodes the heavy chain or an antigen-binding portion thereof, a nucleotide sequence that encodes a light chain or an antigen-binding portion thereof, or both, of an anti-PD-1 antibody as described herein; and a nucleotide sequence that encodes a heavy chain or an antigen-binding portion thereof, a nucleotide sequence that encodes a light chain or an antigen-binding portion thereof, or both, of an anti-LAG-3 antibody as described herein;

- a nucleotide sequence that encodes the heavy chain or an antigen-binding portion thereof, a nucleotide sequence that encodes a light chain or an antigen-binding portion thereof, or both, of an anti-TIM-3 antibody as described herein; and a nucleotide sequence that encodes a heavy chain or an antigen-binding portion thereof, a nucleotide sequence that encodes a light chain or an antigen-binding portion thereof, or both, of an anti-LAG-3 antibody as described herein; or

- a nucleotide sequence that encodes the heavy chain or an antigen-binding portion thereof, a nucleotide sequence that encodes a light chain or an antigen-binding portion thereof, or both, of an anti-PD-1 antibody as described herein; a nucleotide sequence that encodes the heavy chain or an antigen-binding portion thereof, a nucleotide sequence that encodes a light chain or an antigen-binding portion thereof, or both, of an anti-TIM-3 antibody as described herein; and a nucleotide sequence that encodes the heavy chain or antigen-binding portion thereof, a nucleotide sequence that encodes the light chain or antigen-binding portion thereof, or both, of an anti-LAG-3 antibody as described herein.

Pharmaceutical compositions

[0294] In yet another aspect of the invention, there is provided a pharmaceutical composition comprising, as active ingredients (e.g., as sole active ingredients):

at least one anti-PD-1 antibody, or antigen-binding portion thereof, as described herein, and at least one anti-TIM-3 antibody, or antigen-binding portion thereof, as described herein;

at least one anti-PD-1 antibody, or antigen-binding portion thereof, as described herein, and at least one anti-LAG-3 antibody, or antigen-binding portion thereof, as described herein;

at least one anti-TIM-3 antibody or antigen-binding portion thereof, as described herein, and at least one anti-LAG-3 antibody, or antigen-binding portion thereof, as described herein; or

at least one anti-PD-1 antibody or antigen-binding portion thereof as described herein, at least one anti-TIM-3 antibody or antigen-binding portion thereof as described herein, and at least one anti-LAG antibody; 3 or an antigen-binding portion thereof, as described herein.

In some aspects, the pharmaceutical composition comprises a multispecific binding molecule (e.g., a multispecific binding molecule that has the binding specificity of an anti-PD-1 antibody as described herein and an anti-TIM-3 or anti-LAG-3 antibody as described herein; or anti-PD1 antibodies, anti-TIM-3 antibodies, and anti-LAG-3 antibodies as described herein).

[0295] In some embodiments, the implementation of the pharmaceutical composition may further contain one or more additional antibodies that target one or more appropriate cell surface receptors, for example, one or more cancer-relevant receptors.

[0296] In some embodiments, the implementation of the pharmaceutical composition is for the improvement, prevention and/or treatment of a disorder, disease or condition that improves or slows its progression by modulating PD-1, TIM-3 and/or LAG-3. In some embodiments, the implementation of the pharmaceutical composition is for the improvement, prevention and/or treatment of cancer. In some embodiments, the implementation of the pharmaceutical composition is designed to activate the immune system.

[0297] The ratio between the antibodies or antigen-binding portions thereof in a pharmaceutical composition of the invention (or the individual antibodies or portions described herein administered simultaneously, sequentially or separately) will often be such that the antibodies are administered in equal amounts, but this need not be be so. Thus, a composition of the invention comprising an anti-PD-1 antibody and an anti-TIM-3 antibody, an anti-PD-1 antibody and an anti-LAG-3 antibody, or an anti-TIM-3 antibody and an anti-LAG-3 antibody may contain these antibodies in a ratio of approximately 1:1. A composition of the invention containing an anti-PD-1 antibody, an anti-TIM-3 antibody, and an anti-LAG-3 antibody may contain these antibodies in a ratio of approximately 1:1:1: (ie, in equal amounts). However, depending on the characteristics of the individual antibodies, it may be desirable to use unequal amounts of different antibodies. Suitable ratios for various antibodies in the compositions of the invention can be determined as described in PCT publication WO 2010/040356, which describes methods for identifying and selecting the optimal stoichiometric ratio between chemicals in a combined drug product, for example, in a polyclonal antibody composition, to obtain combinatorial drug with optimal action and efficiency.

[0298] In general, the pharmaceutical compositions described herein are suitable for administration as a formulation in combination with one or more pharmaceutically acceptable adjunct(s), for example, as described below.

[0299] The term "adjuvant" is used herein to describe any ingredient other than the compound(s) of the invention. The choice of adjuvant(s) will largely depend on factors such as the particular route of administration, the effect of the adjuvant on solubility and stability, and the nature of the dosage form. For the purposes of the present invention, the term "pharmaceutically acceptable adjuvant" includes any and all solvents, dispersion media, coatings, antibacterial and antifungal agents, isotonic and absorption delaying agents, and the like, which are physiologically compatible. Some examples of pharmaceutically acceptable adjuvants are water, saline, phosphate buffered saline, dextrose, glycerol, ethanol, and the like, and combinations thereof. In many cases it will be preferable to include isotonic agents, for example sugars, polyalcohols such as mannitol, sorbitol or sodium chloride, in the composition. Additional examples of pharmaceutically acceptable substances are wetting agents or minor amounts of excipients such as wetting or emulsifying agents, preservatives or buffers that increase the shelf life or effectiveness of the antibody.

[0300] Pharmaceutical compositions according to the present invention and methods for their preparation will be obvious to those skilled in the art. Such compositions and methods for their preparation can be found, for example, in Remington's Pharmaceutical Sciences, 19th Edition (Mack Publishing Company, 1995). Pharmaceutical compositions are preferably manufactured under GMP (Good Manufacturing Practice) conditions.

[0301] The pharmaceutical composition according to the invention can be prepared, packaged or sold in bulk as a single single dose or multiple individual single doses. In the context of the present invention, a "single dose" is a discrete amount of a pharmaceutical composition containing a predetermined amount of an active ingredient. The amount of active ingredient is usually equal to the dosage of the active ingredient that is administered to the subject, or a suitable fraction of such dosage, such as, for example, half or a third of such dosage.

[0302] Any method of administering peptides, proteins, or antibodies accepted in the art can be suitably used for the antibodies and antigen-binding portions described herein.

[0303] The pharmaceutical compositions of the invention are generally suitable for parenteral administration. For the purposes of the present invention, "parenteral administration" of a pharmaceutical composition includes any route of administration characterized by physical injury to the subject's tissue and administration of the pharmaceutical composition through the tissue breach, typically resulting in direct administration to the bloodstream, muscle, or internal organ. Thus, parenteral administration includes, but is not limited to, administering a pharmaceutical composition by injecting the composition, applying the composition through a surgical incision, applying the composition through a tissue-penetrating non-surgical wound, and the like. In particular, parenteral administration is intended to include, but is not limited to, subcutaneous, intraperitoneal, intramuscular, intrasternal, intravenous, intraarterial, intrathecal, intraventricular, intraurethral, intracranial, intratumoral, and intraarticular injection or infusion; and infusion technologies for kidney dialysis. Regional perfusion is also provided. Specific embodiments include intravenous and subcutaneous routes.

[0304] Formulations of a pharmaceutical composition suitable for parenteral administration typically contain the active ingredient in combination with a pharmaceutically acceptable carrier such as sterile water or sterile isotonic saline. Such formulations may be prepared, packaged or sold in a form suitable for bolus administration or for continuous administration. Injectable formulations may be prepared, packaged or sold in unit dosage form such as ampoules or multi-dose containers containing a preservative. Formulations for parenteral administration include, but are not limited to, suspensions, solutions, emulsions in oily or aqueous neutral bases, pastes, and the like. Such formulations may further contain one or more additional ingredients, including, but not limited to, suspending, stabilizing, or dispersing agents. In one embodiment of the parenteral formulation, the active ingredient is presented in a dry (ie powder or granular) form for reconstitution with a suitable neutral base (eg sterile pyrogen-free water) prior to parenteral administration of the reconstituted composition. Parenteral formulations also include aqueous solutions which may contain adjuvants such as salts, carbohydrates, and buffers (preferably up to a pH of 3 to 9), but for some applications they may be more suitably prepared as a sterile non-aqueous solution. or as a dried form for use in combination with a suitable neutral base such as sterile, pyrogen-free water. Exemplary forms for parenteral administration include solutions or suspensions in sterile aqueous solutions, such as aqueous solutions of propylene glycol or dextrose. If necessary, such dosage forms can be properly buffered. Other useful parenteral formulations include those that contain the active ingredient in microcrystalline form or in a liposomal formulation. Formulations for parenteral administration can be prepared for immediate and/or modified release formulations for modified release include delayed, sustained, pulsed, controlled, targeted and programmed release.

[0305] For example, in one aspect, sterile injectable solutions can be obtained by combining the compositions in the required amount in a suitable solvent with one or a combination of the ingredients listed above, as necessary, followed by filtered sterilization. Typically, dispersions are prepared by incorporating the active compound into a sterile vehicle which contains the basic dispersion medium and the necessary other ingredients listed above. In the case of sterile powders for the preparation of sterile injectable solutions, vacuum drying and freeze drying are preferred methods of preparation, which yield a powder of the active ingredient plus any additional desired ingredient from its pre-sterile filtered solution. Proper fluidity of the solution can be maintained, for example, by using a coating such as lecithin, by maintaining the desired particle size in the case of a dispersion, and by using surfactants. Prolonged absorption of injectable compositions can be achieved by including in the composition an agent that delays absorption, such as monostearate and gelatin salts, and/or through the use of modified release coatings (eg, slow release coatings).

Therapeutic use of combination drugs and compositions according to the invention

In one aspect, combination drugs and compositions of the invention are used to enhance or activate the immune system in a patient (eg, human) in need thereof. In some embodiments, the patient is immunosuppressed. In some embodiments, the physician may enhance the anti-cancer activity of the patient's own immune system by administering a combination drug or composition of the present invention, alone or in combination with other therapeutic agents (sequentially or simultaneously). The combination drug or composition modulates the activity of PD-1, TIM-3 and/or LAG-3 in immune cells, resulting in increased anti-cancer immunity. In some embodiments, combination medicaments and compositions of the invention are for use in the treatment of cancer, such as cancer that occurs in tissues such as skin, lungs, intestines, colon, ovary, brain, prostate, kidney, soft tissues, hematopoietic system, head and neck, liver, bladder, breast, stomach, uterus and pancreas, and any cancers or other conditions that depend on PD-1, TIM-3 and/or LAG-3 activity, and/ or in which the patient expresses or overexpresses a ligand of any of them.

[0307] In some embodiments, cancers treated with combination therapies and compositions of the invention may include, for example, melanoma (e.g., progressive or metastatic melanoma), non-small cell lung cancer, head and neck squamous cell carcinoma, renal cell carcinoma, Hodgkin's lymphoma, non-Hodgkin's lymphoma, glioblastoma, glioma, squamous cell lung cancer, small cell lung cancer, hepatocellular carcinoma, bladder cancer, upper urinary tract cancer, esophageal cancer, esophagogastric junction cancer, gastric cancer, liver cancer, colon cancer, colorectal cancer carcinoma, multiple myeloma, sarcomas, acute myeloid leukemia, chronic myeloid leukemia, myelodysplastic syndrome, nasopharyngeal cancer, chronic lymphocytic leukemia, acute lymphoblastic leukemia, lymphocytic lymphoma, ovarian cancer, gastrointestinal tract cancer, primary peritoneal cancer, fallopian tube cancer, cancer urothelium, HTLV-associated T-cell leukemia/lymphoma, prostate cancer, genitourinary system cancer, meningioma, adenocortical cancer, gliosarcoma, fibrosarcoma, kidney cancer, breast cancer, pancreatic cancer, endometrial cancer, basal cell skin cancer, cancer appendix, bile duct cancer, salivary gland cancer, progressive Merkel cell cancer, diffuse large B-cell lymphoma, follicular lymphoma, mesothelioma, neuroendocrine tumors, genitourinary tract cancer, bone cancer, chest cancer, respiratory tract cancer, adenoid cystic carcinoma, cancer cervical, astrocytoma, chordoma, neuroblastoma, oral cancer, squamous cell carcinoma of the skin, thyroid cancer, Kaposi's sarcoma, anal cancer, gallbladder cancer, thymus cancer, uterine cancer and solid tumors. The cancer may be, for example, at an early, middle, late or metastatic stage.

[0308] In certain embodiments, cancers treated with combination therapies and compositions of the invention may include, for example, melanoma (e.g., progressive melanoma or unresectable or metastatic melanoma), non-small cell lung cancer (e.g., progressive non-small cell lung cancer) , lung carcinoma, head and neck squamous cell carcinoma, glioblastoma (eg, recurrent glioblastoma), gliosarcoma, Merkel cell carcinoma, fibrosarcoma, ovarian cancer, bladder cancer, renal cell carcinoma, colon cancer, Hodgkin's lymphoma, non-Hodgkin's lymphoma, leukemia (eg , acute myeloid leukemia), hematologic malignancies, solid tumors (eg, progressive or metastatic solid tumors), MSI-high tumors, HPV and HIV-associated malignancies, and tumors with BRAC1 and BRAC2 mutations.

[0309] In some embodiments, the pharmaceutical compositions of the invention are for the treatment of an immune-mediated disorder such as psoriasis, systemic lupus erythematosus, MLS (sclerosis), Crohn's disease, diabetes mellitus, and/or ulcerative colitis.

[0310] In some embodiments, the implementation of the combined drug or composition is for use in the treatment of viral and/or parasitic infections, for example, when pathogens inhibit the immune response of the host. For example, the causative agent may be, for example, HIV, hepatitis (A, B, or C), human papillomavirus (HPV), lymphocytic choriomeningitis virus (LCMV), adenovirus, flavivirus, echovirus, rhinovirus, coxsackievirus, coronovirus, respiratory syncytial virus, mumps virus, rotavirus, measles virus, rubella virus, parvovirus, vaccinia virus, human T-cell lymphotrophic virus (HTLV), human cytomegalovirus (HCMV), dengue virus, molluscum virus, poliovirus, rabies virus, John Cunningham (JC) virus ), arbovirus encephalitis virus, simian immunodeficiency virus (SIV), influenza, herpes, Giardia, malaria, Leishmania, Staphylococcus aureus, or Pseudomonas aeruginosa.

[0311] In some embodiments, the implementation of the combined drugs and compositions according to the invention can be used to treat a patient who is immunocompromised or at risk (for example, due to chemotherapy or radiation therapy).

[0312] In some embodiments, combination drugs and compositions of the invention can be used to activate and expand antigen-specific T cells ex vivo.

[0313] In some embodiments, the patient may have previously been treated for a condition characterized by overexpression or overactivity of PD-1, TIM-3, and/or LAG-3 or any of their ligands (eg, cancer or an immune disorder). For example, a patient may have been treated with one or more drugs that target PD-1, TIM-3, and/or LAG-3 and may have become resistant to said drug(s).

[0314] "Treat", "in the treatment" and "treatment" refer to a method of alleviating or eliminating a biological disorder and/or at least one of its accompanying symptoms. As used herein, the term "alleviate" a disease, disorder, or condition means reducing the severity and/or frequency of symptoms of the disease, disorder, or condition. In addition, references herein to "treatment" include references to definitive, palliative, and prophylactic treatment.

[0315] A "therapeutically effective amount" refers to an amount of a therapeutic agent administered that will relieve one or more of the symptoms of the disorder being treated to some extent. A therapeutically effective amount of an anticancer therapeutic agent may, for example, result in a reduction in tumor size, increased survival, removal of cancer cells, reduced disease progression, reversal of metastasis, or other clinical endpoints desired by healthcare professionals.

[0316] In some embodiments, the antibodies, antigen-binding moieties, or polyspecific binding molecules in the combination drug of the invention are administered in a single composition. In other embodiments, the antibodies, antigen-binding moieties, or multispecific binding molecules are administered in more than one composition. For example, a combination drug containing an anti-PD-1 antibody, an anti-TIM-3 antibody, and an anti-LAG-3 antibody may include administering a separate composition containing all three antibodies, a composition containing two antibodies, and a composition containing one of the antibodies or a separate composition for each antibody. Where there is more than one composition, the compositions may be administered simultaneously, sequentially, separately, or in any combination.

[0317] Combination drugs and compositions according to the invention can be administered alone or in combination with one or more other drugs or antibodies (or any combination thereof). Thus, the pharmaceutical compositions, methods and uses of the invention also cover combinations (co-administration) with other active agents, as detailed below.

[0318] For the purposes of the present invention, the terms "co-administration", "co-administered", and "in combination with", referring to combined medicinal products or compositions of the invention with one or more other therapeutic agents, are intended to mean and refer to and include following:

- the simultaneous administration of such combination drug (or component) or composition and therapeutic agent (s) to a patient in need of treatment, when such components are formulated together in a single dosage form, which essentially simultaneously provides these components to the specified patient,

- the substantially simultaneous administration of such combination medicinal product (or component thereof) or composition and therapeutic agent (s) to a patient in need of treatment, when such components are formulated separately from each other in the form of separate dosage forms, which the specified patient takes essentially simultaneously, when wherein said components are provided to said patient substantially simultaneously,

- sequential administration of such a combined drug (or component) or composition and therapeutic agent (s) to a patient in need of treatment, when such components are formulated separately from each other in the form of separate dosage forms, which the specified patient takes sequentially with significant time intervals between each administration, wherein said components are provided to said patient at substantially different times; And

- sequential administration of such a combination drug (or component) or composition and therapeutic agent(s) to a patient in need of treatment, when such components are formulated together in a single dosage form that releases these components in a controlled manner, while they are provided to the specified patient at the same time , sequentially and/or with overlapping release at the same and/or different times, and each part can be entered either in the same or in a different way.

[0319] Combination drugs and compositions according to the invention can be administered without additional therapeutic interventions, i. as a separate therapy (i.e. monotherapy). Alternatively, treatment with a combination drug or composition of the invention may include at least one additional therapeutic intervention, such as another immunostimulatory agent, anticancer agent, antiviral agent, or vaccine (eg, a tumor vaccine). In some embodiments, the combination drug or composition may be co-administered or formulated with another drug/drug for the treatment of cancer. Additional therapeutic intervention may include, for example, a chemotherapeutic, antineoplastic or antiangiogenic agent, another anticancer antibody, and/or radiation therapy.

[0320] The combination of combination drugs and compositions according to the invention with agents known to induce terminal differentiation of cancer cells can further improve the effect. Such compounds may, for example, be selected from the group consisting of retinoic acid, trans-retinoic acids, cis-retinoic acids, phenylbutyrate, nerve growth factor, dimethyl sulfoxide, active form of vitamin D3, peroxisome proliferator-activated receptor gamma, 12-O- tetradecanoylphorbol 13-acetate, hexamethylene bis-acetamide, transforming growth factor-beta, butyric acid, cyclic AMP and vesnarinone. In some embodiments, the compound is selected from the group consisting of retinoic acid, phenyl butyrate, all-trans retinoic acid, and an active form of vitamin D.

[0321] Pharmaceutical products containing a combined drug or composition according to the invention and at least one other agent (for example, a chemotherapeutic, antitumor or antiangiogenic agent) can be used as a combined treatment for simultaneous, separate or sequential administration in the treatment of cancer. The other agent may be any agent suitable for the treatment of the particular cancer in question, for example an agent selected from the group consisting of alkylating agents, for example platinum derivatives such as cisplatin, carboplatin and/or oxaliplatin; vegetable alkoids, for example paclitaxel, docetaxel and/or irinotecan; antitumor antibiotics, eg doxorubicin (adriamycin), daunorubicin, epirubicin, idarubicin mitoxantrone, dactinomycin, bleomycin, actinomycin, lutomycin and/or mitomycin; topoisomerase inhibitors such as topotecan; and/or antimetabolites, for example fluorouracil and/or other fluoropyrimidines. In some embodiments, the other agent is dacarbazine or gemcitabine.

[0322] The combination drug or composition of the invention can also be used in combination with other anti-cancer drugs such as vaccines, cytokines, enzyme inhibitors, immunostimulatory compounds, and T-cell drugs. In the case of a vaccine, this may be, for example, a protein, peptide or DNA vaccine containing one or more antigens that are relevant to the cancer being treated, or a vaccine containing dendritic cells together with an antigen. Suitable cytokines include, for example, IL-2, IFN-gamma, and GM-CSF. An example of a type of enzyme inhibitor that has anti-cancer activity is an indoleamine-2,3-dioxygenase (IDO) inhibitor, such as 1-methyl-D-tryptophan (1-D-MT). Adoptive T cell therapy refers to various immunotherapies that involve reproducing or constructing patients' own T cells to recognize and attack their tumors.

[0323] It is also contemplated that the combination drug or composition of the invention may be used in adjunctive therapy in combination with tyrosine kinase inhibitors. These are synthetic, primarily derivatives of quinazoline, low molecular weight molecules that interact with the intracellular tyrosine kinase domain of receptors and inhibit ligand-induced receptor phosphorylation by competing for the intracellular Mg-ATP binding site.

[0324] In some embodiments, the combination drug or composition can be used in combination with another drug/drug that mediates immune system activation, including, but not limited to, an agent that modulates the expression or activity of A2AR, BTLA, B7-H3, B7-H4, CTLA-4, CD27, CD28, CD39, CD40, CD47, CD55, CD73, CD122, CD137, CD160, CGEN-15049, LY108, CHK1, CHK2, CTLA-3, CEACAM (e.g. CEACAM-1 and /or CEACAM-5), GAL9, GITR, HVEM, ICOS, IDO, KIR, LAIR1, NKG2A, OX40, PD-L1/PD-L2, LILRB2, CMTM6, TIGIT, TGFR-beta, TNFR2, VISTA and/or 2B4 . In some embodiments, the agent is an antibody, or an antigen-binding fragment thereof, that binds to one of the molecules listed above. In certain embodiments, an antibody or antigen-binding portion thereof, a composition or a bispecific binding molecule of the invention may be administered in combination with a CTLA-4 inhibitor (eg, an anti-CTLA-4 antibody such as trimelimumab or ipilimumab). In one embodiment, an antibody or antigen-binding portion thereof, composition or bespecifically binding molecule of the invention may be administered in combination with ipilimumab. It is also contemplated that the combination drug or composition of the invention may be used in combination with a cytokine (eg IL-1, IL-2, IL-12, IL-15 or IL-21), an EGFR inhibitor, a VEGF inhibitor, etc. .

[0325] In some aspects, combination drugs and compositions of the invention may be administered in combination with another PD-1, TIM-3, or LAG-3 pathway inhibitor that may target PD-1, TIM-3, LAG-3, or alone. or more ligands of any of these targets. Examples of such inhibitors include:

- other anti-PD-1 antibodies and antibodies that target PD-1 ligands and/or co-receptors such as PD-L1 or PD-L2 (eg pembrolizumab and/or nivolumab);

- other anti-TIM-3 antibodies and antibodies that target TIM-3 ligands and/or co-receptors such as galectin-9, HMGB-1, phosphatidylserine lipids, CEACAM1, LILRA1-6 or LILRB1-5 (e.g. MGB453, TSR -022 and/or LY3321367); And

- other anti-LAG-3 antibodies and antibodies that target LAG-3 ligands and/or co-receptors such as MHCII, Galectin-3, and LSECtin (e.g. BMS-986016, GSK2831781, REGN3767, BAP050 or BAP050-chi or LAG525 ).

[0326] It is understood that the combination drugs and compositions of the invention can be used in a method of treatment as described herein, can be used in a treatment as described herein, and/or can be used to produce a medicament for treatment as described in this document. The invention also provides kits and finished products containing combined drugs or compositions according to the invention, which are described in this document.

Dose and route of administration

[0327] Combination drugs and compositions according to the invention should be administered in an effective amount for the treatment of the condition in question, i. in dosages and for periods of time necessary to achieve the desired result. The therapeutically effective amount may vary depending on factors such as the particular condition being treated, the age, sex, and weight of the patient, as well as whether the antibodies are administered as a stand-alone treatment or in combination with one or more additional cancer treatments.

[0328] Schemes of reception can be adjusted to provide the optimal desired response. For example, a single bolus may be administered, multiple divided doses may be administered over time, or the dose may be proportionally reduced or increased as indicated depending on the therapeutic situation. It is particularly advantageous to formulate parenteral compositions in unit dosage form for ease of administration and dosage uniformity. In the context of the present invention, unit dosage form refers to physically discrete units suitable as unit doses for the patients/subjects to be treated; each unit contains a predetermined amount of the active compound calculated to produce the desired therapeutic effect in combination with the required pharmaceutical carrier. The specification of unit dosage forms according to the invention is usually determined by and directly dependent on (a) the unique characteristics of the chemotherapeutic agent and the particular therapeutic or prophylactic effect to be achieved, and (b) the limitations for sensitivity in individuals according to the state of the art in formulating such an active compound for treatment. .

[0329] Thus, based on the disclosure presented herein, a person skilled in the art should understand that the dose and dosage regimen are adjusted in accordance with methods well known in the field of these medicines. That is, the maximum allowable dose can be easily set, and the effective amount that provides a detectable therapeutic benefit to the patient, as well as the time requirement for the administration of each agent to provide a detectable therapeutic benefit to the patient, can also be determined. Accordingly, although a certain dose and administration regimens are given as examples herein, these examples do not in any way limit the dose and administration regimen that can be provided to a patient by practicing the present invention.

[0330] It should be noted that dosage values may vary depending on the type and severity of the condition to be alleviated, and may include single or multiple doses. In addition, it should be understood that for any particular subject, particular dosage regimens will need to be adjusted over time in accordance with individual need and the professional judgment of the person administering or supervising the administration of the compositions, and that the dosage ranges set forth herein are illustrative only and not are intended to limit the scope or practical use of the completed combination medicinal product. In addition, the combination drug regimen and compositions of this invention may be based on a variety of factors, including disease type, age, weight, sex, medical condition of the patient, severity of the condition, route of administration, and the particular antibody used. Thus, the treatment regimen can vary widely, but can be determined in a conventional manner using standard methods. For example, doses may be adjusted based on pharmacokinetic or pharmacodynamic parameters, which may include clinical effects such as toxic effects and/or laboratory values. Thus, the present invention encompasses individual dose escalation as determined by one of ordinary skill in the art. The definition of suitable dosages and schedules is well known in the relevant field and should be clear to a person skilled in the art after the ideas disclosed herein are presented.

[0331] It is contemplated that a suitable dose of an antibody in a combination drug or composition of the invention will be in the range of 0.1-100 mg/kg, e.g., about 0.5-50 mg/kg, e.g., about 1-20 mg/kg. kg. The antibody can, for example, be administered at a dosage of at least 0.25 mg/kg, such as at least 0.5 mg/kg, such as at least 1 mg/kg, such as at least 1.5 mg/kg. kg, eg at least 2 mg/kg, eg at least 3 mg/kg, eg at least 4 mg/kg, eg at least 5 mg/kg; and eg at most 50 mg/kg, eg at most 30 mg/kg, eg at most 20 mg/kg, eg at most 15 mg/kg. In general, the administration should be repeated at suitable intervals, for example, once a week, once every two weeks, once every three weeks, or once every four weeks, and for as long as the responsible physician deems appropriate, who may increase or decrease as desired. reduce dosage as needed.

[0332] An effective amount for treating a tumor can be measured by its ability to stabilize the progression of the disease and/or alleviate the patient's symptoms, and preferably reverse the progression of the disease, for example, by reducing the size of the tumor. The ability of the combination drug of the invention to inhibit cancer can be assessed using in vitro assays, eg as described in the examples, as well as suitable animal models predictive of efficacy in human tumors (see, eg, Examples). Appropriate treatment regimens should be selected to ensure the optimal therapeutic response in each particular situation, for example, for administration as a single bolus or as a continuous infusion and with possible dosage adjustments as indicated on a case-by-case basis.

Finished Products & Kits

[0333] The present invention also provides finished articles containing an anti-PD-1 antibody that competes with an antibody selected from the group consisting of 12777.15382, 12760.15375 and 13112.15380, for linking to human PD-1 or binds to the same human PD-1 epitope as it; and an anti-TIM-3 antibody or an anti-LAG-3 antibody.

[0334] In some embodiments, the implementation of the finished product contains:

at least one anti-PD-1 antibody, or antigen-binding portion thereof, as described herein, and at least one anti-TIM-3 antibody, or antigen-binding portion thereof, as described herein;

at least one anti-PD-1 antibody, or antigen-binding portion thereof, as described herein, and at least one anti-LAG-3 antibody, or antigen-binding portion thereof, as described herein;

- at least one anti-TIM-3 antibody or antigen-binding portion as described herein and at least one anti-LAG-3 antibody or antigen-binding portion as described herein; or

at least one anti-PD-1 antibody or antigen-binding portion thereof as described herein, at least one anti-TIM-3 antibody or antigen-binding portion thereof as described herein, and at least one anti-LAG antibody; 3, or an antigen-binding portion thereof, as described herein;

as well as methods of manufacturing these products.

[0335] The present invention also provides kits containing an anti-PD-1 antibody that competes with an antibody selected from the group consisting of 2777.15382, 12760.15375 and 13112.15380, for binding to PD -1 human or binds to the same human PD-1 epitope as it; and an anti-TIM-3 antibody or an anti-LAG-3 antibody.

[0336] In some embodiments, the kit contains:

at least one anti-PD-1 antibody, or antigen-binding portion thereof, as described herein, and at least one anti-TIM-3 antibody, or antigen-binding portion thereof, as described herein;

at least one anti-PD-1 antibody, or antigen-binding portion thereof, as described herein, and at least one anti-LAG-3 antibody, or antigen-binding portion thereof, as described herein;

- at least one anti-TIM-3 antibody or antigen-binding portion as described herein and at least one anti-LAG-3 antibody or antigen-binding portion as described herein; or

at least one anti-PD-1 antibody or antigen-binding portion thereof as described herein, at least one anti-TIM-3 antibody or antigen-binding portion thereof as described herein, and at least one anti-LAG antibody; 3 or an antigen-binding portion thereof, as described herein.

[0337] Unless otherwise indicated herein, scientific and technical terms used in connection with the present invention shall have the meanings commonly understood by those skilled in the art. illustrative methods and materials are described below, although methods and materials similar or equivalent to those described herein may also be used in the practice or testing of the present invention. In the event of a conflict, the present description, including definitions, will govern.

[0338] Generally, the nomenclature and technologies used in connection with methods of cell and tissue culture, molecular biology, immunology, microbiology, genetics, analytical chemistry, synthetic organic chemistry, medicinal and pharmaceutical chemistry, and protein and nucleic acid chemistry and hybridization described in this document are well known and widely used in this field. Enzymatic reactions and purification methods are performed according to the manufacturer's specifications, as is commonly done in the art or as described herein.

[0339] In addition, unless the context otherwise requires, terms in the singular include the plural, and terms in the plural include the singular. In this description and embodiments, the words "have" and "comprise", or variations such as "has", "having", "comprises", or "comprising", should be understood to mean the inclusion of the specified integer or group of integers, but not exclusion of any other integer or group of integers.

[0340] All publications and other references mentioned herein are incorporated by reference in their entirety. Although a number of documents are cited in this document, this citation is not an admission that any of these documents is part of the general knowledge in this area.

[0341] For a better understanding of this invention, the following examples are given. These examples are for illustrative purposes only and should in no way be construed as limiting the scope of the invention.

Examples

Example 1 Increased In Vitro Activity of Combination Targeting PD-1/TIM-3 in a One Way MLR Assay

[0342] This example demonstrates that combined targeting of PD-1 and TIM-3 using anti-PD-1 antibody 12819 and anti-TIM-3 antibody 15086.17145 enhances IFN-γ secretion in a mixed lymphocyte culture unidirectional reaction (MLR) assay.

[0343] In the unidirectional MLR assay, dendritic cells (DCs) and CD4+ T cells isolated from two different healthy human donors were co-cultured to induce an alloantigen-specific response leading to cytokine production and T cell activation/proliferation. Dendritic cells (DC) were differentiated from CD14+ monocytes on day 6 of culture with 20 ng/ml granulocyte-macrophage colony-stimulating factor (GM-CSF) and 20 ng/ml interleukin-4 (IL-4) and mixed in a 1:10 ratio with CD4+ T-cells isolated from peripheral blood mononuclear cells (PBMCs) from a healthy human donor. These antibodies or mixture of antibodies were added to a final total concentration of 10 μg/ml. The antibody mixture contained anti-PD-1 and anti-TIM-3 antibodies in a 1:1 ratio. After 5 days of culture, supernatants were harvested and IFN-γ levels were determined using a Meso Scale electrochemiluminescent cytokine assay. For statistical analysis, an unpaired Student's t-test was used, and Bonferroni's correction was used to adjust for multiple comparisons. An adjusted p value <0.05 is considered statistically significant.

[0344] FIG. 1 shows the effect of anti-PD-1 and anti-TIM-3 antibodies on IFN-γ secretion in a unidirectional MLR assay in three independent donor pairs. In the unidirectional MLR assay, both anti-PD-1 (12819) and anti-TIM-3 (15086) antibodies were functional and increased IFN-γ secretion in all three donor pairs. In addition, the combination of anti-PD-1 and anti-TIM-3 antibodies showed increased activity, causing a statistically significant increase in IFN-γ compared to single antibodies.

Example 2 Increased In Vitro Activity of Co-Targeting PD-1/TIM-3 in a Bidirectional MLR Assay

[0345] This example demonstrates that combined targeting of PD-1 and TIM-3 using anti-PD-1 antibody 12819 and anti-TIM-3 antibody 15086.17145 enhances IFN-γ secretion in a bidirectional MLR assay.

[0346] In the bidirectional MLR assay, PBMCs from two different healthy human donors were co-cultured to induce an alloantigen-specific response leading to cytokine production and T cell activation/proliferation. PBMCs from two different donors were mixed in a 1:1 ratio. Antibodies were tested at a final total antibody concentration of 10 μg/ml. After 5 days of culture, supernatants were harvested and IFN-γ levels were determined using a Meso Scale electrochemiluminescent cytokine assay. For statistical analysis, an unpaired Student's t-test was used, and Bonferroni's correction was used to adjust for multiple comparisons. An adjusted p value <0.05 is considered statistically significant.

[0347] FIG. 2 shows the effect of anti-PD-1 and anti-TIM-3 antibodies on IFN-γ secretion in a bidirectional MLR assay in three independent pairs of human donors. In the bidirectional MLR assay, anti-PD-1 and anti-TIM-3 antibodies enhanced IFN-γ secretion. In addition, the combination of anti-PD-1 and anti-TIM-3 antibodies showed increased activity, inducing increased secretion of IFN-γ compared to single antibodies.

Example 3: Anti-TIM-3 antibody induces T cell proliferation in vitro in a unidirectional MLR assay

[0348] The ability of anti-TIM-3 antibody 15086.17145 to induce T cell proliferation was examined in a unidirectional MLR assay. Anti-TIM-3 antibody, positive control anti-PD-1 antibody (12819) or negative control IgG2 antibody was added to a final concentration of 25 μg/ml and incubated for 5 days before adding 1 μCi/well of 3H-thymidine for a further 18 hours. Cells were harvested and 3H-thymidine incorporation was determined using a liquid scintillation counter (MicroBeta2).

[0349] As shown in FIG. 3, anti-TIM-3 antibody 15086.17145 induced both CD4+ and CD8+ T cell proliferation to the same extent as positive control anti-PD-1 antibody (Panel A). The addition of soluble anti-CD3 antibody enhanced the proliferation induced by anti-TIM-3 antibody (Panel B).

Example 4: Anti-TIM-3 antibody induces secretion of IL-12p40 from dendritic cells

[0350] Monocyte-derived dendritic cells were obtained from healthy donor material as described previously in Example 1. Dendritic cells were incubated for 5 days with 10 μg/ml of anti-TIM-3 antibody 15086.17145 or negative control IgG2 antibody, or no treatment, and IL-12p40 levels in supernatants were determined using a standard cytokine ELISA assay.

[0351] As shown in FIG. 4, TIM-3 ligation with anti-TIM-3 antibody 15086.17145 resulted in increased secretion of IL-12p40 from dendritic cells.

Example 5 Anti-TIM-3 Antibody Induces Expression of Activation Markers in Dendritic Cells

[0352] To further investigate the functional role of TIM-3 targeting, expression levels of selected activation markers on monocyte-derived dendritic cells were determined after treatment with anti-TIM-3 antibody 15086.17145.

[0353] Dendritic cells were treated with 25 μg/ml of anti-TIM-3 antibody for 24 hours, and co-stimulatory molecule gene expression was determined using NaNOtring Technologies. Gene expression levels were normalized to 30 housekeeping genes with uniform expression. Data for selected relevant genes are presented as fold change relative to untreated control cells.

[0354] Gene expression analysis showed upregulation of several activation markers and costimulatory molecules, including MHC-II (HLA-DQB1 and HLA DQA1), CD80 and CD86 (FIG. 5, panel A). Increased cell surface expression of CD80 and CD86 upon treatment with anti-TIM-3 antibody 15086.17145 was confirmed using FACS analysis (FIG. 5, panel B). The histogram overlays shown represent CD11c+ dendritic cells and the numbers adjacent to the histograms denote MFI values.

Example 6 In Vivo Efficacy of Anti-TIM-3 Antibody 15086 on Human PDX Lung Tumor Growth

[0355] This example shows the in vivo efficacy of anti-TIM-3 antibody 15086.17145 against a human patient lung (PDX) xenograft tumor model in CD34+ humanized NSG-SGM3 mice.

[0356] NSG-SGM3 mice were humanized using CD34+ cells derived from cord blood and xenografted on the right side with patient-derived lung tumor fragments (LG1306). With tumor sizes of 50-150 mm ³ mice were randomized and treatment started. Mice were intraperitoneally injected with vehicle or anti-15086 TIM-3 antibody at an initial dose of 10 mg/kg followed by 5 mg/kg 5x Q5D. Tumors were measured three times a week with a caliper in two dimensions, and tumor volume in mm ³ was calculated by the formula: (width) 2 x length x 0.5. The gray area indicates the treatment period. Two-way ANOVA with Bonferroni's multiple comparison test was used to compare tumor volumes at each time point between treatment groups. Data are presented as mean ± SEM, ** p < 0.01.

[0357] Treatment with anti-TIM-3 antibody 15086 resulted in significant inhibition of tumor growth in the human PDX lung model in CD34+ humanized NSG-SGM3 mice (FIG. 6).

Example 7 Enhanced Impact of Pooled Targeting on PD-1/LAG-3, PD-1/TIM-3 or PD-1/TIM-3/LAG-3 in PBMC+SEB Assay

[0358] This example describes the enhanced effect of combining anti-PD-1 antibody 12819 with anti-LAG-3 antibody 15532 or anti-TIM-3 antibody 15086.17145 in a PBMC+SEB (Staphylococcal Enterotoxin B) assay.

[0359] SEB is a super antigen that binds to MHC class II molecules and specific regions of Vβ T cell receptors (TCRs) and activates non-specific stimulation of T cells. This leads to the activation/proliferation of polyclonal T cells and the release of cytokines, including IL-2. Human PBMCs isolated from buffy coats from healthy donors were plated in 384-well plates and left untreated or treated with 10 ng/ml SEB and 10 μg/ml of the indicated individual antibodies or antibody mixtures. Antibody combinations were 1:1 or 1:1:1 mixtures of the indicated antibodies. After 48 hours in a humidified incubator at 37° C., supernatants were removed and analyzed for IL-2 levels using an IL-2 ELISA kit (Life Technologies). Data are presented as mean ± SEM. Significant differences were tested using Student's t-test with Bonferroni's correction.

[0360] FIG. 7 shows the increase in IL-2 secretion after treatment with a single anti-PD-1, anti-LAG-3, or anti-TIM-3 antibody, a mixture of two antibodies, or a mixture of all three antibodies. The data showed that IL-2 levels were increased by single treatment with anti-PD-1, anti-LAG-3, or anti-TIM-3 antibody, while IL-2 secretion was further increased by treatment with a combination of anti-PD-1 and anti-LAG-3 antibodies or antibodies against PD-1 and against TIM-3. The triple combination of anti-PD-1, anti-LAG-3, and anti-TIM-3 antibodies increased IL-2 secretion to a greater extent than any of the combinations of the two antibodies.

Example 8 Enhanced In Vivo Efficacy of Combining Anti-PD-1 and Anti-LAG-3 Antibodies in Two Syngeneic Mouse Tumor Models

[0361] This example demonstrates the in vivo efficacy of combining anti-PD-1 antibody 12819 with anti-LAG-3 antibody C9B7W (mouse LAG-3 reactive; BioXcell) or anti-LAG-3 antibody 15011 in two syngeneic mouse tumor models.

[0362] 0.5×10 ⁶ MC38 (colon carcinoma) or 5×10 ⁶ ASB-XIV (lung carcinoma) cells were subcutaneously inoculated into the flank of 6-8 week old female BALB/cAnNRj (ASB-XIV) or C57BL/ mice. 6 (MC38), respectively. Tumors were measured three times a week with a caliper in two dimensions, and tumor volume in mm ³ was calculated by the formula: (width) 2 x length x 0.5. On the 5th (ASB-XIV) or 13th (MC38) day after inoculation, with an average tumor size of 30-50 mm ³ , mice were randomized into four groups of ten animals, and treatment began. Mice were treated three times per week, for a total of six treatments, by intraperitoneal injection of neutral base buffer, anti-PD-1 antibody 12819, anti-LAG-3 antibody C9B7W, anti-LAG-3 antibody 15011, or a combination of anti-PD-1 and anti-PD-1 antibodies. against LAG-3. Antibody treatment was performed at a dose of 10 mg/kg/target. Two-way ANOVA with Bonferroni's multiple comparison test was used to compare tumor volumes at each time point between treatment groups. Statistical analysis was performed using GraphPad Prism version 5.0 (GraphPad Software, Inc.).

[0363] Syngeneic MC38 tumors treated with anti-PD-1 monoclonal antibody 12819 exhibited continuous tumor growth, albeit with slower growth kinetics than neutral base treated tumors (FIG. 8). No effect of treatment with anti-LAG-3 antibody C9B7W alone was observed. The combination of anti-PD-1 antibody and anti-LAG-3 antibody showed increased tumor growth inhibition compared to anti-PD-1 antibody treatment and significant tumor growth inhibition compared to neutral base-treated tumors (p<0.001) (Figure 8).

[0364] ASB-XIV syngene tumors treated with anti-PD-1 antibody 12819 showed slower tumor growth compared to neutral base treated tumors (FIGS. 8 and 9). No effect of treatment with anti-LAG-3 antibody C9B7W alone was observed (FIG. 8), while anti-LAG-3 antibody 15011 significantly inhibited tumor growth compared to neutral base treatment (p<0.05) (FIG. 9). The combination of anti-PD-1 antibody and anti-LAG-3 antibody C9B7W significantly increased antitumor efficacy compared to neutral base treatment (FIG. 8). A significantly enhanced tumor inhibitory effect was also observed with the combination of anti-PD-1 antibody and anti-LAG-3 antibody 15011 compared with a single treatment with anti-PD-1 antibody (p<0.0001) or anti-LAG-3 antibody (p<0.05 ) (Fig. 9).

Example 9 Enhanced In Vivo Efficacy of Anti-PD-1 and Anti-TIM-3 Antibody Combination in Two Syngeneic Mouse Tumor Models

[0365] This example demonstrates the in vivo efficacy of combining anti-PD-1 antibody 12819 and anti-TIM-3 antibody 5D12 (reactive with mouse TIM-3; Anderson et al. Science 318:1141-43 (2007)) in two syngeneic mouse tumors. models.

[0366] 0.2×10 ⁶ Sa1N (fibrosarcoma) or 5×106 ASB-XIV (lung carcinoma) cells were subcutaneously inoculated into the flank of female A/J (Sa1N) and BALB/cAnNRj (ASB-XIV) mice aged 6- 8 weeks respectively. Tumors were measured three times a week with a caliper in two dimensions, and tumor volume in mm ³ was calculated by the formula: (width) 2 x length x 0.5. With an average tumor size of 60-110 mm ³ mice were randomized and treatment started. Mice were treated with a single dose (Sa1N) or treated three times a week for a total of six treatments (ASB-XIV), by intraperitoneal injection of neutral base buffer, anti-PD-1 antibody 12819 and/or anti-TIM-3 antibody 5D12. Mice with ASB-XIV tumors were treated with antibodies at a dose of 10 mg/kg/target. Mice with Sa1N tumors were injected with anti-PD-1 and anti-TIM-3 antibodies at a dose of 1 mg/kg and 10 mg/kg, respectively. Two-way ANOVA with Bonferroni's multiple comparison test was used to compare tumor volumes at each time point between treatment groups. Statistical analysis was performed using GraphPad Prism version 5.0 (GraphPad Software, Inc.).

[0367] On the 6th day after inoculation of tumor cells ASB-XIV with an average tumor size of 56 mm ³ mice were randomized into four groups of ten animals, and began treatment. Treatment with anti-PD-1 antibody 12819 delayed tumor growth, while treatment with anti-TIM-3 antibody 5D12 had no effect on tumor growth compared to treatment with a neutral base. A pronounced tumor inhibitory effect was observed by combining anti-PD-1 antibody with anti-TIM-3 antibody compared to a single treatment with either antibody (p<0.001) (FIG. 10).

[0368] On the 13th day after the inoculation of Sa1N tumor cells with an average tumor size of 110 mm ³ mice were randomized into four groups of ten animals and received one treatment with antibodies. The results showed an initial delay in tumor growth after treatment with a single antibody, anti-PD-1 antibody 12819 or anti-TIM-3 antibody 5D12. An enhanced antitumor effect was observed when anti-PD-1 antibody was combined with anti-TIM-3 antibody compared to treatment with the antibody alone. The combination treatment also significantly inhibited tumor growth compared to the neutral base treatment (p < 0.0001) (FIG. 10).

Example 10: In Vivo Efficacy of Combining Anti-PD-1 and Anti-TIM-3 Antibodies in a Human Tumor Xenograft Model

[0369] This example demonstrates the increased in vivo efficacy of combining anti-PD-1 antibody 12819 with anti-TIM-3 antibody 15086.17145 in a human tumor xenograft model where A375 (human melanoma) cells were implanted in mice with reconstituted human PBMCs.

[0370] Human PBMC was intraperitoneally injected into NOG (donor 1 and donor 2) or NOG-EXL (hGM-CSF/hIL-3-NOG) (donor 3) mice one day prior to subcutaneous implantation of human A375 melanoma cells. Treatment was initiated on the day of PBMC injection and mice were treated three times a week with a total of six treatments by intraperitoneal injection of neutral base buffer, anti-PD-1 antibody 12819, anti-TIM-3 antibody 15086.17145, or a combination of anti-PD-1 and anti-TIM- 3. Antibody treatment was performed at a dose of 10 mg/kg/target. Tumors were measured three times a week with a caliper in two dimensions, and the volume of the tumor in mm ³ was calculated by the formula: (width) 2 × length × 0.5. Two-way ANOVA with Bonferroni's multiple comparison test was used to compare tumor volumes at each time point between treatment groups. Statistical analysis was performed using GraphPad Prism version 5.0 (GraphPad Software, Inc.).

[0371] As shown in FIG. 11, treatment with a combination of anti-PD-1 and anti-TIM-3 antibodies resulted in a significant (and synergistic, at least in Donor 3) tumor growth delay (p<0.05 and p<0.01), while treatment with a single antibody (against PD-1 or against TIM-3) showed a limited effect on tumor growth compared to the neutral base treatment group.

Example 11 Co-Targeting of PD-1 and TIM-3 Leads to Increased Survival in Mice Coimplanted with Human Immune and Tumor Cells

[0372] This example demonstrates the in vivo efficacy of combining anti-PD-1 antibody 12819 with anti-TIM-3 antibody 15086.17145 in mouse models of human tumors.

[0373] 2×10 ⁶ A375 (melanoma) cells were mixed with 2×10 ⁶ human PBMC and inoculated subcutaneously in the flank of 6-8 week old female NOD-scid mice. Treatment was started at the time of cell inoculation. Mice were treated three times per week for a total of six treatments by intraperitoneal injection of neutral base buffer, anti-PD-1 antibody 12819, anti-TIM-3 antibody 15086.17145, or a combination of anti-PD-1 and anti-TIM-3 antibodies. Antibody treatment was performed at a dose of 10 mg kg for each antibody. Tumors were measured three times a week with a caliper in two dimensions, and tumor volume in mm ³ was calculated by the formula: (width) 2 x length x 0.5.

[0374] Survival was defined as the presence of a tumor less than 400 mm ³ in size. The results showed an increase in survival of mice treated with the dual combination of anti-PD-1 and anti-TIM-3 antibodies compared to either antibody treatment alone (FIG. 12, panels AE).

Example 12 Combined targeting of PD-1, LAG-3 and TIM-3 results in increased survival in a syngeneic mouse tumor model

[0375] This example demonstrates the in vivo efficacy of combining anti-PD-1 antibody 12819 with anti-LAG-3 antibody C9B7W and anti-TIM-3 antibody 5D12 in a syngeneic mouse tumor model.

[0376] Cells 5×10 ⁶ ASB-XIV (lung carcinoma) were subcutaneously inoculated into the flank of 6-8 week old female BALB/cAnNRj mice. Tumors were measured three times a week with a caliper in two dimensions, and tumor volume in mm ³ was calculated by the formula: (width) 2 x length x 0.5. On the 5th day after inoculation, with an average tumor size of 50 mm ³ mice were randomized into seven groups of ten animals, and treatment began. Mice were treated three times a week with a total of six treatments by intraperitoneal injection of neutral base buffer, 12819 anti-PD-1 antibody, C9B7W anti-LAG-3 antibody, 5D12 anti-TIM-3 antibody, or a combination of anti-PD-1 and anti-LAG- 3, against PD-1 and against TIM-3 or against PD-1, against LAG-3 and against TIM-3. Antibody treatment was performed at a dose of 10 mg/kg for each antibody.

[0377] Survival was defined as the presence of a tumor less than 400 mm ³ in size. The results showed improved survival in mice treated with the triple combination of anti-PD-1, anti-LAG-3, and anti-TIM-3 antibodies compared to either one or two antibodies (FIG. 13, panels AH).

Table 1: Antibody Sequence Identifiers

Target Ab DNA Protein H-CDR1 H-CDR2 H-CDR3 L-CDR1 L-CDR2 L-CDR3 vh VL vh VL TIM-3 15086.15086 1 2 3 4 8 9 10 eleven 12 13 15086.16837
15086.17145
15086.17144 5 6 7 15105 14 15 16 17 18 19 20 21 22 23 15107 24 25 26 27 28 29 thirty 31 32 33 15109 34 35 36 37 38 39 40 41 42 43 15174 44 45 46 47 48 49 50 51 52 53 15175 54 55 56 57 58 59 60 61 62 63 15260 64 65 66 67 68 69 70 71 72 73 15284 74 75 76 77 78 79 80 81 82 83 15299 84 85 86 87 88 89 90 91 92 93 15353 94 95 96 97 98 99 100 101 102 103 15354 104 105 106 107 108 109 110 111 112 113 17244 114 115 116 117 118 119 120 121 122 123 17245 124 125 126 127 128 129 130 131 132 133 19324 134 135 136 137 138 139 140 141 142 143 19416 144 145 146 147 148 149 150 151 152 153 19568 154 155 156 157 158 159 160 161 162 163 20131 164 165 166 167 168 169 170 171 172 173

20185 174 175 176 177 178 179 180 181 182 183 20293 184 185 186 187 188 189 190 191 192 193 20300 194 195 196 197 198 199 200 201 202 203 20362 204 205 206 207 208 209 210 211 212 213 20621 214 215 216 217 218 219 220 221 222 223 PD-1 12819.15384 224 225 226 227 228 229 230 231 232 233 12748.15381 234 235 236 237 238 239 240 241 242 243 12865.15377 244 245 246 247 248 249 250 251 252 253 12892.15378 254 255 256 257 258 259 260 261 262 263 12796.15376 264 265 266 267 268 269 270 271 272 273 12777.15382 274 275 276 277 278 279 280 281 282 283 12760.15375 284 285 286 287 288 289 290 291 292 293 13112.15380 294 295 296 297 298 299 300 301 302 303 12748.16124 234 391 236 392 238 239 240 393 394 395 LAG-3 15646 304 305 306 307 308 309 310 311 312 313 15532 314 315 316 317 318 319 320 321 322 323 15723 324 325 326 327 328 329 330 331 332 333

15595 334 335 336 337 338 339 340 341 342 343 15431 344 345 346 347 348 349 350 351 352 353 15572 354 355 356 357 358 359 360 361 362 363 15011 364 365 366 367 368 369 370 371 372 373

Table 2: Constant region sequences

SEQID NO Description Subsequence 374 IgG1 heavy chain constant region protein sequence ASTKGPSVFPLAPSSKSTSGGTAALGCLVKDYFPEPVTVSWNSGALTSGVHTFPAVLQSSGLYSLSSVVTVPSSSLGTQTYICNVNHKPSNTKVDKRVEPKSCDKTHTCPPCPAPELLGGPSVFLFPPKPKDTLMISRTPEVTCVVVDVSHEDPEVKFNWYVDGVEVHNAKTKPREEQYNSTYRVVSVLTVLH QDWLNGKEYKCKVSNKALPAPIEKTISKAKGQPREPQVYTLPPSREEMTKNQVSLTCLVKGFYPSDIAVEWESNGQPENNYKTTPPVLDSDGSFFLYSKLTVDKSRWQQGNVFSCSVMHEALHNHYTQKSLSLSPGK 375 IgG1-LALA heavy chain constant region protein sequence ASTKGPSVFPLAPSSKSTSGGTAALGCLVKDYFPEPVTVSWNSGALTSGVHTFPAVLQSSGLYSLSSVVTVPSSSLGTQTYICNVNHKPSNTKVDKRVEPKSCDKTHTCPPCPAPEAAGGPSVFLFPPKPKDTLMISRTPEVTCVVVDVSHEDPEVKFNWYVDGVEVHNAKTKPREEQYNSTYRVVSVLTVLH QDWLNGKEYKCKVSNKALPAPIEKTISKAKGQPREPQVYTLPPSREEMTKNQVSLTCLVKGFYPSDIAVEWESNGQPENNYKTTPPVLDSDGSFFLYSKLTVDKSRWQQGNVFSCSVMHEALHNHYTQKSLSLSPGK 376 IgG4 heavy chain constant region protein sequence (S228P) ASTKGPSVFPLAPCSRSTSESTAALGCLVKDYFPEPVTVSWNSGALTSGVHTFPAVLQSSGLYSLSSVVTVPSSSLGTKTYTCNVDHKPSNTKVDKRVESKYGPPCPPCPAPEFLGGPSVFLFPPKPKDTLMISRTPEVTCVVVDVSQEDPEVQFNWYVDGVEVHNAKTKPREEQFNSTYRVVSVLTVLHQD WLNGKEYKCKVSNKGLPSSIEKTISKAKGQPREPQVYTLPPSQEEMTKNQVSLTCLVKGFYPSDIAVEWESNGQPENNYKTTPPVLDSDGSFFLYSRLTVDKSRWQEGNVFSCSVMHEALHNHYTQKSLSLSLGK

377 IgG2 heavy chain constant region protein sequence ASTKGPSVFPLAPCSRSTSESTAALGCLVKDYFPEPVTVSWNSGALTSGVHTFPAVLQSSGLYSLSSVVTVPSSNFGTQTYTCNVDHKPSNTKVDKTVERKCCVECPPCPAPPVAGPSVFLFPPKPKDTLMISRTPEVTCVVVDVSHEDPEVQFNWYVDGVEVHNAKTKPREEQFNSTFRVVSVLTVVHQDW LNGKEYKCKVSNKGLPAPIEKTISKTKGQPREPQVYTLPPSREEMTKNQVSLTCLVKGFYPSDIAVEWESNGQPENNYKTTPPMLDSDGSFFLYSKLTVDKSRWQQGNVFSCSVMHEALHNHYTQKSLSLSPGK 378 Kappa light chain constant region protein sequence RTVAAPSVFIFPPSDEQLKSGTASVVCLLNNFYPREAKVQWKVDNALQSGNSQESVTEQDSKDSTYSLSSTLTLSKADYEKHKVYACEVTHQGLSSPVTKSFNRGEC 379 Protein sequence of lambda light chain constant region GQPKANPTVTLFPPSSEELQANKATLVCLISDFYPGAVTVAWKADGSPVKAGVETTKPSKQSNNKYAASSYLSLTPEQWKSHRSYSCQVTHEGSTVEKTVAPTECS 380 IgG1-LALA heavy chain constant region DNA sequence excluding introns GCCTCCACCAAGGGCCCATCGGTCTTCCCCCTGGCACCCTCCTCCAAGAGCACCTCTGGGGCACAGCGGCCCTGGGCTGCCTGGTCAAGGACTACTTCCCCGAACCGGTGACGGTGTCGTGGAACTCAGGCGCCCTGACCAGCGGCGTGCACACCTTCCCGGCTGTCCTACAGTCCTCAGGACTCTACTCCCTCAGCAGCGTGGTGACCGTGCCCTCCAGCAG CTTGGGCACCCAGACCTACATCTGCAACGTGAATCACAAGCCCAGCAACACCAAGGTGGACAAGAGAGTTGAGCCCAAATCTTGTGACAAAACTCACACATGCCCACCGTGCCCAGCACCTGAAGCCGCCGGGGGACCGTCAGTCTTCCTCTTCCCCCCAAAACCCAAGGACACCCTCATGATCTCCCGGACCCCTGAGGTCACATGCGTGGTGGTGGACGTGAGCCACGAAGACCC TGAGGTCAAGTTCAACTGGTACGTGGACGGCGTGGAGGTGCATAATGCCAAGACAAAGCCGCGGGAGGAGCAGTACAACAGCACGTACCGTGTGTGTCAGCGTCCTCACCGTCCTGCACCAGGACTGGCTGAATGGCAAGGTCTCCAACAAAGCCTCCCAGCCCCCATCGAGAAAACCATCTCCAAAGCCAAAGGGCAGCCCCGAGAACCAAG GTGTACACCCTGCCCCCATCCCGGGAGGATGACCAAGAACCAGGTCAGCCTGACCTGCCTGGTCAAAGGCTTCTATCCCAGCGACATCGCCGTGGAGTGGGAGAGCAATGGGCAGCCGGAGAACAACTACAAGACCACGCCTCCCGTGCTGGACTCCGACGGCTCCTTCTTCCTCTATAGCAAGCTCACCGTGTGCAAGAGCAGGTGGCAGCAGGGGAACGTCTTCT CATGCTCCGTGATGCATGAGGCCTGCACAACCACTACACCGCAGAAGAGCCTCTCCCTGTCCCCGGGTAAA

381 DNA sequence of IgG1-LALA heavy chain constant region including introns GCCTCCACCAAGGGCCCATCGGTCTTCCCCCTGGCACCCTCCTCCAAGAGCACCTCTGGGGCACAGCGGCCCTGGGCTGCCTGGTCAAGGACTACTTCCCCGAACCGGTGACGGTGTCGTGGAACTCAGGCGCCCTGACCAGCGGCGTGCACACCTTCCCGGCTGTCCTACAGTCCTCAGGACTCTACTCCCTCAGCAGCGTGGTGACCGTGCCCTCCAGCAG CTTGGGCACCCCAGACCTACATCTGCAACGTGAATCACAAGCCCAGCAACACCAAGGTGGACAAGAGAGTTGGTGAGAGGCCAGCACAGGGAGGGAGGTGTCTGCTGGAAGCCAGGCTCAGCGCTCCTGCCTGGACGCATCCCGGCTATGCAGTCCCAGTCCAGGGCAGCAAGGCAGGCCCCGTCTGCCTCTTCACCCGGAGCCTCTGCCCGCCCCACTCATGCTCAGGGA GAGGGTCTTCTGGCTTTTTTCCCCAGGCTCTGGGCAGGCACAGGCTAGGTGCCCCTAACCCAGGCCCTGCACACAAAGGGCAGGTGCTGGGCTCAGACCTGCCAAGAGCCATATCCGGGAGGACCCTGCCCCTGACCTAAGCCCACCCCAAAGGCCAAACTCTCCACTCCCTCAGCTCGGACACCTTCTCTCCTCCCAGATTCCAGTAACTCCCAATCTTCTCTCTGCAGA GCCCAAATCTTGTGACAAAACTCACACATGCCCACCGTGCCCAGGTAAGCCAGCCCAGGCCTCGCCCTCCAGCTCAAGGCGGGACAGGTGCCCTAGAGTAGCCTGCATCCAGGGACAGGCCCCAGCCGGGTGCTGACACGTCCACCTCCATCTCTTCCTCAGCACCTGAAgccgccGGGGGACCGTCAGTCTTCCTCTTCCCCCAAAAACCCAAGGACACCCTCATGATC TCCCGGACCCCTGAGGTCACATGCGTGGTGGTGGACGTGAGCCACGAAGACCCTGAGGTCAAGTTCAACTGGTACGTGGACGGCGTGGAGGTGTGCATAATGCCAAGACAAAGCCGCGGGAGGAGCAGTACAACAGCACGTACCGTGTGGTCAGCGTCCTCACCGTCCTGCACCAGGACTGGCTGAATGGCAAGGAGTACAAGTGCAAGGTCTCCAACAAAGCCCTC CCAGCCCCCATCGAGAAAACCATCTCCAAAGCCAAAGGTGGGACCCGTGGGGTGCGAGGGCCACATGGACAGAGGCCGGCTCGGCCCACCCTCTGCCCTGAGAGTGACCGCTGTACCAACCTCTGTCCCTACAGGGCAGCCCCGAGAACCACAGGTGTACACCCTGCCCCCATCCCGGGAGGATGACCAAGAACCAGGTCAGCCCTGACCTGCCTGGTCAAAGGCTT CTATCCCAGCGACATCGCCGTGGAGTGGGAGAGCAATGGGCAGCCGGAGAACAACTACAAGACCACGCCTCCCGTGCTGGACTCCGACGGCTCCTTCTTCCTCTATAGCAAGCTCACCGTGGACAAGAGCAGGTGGCAGCAGGGGAACGTCTTCTCATGCTCCGTGATGCATGAGGCTCTGCACAACCACTACACGCAGAAGCCTCTCCCTGTCCCCGGGTAAA

382 IgG4 heavy chain constant region DNA sequence (S228P), excluding introns GCTTCCACCAAGGGCCCATCGGTCTTCCCCCTGGCGCCCTGCTCCAGGAGCACCTCCGAGAGCACAGCCGCCCTGGGCTGCCTGGTCAAGGACTACTTCCCGAACCGGTGACGTGTCGTGGAACTCAGGCGCCCTGACCAGCGGCGTGCACACCTTCCCGGCTGTCCTACAGTCCTCAGGACTCTACTCCCTCAGCAGCGTGGTGACCGTGCCCTCCAGCAGCTTG GGCACGAAGACCTACACCTGCAACGTAGATCACAAGCCCAGCAACACCAAGGTGGACAAGAGAGTTGAGTCCAAATATGGTCCCCCATGCCCAcCATGCCCAGCACCTGAGTTCCTGGGGGGACCATCAGTCTTCCTGTTCCCCCCAAAACCCAAGGACACTCTCATGATCCCGGACCCCTGAGGTCACGTGCGTGGTGGTGGACGTGAGCCAGGAAGACCCCGAGGTC CAGTTCAACTGGTACGTGGATGGCGTGGAGTGCATAATGCCAAGACAAAGCCGCGGGAGGAGCAGTTCAACAGCACGTACCGTGTGGTCAGCGTCCTCACCGTCCTGCACCAGGACTGGCTGAACGGCAAGGAGTACAAGTGCAAGGTCTCCAACAAAGGCCTCCCGTCCTCCATCGAGAAAACCATCTCCAAAGCCAAAGGGCAGCCCCGAGAGCCACAGGTGTACA CCCTGCCCCCATCCCAGGAGGAGATGACCAAGAACCAGGTCAGCCTGACCTGCCTGGTCAAAGGCTTCTACCCCAGCGACATCGCCGTGGAGTGGGAGAGCAATGGGCAGCCGGAGAACAACTACAAGACCACGCCTCCCGTGCTGGACTCCGACGGCTCCTTCTTCCTCTACAGCAGGCTCACCGTGGACAAGAGCAGGTGGCAGGAGGGGAATGTCTTCTCATGCTCCG TGATGCATGAGGCTCTGCACAACCACTACACACAGAAGAGCCTCTCCCTGTCTCTGGGTAAA

383 DNA sequence of IgG4 heavy chain constant region (S228P), including introns GCTTCCACCAAGGGCCCATCGGTCTTCCCCCTGGCGCCCTGCTCCAGGAGCACCTCCGAGAGCACAGCCGCCCTGGGCTGCCTGGTCAAGGACTACTTCCCGAACCGGTGACGTGTCGTGGAACTCAGGCGCCCTGACCAGCGGCGTGCACACCTTCCCGGCTGTCCTACAGTCCTCAGGACTCTACTCCCTCAGCAGCGTGGTGACCGTGCCCTCCAGCAGCTTG GGCACGAAGACCTACACCTGCAACGTAGATCACAAGCCCAGCAACACCAAGGTGGACAAGAGAGTTGTGGAAGGCCAGCACAGGGAGGGAGGGTGTCTGCTGGAAGCCAGGCTCAGCCCTCCTGCCTGGACGCACCCCGGCTGTGCAGCCCCAGCCCAGGGCAGCAAGGCAGGCCCCATCTGTCTCCTCACCCGGAGGCTCTGACCACCCCACTCATGCTCAGGGAGAG GGTCTTCTGGATTTTTCCACCAGGCTCCGGGCAGCCACAGGCTGGATGCCCCTACCCCAGGCCCTGaGCATACAGGGGCAGGTGCTGCGCTCAGACCTGCCAAGAGCCATATCCGGGAGGACCCTGCCCCTGACCTAAGCCCACCCCAAAGGCCAAACTCTCCACTCCCTCAGCTCAGACACCTTCTCTCCTCCCAGATCTGAGTAACTCCCAATCTTCTCTCTGCAGAGTCCAAATA TGGTCCCCCATGCCCAcCATGCCCAGGTAAGCCAACCCAGGCCTCGCCCTCCAGCTCAAGGCGGACAGGTGCCCTAGAGTAGCCTGCATCCAGGGACAGGCCCCAGCCGGGTGCTGACGCATCCACTCCATCTCTTCTCAGCACCTGAGTTCCTGGGGGGACCATCAGTCTTCCTGTTCCCCCAAAAACCCAAGGACACTCTCATGATCTCCCGGACCCCTGAGG TCACGTGCGTGGTGGTGGACGTGAGCCAGGAAGACCCCGAGGTCCAGTTCAACTGGTACGTGGATGGCGTGGAGGTGCATAATGCCAAGACAAAGCCGCGGGAGGAGCAGTTCAACAGCACGTACCGTGTGGTCAGCGTCCTCACCGTCCTGCACCAGGACTGGCTGAACGGCAAGGAGTACAAGTGCAAGGTCTCCAACAAAGGCCTCCCGTCTCCATCGAGAAA ACCATCTCCAAAGCCAAAGGTGGGACCCACGGGGTGCGAGGGCCACATGGACAGAGGTCAGCTCGGCCCACCCTCTGCCCTGGAGTGACCGCTGTGCCAACCTCTGTCCCTACAGGGCAGCCCCGAGAGCCACAGGTGTACACCCTGCCCCCATCCCAGGAGGAGATGACCAAGAACCAGGTCAGCCTGACCTGCCTGGTCAAAGGCTTCTACCCCAGCGACATCG CCGTGGAGTGGGAGAGCAATGGGCAGCCGGAGAACAACTACAAGACCACGCCTCCCGTGCTGGACTCCGACGGCTCCTTCTTCCTACAGCAGGCTCACCGTGGACAAGAGCAGGTGGCAGGAGGGGAATGTCTTCTCATGCTCCGTGATGCATGAGGCTCTGCACAACCACTACACACAGAAGCCTCTCCCTGTCTCTGGGTAAA

384 IgG2 heavy chain constant region DNA sequence excluding introns GCCTCCACCAAGGGCCCATCGGTCTTCCCCCTGGCGCCCTGCTCCAGGAGCACCTCCGAGAGCACAGCCGCCCTGGGCTGCCTGGTCAAGGACTACTTCCCGAACCGGTGACGTGTCGTGGAACTCAGGCGCCTCTGACCAGCGGCGTGCACACCTTCCCAGCTGTCCTACAGTCCTCAGGACTCTACTCCCTCAGCAGCGTGGTGACCGTGCCCTCCAGCAACTTCG GCACCCAGACCTACACCTGCAACGTAGATCACAAGCCCAGCAACACCAAGGTGGACAAGACAGTTGAGCGCAAATGTTGTGTGTCGAGTGCCCACCGTGTCCAGCACCACCTGTGGCAGGACCGTCAGTCTTCCTCTTCCCCCAAAAACCCAAGGACACCCTCATGATCTCCCGGACCCCTGAGGTCACGTGCGTGGTGGTGGACGTGAGCCACGAAGACCCCGAGGTCCAGTTCA ACTGGTACGTGGACGGCGTGGAGTGCATAATGCCAAGACAAAGCCACGGGAGGAGCAGTTCAACAGCACGTTCCGTGTGTGGTCAGCGTCCTCACCGTTGTGCACCAGGACTGGCTGAACGGCAAGGAGTACAAGTGCAAGGTCTCCAACAAAGGCCTCCCAGCCCCCATCGAGAAAACCATCTCCAAAACCAAAGGGCAGCCCCGAGAACCACAGGTGTACACCCTGCC CCCATCCCGGGAGGAGATGACCAAGAACCAGGTCAGCCTGACCTGCCTGGTCAAAGGCTTCTACCCCAGCGACATCGCCGTGTGGAGTGGGAGAGCAATGGGCAGCCGGAGAACAACTACAAGACCACACCTCCCATGCTGGACTCCGACGGCTCCTTCTTCCTCTACAGCAAGCTCACCGTGGACAAGAGCAGGTGGCAGCAGGGGAACGTCTTCTCATGCTCCGTGATGCATGA GGCTCTCGCACAACCACTACACCGCAGAAGAGCCTCTCCCTGTCTCCGGGTAAA 385 DNA sequence of the IgG2 heavy chain constant region, including introns GCCTCCACCAAGGGCCCATCGGTCTTCCCCCTGGCGCCCTGCTCCAGGAGCACCTCCGAGAGCACAGCCGCCCTGGGCTGCCTGGTCAAGGACTACTTCCCGAACCGGTGACGTGTCGTGGAACTCAGGCGCCTCTGACCAGCGGCGTGCACACCTTCCCAGCTGTCCTACAGTCCTCAGGACTCTACTCCCTCAGCAGCGTGGTGACCGTGCCCTCCAGCAACTTCG GCACCCAGACCTACACCTGCAACGTAGATCACAAGCCCAGCAACACCAAGGTGGACAAGACAGTTGTGGAAGGCCAGCTCAGGGAGGGAGGGTGTCTGCTGGAAGCCAGGCTCAGCCCTCCTGCCTGGACGCACCCCGGCTGTGCAGCCCCAGCCCAGGGCAGCAAGGCAGGCCCCATCTGTCTCCTCACCCGGAGCCTCTGCCCGCCCCACTCATGCTCAGGGAGAGG GTCTTCTGGCTTTTTCCACCAGGCTCCAGGCAGGCACAGGCTGGGTGCCCCTACCCCAGGCCCTTCACACACAGGGGCAGGTGCTTGGCTCAGACCTGCCAAAAGCCATATCCGGGAGGACCCTGCCCCTGACCTAAGCCGACCCCAAAGGCCAAACTGTCCACTCCCTCAGCTCGGACACCTTCTCTCCTCCCAGATCCGAGTAACTCCCAATCTTCTCTCTGCAGAGCGCAA ATGTTGTGTCGAGTGCCCACCGTGCCCCAGGTAAGCCAGCCCCAGGCCTCGCCCTCCAGCTCAAGGCGGGACAGGTGCCCTAGAGTAGCCTGCATCCAGGGACAAGGCCCCAGCTGGGTGCTGACACGTCCACCTCCATCTCTTCCTCAGCACCACCTGTGGCAGGACCGTCAGTCTTCCTCTTCCCCCAAAAACCCAAGGACACCCTCATGATCTCCCGGACCCCTGAGGTC ACGTGCGTGGTGGTGGACGTGAGCCACGAAGACCCCGAGGTCCAGTTCAACTGGTACGTGGACGGCGTGGAGGTGCATAATGCCAAGACAAAGCCACGGGAGGAGCAGTTCAACAGCACGTTCCGTGTGGTCAGCGTCCTCACCGTTGTGCACCAGGACTGGCTGAACGGCAAGGAGTACAAGTGCAAGGTCTCCAACAAAGGCCTCCCAGCCCCCATCGAGAAAAC CATCTCCAAAACCAAAGGTGGGACCCGCGGGGTATGAGGGCCACATGGACAAGGCCGGCTCGGCCCACCCTCTGCCCTGGAGTGACCGCTGTGCCAACCTCTGTCCCTACAGGGCAGCCCCGAGAACCACAGGTGTACACCCTGCCCCCATCCCGGGAGGAGATGACCAAGAACCAGGTCAGCCTGACCTGCCTGGTCAAAGGCTTCTACCCCAGCGACATCGCC GTGGAGTGGGAGAGCAATGGGCAGCCGGAGAACAACTACAAGACCACCTCCCATGCTGGACTCCGACGGCTCCTTCTTCCTCTACAGCAAGCTCACCGTGGACAAGAGCAGGTGGCAGCAGGGGAACGTCTTCTGCTCCGTGATGCATGAGGCTCTGCACAACCACTACACGCAGAAGAGCCTCTCCCTGTCTCCGGGTAAA 386 DNA sequence of the Kappa light chain constant region CGTACGGTGGCTGCACCATCTGTCTTCATCTTCCCGCCATCTGATGAGCAGTTGAAATCTGGAACTGCCTCTGTTTGTGTGCCTGCTGAATAACTTCTATCCCAGAGAGGCCAAAGTACAGTGGAAGGTGGATAACGCCCTCCAATCGGGTAACTCCCAGGAGAGTGTCACAGAGCAGGACAGCAAGGACAGCACCTACAGCCTCAGCAGCACCCTGACGCTGAGCAAAGCAGACT ACGAGAAACACAAAGTCTACGCCTGCGAAGTCACCCATCAGGGCCTGAGCTCGCCCGTCACAAAGAGCTTCAACAGGGGAGAGTGT

387 DNA sequence of lambda light chain constant region CCTAGGTCAGCCCAAGGCCAACCCCACTGTCACTCTGTTCCCGCCCTCCTGAGGAGCTCCAAGCCAACAAGGCCACACTAGTGTGTCTGATCAGTGACTTCTACCCGGGAGCTGTGACAGTGGCCTGGAAGGCAGATGGCAGCCCCGTCAAGGCGGGAGTGGAGACCACCAAACCCTCCAAACAGAGCAACAACAAGTACGCGGCCAGCAGCTACCTGAGCCTGACGCCC GAGCAGTGGAAGTCCCACAGAAGCTACAGCTGCCAGGTCACGCATGAAGGGAGCACCGTGGAGAAGACAGTGGCCCCTACAGAATGTTCATAA

Table 3: Target Protein Sequences

Protein Amino acid sequence Human PD-1 UniProt Q15116 (SEQ ID NO: 388) MQIPQAPWPVVWAVLQLGWRPGWFLDSPDRPWNPPTFSPALLVVTEGDNATFTCSFSNTS
ESFVLNWYRMSPSNQTDKLAAFPEDRSQPGQDCRFRVTQLPNGRDFHMSVVRARRNDSGT
YLCGAISLAPKAQIKESLRAELRVTERRAEVPTAHPSPSPRPAGQFQTLVVGVVGGLLGS
LVLLVWVLAVICSRAARGTIGARRTGQPLKEDPSAVPVFSVDYGELDFQWREKTPEPPVP
CVPEQTEYATIVFPSGMGTSSPARRGSADGPRSAQPLRPEDGHCSWPL TIM-3 human
UniProt Q8TDQ0
(SEQ ID NO: 389) MFSHLPFDCVLLLLLLLTRSSEVEYRAEVGQNAYLPCFYTPAAPGNLVPVCWGKGACPV
FECGNVVLRTDERDVNYWTSRYWLNGDFRKGDVSLTIENVTLADSGIYCCRIQIPGIMND
EKFNLKLVIKPAKVTPAPTRQRDFTAAFPRMLTTRGHGPAETQTLGSLPDINLTQISTLA
NELRDSRLANDLRDSGATIRIGIYIGAGICAGLALALIFGALIFKWYSHSKEKIQNLSLI
SLANLPPSGLANAVAEGIRSEENIYTIEENVYEVEEPNEYYCYVSSRQQPSQPLGCRFAM
P LAG-3 people
UniProt P18627
(SEQ ID NO: 390) MWEAQFLGLLFLQPLWVAPVKPLQPGAEVPVVWAQEGAPAQLPCSPTIPLQDLSLLRRAG
VTWQHQPDSGPPAAAPGHPLAPGPHPAAPSSWGPRPRRYTVLSVGPGGLRSGRLPLQPRV
QLDERGRQRGDFSLWLRPARRADAGEYRAAVHLRDRALSCRLRLRLGQASMTASPPGSLR
ASDWVILNCSFSRPDRPASVHWFRNRGQGRVPVRESPHHHLAESFLFLPQVSPMDSGPWG
CILTYRDGFNVSIMYNLTVLGLLEPPPTPLTVYAGAGSRVGLPCRLPAGVGTRSFLTAKWTP
PGGGPDLLVTGDNGDFTLRLEDVSQAQAGTYTCHIHLQEQQLNATVTLAIITVTPKSFGS
PGSLGKLLCEVTPVSGQERFVWSSLDTPSQRSFSGPWLEAQEAQLLSQPWQCQLYQGERL
LGAAVYFTELSSPGAQRSGRAPGALPAGHLLLFLILGVLSLLLLVTGAFGFHLWRRQWRP
RRFSALEQGIHPPQAQSKIEELEQEPEPEPEPEPEPEPEPEPEQL

Table 4: Nucleotide sequences of the heavy and light chain variable domains of an anti-TIM-3 antibody

Ab Sequence (5'-3') 15086.15086 VH CAGGTGCAGCTACAGCAGTCGGGCCCAGGACTGGTGAAGCCTTCACAGACCCTGTCCCTCACCTGCACTGTCTCTGGTGGCTCCATCAGCAGTGGTGGTTACTACTGGAGTTGGACCCGTCAGCACCAGGGATGGGCCTGGAGTGGATTGGATACATCTCTTACAGTGGGAGTATCTATTACACTCCGTCCCTCAAGAGTCGACTTACCATATCAGTGGACACGTC TAAGAACCAGTTCTCCCTGAAGCTGAGCTCTGTGACTGCCGCGGACACGGCCGTATATTACTGTGCGAGTTTGGATTCCTGGGGATCTAACCGTGACTACTGGGGCCAGGGAACCCTGGTCACCGTCTCGAGT (SEQ ID NO: 1) 15086.15086 VL GAAATTGTGTTGACGCAGTCTCAGCCACCCTGTCTTTGTCTCCAGGGGAAAGAGCCACCCTCTCCTGCAGGGCCAGTCAGAGTGTTAGCAGCTACTTAGCCTGGTACCAACAGAAACCTGGCCAGGCTCCCAGGCTCCTCATCTATGATGCATCCAACAGGGCCACTGGCATCCCAGCCAGGTTCAGTGGCAGTGGGTCTGGGACAGACTTCACTCTCACCATCA GCAGCCTAGAGCCTGAAGATTTTGCAGTTTATTACTGTCAGCAGCGTAGCAACTGGCCGCTCACTTTCGGCGGAGGGACCAAGGTGGAGATTAAG (SEQ ID NO: 2) 15086.16837/15086.17145/15086.17144 VH CAGGTGCAGCTGCAGGAGAGTGGCCCCGGACTGGTCAAGCCTTCACAGACTCTGAGCCTGACCCTGCACAGTGTCTGGCGGAAGTATCAGCTCCGGGGGTTACTATTGGAGCTGGACCCGACAGCACCCAGGAATGGGTCTGGAATGGATCGGGTACATTTCATATAGCGGCTCCATCTACTATACACCTCACTGAAAAGCAGGCTGACCATTTCCGTGGACACATCTA AGAACCAGTTCAGCCTGAAACTGTCTAGTGTGACAGCCGCTGATACTGCAGTCTACTATTGTGCCTCCCTGGACTCTTGGGGCAGTAATAGAGATTACTGGGGCCAGGGAACTCTGGTCACCGTCTCGAGT (SEQ ID NO: 5) 15086.16837/ 15086.17145/ 15086.17144 VL GAGATCGTGCTGACTCAGTCCCAGCCACCCTGTCACTGAGCCCAGGAGAACGAGCAACCCTGTCTTGCAGGGCCTCCCAGTCTGTCAGCTCCTACCTGGCTTGGTATCAGCAGAAGCCCGGGCAGGCACCTCGACTGCTGATCTACGACGCCAGTAACAGAGCTACCGGTATTCCCGCCCGCTTCAGTGGTTCAGGCAGCGGAACAGACTTTACCCCTGACAATCTCTAGTCTG GAGCCTGAAGATTTCGCCGTGTACTATTGTCAGCAGAGGTCTAATTGGCCACTGACATTTGGCGGAGGGACTAAGGTCGAGATCAAG (SEQ ID NO: 6) 15105 VH CAGGTCACCTTGAGGAGTGGGGCGCAGGACTGTTGAGGCCCTCGGAGACCCTGTCCCTCACCTGCGCTGTCTATGGTGGGTCCTTCAGTGGTTACTACTGGAGCTGGATCCGCCAGCCCCAGGGAAGGGCTGGAGTGGATAGGGGAAATCAATCATAGTGGAAGCACCAACTACAACCCGTCCCTCAAGAGTCGAGTCACCATATATCAGTAGACGCGAC CAAGAAACAATTCTCCCTGAAGCTGACCTCTGTGACCGCCGCGGACACGGCTGTGTGTATTACTGTGCGAGATATTGGGAGCTCCCTGACTACTGGGGCCAGGGCACCCTGGTCACCGTCTCGAGT (SEQ ID NO: 14) 15105 VL GACATCCAGTTGACCAGTCTCCATCCTCCCTGTCTGCATCTGTAGGAGACAGTCACCATCACTTGCCGGGCAAGTCAGGGCATTAGAAATGATTTAGGCTGGTATCAGCAGAAACCAGGGAAAGCCCCTAAGCGCCTGATCTATGCTGCATCCAGTTTGCAAAGTGGGGTCCCATCAAGGTTCAGCGGCAGTGGATCTGGGACAGAATTCACTCTCACAATCAGCAG CCTGCAGCCTGAAGATTTTGCAACTTATTACTGTCTACAGCATAATAGTTACCCTCGACGTTCGGCCAAGGGACCAAGGTGGAAATCAAG (SEQ ID NO: 15) 15107 VH CAGATGCAGCTGGTGCAGTGGGGCGCAGGACTGTTGAAGCCTTCGGAGACCCTGTCCCTCACCTGCGCTGTCTATGGTGGGTCCTTCAGTGTGGTTACTACTGGAGCTGGATCCGCCAGCCCCAGGGAAGGGCTGGAGTGGATTGGGGAAATCAATCATAGTGGAAGCACCAACTACAACCCGTCCCTCAAGAGTCGAGTCACCATGTCAGTTGACACGTCCA (SEQ ID NO: 24) 15107 VL GAAATTGTGTTGACCAGTCTCCATCCTCCCTGTCTGCATCTGTAGGAGACAAGTCACCATCACTTGCCGGGCAAGTCAGGCATTAGAAATGATTTAGGCTGGTATCAGCAGAAACCAGGGAAAGCCCCTAAGCGCCTGATCTATGCTGCATCCAGTTTGCAAAGTGGGGTCCCATCAAGGTTCAGCGGCAGTGGATCTGGGACAGAATTCACTCTCACAATCAGCAG CCTGCAGCCTGAAGATTTTGCAACTTATTACTGTCTACAGCATAATAGTTACCCGTGGACGTTCGGCCAAGGGACCAAGGTGGAAATCAAG (SEQ ID NO: 25) 15109 VH CAGATGCAGCTGGTGCAATGGGGCGCAGGACTGTTGAAGCCTTCGGAGACCCTGTCCCTCACCTGCGCTGTCTATGGTGGGTCCTTCAGTGTGGTTACTACTGGAGCTGGATCCGCCAGCCCCAGGGAAGGGCTGGAGTGGATTGGGGAAATCAATCATAGTGGAAGCACCAACTACAACCCGTCCCTCAAGAGTCGAGTCACCATATATCAGTAGACACGTCCA (SEQ ID NO: 34) 15109 VL GAAATTGTGTTGACGCAGTCTCCTTCCACCCTGTCTGCATCTGTAGGAGACAAGTCACCATCACTTGCCGGCCAGTCAGAGTATTAGTAGCTGGTTGGCCTGGTATCAGCAGAAACCAGGGACAGCCCCTAAGCTCCTGATCTATAAGGCGTCTAGTTTAGAAAGTGGGGTCCCATCAAGGTTCAGCGGCAGTGGATCTGGGACAGAATTCACTCTCACCAT CAGCAGCCTGCAGCCTGATGATTTTGCAACTTATTACTGCCAACAGTATAATAGTTATTCCACTTTCGGCGGAGGGACCAAGGTGGAGATCAAA (SEQ ID NO: 35) 15174 VH CAGGTGCAGCTGCAGCAGTCGGGCCCAGGACTGGTGAAGCCTTCGGAGACCCTGTCCCTCACCTGCACTGTCTCTGGTGGCTCCATCAGCAGTAGTAATTACTACTGGGGCTGGATCCGCCAGCCCCCAGGGAAGGGGCTGGAGTGGATTGGGAGTATCTATTATAGTGGGAACACCTACTACAACCCGTCCCTCAAGAGTCGAGTCACCATATCCGTAGACA CGTCCAAGAACCAGTTCTCCCTGAAGCTGAGTTCTGTGACCGCCGCAGACACGGCTGTGTATTACTGTGCGAGACAGACAGTGGCTGGCCCCCTCTTTGACTACTGGGGCCAGGGAACCCTGGTCACCGTCTCGAGT (SEQ ID NO: 44) 15174 VL GAAATTGTGATGACGCAGTCTCCTTCCACCCTGTCTGCATCTGTAGGAGACAAGTCACCATCACTTGCCGGCCAGTCAGAGTATTAGTAGCTGGTTGGCCTGGTATCAGCAGAAACCAGGGAAAGCCCCTAAGGTCCTGATCTATAAGGCGTCTAGTTTAGAAAGTGGGGTCCCATCAAGGTTCAGCGGCAGTGGATCTGGGACAGAACTCACTCTCAC CATCAGCAGCCTGCAGCCTGATGATTTTGCAACTTATTACTGCCAACAGTATAATAGTTATTCATTCACTTTCGGCCCTGGGACCAAAGTGGATATCAAG (SEQ ID NO: 45) 15175 VH CAGGTCCAGCTGGTGCAATCTGGGGCTGAGGTGAAGAAGCCTGGGGCCTCAGTGAAGGTCTCCTGCAAGGCTGCTGGATACACCTTAACCGGCTACTATATGCACTGGGTGCGACAGGCCCCTGGACAAGGCCTTGAGTGGATGGGACGGATCAACCCTAACAGTGGTGGCTCAAACAATGCACAGAAGTTTCAGGGCAGGGTCACCATGACCAGGGACA (SEQ ID NO: 54) 15175 VL GAAATTGTGATGACGCAGTCTCCTTCCACCCTGTCTGCATCTGTAGGAGACAAGTCACCATCACTTGCCGGCCAGTCAGAGTATTAGTAGTTGGTTGGCCTGGTATCAGCAGAAACCAGGGAAAGCCCCTAAGCTCCTGATCTATAAGGCGTCTAGTTTAGAAAGTGGGGTCCCATCAAGGTTCAGCGGCAGTGGATCTGGGACAGAATTCACTCTCAC CATCAGCAGCCTGCAGCCTGATGATTTTGCAACTTATTACTGCCAACAGTATAATAGTTATTCTCCGGGGCTCACTTTCGGCGGAGGACCAAGGTGGAGATCAAG (SEQ ID NO: 55) 15260VH CAGATGCAGCTACAGCAGTCAGGTCCAGGACTGGTGAAGCCCTCGCAGACCCTCTCACTCACCTGTGTCCATCTCCGGGGACAGTGTCTCTAGCAACAGTGCTGCTTGGAACTGGATCAGGCAGTCCCCATCGAGAGGCCTTGAGTGGCTGGGAAGGACATACTACAGGTCCAAGTGGTATTCTGCTTTTGCAGTATCTGTGAAAAGTCGAATAACCATCAACCCAGACACATCC AAGAACCAGTTCTCCCTGCAGCTGAACTCTGTGACTCCCGAGGACACGGCTGTGTATTACTGTGCAAGAGAGGGTAGCAGTGGCTGGTACGGATACGTCCACCACTGGGGCCAGGGCACCCTGGTCACCGTCTCGAGT (SEQ ID NO: 64) 15260 VL GAAATTGTGTTGACGCAGTCTCAGCTTCCCTGTCTGTATCTCTGGGAGAAACTGTCACCATCGAATGTCGAGCAAGTGAGGACATTTACAATGGTTTAGCATGGTATCAGCAGAAGCCAGGGAAATCTCCTCAGCTCCTGATCTATAATGCAAATAGCTTGCATACTGGGTCCCATCACGGTTCAGTGGCAGTGGATCTGGTACACAAGTATTCTCTCAAGATAAACAG CCTGCAATCTGAAGATGTCGCAAGTTATTTCTGTCAACAGTATTACGATTATTCCTCCGACGTTCGGCCAAGGGACCAAGGTGGAAATCAAA (SEQ ID NO: 65) 15284 VH CAGGTGCAGCTGCAGGAGTCGGGCCCAGGACTGGTGAAGCCTTCGGAGACCCTGTCCCTCACCTGCACTGTCTCTGGTGGCTCCTTCAGCAGTAGTAGTTACTACTGGGGCTGGATCCGCCAGCCCCCTGGGAAGGGGCTGGAGTGGATTGGGATCTTCTATTATAGTGGGACCACCTACTACAACCCGTCCCTCAAGAGTCGAGTCACCATATCCGCAC ACACGTCCAAGAGCCAGTTCTCCCTGAAGCTGAGCTCTGTGACCGCCGCAGACACGGCTGTGTATTACTGTGCGAGAGGGGGAGAATATTTTGACCGGTTACTCCCCTTTGACTACTGGGGCCAGGGAACCCTGGTCACCGTCTCGAGT (SEQ ID NO: 74) 15284 VL GAAATTGTGATGACGCAGTCTCCATCCTTCCTGTCTGCATCTGTAGGAGACAGAGTCACCATCACTTGCCGGGCCAGTCAGGGCATTAGCAGTTATTTAGCCTGGTATCAGCAAAAACCAGGGAAAGCCCCTAAGCTCCTGATCTATGCTGCATCCACTTTGGAAAGTGGGGTCCCATCAAGGTTCAGCGGCAGTGGATCTGGGACAGAATTCACTCTCACAATCAGCAG CCTGCAGCCTGAAGATTTTGCAACTTATTACTGTCAACAGCTTAATAGTTACCCATTCACTTTCGGCCCTGGGACCAAAGTGGATATCAAA (SEQ ID NO: 75) 15299 VH CAGGTGCAGCTGGTGGAGTCTGGGGGAGGCTTGGTACAGCCGGGGGGTCCCTGAGACTCTCCTGTACAGCCTCTGGATTCACCTTTAGCAGCTATGCCATGAGCTGGGTCCGCCAGGCTCCAGGGAAGGGGCTGGAGTGGGTCTCAGCTATTGGTGGTAGTGGTGGTAGCACATACTACGCAGACTCCGTGAAGGGCCGGTTCACCATCTCC AGAGACAATTCCAAGAACACGCTGTATCTGCAAATGAACAGCCTGAGAGCCGAGGACACGGCCGTATATTACTGTGTGAAAGATGGGCAGGAGGCTTTGACTACTGGGCCAGGGAACCCTGGTCACCGTCTCGAGT (SEQ ID NO: 84) 15299 VL GATATTGTGATGACGCAGTCTTCATCCTCCCTGTCTGCATCTGTAGGAGACAAGTCACCATCACTTGCCGGGCAAGTCAGGCATTATAAATCATTTAGGCTGGTATCAGCATAAACCAGGGAAAGCCCCTAATCGCCTAATCTATGCTGCATCCAGTTTGCAAAGTGGGGTCCCATCAAGGTTCAGCGGCAGTGGATCTGGGACAGAATTCACTCTCACAATCAGCAG CCTGCAGCCTGAAGATTTTGCAACTTATTACTGTCTACGGCATAATAGTTACCCTCGACGTTCGGCCAAGGGACCAAGGTGGAAATCAAG (SEQ ID NO: 85) 15353 VH CAGGTGCAGCTACAGCAGTCGGGCCCAGGACTGGTGAAGCCTTCACACCCTGTCCCTCACCTGCACTGTCTCTGGTGGCTCCATCAACAGTGGTGGTCACTACTGGAGCTGGATCCGCCAGCACCAGGGAGGGCCTGGAGTGGATTGGGTACATCTATTACAGTGGGAGCATCTACTACAACCCGTCCCTCAAGAGTCGACTTACCATATCAGTAGACACGTC TAAGAACCAGTTCTCCCTGAAGCTGAGCTCTGTGACTGCCGCGGACACGGCCGTGTATTACTGTGCGAGTTATTACTATGCCAGTAGTGGTGATGCTTTTGATATCTGGGGCCAAGGGACAATGGTCACCGTCTCGAGT (SEQ ID NO: 94) 15353 VL GAAACGACACTCAGCAGTCTCAGCCACCCTGTCTTTGTCTCCAGGGGAAAGAGCCACCCTCTCCTGCAGGGCCAGTCAGAGTGTTAGCAGCTACTTAGCCTGGTACCAACAGAAACCTGGCCAGGCTCCCAGGCTCCTCATCTATGATGCATCCAACAGGGCCACTGGCATCCCAGCCAGGTTCAGTGGCAGTGGGTCTGGGACAGACTTCACTCTCACCATCA GCAGCCTAGAGCCTGAAGATTTTGCAGTTTATTACTGTCAGCAGCGTAGCAACTGGCCTCCGACGTTCGGCCAAGGGACCAAGGTGGAAATCAAA (SEQ ID NO: 95) 15354 vh CAGGTGCAGCTGCAGGAGTCTGGGGGAGGCTTGGTACAGCCGGGGGGTCCCTGAGACTCTCCTGTACAGCCTCTGGATTCACCTTTAGTAATTATGCCATGAGCTGGGTCCGCCAGGCTCCAGGGAAGGGGCTGGAGTGGGTCTCAGCTATTAGTGGTCGTGGTGGTAGCACATTCTTCGCAGACTCCGTGAAGGGCCGGTTCACCAT (SEQ ID NO: 104) 15354 VL GAAATTGTGTTGACCAGTCTCAGCCACCCTGTCTGTGTCTCCAGGGGAAAGAGCCACCCTCTCCTGCAGGGCCAGTCAGAGTGTTAGCAGCAACTTAGCCTGGTACCAGCAGAAACCTGGCCAGGCTCCCAGGCTCCTCATCTATGGTGCATCCACCAGGGCCACTGGTATCCCAGCCAGGTTCAGTGGCACTGGTCTGGGACAGAGTTCACTCTCAC CATCAGCAGCCCTGCAGTCTGAAGATTTTGCACTTTATTACTGTCAGCAGTATGATAACTGGCCTCCGTGGACGTTCGGCCAAGGGACCAAGGTGGAAATCAAA (SEQ ID NO: 105) 17244 VH CAGGTGCAGCTGCAGGAGTCTGGGGGAGGCTTGGTCAAGCCTGGAGGGTCCCTGAGACTCTCCTGTGTCAGCCTCTGGATTCACCTTCAGTGACTACTACATGACCTGGATCCGCCAGGCTCCAGGGAAGGGCTGGAGTGGATTTCATACATTAGTGGTGGTGGTGGTTCCATATACTACGCAGACTCTGTGAAGGGCCGATTCACCATCTCCAGGGACAAC GCCAAGAACTCACTGTATCTGCAAATGAACAGCCTGAGAGCCGAGGACACGGCCGTTTATTTCTGTGCGAGAGGGAACTGGGGATCGGCGGCTCTTGATATCTGGGGCCAAGGGACAATGGTCACGGTCTCGAGT (SEQ ID NO: 114) 17244VL GAAATTGTGTTGACGCAGTCTCCATCCTCACTGTCTGCATCTGTAGGAGACAAGTCACCATCACTTGTCGGGCGAGTCAGGGCATTAACAATTATTTAGCCTGGTTTCAGCAGAAACCAGGGAGAGCCCCTAAGTCCCTGATCTATGCTGCATCCAGTTTGCAAAGTGGGGTCCCATCGAAGTTCAGCGGCAGTGGATCTGGGACAGATTTCACTCTCACCATCAGCAG CCTGCAGCCTGAAGATTTTGCAACTTATTACTGCCAACAGTATAATAGTTACCCTCCAACTCTCGGCCCTGGGACCAACGTGGATATCAAA (SEQ ID NO: 115) 17245 VH CAGGTGCAGCTGGTGGAGTCTGGGGGAGGCTTGGTACAGCCGGGGGGTCCCTGAGACTCTCCTGTACAGCCTCTGGATTCACCTTTAGCAGCTATGCCATGAGCTGGGTCCGCCAGGCTCCAGGGAAGGGGCTGGAGTGGGTCTCAGCTATTGGTGGTAGTGGTGGTAGCCATACTACGCAGACTCCGTGAAGGGCCGGTTCACCATCTCC AGAGACAATTCCAAGAACACGCTGTATCTGCAAATGAACAGCCTGAGAGCCGAGGACACGGCCGTATATTACTGTGTGAAAGATGGGCAGGAGGCTTTGACTACTGGGCCAGGGCACCCTGGTCACCGTCTCGAGT (SEQ ID NO: 124) 17245VL GACATCCAGTTGACCAGTCCCCATCCTCCCTGTCTGCATCTGTAGGAGACAAGTCACCATCACTTGCCGGGCAAGTCAGGGCATTAGAAATCATTTAGGCTGGTATCAGCAGAAACCAGGGAAAGCCCCTAAGCGCCTAATCTATGCTGCATCCAGTTTGCAAAGTGGGGTCCCATCAAGGTTCAGCGGCAGTGGATCTGGGACAGAATTCACTCTCACAATCAGCAG CCTGCAGCCTGAAGATTTTGCAACTTATTACTGTCTACAGCATAATAGTTACCCTCGACGTTCGGCCAAGGGACCAAGGTGGAAATCAAG (SEQ ID NO: 125) 19324 VH CAGATGCAGCTACAGCAGTCTGGGGGAGGCTTGGTACAGCCGGGGGGTCCCTGAGACTCTCCTGTGTCAGCCTCTGGATTCACCGTTAGCAGCTATGCCATGAGCTGGGTCCGCCAGGCTCTAGGGAAGGGGCTGGAGTGGGTCTCAGGTATTAGTGGTAGTGGTGGTAGCACATACTACGCAGACTCCGTGAAGGGCCGGTTCACCATCTCC AGAGACAATTCCAAGAATACGCTGTATCTGCAAATGAACAGCCTGAGAGCCGAGGACACGGCCGTATATTACTGTGCGAAGATAGTGGGAGCTACCCACTTTGACTACTGGGGCCAGGGAACCCTGGTCACGGTCTCGAGT (SEQ ID NO: 134) 19324 VL GAAATTGTGATGACACAGTCTCAGACTCCCTGGCTGTGTCTCTGGGCGAGAGGGCACCATCAACTGCAAGTCCAGCCAGAGTGTTTTATACAGCTCCAACAATAAGAACTACTTAGCTTGGTACCAGCAGAAACCAGGACAGCCTCCTAAGCTGCTCATTTACTGGGCATCTACCCGGGAATCCGGGGTCCCTGACCGATTCAGTGGCAGCGGGTCTGGGACAGA TTTCACTCTCACCATCAGCAGCCTGCAGGCTGAAGATGTGGCAGTTTATTACTGTCAGCAATATTATAGTGGTCCGATCACCTTCGGCCAAGGGACACGACTGGAGATTAAG (SEQ ID NO: 135) 19416 VH CAGGTGCAGCTGGTGGAGTCGGGCCCAGGACTGGTGAAGCCTTCACAGACCCTGTCCCTCACCTGCACTGTCTCTGGTGGCTCCATCAACAGTGGTGGTTACTACTGGAGCTGGATCCGCCAGCAACCCAGGGAAGGGCCTGGAGTGGATTGGGTACATCTATTACAGTGGGAGCATCTACTACAACCCGTCCCTCAGGAGTCGACTTACCATATCAGTAGACACGTC TAAGAACCAGTTCTCCCTGAAGCTGAGCTCTGTGACTGCCGCGGACACGGCCGTTTATTACTGTGCGACTCCTTATTACTATGGTTCGGGGAGTTATGGGGACTACTGGGGCCAGGGCACCCTGGTCACTGTCTCGAGT (SEQ ID NO: 144) 19416 VL GACATCCAGATGACCCAGTCTCAGCCACCCTGTCTTTGTCTCCAGGGGAAAGAGCCACCCTCTCCTGCAGGGCCAGTCAGAGTGTTAACAACTTAGCCTGGTACCAACAGAAACCTGGCCAGGCTCCCAGGCTCCTCATCTATGATGCATCCAACAGGGCCACTGGCATCCCAGCCAGGTTCAGTGGCAGTGGGTCTGGGACAGACTTCACTCTCACCATCAGC AGCCTAGAGCCTGAAGATTTTGCAGTTTATTACTGTCAGCAGCGTAGCAACTGGCCCATCACCTTCGGCCAAGGGACACGACTGGAGATTAAA (SEQ ID NO: 145) 19568 VH CAGATGCAGCTGCAGGAGTCGGGCCCAGGACTGGTGAAGCCTTCTCAGACCCTGTCCCTCACCTGCACTGTGTCTGGTGGCTCCATCAGCAGTGTTGGTTACTACTGGAACTGGATCCGCCAGCACCCAGGGAAGGGCCTGGAGTTCATTGGGTACATCTATTACAGTGGGAGCATCTACTACAATCCGTCCCTCAAGAGTCGAGTTACCATATCCGTAGACACGTCTA (SEQ ID NO: 154) 19568 VL GAAATTGTGATGACACAGTCTCAGCCACCCTGTCTTTGTCTCCAGGGGAAAGAGCCACCCTCTCCTGCAGGGCCAGTCAGAGTGTTAGCAGCTACTTAGCCTGGTACCAACAGAAACCTGGCCAGGCTCCCAGGCTCCTCATCTATGATGCATCCAACAGGGCCACTGGCATCCCAGCCAGGTTCAGTGGCAGTGGGTCTGGGACAGACTTCACTCTCACCATCA GCAGCCTAGAGCCTGAAGATTTTGCAGTTTATTACTGTCAGCAGCGTAGCAACTGGCCTATCACCTTCGGCCAAGGGACACGACTGGAGATCAAG (SEQ ID NO: 155) 20131 VH CAGGTGCAGCTACAGCAGTCTGGGGGAGGCTTGGTACAGCCTGGGGGGTCCCTGAGACTCTCCTGTGTCAGCCTCTGGATTCACCTTAAGCAGCTATGCCATGAGCTGGGTCCGCCAGGCTCCAGGGAAGGGGCTGGAGTGGGTCTCAGGTATTAGTGGTAGTGGTGGTAGCACATACAACGCAGACTCCGTGAAGGGCCGGTTCACCATCTCCAG AGACAATTCCAAGAACACGCTGTTTCTGCAAATGAACAGCCTGAGAGCCGAGGACACGGCCGTATATTACTGTGCGAAAATTTTTGGGTCCTACTACTTTGACTACTGGGGCCAGGGAACCCTGGTCACAGTCTCGAGT (SEQ ID NO: 164) 20131 VL GAAATTGTGATGACACAAGTCTCAGACTCCCTGGCTGTGTCTCTGGGCGAGAGGGCCACCATCAACTGCAAGTCCAGCCAGAGTGTTTTATACAGCTCCAACAATAAGAACTACTTAGCTTGGTACCAGCAGAAACCAGGACAGCCTCCTAAGCTGCTCATTTACTGGACATCTACCCGGGAATCCGGGTCCCTAACCGATTCAGTGGCAGCGGGTCTGGGACAGATT TCACTCTCACCATCAGCAGCCTGCAGGCTGAAGATGTGGCAGTTTATTACTGTCAGCAATATTATAGTGGTCCTCCGACGTTCGGCCAAGGGACCAAGGTGGAAATCAAA (SEQ ID NO: 165) 20185 VH CAGGTGCAGCTGGTGGAGTCTGGGGGAGGCTTGGTTCGGCCTGGGGGTCCCTGAGACTCTCCTGTGTCAGTCTCTGGATTCACCTTTAGCAGCTATGCCATGAGCTGGGTCCGCCAGGCTCCAGGGAAGGGGCTGGAGTGGGTCTCAGGTATTAGTGGTAGTGGTGGTAGCACATACAACGCAGACTCCGTGAAGGGCCGGTTCACCATCTCC AGAGACAATTCCAAGAACACGCTGTATCTTCAAATGAACAGCCTGAGAGCCGAGGACACGGCCGTATATTACTGTGCGAAAATTTTTGGGTCCTACTACTTTGACTACTGGGGCCAGGGAACCCTGGTCACCGTCTCGAGT (SEQ ID NO: 174) 20185 VL GAAATTGTGATGACACAGTCTCAGACTCCCTGGCTGTGTCTCTGGGCGAGAGGGCACCATCAACTGCAAGTCCAGCCAGAGTGTTTTATACAGCTCCAATAATAAGAACTACTTAGCTTGGTACCAGCAGAAATCAGGACAGCCTCCTAAGCTGCTCATTTACTGGGCATCTACCCGGGAATCCGGGTCCCTGACCGATTCAGTGGCAGCGGGTCTGGGACAGATT TCACTCTCACCATCAGCAGCCTGCAGGCTGAAGATGTGGCAGTTTATTACTGTCAGCAATATTATAGTGGTCCACCGACGTTCGGCCAAGGGACCAAGGTGGAAATCAAA (SEQ ID NO: 175) 20293 VH ACGTGACAGGGCGCGCCCAGGTCCAGCTGCAGGAGAGCGGTCCCGGACTGGTGAAGCCATCCCAGACACTGAGCCTGACTTGTACTGTGAGCGGCGGTAGCATCTCCAGCGGCGGCTACTATTGGTCCTGGATCAGGCAGCACCCAGGCAAGGGCCTGGAGTGGATCGGCTACATCTACTATAGCGGCTCTATCTACTATAACCCTTCCCTGAAGAGCCGGGTG ACCATCTCTGTGGACACATCCAAGAATCAGTTCTATCTGAAGCTGTCTTCCGTGACCGCCGCTGATACAGCCGTGTACTATTGCGCCTCACTGATGGTCTGGGGGGTCATGGGCGATTACTGGGGGCAGGGCACACTGGTCACAGTCTCGAGT (SEQ ID NO: 184) 20293 VL GAGATTGTGCTGACCAGTCTCCCGCCACCCTGTCTCTGAGTCCTGGCGAGAGCCACCCTGAGCCTGCAGAGCCTCTCAGTCCGTGTCCAGCTATCTGGCCTGGTATCAGCAGAAGCCCGGCCAGGCTCCCCGGCTGCTGATCTACGATGCCTCCAATAGAGCCACCGGCATCCCTGCCAGATTCTCCGGCTCTGGCTCTGGCACCGACTTTACCCTGACCATCTCCAGCCTGGA ACCCGAGGACTTCGCCGTGTACTACTGCCAGCAGCGGTCCGACTGGCCTCCTACATTTGGCCAAGGCACCAAGGTGGAAATCAAG (SEQ ID NO: 185) 20300 VH CAGGTCCAGCTACAGCAGTCTGGGGGAGGCTTGGTTCATCCTGGGGGTCCCTAAGACTCTCCTGTGTCAGCCTCTGGATTCACCGTTGACACCTATGCCATGACCTGGGTCCGCCAGGCTCCAGGGAAGGGGCTGGAGTGGGTCTCAGGTATTAGCGGTAGTGGTGGTAGCACATACTACGCAGACTCCGTGAAGGGCCGGTTCACCATCTCCA GAGACAACTCCAAGAACACGCTGTATCTGCAAATGAACAGCCTGAGACGAGGACACGGCCGTATATTACTGTGCGAAGATAGTGGGAGTTACCCACTTTGACTGGGGCCAGGGCACCCTGGTCACGGTCTCGAGT (SEQ ID NO: 194) 20300L GAAATTGTGATGACGCAGTCTCAGACTCCCTGGCTGTGTCTCTGGGCGAGAGGGCACCATCAACTGCAAGTCCAGCCAGAGTGTTTTATACAGGTCCAACAATAAGAACTATTTAGCTTGGTACCAGCAGAAACCAGGACAGCCTCCTAAGCTGCTCATTTACTGGGCATCTACCCGGGAATCCGGGGTCCCTGACCGATTCAGTGGCAGCGGGTCTGGGACA GATTTCACTCTCACCATCAGCAGCCCTGCAGGCTGAAGATGTGGCAGTTTATTACTGTCAGCAATATTATAGTGGTCCGATCACCTTCGGCCAAGGGACACGACTGGAGATTAAG (SEQ ID NO: 195) 20362 VH CAGGTCACCTTGAGGAGTCGGGCCCAGGACTGGTGAAGCCTTCACACCCTGTCCCTCACCTGCACTGTCTCTGGTGGCTCCATCAGCAGTGGTGGTCATTACTGGAGCTGGATCCGCCAGCAACCCAGGGAAGGGCCTGGAGTGGATTGGGTACATCTCTTACAGTGGGAGCACCTACTACAACCCGTCCCTCAAGAGTCGACTTACCATATCAGTAGACACG TCTAAGAACCAGTTCTCCCTGAAGCTGAGCTCTGTGACTGCCGCGGACACGGCCGTGTATTACTGTGCGACCGCGTATTACGATATTTTGACTGGTTACCCTTTTGACTACTGGGGCCAGGGAACCCTGGTCACGGTCTCGAGT (SEQ ID NO: 204) 20362 VL GAAATTGTGATGACACAGTCTCAGCCACCCTGTCTTTGTCTCCAGGGGAAAGAGCCACCCTCTCCTGCAGGGCCAGTCAGAGTGTTAGCAGCTACTTAGCCTGGTACCAACAGAAACCTGGCCAGGCTCCCAGGCTCCTCATCTATGATGCATCCGACAGGGCCACTGGCATCCCAGCCAGGTTCAGTGGCAGTGGGTCTGGGACAGACTTCACTCTCACCATCA GCAGCCTAGAGCCTGAAGATTTTGCAGTTTATTACTGTCAGCAGCGTAGCAACTGGCCGATCACCTTCGGCCAAGGGACACGACTGGAGATCAAG (SEQ ID NO: 205) 20621 VH CAGGTGCAGCTACAGCAGTCGGGCCCAGGACTGGTGAAGCCTTCACAGACCCTGTCCCTCACCTGCACTGTCTCTGGTGGCTCCATCAGCAGTGGTGGTTACTACTGGAGCTGGATCCGCCAGCACCCAGGGAAGGGCCTGGAGTGGATTGGGTACATTCTCTTATAGTGGGAGTATCTACTACAACCCGTCCCTCAAGAGTCGAGTTACCATTCAGTAGACACG TCTAAGAACCAGTTCTCCCTGAAGCTGAGCTCTGTGACTGCCACGGACACGGCCGTGTATTACTGTGCGACCGCGTATTACGATCTTTTGACTGGTTACCCTTTTGACTACTGGGGCCAGGGAACCCTGGTCACGGTCTCGAGT (SEQ ID NO: 214) 20621 VL GAAATTGTGATGACGCAGTCTCAGCCACCCTGTCTTTGTCTCCAGGGGAAAGAGCCACCCTCTCCTGCAGGGCCAGTCAGAGTGTTAGCAGCTACTTAGCCTGGTACCAACAGAAACCTGGCCAGGCTCCCAGGCTCCTCATCTATGATGCATCCAACAGGGCCACTGGCATCCCAGCCAGGTTCAGTGGCAGTGGGTCTGGGACAGACTTCACTCTCACCATCA GCAGCCTAGAGCCTGAAGATTTTGCAGTTTATTACTGTCAGCAGCGTAGCAACTGGCCGATCACCTTCGGCCAAGGGACACGACTGGAGATTAAG (SEQ ID NO: 215)

Table 5: Nucleotide sequences of the heavy and light chain variable domains of an anti-TIM-3 antibody

(CDRs are in bold and italics)

Ab Sequence (N-terminal to C-terminal)

15086.15086 VH QVQLQQSGPGLVKPSQTLSLTCTVSGGSISSGGYYWSWTRQHPGMGLEWIGYISYSGSIYYTPSLKSRLTISVDTSKNQFSLKLSSVTAADTAVYYCASLDSWGSNRDYWGQGTLVTVSS (SEQ ID NO: 3) 15086.16837 15086.17145 15086.17144
vh QVQLQESGPGLVKPSQTLSLTCTVSGGSISSGGYYWSWTRQHPGMGLEWIGYISYSGSIYYTPSLKSRLTISVDTSKNQFSLKLSSVTAADTAVYYCASLDSWGSNRDYWGQGTLVTVSS (SEQ ID NO: 7) 15086.15086 15086.16837 15086.17145 15086.17144
VL EIVLTQSPATLSLSPGERATLSCRASQSVSSYLAWYQQKPGQAPRLLIYDASNRATGIPARFSGSGSGTDFTLTISSLEPEDFAVYYCQQRSNWPLTFGGGTKVEIK (SEQ ID NO: 4) 15105 VH QVTLKEWGAGLLRPSETLSLTCAVYGGSFSGYYWSWIRQPPGKGLEWIGEINHSGSTNYNPSLKSRVTISVDATKKQFSLKLTSVTAADTAVYYCARYWELPDYWGQGTLVTVSS (SEQ ID NO: 16) 15105 VL DIQLTQSPSSLSASVGDRVTITCRASQGIRNDLGWYQQKPGKAPKRLIYAASSLQSGVPSRFSGSGSGTEFTLTISSLQPEDFATYYCLQHNSYPPTFGQGTKVEIK (SEQ ID NO: 17) 15107 VH QMQLVQWGAGLLKPSETLSLTCAVYGGSFSGYYWSWIRQPPGKGLEWIGEINHSGSTNYNPSLKSRVTMSVDTSKHQFSLKLSSVTAADTAVYYCARWWELPDYWGQGTLVTVSS (SEQ ID NO: 26) 15107 VL EIVLTQSPSSLSASVGDRVTITCRASQGIRNDLGWYQQKPGKAPKRLIYAASSLQSGVPSRFSGSGSGTEFTLTISSLQPEDFATYYCLQHNSYPWTFGQGTKVEIK (SEQ ID NO: 27) 15109 VH QMQLVQWGAGLLKPSETLSLTCAVYGGSFSGYYWSWIRQPPGKGLEWIGEINHSGSTNYNPSLKSRVTISVDTSKNQFSLKLSSVTAADTAVYYCARFYYAPNFDYWGQGTLVTVSS (SEQ ID NO: 36) 15109 VL EIVLTQSPSTLSASVGDRVTITCRASQSISSWLAWYQQKPGTAPKLLIYKASSLESGVPSRFSGSGSGTEFTLTISSLQPDDFATYYCQQYNSYSTFGGGTKVEIK (SEQ ID NO: 37) 15174 VH QVQLQQSGPGLVKPSETLSLTCTVSGGSISSSNYYWGWIRQPPGKGLEWIGSIYYSGNTYYNPSLKSRVTISVDTSKNQFSLKLSSVTAADTAVYYCARQTVAGPLFDYWGQGTLVTVSS (SEQ ID NO: 46) 15174 VL EIVMTQSPSTLSASVGDRVTITCRASQSISSWLAWYQQKPGKAPKVLIYKASSLESGVPSRFSGSGSGTELTLTISSLQPDDFATYYCQQYNSYSFTFGPGTKVDIK (SEQ ID NO: 47)

15175 VH QVQLVQSGAEVKKPGASVKVSCKAAGYTLTGYYMHWVRQAPGQGLEWMGRINPNSGGSNNAQKFQGRVTMTRDTSISTAYMELSRLRSDDTAVYYCAREGPLYSSGWYEGAFDIWGQGTMVTVSS (SEQ ID NO:56) 15175 VL EIVMTQSPSTLSASVGDRVTITCRASQSISSWLAWYQQKPGKAPKLLIYKASSLESGVPSRFSGSGSGTEFTLTISSLQPDDFATYYCQQYNSYSPGLTFGGGTKVEIK (SEQ ID NO: 57) 15260VH QMQLQQSGPGLVKPSQTLSLTCAISGDSVSSNSAAWNWIRQSPSRGLEWLGRTYYRSKWYSAFAVSVKSRITINPDTSKNQFSLQLNSVTPEDTAVYYCAREGSSGWYGYVHHWGQGTLVTVSS (SEQ ID NO: 66) 15260 VL EIVLTQSPASLSVSLGETVTIECRASEDIYNGLAWYQQKPGKSPQLLIYNANSLHTGVPSRFSGSGSGTQYSLKINSLQSEDVASYFCQQYYDYPPTFGQGTKVEIK (SEQ ID NO: 67) 15284 VH QVQLQESGPGLVKPSETLSLTCTVSGGSFSSSSYYWGWIRQPPGKGLEWIGIFYYSGTTYYNPSLKSRVTISAHTSKSQFSLKLSSVTAADTAVYYCARGGEYFDRLLPFDYWGQGTLVTVSS (SEQ ID NO: 76) 15284 VL EIVMTQSPSFLSASVGDRVTITCRASQGISSYLAWYQQKPGKAPKLLIYAASTLESGVPSRFSGSGSGTEFTLTISSLQPEDFATYYCQQLNSYPFTFGPGTKVDIK (SEQ ID NO: 77) 15299 VH QVQLVESGGGLVQPGGSLRLSCTASGFTFSSYAMSWVRQAPGKGLEWVSAIGGSGGSTYYADSVKGRFTISRDNSKNTLYLQMNSLRAEDTAVYYCVKDGAGGFDYWGQGTLVTVSS (SEQ ID NO: 86) 15299 VL DIVMTQSSSSLSASVGDRVTITCRASQGIINHLGWYQHKPGKAPNRLIYAASSLQSGVPSRFSGSGSGTEFTLTISSLQPEDFATYYCLRHNSYPPTFGQGTKVEIK (SEQ ID NO: 87) 15353 VH QVQLQQSGPGLVKPSQTLSLTCTVSGGSINSGGHYWSWIRQHPGRGLEWIGYIYYSGSIYYNPSLKSRLTISVDTSKNQFSLKLSSVTAADTAVYYCASYYYASSGDAFDIWGQGTMVTVSS (SEQ ID NO: 96) 15353 VL (SEQ ID NO: 97)

15354 vh QVQLQESGGGLVQPGGSLRLSCTASGFTFSNYAMSWVRQAPGKGLEWVSAISGRGGSTFFADSVKGRFTISRDNSKSTLYLQTNSLRAEDTAVYYCAKGGPLYNWNDGDGFDIWGQGTTVTVSS (SEQ ID NO: 106) 15354 VL EIVLTQSPATLSVSPGERATLSCRASQSVSSNLAWYQQKPGQAPRLLIYGASTRATGIPARFSGTGSGTEFTLTISSLQSEDFALYYCQQYDNWPPWTFGQGTKVEIK (SEQ ID NO: 107) 17244 VH QVQLQESGGGLVKPGGSLRLSCAASGFTFSDYYMTWIRQAPGKGLEWISYISGGGGSIYYYADSVKGRFTISRDNAKNSLYLQMNSLRAEDTAVYFCARGNWGSAALDIWGQGTMVTVSS (SEQ ID NO: 116) 17244VL EIVLTQSPSSLSASVGDRVTITCRASQGINNYLAWFQQKPGRAPKSLIYAASSLQSGVPSKFSGSGSGTDFTLTISSLQPEDFATYYCQQYNSYPPTLGPGTNVDIK (SEQ ID NO: 117) 17245VH QVQLVESGGGLVQPGGSLRLSCTASGFTFSSYAMSWVRQAPGKGLEWVSAIGGSGGSAYYADSVKGRFTISRDNSKNTLYLQMNSLRAEDTAVYYCVKDGAGGFDYWGQGTLVTVSS (SEQ ID NO: 126) 17245VL DIQLTQSPSSLSASVGDRVTITCRASQGIRNHLGWYQQKPGKAPKRLIYAASSLQSGVPSRFSGSGSGTEFTLTISSLQPEDFATYYCLQHNSYPPTFGQGTKVEIK (SEQ ID NO: 127) 19324 VH QMQLQQSGGGLVQPGGSLRLSCAASGFTVSSYAMSWVRQALGKGLEWVSGISGSGGSTYYADSVKGRFTISRDNSKNTLYLQMNSLRAEDTAVYYCAKIVGATHFDYWGQGTLVTVSS (SEQ ID NO: 136) 19324 VL EIVMTQSPDSLAVSLGERATINCKSSQSVLYSSNNKNYLAWYQQKPGQPPKLLIYWASTRESGVPDRFSGSGSGTDFTLTISSLQAEDVAVYYCQQYYSGPITFGQGTRLEIK (SEQ ID NO: 137) 19416 VH QVQLVESGPGLVKPSQTLSLTCTVSGGSINSGGYYWSWIRQHPGKGLEWIGYIYYSGSIYYNPSLRSRLTISVDTSKNQFSLKLSSVTAADTAVYYCATPYYYGSGSYGDYWGQGTLVTVSS (SEQ ID NO: 146) 19416 VL DIQMTQSPATLSLSPGERATLSCRASQSVNNYLAWYQQKPGQAPRLLIYDASNRATGIPARFSGSGSGTDFTLTISSLEPEDFAVYYCQQRSNWPITFGQGTRLEIK (SEQ ID NO: 147) 19568 VH QMQLQESGPGLVKPSQTLSLTCTVSGGSISSVGYYWNWIRQHPGKGLEFIGYIYYSGSIYYNPSLKSRVTISVDTSKNQFSLKLSSVTAADTALYYCASVGIVGASYFEYWGQGTLVTVSS (SEQ ID NO: 156) 19568 VL EIVMTQSPATLSLSPGERATLSCRASQSVSSYLAWYQQKPGQAPRLLIYDASNRATGIPARFSGSGSGTDFTLTISSLEPEDFAVYYCQQRSNWPITFGQGTRLEIK (SEQ ID NO: 157) 20131 VH QVQLQQSGGGLVQPGGSLRLSCAASGFTLSSYAMSWVRQAPGKGLEWVSGISGSGGSTYNADSVKGRFTISRDNSKNTLFLQMNSLRAEDTAVYYCAKIFGSYYFDYWGQGTLVTVSS (SEQ ID NO: 166) 20131 VL EIVMTQSPDSLAVSLGERATINCKSSQSVLYSSNNKNYLAWYQQKPGQPPKLLIYWTSTRESGVPNRFSGSGSGTDFTLTISSLQAEDVAVYYCQQYYSGPPTFGQGTKVEIK (SEQ ID NO: 167) 20185 VH QVQLVESGGGLVRPGGSLRLSCAVSGFTFSSYAMSWVRQAPGKGLEWVSGISGSGGSTYNADSVKGRFTISRDNSKNTLYLQMNSLRAEDTAVYYCAKIFGSYYFDYWGQGTLVTVSS (SEQ ID NO: 176) 20185 VL EIVMTQSPDSLAVSLGERATINCKSSQSVLYSSNNKNYLAWYQQKSGQPPKLLIYWASTRESGVPDRFSGSGSGTDFTLTISSLQAEDVAVYYCQQYYSGPPTFGQGTKVEIK (SEQ ID NO: 177) 20293 VH QVQLQESGPGLVKPSQTLSLTCTVSGGSISSGGYYWSWIRQHPGKGLEWIGYIYYSGSIYYNPSLKSRVTISVDTSKNQFYLKLSSVTAADTAVYYCASLMVWGVMGDYWGQGTLVTVSS (SEQ ID NO: 186) 20293 VL EIVLTQSPATLSLSPGERATLSCRASQSVSSYLAWYQQKPGQAPRLLIYDASNRATGIPARFSGSGSGTDFTLTISSLEPEDFAVYYCQQRSDWPPTFGQGTKVEIK (SEQ ID NO: 187) 20300 VH QVQLQQSGGGLVHPGGSLRLSCAASGFTVDTYAMTWVRQAPGKGLEWVSGISGSGGSTYYADSVKGRFTISRDNSKNTLYLQMNSLRDEDTAVYYCAKIVGVTHFDYWGQGTLVTVSS (SEQ ID NO: 196) 20300L EIVMTQSPDSLAVSLGERATINCKSSQSVLYRSNNKNYLAWYQQKPGQPPKLLIYWASTRESGVPDRFSGSGSGTDFTLTISSLQAEDVAVYYCQQYYSGPITFGQGTRLEIK (SEQ ID NO: 197)

20362 VH QVTLKESGPGLVKPSQTLSLTCTVSGGSISSGGHYWSWIRQHPGKGLEWIGYISYSGSTYYNPSLKSRLTISVDTSKNQFSLKLSSVTAADTAVYYCATAYYDILTGYPFDYWGQGTLVTVSS (SEQ ID NO: 206) 20362 VL EIVMTQSPATLSLSPGERATLSCRASQSVSSYLAWYQQKPGQAPRLLIYDASDRATGIPARFSGSGSGTDFTLTISSLEPEDFAVYYCQQRSNWPITFGQGTRLEIK (SEQ ID NO: 207) 20621 VH QVQLQQSGPGLVKPSQTLSLTCTVSGGSISSGGYYWSWIRQHPGKGLEWIGYISYSGSIYYNPSLKSRVTISVDTSKNQFSLKLSSVTATDTAVYYCATAYYDLLTGYPFDYWGQGTLVTVSS (SEQ ID NO: 216) 20621 VL EIVMTQSPATLSLSPGERATLSCRASQSVSSYLAWYQQKPGQAPRLLIYDASNRATGIPARFSGSGSGTDFTLTISSLEPEDFAVYYCQQRSNWPITFGQGTRLEIK (SEQ ID NO: 217)

Table 6: Nucleotide sequences of the heavy and light chain variable domains of the anti-PD-1 antibody

Ab Sequence (5'-3') 12819.15384 VH GGCGCGCCGAGGTGCAGCTGCTGGAATCTGGAGGAGGACTGGTCCAGCCAGGTGGATCCCTGCGACTGAGCTGCGCCGCTTCTGGATTCACCTTTACAAGATACGACATGGTGTGGGTCCGCCAGGCACCAGGAAAGGGACTGGAGTGGGTGGCTGGTATCGGCGATAGTAACAAGATGACCCGCTACGCACCTGCCGTCAAAGGGAGGCAACAA (SEQ ID NO: 224) 12819.15384 VL GCTAGCCTCTTACGAGCTGACTCAGGACCCTGCAGTGTGTGTCGCCCTGGGCCAGACAGTGAGAATCACTTGCTCCGGCGGAGGAGCTACGATGGTTCCAGCTACTATGGCTGGTATCAGCAGAAGCCAGGACAGGCACCTGTGACCGTCATCTATAACAATAACAATAGGCCATCTGACATTCCCGATCGGTTCAGTGGATCTAGTTTCAGGGAACACAGCTTCTCTG ACCATTACAGGAGCCCAGGCTGAGGACGAAGCAGATTACTATTGTGGGTCATACGACAGGCCAGAAACAAATTCCGATTATGTGGGAATGTTTGGTAGCGGCACTAAAGTCACCGTCCTAGG (SEQ ID NO: 225) 12748.15381 12748.16124 VH GGCGCGCCGAGGTGCAGCTGCTGGAAAGCGGAGGAGGACTGGTCCAGCCAGGTGGATCTCTGCGACTGAGTTGCGCCGCTTCAGGCTTCACATTTTCTGACTACGCCATGAACTGGGTGAGGCAGGCTCCTGGCAAGGACTGGAGTGGGTCGCAGGAATCGGGAACGATGGAAGTTACACTAATTATGGAGCAGCCGTGAAGGGGAGAGCTACTATTTCCCG CGACAACAGCAAAAATACCCTGTACCTGCAGATGAACTCACTGAGAGCTGAAGATACCGCAGTGTACTATTGTGCCTCTGACATCAGGAGTCGGAATGATTGCTCCTATTTCCTGGGAGGGTGTTCCAGCGGCTTTATTGACGTGTGGGGTCAGGGCACCCTGGTCACAGTCTCGAG (SEQ ID NO: 234) 12748.15381 VL GCTAGCCTCTTACGAGCTGACCCAGGACCCAGCAGTGTCCGTCGCCCTGGGCCAGACAGTGAGAATCACTTGCTCCGGCGGATCCAGCTACAGCTATGGGTGGTTCCAGCAGAAGCCCGGTCAGGCCCCTGTGACCGTCATCTATGAAAGTAACAATAGGCCATCAGACATTCCCGATCGGTTTTCTGGCTCTAGTTCAGGAAACACAGCTAGTCTGACCATCACAGG GGCCCAGGCTGAGGACGAAGCTGATTACTATTGTGGCAATGCAGATTCCAGCTCTGGAATTTTCGGGTCCGGTACTAAAGTCACCGTCCTAGG (SEQ ID NO: 235) 12865.15377 VH GGCGCGCCGAGGTGCAGCTGCTGGAATCCGGAGGAGGACTGGTCCAGCCAGGTGGATCCCTGCGACTGAGCTGCGCCGCTTCTGGATTCGACTTTAGCGATCACGGGATGCAGTGGGTGAGACAGGCACCAGGCAAGGGACTGGAGTACGTGGGTGTCATCGACACCACAGGCCGCTATACATACTATGCACCTGCCGTCAAGGGCAGGGCTACCATTAGTC GGGACAACTCAAAAAATACACTGTACCTGCAGATGAACTCTCTGAGGGCTGAAGATACTGCAGTGTACTATTGCGCCAAAACTACCTGCGTGGGAGGTACCTGTGCAATACCGTCGGAAGTATCGATGCTTGGGGACAGGGGACACTGGTGACTGTCTCGAG (SEQ ID NO: 244) 12865.15377
VL GCTAGCCTCCTACGAGCTGACTCAGGACCCAGCAGTGAGCGTCGCCCTGGGCCAGACAGTGAGAATCACTTGCTCTGGCGGAGGTCCAGCTCTTACTATGGTTGGTACCAGCAGAAGCCCGGCCAGGCTCCTGTGACCGTCATCTATGACGATACAAACAGGCCAAGTGGAATTCCCGATCGGTTCTCAGGTAGTTCATCCGGCAATACAGCTTCTCTGACCATC ACAGGGGCCCAGGCTGAGGACGAAGCAGATTACTATTGTGGTGGCTATGAAGGAAGCTCTCACGCCGGGATTTTTGGAAGTGGGACTAAAGTCACCGTCCTAGG (SEQ ID NO: 245) 12892.15378 VH GGCGCGCCGAGGTGCAGCTGCTGGAAAGTGGAGGAGGACTGGTCCAGCCAGGTGGAAGCCTGAGACTGTCTTGCGCCGCTAGTGGCTTCGACTTTTCCAGCTACACCATGCAGTGGGTGAGGCAGGCACCAGGCAAGGGACTGGAGTGGGTGGGCGTCATCTCTAGTACTGGAGGTCTACCGGGATACGGGCCTGCTGTGAAGGGAAGGGCAACA ATTTCACGGGATAACTCCAAAAATACTCTGTATCTGCAGATGAACAGCCTGAGGGCAGAAGACACAGCCGTGTACTATTGCGTGAAATCAATCTCCGGAGATGCCTGGTCTGTGGACGGGCTGGATGCTTGGGGTCAGGGCACCCTGGTCACAGTCTCGAG (SEQ ID NO: 254) 12892.15378
VL GCTAGCCTCATACGAGCTGACCCAGGACCCAGCAGTGTCCGTCGCCCTGGGACAGACAGTGAGAATCACTTGCTCCGGAGGAGGATCCGCCTACGGTTGGTATCAGCAGAAGCCCGGCCAGGCACCTGTGACCGTCATCTACTATAACAATCAGAGGCCATCTGGGCATTCCCGACCGGTTCAGTGGATCCAGCTCTGGGAACACAGCAAGTCTGACCATCACAGGCGCCAG GCTGAGGACGAAGCCGATTACTATTGTGGAAGCTATGATAGTTCAGCTGTGGGGATTTTTGGTTCTGGCACTAAAGTCACCGTCCTAGG (SEQ ID NO: 255) 12796.15376
vh GGCGCGCCGAGGTGCAGCTGCTGGAAAGTGGAGGAGGACTGGTCCAGCCAGGTGGAAGCCTGAGACTGTCTTGCGCCGCTAGTGGCTTCGACTTTTCCAGCTACACCATGCAGTGGGTGAGGCAGGCACCAGGCAAGGGACTGGAGTGGGTGGGCGTCATCTCTAGTACTGGAGGTCTACCGGGATACGGGCCTGCTGTGAAGGGAAGGGCAACA ATTTCACGGGATAACTCCAAAAATACTCTGTATCTGCAGATGAACAGCCTGAGGGCAGAAGACACAGCCGTGTACTATTGCGTGAAATCAGTCTCCGGAGATGCCTGGTCTGTGGACGGGCTGGATGCTTGGGGTCAGGGCACCCTGGTCACAGTCTCGAG (SEQ ID NO: 264) 12796.15376 VL GCTAGCCTCATACGAGCTGACCCAGGACCCAGCAGTGTCCGTCGCCCTGGGCCAGACAGTGAGAATCACTTGCTCCGGAGGAGGATCCGCCTACGGTTGGTATCAGCAGAAGCCCGGCCAGGCACCTGTGACCGTCATCTACTATAACAATCAGGCCATCTGACATTCCCGATCGGTTCAGTGGATCCAGCTCTGGGAACACAGCAAGTCTGACCATCACAGGCGCCCAGGC TGAGGACGAAGCCGATTACTATTGTGGAAGCTATGATAGTTCAGCTGTGGGGATTTTTGGTTCTGGCACTAAAGTCACCGTCCTAGG (SEQ ID NO: 265) 12777.15382
vh GGCGCGCCGAGGTGCAGCTGCTGGAATCCGGAGGAGGACTGGTCCAGCCAGGTGGAAGCCTGCGACTGTCTTGCGCCGCTAGTGGATTCGACTTTTCCAGCTACGGAATGCAGTGGGTGAGGCAGGCACCAGGCAAGGGACTGGAGTGGGTGGGCGTCATCTCTGGAAGTGGGATTACCACACTGTACGCACCTGCCGTCAAGGGAAGGGCTACTAT CTCACGGGACAACTCTAAAAATACAGTGTATCTGCAGATGAACTCCCTGAGAGCTGAAGATACCGCAGTCTACTATTGTACACGCTCACCCTCCATCACAGACGGCTGGACTTATGGAGGGGCCTGGATTGATGCTTGGGGTCAGGGCACTCTGGTGACCGTCTCGAG (SEQ ID NO: 274) 12777.15382
VL GCTAGCCAGCTACGAGCTGACCCAGGACCCAGCAGTGTCCGTCGCCCTGGGCCAGACAGTGAGAATCACTTGCAGTGGCGGAGATGGGTCATACGGTTGGTTCCAGCAGAAGCCCGGACAGGCCCCTGTGACCGTCATCTATGACAACGATAATAGGCCATCTGACATTCCCGATCGGTTTAGTGGCTCCAGCTCTGGAAACACAGCTTCTCTGACCATCACAGGGGCCC AGGCTGAGGACGAAGCTGATTACTATTGTGGCAATGCAGACCTGTCCGGGGGTATTTTCGGCAGCGGAACTAAAGTCACCGTCCTAGG (SEQ ID NO: 275) 12760.15375
vh GGCGCGCCGAGGTGCAGCTGCTGGAATCTGGAGGAGGACTGGTCCAGCCAGGTGGATCCCTGAGACTGAGCTGCGCCGCTTCTGGATTCACCTTTAGTACATTCAACATGGTGTGGGTCAGGCAGGCACCTGGAAAGGGACTGGAGTACGTGGCTGAAATCTCCAGCGACGGCTCTTTTACATGGTATGCAACTGCCGTCAAGGGCAGGGCACCATTAG TCGGGATAACTCAAAAAATACAGTGTACCTGCAGATGAATTCCCTGAGGGCTGAGGACACCGCAGTCTACTATTGCGCAAAATCCGATTGTTCTAGTTCATACTATGGATATAGCTGTATCGGGATCATTGACGCTTGGGGTCAGGGCACTCTGGTGACCGTCTCGAG (SEQ ID NO: 284) 12760.15375
VL GCTAGCCTCCTATGAGCTGACCCAGGACCCAGCAGTGAGCGTCGCCCTGGGCCAGACAGTGAGAATCACTTGCTCCGGCGGAATTAGCGACGATGGCTCTTACTATTACGGATGGTTCCAGCAGAAGCCCGGACAGGCCCCTGTGACCGTCATCTATATTAACGACAGGCGGCCAAGTAATATCCCCGATAGGTTTTCAGGGTCCAGCTCTGGTAACACAGCTTCTCTGACCAT TACAGGGGCCCAGGCTGAGGACGAAGCTGATTATTACTGTGGCTCTTACGATAGTTCAGCAGGGGTGGGTATCTTCGGCAGTGGAACTAAAGTCACCGTCCTAGG (SEQ ID NO: 285) 13112.15380
vh GGCGCGCCGAGGTGCAGCTGCTGGAAAGTGGAGGAGGACTGGTCCAGCCAGGTGGATCACTGAGACTGTCCTGCGCCGCCCGGCTTCACCTTTTCCAGCTACAACATGTTCTGGTGCGCCAGGCACCAGGAAAGGGACTGGAGTTTGTCGCTGAAATCTCTGGTAGTAATACTGGAAGCCGAACCTGGTACGCACCTGCCGTGAAGGGCAGGGC (SEQ ID NO: 294) 13112.15380
VL GCTAGCCTCATACGAGCTGACCCAGGACCCAGCAGTGTCCGTCGCCCTGGGCCAGACAGTGAGAATCACTTGCAGTGGCGGATCCAGCGATTACTATGGGTGGTTCCAGCAGAAGCCCGGTCAGGCCCCTGTGTCAGTCATCTACTATAACAACAAGGCCATCTGACATTCCCGATCGGTTTAGTGGCTCTAGTTCAGGAAACACAAGCCTCCCTGACCATTACAGGGGC CCAGGCTGAGGACGAAGCTGATTACTATTGTGGCAATGCAGACTCCAGCGTGGGAGTCTTCGGGTCTGGTACTAAGGTGACCGTCCTAGG (SEQ ID NO: 295) 12748.16124
VL GCTAGCCTCTTACGAGCTGACTCAGCCACCTTCCGTGTCCGTGTCCCCAGGACAGACCGCAAGAATCACATGCAGTGGCGGATCCAGCTACTCATATGGGTGGTTCCAGCAGAAGCCTGGTCAGGCCCCCGTGACAGTCATCTATGAGAGCAACAATAGGCCTTCTGACATTCCAGAACGGTTTAGTGGCTCTAGTTCAGGAACCAAGTGACTCTGACCATCAGCGGG GTCCAGGCCGAGGACGAAGCTGATTACTATTGTGGCAACGCTGATTCCAGCTCTGGAATTTTCGGGTCCGGTACAAAAGTGACTGTCCTAGG (SEQ ID NO: 391)

Table 7: Nucleotide sequences of the heavy and light chain variable domains of the anti-PD-1 antibody

(CDRs are in bold and italics)

Ab Sequence (N-terminal to C-terminal) 12819.15384
vh EVQLLESGGGLVQPGGSLRLSCAASGFTFTRYDMVWVRQAPGKGLEWVAGIGDSNKMTRYAPAVKGRATISRDNSKNTLYLQMNSLRAEDTAVYYCAKGSCIACWDEAGRIDAWGQGTLVTVSS (SEQ ID NO: 226) 12819.15384
VL SYELTQDPAVSVALGQTVRITCSGGGSYDGSSYYGWYQQKPGQAPVTVIYNNNNRPSDIPDRFSGSSSGNTASLTITGAQAEDEADYYCGSYDRPETNSDYVGMFGSGTKVTVL (SEQ ID NO: 227) 12748.15381
12748.16124
vh EVQLLESGGGLVQPGGSLRLSCAASGFTFSDYAMNWVRQAPGKGLEWVAGIGNDGSYTNYGAAVKGRATISRDNSKNTLYLQMNSLRAEDTAVYYCASDIRSRNDCSYFLGGCSSGFIDVWGQGTLVTVSS (SEQ ID NO: 236)

12748.15381
VL SYELTQDPAVSVALGQTVRITCSGGSSYSYGWFQQKPGQAPVTVIYESNNRPSDIPDRFSGSSSGNTASLTITGAQAEDEADYYCGNADSSSGIFGSGTKVTVL (SEQ ID NO: 237) 12865.15377
vh EVQLLESGGGLVQPGGSLRLSCAASGFDFSDHGMQWVRQAPGKGLEYVGVIDTTGRYTYYAPAVKGRATISRDNSKNTLYLQMNSLRAEDTAVYYCAKTTCVGGYLCNTVGSIDAWGQGTLVTVSS (SEQ ID NO: 246) 12865.15377
VL SYELTQDPAVSVALGQTVRITCSGGGSSSYYGWYQQKPGQAPVTVIYDDTNRPSGIPDRFSGSSSGNTASLTITGAQAEDEADYYCGGYEGSSHAGIFGSGTKVTVL (SEQ ID NO: 247) 12892.15378
vh EVQLLESGGGLVQPGGSLRLSCAASGFDFSSYTMQWVRQAPGKGLEWVGVISSTGGSTGYGPAVKGRATISRDNSKNTLYLQMNSLRAEDTAVYYCVKSISGDAWSVDGLDAWGQGTLVTVSS (SEQ ID NO: 256) 12892.15378
VL SYELTQDPAVSVALGQTVRITCSGGGSAYGWYQQKPGQAPVTVIYYNNQRPSGIPDRFSGSSSGNTASLTITGAQAEDEADYYCGSYDSSAVGIFGSGTKVTVL (SEQ ID NO: 257) 12796.15376
vh EVQLLESGGGLVQPGGSLRLSCAASGFDFSSYTMQWVRQAPGKGLEWVGVISSTGGSTGYGPAVKGRATISRDNSKNTLYLQMNSLRAEDTAVYYCVKSVSGDAWSVDGLDAWGQGTLVTVSS (SEQ ID NO: 266) 12796.15376
VL SYELTQDPAVSVALGQTVRITCSGGGSAYGWYQQKPGQAPVTVIYYNNQRPSDIPDRFSGSSSGNTASLTITGAQAEDEADYYCGSYDSSAVGIFGSGTKVTVL (SEQ ID NO: 267) 12777.15382
vh EVQLLESGGGLVQPGGSLRLSCAASGFDFSSYGMQWVRQAPGKGLEWVGVISGSGITTLYAPAVKGRATISRDNSKNTVYLQMNSLRAEDTAVYYCTRSPSITDGWTYGGAWIDAWGQGTLVTVSS (SEQ ID NO: 276) 12777.15382
VL SYELTQDPAVSVALGQTVRITCSGGDGSYGWFQQKPGQAPVTVIYDNDNRPSDIPDRFSGSSSGNTASLTITGAQAEDEADYYCGNADLSGGIFGSGTKVTVL (SEQ ID NO: 277) 12760.15375
vh EVQLLESGGGLVQPGGSLRLSCAASGFTFSTFNMVWVRQAPGKGLEYVAEISSDGSFTWYATAVKGRATISRDNSKNTVYLQMNSLRAEDTAVYYCAKSDCSSSYYGYSCIGIIDAWGQGTLVTVSS (SEQ ID NO: 286) 12760.15375
VL SYELTQDPAVSVALGQTVRITCSGGISDDGSYYYGWFQQKPGQAPVTVIYINDRRPSNIPDRFSGSSSGNTASLTITGAQAEDEADYYCGSYDSSAGVGIFGSGTKVTVL (SEQ ID NO: 287)

13112.15380
vh EVQLLESGGGLVQPGGSLRLSCAASGFTFSSYNMFWVRQAPGKGLEFVAEISGSNTGSRTWYAPAVKGRATISRDNSKNTLYLQMNSLRAEDTAVYYCAKSIYGGYCAGGYSCGVGLIDAWGQGTLVTVSS (SEQ ID NO: 296) 13112.15380
VL SYELTQDPAVSVALGQTVRITCSGGSSDYYGWFQQKPGQAPVTVIYYNNKRPSDIPDRFSGSSSGNTASLTITGAQAEDEADYYCGNADSSVGVFGSGTKVTVL (SEQ ID NO: 297) 12748.16124
VL SYELTQPPSVSVSPGQTARITCSGGSSYSYGWFQQKPGQAPVTVIYESNNRPSDIPERFSGSSSGTTVTLTISGVQAEDEADYYCGNADSSSGIFGSGTKVTVL (SEQ ID NO: 392)

Table 8: Nucleotide sequences of the heavy and light chain variable domains of an anti-LAG-3 antibody

Ab Sequence (5'-3') 15646 VH CAGGTGCAGCTGCAGCAGTGGGGTGCCGGTCTGCTGAAGCCTTCTGAAACTCTGTCTCTGACTTGTGCCGTCTATGGTGGATCATTCAGCGGCTACTATTGGTCCTGGATCAGGCAGCCCCCTGGCAAGGGCCTGGAGTGGATCGGCGAGATCAACCACCGGGGCCTACCAACTACAATCCCTCTCTGAAGAGCAGGTGACCATCTCCGTGGACACATCTAA GAATCAGTTCAGCCTGAAGCTGAGCTCCGTGACCGCCGCTGATACAGCCGTGTACTATTGCACAAGGGGGAGGAATGGGAGTCACTGTTCTTTGATTACTGGGGGCAGGGGACACTGGTCACAGTCTCGAGT (SEQ ID NO: 304) 15646 VL GAAATCGTCCTGACCAGTCCCCCGCCACCCTGAGCCTGAGCCCCGGAGAAAGAGCCACCCTGTCCTGCCGAGCAAGCCAGTCCATCAGCTCCTATCTCGCCTGGTATCAGCAGAAACCAGGCCAGGCTCCCCGGCTGCTGATCTACGGCGCCTCCAACAGAGCTACAGGAATCCCAGCCCGCTTCAGCGGCTCCGGCTCTGGCACAGACTTTACCCCTGACAATCTCTAGCCTGGAGC CTGAGGATTTCGCCGTGTACTATTGCCAGCAGAGATCTAATTGGCCACTGACATTCGGCGGCGGCACACGGGTGGAGATCAAG (SEQ ID NO: 305) 15532 VH CAGGTTCAGCTGCAGCAGTGGGGCGCCGGCCTGCTGAGACCAAGCGAGACCCTGTCCCTGACATGCGCCGTGTATGGCGAGAGCTTCTCCGGCTATTACTGGAACTGGATCCGGCAGCCTCCCGGCAAGGGCCTGGAGTGGATCGGCGAGATCAATCACTCCGGCTCCACCAATTACAACCCATCCCTGAAGTCTCGGGTGACAATCAGCGTGGATACAAGCAAGACCCAG TTCAGCCTGAAGCTGAGCTCCGTGACAGCTGCCGATACCGCCGTGTATTACTGCGCCAGAGGCTGGGACCTGCTGGATTGGAATGACTACTGGAATGAGTACTGGGGCCAGGGGACCCTGGTGACCGTCTCGAGT (SEQ ID NO: 314) 15532 VL GAGATCGTGCTGACCAGTCCCCTGCCACCCTGTCTCTGTCCCCTGGCGAGCGGGCACCCTGTCCTGTAGAGCTTCTCAGTCCGTGTCTTCCTACCTGGCTTGGTACCAGCAGAAGCCAGGACAGGCCCCAAGACTGCTGATCTATGACGCTTCCAATCGGGCTACCGGCATCCCAGCTCGCTTTAGCGGCTCCGGCTCCGGCACCGACTTCACCCCTGACAATCAGCTC CCTGGAGCCAGAGGATTTTGCCGTGTATTACTGTCAGCAGAGGTCCAATTGGCCACTGACATTTGGCGGCGGCACAAAGGTTGAGATCAAG (SEQ ID NO: 315) 15723 VH CAGGTTCAGCTGCAGCAGTGGGGCGCTGGCCTGCTGAAGCCCTCTGAGACCCTGTCTCTGACCTGTGCCGTGTATGGCGGCAGCTTCTCCGGCTATTACTGGAACTGGATCCGCCAGCCCCCCGGCAAGGGCCTGGAGTGGATCGGCGAGATCAACCACTCCGGCCTACCAACTACAATCCTTCTGAAGTCCAGGGTGACAATCAGCGTGGACACCAGCAAGAA (SEQ ID NO: 324) 15723 VL GAGATCGTGTCTGACCCAGTCCCCTGCCACCCTGTCTCTGTCCCCTGGCGAGCGGGCCACCCTGAGCTGTCGGGCTCCCAGTCCGTGAGCTCCTACCTGGCTTGGTATCAGCAGAAGCCAGGACAGGCCCCAAGACTGCTGATCTACGCCGCTTCCAATCGGGCCACCGGCATCCCCGCCAGATTTTCCGGCTCTGGCTCCGGCACCGATTTCACCCTGACAATCAGCTC CCTGGAGCCAGAGGACTTCGCCGTGTACTACTGCCAGCAGAGGTCTAATTGGCCACTGACATTTGGCGGCGGCACCAAGGTTGAGATCAAG (SEQ ID NO: 325) 15595 vh CAGGTTCAGCTGGTGCAGTCCGGCGCTGAGGTGAAGAAGCCTGGAGCTTCTGTGAAGGTTTCCTGTAAGGTTTCCGGCTATAGCCTGACCGAGAATCTCTATGCACTGGGTACGGCAAGCCCCCGGCAAGGGCCTGGAGTGGATGGGCGGCTTTGACCCAGAGGATGGCGAGACCATCTACGCTCAGAGGTTTCAGGGGCGCGTGTGATCATGACCGAGGATA CCAGCACCGATACCGCCTACATGGAGCTGTCCAGCCTGAGATCCGAGGATACCGCCGTGTATTACTGCGCTACTGGTGGCTGGGGCCCCAATTGGTTCGATCCTTGGGGCCAGGGGACCCTGGTGACCGTCTCGAGT (SEQ ID NO: 334) 15595 VL GACATCCAGATGACACAGTCTCCTTCCTCTGTGAGCGCCTCTGTGGGCGACCGCGTGACCATCACATGCCGCGCTTCCCAGGGGATCTCTTCCTGGCTGGCTTGGTACCAGCAGAAGCCCGGCAAGGCCCCCAAGCTGCTGATCTATGCTGCCAGCAGCCTGCAGTCCGGCGTGCCTTCCAGGTTTAGCGGCTCCGGCTCCGGCACCGACTTTACACTGACAATCAGCTCCCT GCAGCCCGAGGATTTTGCCACCTATTACTGTCAGCAGGCGAATTCCTTCCCTTTTTACATTCGGCCCTGGCACCAAGGTTGATATCAAG (SEQ ID NO: 335)

15431 VH CAGGTTCAGCTGCAGCAGTCCGGCCCCGGCCTGGTGAAGCCAAGCCAGACCCTGTCTCTGACATGCGCCATCTCCGGCGACAGCGTGTCCTTAACTCCGCCGCTTGGAATTGGATCCGGCAGTCTCCATCCAGAGGCCTGGAGTGGCTGGGCAGAACCTATTACCGGTCCAAGTGGTACAACGATTATGCCGTGTCCGTGAAGAGCAGAATCACCATCAACCCTGATACCAGCAAG AACCAGTTCAGCCTGCAGCTGAATTCCGTGACCCCAGAGGATACAGCCGTGTATTACTGTGCTAGGGACGATGATTGGAATGACTTCGATTACTGGGGCCAGGGGACCCTGGTGACAGTCTCGAGT (SEQ ID NO: 344) 15431 VL GAGATCGTGCTGACCAGTCCCAGCTACACTGTCCCTGTCTCCCGGCGAGCGGGCCACCCTGAGCTGTAGAGCTTCCCAGTCCGTGTCTTCCTATCTGGCTTGGTATCAGCAGAAGCCAGGACAGGCCCCAAGGCTGCTGATCTACGACGCCTCCAATAGAGCCACCGGCATCCCAAGCTAGATTTTCTGGCTCCGGCTCCGGCACCGATTTCACACTGACCATCTCTAGCC TGGAGCCAGAGGATTTTGCTGTATATTACTGCCAGCAGCGCAGCAACTGGCCCCTGACATTTGGCGGCGGCACCAAGGTTGAGATCAAG (SEQ ID NO: 345) 15572 VH CAGCTGCAGCTGCAGGAAAGCGGCCCCGGCCTGGTGAAGCCCTCTGAGACCCTGTCCCTGACATGCACCGTGAGCGGCGATTCCATCAGCTCTTCCAGCTATTACTGGGGCTGGATCCGGCAGCCCCCCGGCAAGGGCCTGGAGTGGATCGGCAGCATCTTCTACTCCGGCAATACATATTATAATCCTTCTCTGAAGAGCAGGGTGACAATCAGCGTGGATACCTCCA AGAATCAGTTTAGCCTGAAGCTGAGCTCCGTGACAGCTGCCGATACAGCCGTGTATTACTGCGCTAGGGAGGACGATTTTCTGACCGATTATTACGGCGCTTTCGACATCTGGGGCCAGGGGACAATGGTGACAGTCTCGAGT (SEQ ID NO: 354) 15572 VL GATATCCAGATGACCCAGTCTCCAAGCACCCTGAGCCGCCTCTGTGGGCGATCGGGTGACCATCACATGTCGGGCTTTCTCAGTCCATCAGCAGCTGGCTGGCTTGGTATCAGCAGAAGCCCGGCAAGGCCCCAAAGCTGCTGATCTACAAGGCCTCTTCCAGCGAGAGCGGCGTGCCATCCAGGTTTAGCGGCTCCGGCTCCGGCACCGAGTTTACCCTGACCATCTCTTC CCTGCAGCCCGATGACTTTGCCACCTACTACTGTCAGCAGTACAATTCCTATCTGACATTCGGCGGCGGCACCAAGGTTGAGATCAAG (SEQ ID NO: 355) 15011 VH GAGGTGCAGCTGCTGGAATCCGGAGGAGGACTGGTCCAGCCAGGTGGATCCCTGCGACTGAGCTGCGCCGCTTCTGGCTTCGACTTTAGAAGCTACGCAATGATGTGGGTCCGCCAGGCACCAGGAAAGGACTGGAGTGGGTGGGAGGGATCAACGGTGAAGTCGGTGGCTCTAATACATACTATGCACCTGCCGTCAAGGGAAGGGCTACTATTAG TCGGGACAACTCAAAAAATACCCTGTATCTGCAAATGAACAGTCTGAGGGCCGAGGATACCGCCGTGTACTATTGCGTGAAAGGTGCTGGCGCATGCGGCATCTGTAATGACGATATTGATGCATGGGGACAGGGGACCCTGGTGACAGTCTCGAGT (SEQ ID NO: 364) 15011 VL AGTTATGAGCTGACTCAGGACCCAGCAGTGTCAGTCGCCCTGGGCCAGACAGTGAGAATCACTTGCAGTGGGGCTGGTTCATATGCAGGCTCCTACTATTACGGATGGCACCAGCAGAAGCCCGGACAGGCACCTGTGACAGTCATCTACGACAACGATAAAAGGCCAAGCAATATTCCCGACCGGTTCTCTGGGTCCAGCTCTGGTAACACCGCCTCCCTGACCATTACTG GGGCCCAGGCTGAGGACGAAGCTGATTATTACTGTGGCTCTACAAACGATAATGACGATGGCGGACTGTTTGGCTCCGGAACTAAGGTCACCGTCCTA (SEQ ID NO: 365)

Table 9: Nucleotide sequences of the heavy and light chain variable domains of an anti-LAG-3 antibody

(CDRs are in bold and italics)

Ab Sequence (N-terminal to C-terminal) 15646 VH QVQLQQWGAGLLKPSETLSLTCAVYGGSFSGYYWSWIRQPPGKGLEWIGEINHRGSTNYNPSLKSRVTISVDTSKNQFSLKLSSVTAADTAVYYCTRGEEWESLFFDYWGQGTLVTVSS (SEQ ID NO: 306) 15646 VL EIVLTQSPATLSLSPGERATLSCRASQSISSYLAWYQQKPGQAPRLLIYGASNRATGIPARFSGSGSGTDFTLTISSLEPEDFAVYYCQQRSNWPLTFGGGTRVEIK (SEQ ID NO: 307) 15532 VH QVQLQQWGAGLLRPSETLSLTCAVYGESFSGYYWNWIRQPPGKGLEWIGEINHSGSTNYNPSLKSRVTISVDTSKTQFSLKLSSVTAADTAVYYCARGWDLLDWNDYWNEYWGQGTLVTVSS (SEQ ID NO: 316) 15532 VL EIVLTQSPATLSLSPGERATLSCRASQSVSSYLAWYQQKPGQAPRLLIYDASNRATGIPARFSGSGSGTDFTLTISSLEPEDFAVYYCQQRSNWPLTFGGGTKVEIK (SEQ ID NO: 317) 15723 VH QVQLQQWGAGLLKPSETLSLTCAVYGGSFSGYYWNWIRQPPGKGLEWIGEINHSGSTNYNPSLKSRVTISVDTSKNQFSLKLSSVTAADTAVYYCARGEDWGESFFDYWGQGTLVTVSS (SEQ ID NO: 326)

15723 VL EIVLTQSPATLSLSPGERATLSCRASQSVSSYLAWYQQKPGQAPRLLIYAASNRATGIPARFSGSGSGTDFTLTISSLEPEDFAVYYCQQRSNWPLTFGGGTKVEIK (SEQ ID NO: 327) 15595 vh QVQLVQSGAEVKKPGASVKVSCKVSGYSLTEISMHWVRQAPGKGLEWMGGFDPEDGETIYAQRFQGRVIMTEDTSTDTAYMELSSLRSEDTAVYYCATGGWGPNWFDPWGQGTLVTVSS (SEQ ID NO: 336) 15595 VL DIQMTQSPSSVSASVGDRVTITCRASQGISSWLAWYQQKPGKAPKLLIYAASSLQSGVPSRFSGSGSGTDFTLTISSLQPEDFATYYCQQANSFPFTFGPGTKVDIK (SEQ ID NO: 337) 15431 VH QVQLQQSGPGLVKPSQTLSLTCAISGDSVSSNSAAWNWIRQSPSRGLEWLGRTYYRSKWYNDYAVSVKSRITINPDTSKNQFSLQLNSVTPEDTAVYYCARDDDWNDFDYWGQGTLVTVSS (SEQ ID NO: 346) 15431 VL EIVLTQSPATLSLSPGERATLSCRASQSVSSYLAWYQQKPGQAPRLLIYDASNRATGIPARFSGSGSGTDFTLTISSLEPEDFAVYYCQQRSNWPLTFGGGTKVEIK (SEQ ID NO: 347) 15572 VH QLQLQESGPGLVKPSETLSLTCTVSGDSISSSSYYWGWIRQPPGKGLEWIGSIFYSGNTYYNPSLKSRVTISVDTSKNQFSLKLSSVTAADTAVYYCAREDDFLTDYYGAFDIWGQGTMVTVSS (SEQ ID NO: 356) 15572 VL DIQMTQSPSTLSASVGDRVTITCRASQSISSWLAWYQQKPGKAPKLLIYKASSSESGVPSRFSGSGSGTEFTLTISSLQPDDFATYYCQQYNSYLTFGGGTKVEIK (SEQ ID NO: 357) 15011 VH EVQLLESGGGLVQPGGSLRLSCAASGFDFRSYAMMWVRQAPGKGLEWVGGINGEVGGSNTYYAPAVKGRATISRDNSKNTLYLQMNSLRAEDTAVYYCVKGAGACGICNDDIDAWGQGTLVTVSS (SEQ ID NO: 366) 15011 VL SYELTQDPAVSVALGQTVRITCSGAGSYAGSYYYGWHQQKPGQAPVTVIYDNDKRPSNIPDRFSGSSSGNTASLTITGAQAEDEADYYCGSTNDNDGGLFGSGTKVTVL (SEQ ID NO: 367)

--->

SEQUENCE LIST

<110> SYMPHOGEN A/S

<120> COMBINATION MEDICINES TARGETED

ON PD-1, TIM-3 AND LAG-3

<130> 022675.WO058

<140>

<141>

<150> 62/481.973

<151> 2017-04-05

<160> 397

<170>PatentIn version 3.5

<210> 1

<211> 360

<212> DNA

<213> Artificial sequence

<220>

<221> source

<223> /note="Description of artificial

sequences:Synthetic polynucleotide"

<400> 1

60

acctgcactg tctctggtgg ctccatcagc agtggtggtt actactggag ttggacccgt 120

cagcacccag ggatgggcct ggagtggatt ggatacatct cttacagtgg gagtatctat 180

tacactccgt ccctcaagag tcgacttacc atatcagtgg acacgtctaa gaaccagttc 240

tccctgaagc tgagctctgt gactgccgcg gacacggccg tatattactg tgcgagtttg 300

gattcctggg gatctaaccg tgactactgg ggccagggaa ccctggtcac cgtctcgagt 360

<210> 2

<211> 321

<212> DNA

<213> Artificial sequence

<220>

<221> source

<223> /note="Description of the artificial sequence:

Synthetic polynucleotide"

<400> 2

gaaattgtgt tgacgcagtc tccagccacc ctgtctttgt ctccagggga aagagccacc 60

ctctcctgca gggccagtca gagtgttagc agctacttag cctggtacca acagaaacct 120

ggccaggctc ccaggctcct catctatgat gcatccaaca gggccactgg catcccagcc 180

aggttcagtg gcagtgggtc tgggacagac ttcactctca ccatcagcag cctagagcct 240

gaagattttg cagtttatta ctgtcagcag cgtagcaact ggccgctcac tttcggcgga 300

ggaccaagg tggagattaa g 321

<210> 3

<211> 120

<212> PRT

<213> Artificial sequence

<220>

<221> source

<223> /note="Description of the artificial sequence:

Synthetic polypeptide"

<400> 3

Gln 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 Thr Val Ser Gly Gly Ser Ile Ser Ser Gly

20 25 30

Gly Tyr Tyr Trp Ser Trp Thr Arg Gln His Pro Gly Met Gly Leu Glu

35 40 45

Trp Ile Gly Tyr Ile Ser Tyr Ser Gly Ser Ile Tyr Tyr Thr Pro Ser

50 55 60

Leu Lys Ser Arg Leu Thr Ile Ser Val Asp Thr Ser Lys Asn Gln Phe

65 70 75 80

Ser Leu Lys Leu Ser Ser Val Thr Ala Ala Asp Thr Ala Val Tyr Tyr

85 90 95

Cys Ala Ser Leu Asp Ser Trp Gly Ser Asn Arg Asp Tyr Trp Gly Gln

100 105 110

Gly Thr Leu Val Thr Val Ser Ser

115 120

<210> 4

<211> 107

<212> PRT

<213> Artificial sequence

<220>

<221> source

<223> /note="Description of the artificial sequence:

Synthetic polypeptide"

<400> 4

Glu Ile Val 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 Ser Ser Tyr

20 25 30

Leu Ala Trp Tyr Gln Gln Lys Pro Gly Gln Ala Pro Arg Leu Leu Ile

35 40 45

Tyr Asp Ala Ser Asn Arg Ala Thr Gly Ile Pro Ala Arg Phe Ser Gly

50 55 60

Ser Gly Ser Gly Thr Asp Phe Thr Leu Thr Ile Ser Ser Leu Glu Pro

65 70 75 80

Glu Asp Phe Ala Val Tyr Tyr Cys Gln Gln Arg Ser Asn Trp Pro Leu

85 90 95

Thr Phe Gly Gly Gly Thr Lys Val Glu Ile Lys

100 105

<210> 5

<211> 360

<212> DNA

<213> Artificial sequence

<220>

<221> source

<223> /note="Description of the artificial sequence:

Synthetic polynucleotide"

<400> 5

caggtgcagc tgcaggagag tggccccgga ctggtcaagc cttcacagac tctgagcctg 60

acctgcacag tgtctggcgg aagtatcagc tccggggggtt actattggag ctggacccga 120

cagcacccag gaatgggtct ggaatggatc gggtacattt catatagcgg ctccatctac 180

tatacaccct cactgaaaag caggctgacc atttccgtgg acacatctaa gaaccagttc 240

agcctgaaac tgtctagtgt gacagccgct gatactgcag tctactattg tgcctccctg 300

360

<210> 6

<211> 321

<212> DNA

<213> Artificial sequence

<220>

<221> source

<223> /note="Description of the artificial sequence:

Synthetic polynucleotide"

<400> 6

gagatcgtgc tgactcagtc cccagccacc ctgtcactga gcccaggaga acgagcaacc 60

ctgtcttgca gggcctccca gtctgtcagc tcctacctgg cttggtatca gcagaagccc 120

gggcaggcac ctcgactgct gatctacgac gccagtaaca gagctaccgg tattcccgcc 180

cgcttcagtg gttcaggcag cggaacagac tttaccctga caatctctag tctggagcct 240

gaagatttcg ccgtgtacta ttgtcagcag aggtctaatt ggccactgac atttggcgga 300

gggactaagg tcgagatcaa g 321

<210> 7

<211> 120

<212> PRT

<213> Artificial sequence

<220>

<221> source

<223> /note="Description of the artificial sequence:

Synthetic polypeptide"

<400> 7

Gln Val Gln Leu Gln Glu Ser Gly Pro Gly Leu Val Lys Pro Ser Gln

1 5 10 15

Thr Leu Ser Leu Thr Cys Thr Val Ser Gly Gly Ser Ile Ser Ser Gly

20 25 30

Gly Tyr Tyr Trp Ser Trp Thr Arg Gln His Pro Gly Met Gly Leu Glu

35 40 45

Trp Ile Gly Tyr Ile Ser Tyr Ser Gly Ser Ile Tyr Tyr Thr Pro Ser

50 55 60

Leu Lys Ser Arg Leu Thr Ile Ser Val Asp Thr Ser Lys Asn Gln Phe

65 70 75 80

Ser Leu Lys Leu Ser Ser Val Thr Ala Ala Asp Thr Ala Val Tyr Tyr

85 90 95

Cys Ala Ser Leu Asp Ser Trp Gly Ser Asn Arg Asp Tyr Trp Gly Gln

100 105 110

Gly Thr Leu Val Thr Val Ser Ser

115 120

<210> 8

<211> 10

<212> PRT

<213> Artificial sequence

<220>

<221> source

<223> /note="Description of the artificial sequence:

Synthetic peptide"

<400> 8

Gly Gly Ser Ile Ser Ser Gly Gly Tyr Tyr

1 5 10

<210> 9

<211> 7

<212> PRT

<213> Artificial sequence

<220>

<221> source

<223> /note="Description of the artificial sequence:

Synthetic peptide"

<400> 9

Ile Ser Tyr Ser Gly Ser Ile

15

<210> 10

<211> 14

<212> PRT

<213> Artificial sequence

<220>

<221> source

<223> /note="Description of the artificial sequence:

Synthetic peptide"

<400> 10

Cys Ala Ser Leu Asp Ser Trp Gly Ser Asn Arg Asp Tyr Trp

1 5 10

<210> 11

<211> 6

<212> PRT

<213> Artificial sequence

<220>

<221> source

<223> /note="Description of the artificial sequence:

Synthetic peptide"

<400> 11

Gln Ser Val Ser Ser Tyr

15

<210> 12

<211> 3

<212> PRT

<213> Artificial sequence

<220>

<221> source

<223> /note="Description of the artificial sequence:

Synthetic peptide"

<400> 12

Asp Ala Ser

1

<210> 13

<211> 11

<212> PRT

<213> Artificial sequence

<220>

<221> source

<223> /note="Description of the artificial sequence:

Synthetic peptide"

<400> 13

Cys Gln Gln Arg Ser Asn Trp Pro Leu Thr Phe

1 5 10

<210> 14

<211> 345

<212> DNA

<213> Artificial sequence

<220>

<221> source

<223> /note="Description of the artificial sequence:

Synthetic polynucleotide"

<400> 14

caggtcacct tgaaggagtg gggcgcagga ctgttgaggc cctcggagac cctgtccctc 60

acctgcgctg tctatggtgg gtccttcagt ggttactact ggagctggat ccgccagccc 120

ccagggaagg ggctggagtg gataggggaa atcaatcata gtggaagcac caactacaac 180

ccgtccctca agagtcgagt caccatatca gtagacgcga ccaagaaaca attctccctg 240

aagctgacct ctgtgaccgc cgcggacacg gctgtgtatt actgtgcgag atattgggag 300

ctccctgact actggggcca gggcaccctg gtcaccgtct cgagt 345

<210> 15

<211> 321

<212> DNA

<213> Artificial sequence

<220>

<221> source

<223> /note="Description of the artificial sequence:

Synthetic polynucleotide"

<400> 15

gacatccagt tgacccagtc tccatcctcc ctgtctgcat ctgtaggaga cagagtcacc 60

atcacttgcc gggcaagtca gggcattaga aatgatttag gctggtatca gcagaaacca 120

gggaaagccc ctaagcgcct gatctatgct gcatccagtt tgcaaagtgg ggtcccatca 180

aggttcagcg gcagtggatc tgggacagaa ttcactctca caatcagcag cctgcagcct 240

gaagattttg caacttatta ctgtctacag cataatagtt accctccgac gttcggccaa 300

gggaccaagg tggaaatcaa g 321

<210> 16

<211> 115

<212> PRT

<213> Artificial sequence

<220>

<221> source

<223> /note="Description of the artificial sequence:

Synthetic polypeptide"

<400> 16

Gln Val Thr Leu Lys Glu Trp Gly Ala Gly Leu Leu Arg Pro Ser Glu

1 5 10 15

Thr Leu Ser Leu Thr Cys Ala Val Tyr Gly Gly Ser Phe Ser Gly Tyr

20 25 30

Tyr Trp Ser Trp Ile Arg Gln Pro Pro Gly Lys Gly Leu Glu Trp Ile

35 40 45

Gly Glu Ile Asn His Ser Gly Ser Thr Asn Tyr Asn Pro Ser Leu Lys

50 55 60

Ser Arg Val Thr Ile Ser Val Asp Ala Thr Lys Lys Gln Phe Ser Leu

65 70 75 80

Lys Leu Thr Ser Val Thr Ala Ala Asp Thr Ala Val Tyr Tyr Cys Ala

85 90 95

Arg Tyr Trp Glu Leu Pro Asp Tyr Trp Gly Gln Gly Thr Leu Val Thr

100 105 110

Val Ser Ser

115

<210> 17

<211> 107

<212> PRT

<213> Artificial sequence

<220>

<221> source

<223> /note="Description of the artificial sequence:

Synthetic polypeptide"

<400> 17

Asp 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 Arg Asn Asp

20 25 30

Leu Gly Trp Tyr Gln Gln Lys Pro Gly Lys Ala Pro Lys Arg 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 Glu Phe Thr Leu Thr Ile Ser Ser Leu Gln Pro

65 70 75 80

Glu Asp Phe Ala Thr Tyr Tyr Cys Leu Gln His Asn Ser Tyr Pro Pro

85 90 95

Thr Phe Gly Gln Gly Thr Lys Val Glu Ile Lys

100 105

<210> 18

<211> 8

<212> PRT

<213> Artificial sequence

<220>

<221> source

<223> /note="Description of the artificial sequence:

Synthetic peptide"

<400> 18

Gly Gly Ser Phe Ser Gly Tyr Tyr

15

<210> 19

<211> 7

<212> PRT

<213> Artificial sequence

<220>

<221> source

<223> /note="Description of the artificial sequence:

Synthetic peptide"

<400> 19

Ile Asn His Ser Gly Ser Thr

15

<210> 20

<211> 11

<212> PRT

<213> Artificial sequence

<220>

<221> source

<223> /note="Description of the artificial sequence:

Synthetic peptide"

<400> 20

Cys Ala Arg Tyr Trp Glu Leu Pro Asp Tyr Trp

1 5 10

<210> 21

<211> 6

<212> PRT

<213> Artificial sequence

<220>

<221> source

<223> /note="Description of the artificial sequence:

Synthetic peptide"

<400> 21

Gln Gly Ile Arg Asn Asp

15

<210> 22

<211> 3

<212> PRT

<213> Artificial sequence

<220>

<221> source

<223> /note="Description of the artificial sequence:

Synthetic peptide"

<400> 22

Ala Ala Ser

1

<210> 23

<211> 11

<212> PRT

<213> Artificial sequence

<220>

<221> source

<223> /note="Description of the artificial sequence:

Synthetic peptide"

<400> 23

Cys Leu Gln His Asn Ser Tyr Pro Pro Thr Phe

1 5 10

<210> 24

<211> 345

<212> DNA

<213> Artificial sequence

<220>

<221> source

<223> /note="Description of the artificial sequence:

Synthetic polynucleotide"

<400> 24

cagatgcagc tggtgcagtg gggcgcagga ctgttgaagc cttcggagac cctgtccctc 60

acctgcgctg tctatggtgg gtccttcagt ggttactact ggagctggat ccgccagccc 120

ccagggaagg ggctggagtg gattggggaa atcaatcata gtggaagcac caactacaac 180

ccgtccctca agagtcgagt caccatgtca gttgacacgt ccaagcacca gttctccctg 240

aagctgagct ctgtgaccgc cgcggacacg gctgtgtatt actgtgcgag atggtgggag 300

cttcctgact actggggcca gggaaccctg gtcaccgtct cgagt 345

<210> 25

<211> 321

<212> DNA

<213> Artificial sequence

<220>

<221> source

<223> /note="Description of the artificial sequence:

Synthetic polynucleotide"

<400> 25

gaaattgtgt tgacgcagtc tccatcctcc ctgtctgcat ctgtaggaga cagagtcacc 60

atcacttgcc gggcaagtca gggcattaga aatgatttag gctggtatca gcagaaacca 120

gggaaagccc ctaagcgcct gatctatgct gcatccagtt tgcaaagtgg ggtcccatca 180

aggttcagcg gcagtggatc tgggacagaa ttcactctca caatcagcag cctgcagcct 240

gaagattttg caacttatta ctgtctacag cataatagtt acccgtggac gttcggccaa 300

gggaccaagg tggaaatcaa g 321

<210> 26

<211> 115

<212> PRT

<213> Artificial sequence

<220>

<221> source

<223> /note="Description of the artificial sequence:

Synthetic polypeptide"

<400> 26

Gln Met Gln Leu Val Gln Trp Gly Ala Gly Leu Leu Lys Pro Ser Glu

1 5 10 15

Thr Leu Ser Leu Thr Cys Ala Val Tyr Gly Gly Ser Phe Ser Gly Tyr

20 25 30

Tyr Trp Ser Trp Ile Arg Gln Pro Pro Gly Lys Gly Leu Glu Trp Ile

35 40 45

Gly Glu Ile Asn His Ser Gly Ser Thr Asn Tyr Asn Pro Ser Leu Lys

50 55 60

Ser Arg Val Thr Met Ser Val Asp Thr Ser Lys His Gln Phe Ser Leu

65 70 75 80

Lys Leu Ser Ser Val Thr Ala Ala Asp Thr Ala Val Tyr Tyr Cys Ala

85 90 95

Arg Trp Trp Glu Leu Pro Asp Tyr Trp Gly Gln Gly Thr Leu Val Thr

100 105 110

Val Ser Ser

115

<210> 27

<211> 107

<212> PRT

<213> Artificial sequence

<220>

<221> source

<223> /note="Description of the artificial sequence:

Synthetic polypeptide"

<400> 27

Glu Ile Val 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 Arg Asn Asp

20 25 30

Leu Gly Trp Tyr Gln Gln Lys Pro Gly Lys Ala Pro Lys Arg 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 Glu Phe Thr Leu Thr Ile Ser Ser Leu Gln Pro

65 70 75 80

Glu Asp Phe Ala Thr Tyr Tyr Cys Leu Gln His Asn Ser Tyr Pro Trp

85 90 95

Thr Phe Gly Gln Gly Thr Lys Val Glu Ile Lys

100 105

<210> 28

<211> 8

<212> PRT

<213> Artificial sequence

<220>

<221> source

<223> /note="Description of the artificial sequence:

Synthetic peptide"

<400> 28

Gly Gly Ser Phe Ser Gly Tyr Tyr

15

<210> 29

<211> 7

<212> PRT

<213> Artificial sequence

<220>

<221> source

<223> /note="Description of the artificial sequence:

Synthetic peptide"

<400> 29

Ile Asn His Ser Gly Ser Thr

15

<210> 30

<211> 11

<212> PRT

<213> Artificial sequence

<220>

<221> source

<223> /note="Description of the artificial sequence:

Synthetic peptide"

<400> 30

Cys Ala Arg Trp Trp Glu Leu Pro Asp Tyr Trp

1 5 10

<210> 31

<211> 6

<212> PRT

<213> Artificial sequence

<220>

<221> source

<223> /note="Description of the artificial sequence:

Synthetic peptide"

<400> 31

Gln Gly Ile Arg Asn Asp

15

<210> 32

<211> 3

<212> PRT

<213> Artificial sequence

<220>

<221> source

<223> /note="Description of the artificial sequence:

Synthetic peptide"

<400> 32

Ala Ala Ser

1

<210> 33

<211> 11

<212> PRT

<213> Artificial sequence

<220>

<221> source

<223> /note="Description of the artificial sequence:

Synthetic peptide"

<400> 33

Cys Leu Gln His Asn Ser Tyr Pro Trp Thr Phe

1 5 10

<210> 34

<211> 351

<212> DNA

<213> Artificial sequence

<220>

<221> source

<223> /note="Description of the artificial sequence:

Synthetic polynucleotide"

<400> 34

cagatgcagc tggtgcaatg gggcgcagga ctgttgaagc cttcggagac cctgtccctc 60

acctgcgctg tctatggtgg gtccttcagt ggttactact ggagctggat ccgccagccc 120

ccagggaagg ggctggagtg gattggggaa atcaatcata gtggaagcac caactacaac 180

ccgtccctca agagtcgagt caccatatca gtagacacgt ccaagaacca gttctccctg 240

aagctgagct ctgtgaccgc cgcggacacg gctgtgtatt actgtgcgag gttttactat 300

gctccgaact ttgactactg gggccagggc accctggtca ccgtctcgag t 351

<210> 35

<211> 318

<212> DNA

<213> Artificial sequence

<220>

<221> source

<223> /note="Description of the artificial sequence:

Synthetic polynucleotide"

<400> 35

gaaattgtgt tgacgcagtc tccttccacc ctgtctgcat ctgtaggaga cagagtcacc 60

atcacttgcc gggccagtca gagtattagt agctggttgg cctggtatca gcagaaacca 120

gggacagccc ctaagctcct gatctataag gcgtctagtt tagaaagtgg ggtcccatca 180

aggttcagcg gcagtggatc tgggacagaa ttcactctca ccatcagcag cctgcagcct 240

gatgattttg caacttatta ctgccaacag tataatagtt attccacttt cggcggaggg 300

accaaggtgg agatcaaa 318

<210> 36

<211> 117

<212> PRT

<213> Artificial sequence

<220>

<221> source

<223> /note="Description of the artificial sequence:

Synthetic polypeptide"

<400> 36

Gln Met Gln Leu Val Gln Trp Gly Ala Gly Leu Leu Lys Pro Ser Glu

1 5 10 15

Thr Leu Ser Leu Thr Cys Ala Val Tyr Gly Gly Ser Phe Ser Gly Tyr

20 25 30

Tyr Trp Ser Trp Ile Arg Gln Pro Pro Gly Lys Gly Leu Glu Trp Ile

35 40 45

Gly Glu Ile Asn His Ser Gly Ser Thr Asn Tyr Asn Pro Ser Leu Lys

50 55 60

Ser Arg Val Thr Ile Ser Val Asp Thr Ser Lys Asn Gln Phe Ser Leu

65 70 75 80

Lys Leu Ser Ser Val Thr Ala Ala Asp Thr Ala Val Tyr Tyr Cys Ala

85 90 95

Arg Phe Tyr Tyr Ala Pro Asn Phe Asp Tyr Trp Gly Gln Gly Thr Leu

100 105 110

Val Thr Val Ser Ser

115

<210> 37

<211> 106

<212> PRT

<213> Artificial sequence

<220>

<221> source

<223> /note="Description of the artificial sequence:

Synthetic polypeptide"

<400> 37

Glu Ile Val Leu 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 Ser Ser Trp

20 25 30

Leu Ala Trp Tyr Gln Gln Lys Pro Gly Thr Ala Pro Lys 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 Tyr Asn Ser Tyr Ser Thr

85 90 95

Phe Gly Gly Gly Thr Lys Val Glu Ile Lys

100 105

<210> 38

<211> 8

<212> PRT

<213> Artificial sequence

<220>

<221> source

<223> /note="Description of the artificial sequence:

Synthetic peptide"

<400> 38

Gly Gly Ser Phe Ser Gly Tyr Tyr

15

<210> 39

<211> 7

<212> PRT

<213> Artificial sequence

<220>

<221> source

<223> /note="Description of the artificial sequence:

Synthetic peptide"

<400> 39

Ile Asn His Ser Gly Ser Thr

15

<210> 40

<211> 13

<212> PRT

<213> Artificial sequence

<220>

<221> source

<223> /note="Description of the artificial sequence:

Synthetic peptide"

<400> 40

Cys Ala Arg Phe Tyr Tyr Ala Pro Asn Phe Asp Tyr Trp

1 5 10

<210> 41

<211> 6

<212> PRT

<213> Artificial sequence

<220>

<221> source

<223> /note="Description of the artificial sequence:

Synthetic peptide"

<400> 41

Gln Ser Ile Ser Ser Trp

15

<210> 42

<211> 3

<212> PRT

<213> Artificial sequence

<220>

<221> source

<223> /note="Description of the artificial sequence:

Synthetic peptide"

<400> 42

Lys Ala Ser

1

<210> 43

<211> 10

<212> PRT

<213> Artificial sequence

<220>

<221> source

<223> /note="Description of the artificial sequence:

Synthetic peptide"

<400> 43

Cys Gln Gln Tyr Asn Ser Tyr Ser Thr Phe

1 5 10

<210> 44

<211> 360

<212> DNA

<213> Artificial sequence

<220>

<221> source

<223> /note="Description of the artificial sequence:

Synthetic polynucleotide"

<400> 44

caggtgcagc tgcagcagtc gggcccagga ctggtgaagc cttcggagac cctgtccctc 60

acctgcactg tctctggtgg ctccatcagc agtagtaatt actactgggg ctggatccgc 120

cagcccccag ggaaggggct ggagtggatt gggagtatct attatagtgg gaacacctac 180

tacaacccgt ccctcaagag tcgagtcacc atatccgtag acacgtccaa gaaccagttc 240

tccctgaagc tgagttctgt gaccgccgca gacacggctg tgtattactg tgcgagacag 300

acagtggctg gccccctctt tgactactgg ggccagggaa ccctggtcac cgtctcgagt 360

<210> 45

<211> 321

<212> DNA

<213> Artificial sequence

<220>

<221> source

<223> /note="Description of the artificial sequence:

Synthetic polynucleotide"

<400> 45

gaaattgtga tgacgcagtc tccttccacc ctgtctgcat ctgtaggaga cagagtcacc 60

atcacttgcc gggccagtca gagtattagt agctggttgg cctggtatca gcagaaacca 120

gggaaagccc ctaaggtcct gatctataag gcgtctagtt tagaaagtgg ggtcccatca 180

aggttcagcg gcagtggatc tgggacagaa ctcactctca ccatcagcag cctgcagcct 240

gatgattttg caacttatta ctgccaacag tataatagtt attcattcac tttcggccct 300

gggaccaaag tggatatcaa g 321

<210> 46

<211> 120

<212> PRT

<213> Artificial sequence

<220>

<221> source

<223> /note="Description of the artificial sequence:

Synthetic polypeptide"

<400> 46

Gln 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 Thr Val Ser Gly Gly Ser Ile Ser Ser Ser

20 25 30

Asn Tyr Tyr Trp Gly Trp Ile Arg Gln Pro Pro Gly Lys Gly Leu Glu

35 40 45

Trp Ile Gly Ser Ile Tyr Tyr Ser Gly Asn Thr Tyr Tyr Asn Pro Ser

50 55 60

Leu Lys Ser Arg Val Thr Ile Ser Val Asp Thr Ser Lys Asn Gln Phe

65 70 75 80

Ser Leu Lys Leu Ser Ser Val Thr Ala Ala Asp Thr Ala Val Tyr Tyr

85 90 95

Cys Ala Arg Gln Thr Val Ala Gly Pro Leu Phe Asp Tyr Trp Gly Gln

100 105 110

Gly Thr Leu Val Thr Val Ser Ser

115 120

<210> 47

<211> 107

<212> PRT

<213> Artificial sequence

<220>

<221> source

<223> /note="Description of the artificial sequence:

Synthetic polypeptide"

<400> 47

Glu 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 Ile Ser Ser Trp

20 25 30

Leu Ala Trp Tyr Gln Gln Lys Pro Gly Lys Ala Pro Lys Val 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 Leu Thr Leu Thr Ile Ser Ser Leu Gln Pro

65 70 75 80

Asp Asp Phe Ala Thr Tyr Tyr Cys Gln Gln Tyr Asn Ser Tyr Ser Phe

85 90 95

Thr Phe Gly Pro Gly Thr Lys Val Asp Ile Lys

100 105

<210> 48

<211> 10

<212> PRT

<213> Artificial sequence

<220>

<221> source

<223> /note="Description of the artificial sequence:

Synthetic peptide"

<400> 48

Gly Gly Ser Ile Ser Ser Ser Asn Tyr Tyr

1 5 10

<210> 49

<211> 7

<212> PRT

<213> Artificial sequence

<220>

<221> source

<223> /note="Description of the artificial sequence:

Synthetic peptide"

<400> 49

Ile Tyr Tyr Ser Gly Asn Thr

15

<210> 50

<211> 14

<212> PRT

<213> Artificial sequence

<220>

<221> source

<223> /note="Description of the artificial sequence:

Synthetic peptide"

<400> 50

Cys Ala Arg Gln Thr Val Ala Gly Pro Leu Phe Asp Tyr Trp

1 5 10

<210> 51

<211> 6

<212> PRT

<213> Artificial sequence

<220>

<221> source

<223> /note="Description of the artificial sequence:

Synthetic peptide"

<400> 51

Gln Ser Ile Ser Ser Trp

15

<210> 52

<211> 3

<212> PRT

<213> Artificial sequence

<220>

<221> source

<223> /note="Description of the artificial sequence:

Synthetic peptide"

<400> 52

Lys Ala Ser

1

<210> 53

<211> 11

<212> PRT

<213> Artificial sequence

<220>

<221> source

<223> /note="Description of the artificial sequence:

Synthetic peptide"

<400> 53

Cys Gln Gln Tyr Asn Ser Tyr Ser Phe Thr Phe

1 5 10

<210> 54

<211> 375

<212> DNA

<213> Artificial sequence

<220>

<221> source

<223> /note="Description of the artificial sequence:

Synthetic polynucleotide"

<400> 54

caggtccagc tggtgcaatc tggggctgag gtgaagaagc ctggggcctc agtgaaggtc 60

tcctgcaagg ctgctggata caccttaacc ggctactata tgcactgggt gcgacaggcc 120

cctggacaag gccttgagtg gatgggacgg atcaacccta acagtggtgg ctcaaacaat 180

gcacagaagt ttcaggggcag ggtcaccatg accagggaca cgtccatcag cacagcctac 240

atggagctga gcaggctgag atctgacgac acggccgtgt attactgtgc gagagagggt 300

cccctgtata gcagtggctg gtacgagggt gcttttgata tctggggcca agggacaatg 360

gtcaccgtct cgagt 375

<210> 55

<211> 327

<212> DNA

<213> Artificial sequence

<220>

<221> source

<223> /note="Description of the artificial sequence:

Synthetic polynucleotide"

<400> 55

gaaattgtga tgacgcagtc tccttccacc ctgtctgcat ctgtaggaga cagagtcacc 60

atcacttgcc gggccagtca gagtattagt agttggttgg cctggtatca gcagaaacca 120

gggaaagccc ctaagctcct gatctataag gcgtctagtt tagaaagtgg ggtcccatca 180

aggttcagcg gcagtggatc tgggacagaa ttcactctca ccatcagcag cctgcagcct 240

gatgattttg caacttatta ctgccaacag tataatagtt attctccggg gctcactttc 300

ggcgggaggga ccaaggtgga gatcaag 327

<210> 56

<211> 125

<212> PRT

<213> Artificial sequence

<220>

<221> source

<223> /note="Description of the artificial sequence:

Synthetic polypeptide"

<400> 56

Gln 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 Ala Gly Tyr Thr Leu Thr Gly Tyr

20 25 30

Tyr Met His Trp Val Arg Gln Ala Pro Gly Gln Gly Leu Glu Glu Trp Met

35 40 45

Gly Arg Ile Asn Pro Asn Ser Gly Gly Ser Asn Asn Ala Gln Lys Phe

50 55 60

Gln Gly Arg Val Thr Met Thr Arg Asp Thr Ser Ile Ser Thr Ala Tyr

65 70 75 80

Met Glu Leu Ser Arg Leu Arg Ser Asp Asp Thr Ala Val Tyr Tyr Cys

85 90 95

Ala Arg Glu Gly Pro Leu Tyr Ser Ser Gly Trp Tyr Glu Gly Ala Phe

100 105 110

Asp Ile Trp Gly Gln Gly Thr Met Val Thr Val Ser Ser

115 120 125

<210> 57

<211> 109

<212> PRT

<213> Artificial sequence

<220>

<221> source

<223> /note="Description of the artificial sequence:

Synthetic polypeptide"

<400> 57

Glu 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 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 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 Tyr Asn Ser Tyr Ser Pro

85 90 95

Gly Leu Thr Phe Gly Gly Gly Thr Lys Val Glu Ile Lys

100 105

<210> 58

<211> 8

<212> PRT

<213> Artificial sequence

<220>

<221> source

<223> /note="Description of the artificial sequence:

Synthetic peptide"

<400> 58

Gly Tyr Thr Leu Thr Gly Tyr Tyr

15

<210> 59

<211> 8

<212> PRT

<213> Artificial sequence

<220>

<221> source

<223> /note="Description of the artificial sequence:

Synthetic peptide"

<400> 59

Ile Asn Pro Asn Ser Gly Gly Ser

15

<210> 60

<211> 20

<212> PRT

<213> Artificial sequence

<220>

<221> source

<223> /note="Description of the artificial sequence:

Synthetic peptide"

<400> 60

Cys Ala Arg Glu Gly Pro Leu Tyr Ser Ser Gly Trp Tyr Glu Gly Ala

1 5 10 15

Phe Asp Ile Trp

20

<210> 61

<211> 6

<212> PRT

<213> Artificial sequence

<220>

<221> source

<223> /note="Description of the artificial sequence:

Synthetic peptide"

<400> 61

Gln Ser Ile Ser Ser Trp

15

<210> 62

<211> 3

<212> PRT

<213> Artificial sequence

<220>

<221> source

<223> /note="Description of the artificial sequence:

Synthetic peptide"

<400> 62

Lys Ala Ser

1

<210> 63

<211> 13

<212> PRT

<213> Artificial sequence

<220>

<221> source

<223> /note="Description of the artificial sequence:

Synthetic peptide"

<400> 63

Cys Gln Gln Tyr Asn Ser Tyr Ser Pro Gly Leu Thr Phe

1 5 10

<210> 64

<211> 372

<212> DNA

<213> Artificial sequence

<220>

<221> source

<223> /note="Description of the artificial sequence:

Synthetic polynucleotide"

<400> 64

cagatgcagc tacagcagtc aggtccagga ctggtgaagc cctcgcagac cctctcactc 60

acctgtgcca tctccggggga cagtgtctct agcaacagtg ctgcttggaa ctggatcagg 120

cagtccccat cgagaggcct tgagtggctg ggaaggacat actacaggtc caagtggtat 180

tctgcttttg cagtatctgt gaaaagtcga ataaccatca acccagacac atccaagaac 240

cagttctccc tgcagctgaa ctctgtgact cccgaggaca cggctgtgta ttactgtgca 300

agagagggta gcagtggctg gtacggatac gtccaccact ggggccaggg caccctggtc 360

accgtctcga gt 372

<210> 65

<211> 321

<212> DNA

<213> Artificial sequence

<220>

<221> source

<223> /note="Description of the artificial sequence:

Synthetic polynucleotide"

<400> 65

gaaattgtgt tgacgcagtc tccagcttcc ctgtctgtat ctctgggaga aactgtcacc 60

atcgaatgtc gagcaagtga ggacatttac aatggtttag catggtatca gcagaagcca 120

gggaaatctc ctcagctcct gatctataat gcaaaatagct tgcatactgg ggtcccatca 180

cggttcagtg gcagtggatc tggtacacag tattctctca agataaacag cctgcaatct 240

gaagatgtcg caagttattt ctgtcaacag tattacgatt atcctccgac gttcggccaa 300

gggaccaagg tggaaatcaa a 321

<210> 66

<211> 124

<212> PRT

<213> Artificial sequence

<220>

<221> source

<223> /note="Description of the artificial sequence:

Synthetic polypeptide"

<400> 66

Gln Met 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 Ser Ala Phe 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 Glu Gly Ser Ser Gly Trp Tyr Gly Tyr Val His

100 105 110

His Trp Gly Gln Gly Thr Leu Val Thr Val Ser Ser

115 120

<210> 67

<211> 107

<212> PRT

<213> Artificial sequence

<220>

<221> source

<223> /note="Description of the artificial sequence:

Synthetic polypeptide"

<400> 67

Glu Ile Val Leu Thr Gln Ser Pro Ala Ser Leu Ser Val Ser Leu Gly

1 5 10 15

Glu Thr Val Thr Ile Glu Cys Arg Ala Ser Glu Asp Ile Tyr Asn Gly

20 25 30

Leu Ala Trp Tyr Gln Gln Lys Pro Gly Lys Ser Pro Gln Leu Leu Ile

35 40 45

Tyr Asn Ala Asn Ser Leu His Thr Gly Val Pro Ser Arg Phe Ser Gly

50 55 60

Ser Gly Ser Gly Thr Gln Tyr Ser Leu Lys Ile Asn Ser Leu Gln Ser

65 70 75 80

Glu Asp Val Ala Ser Tyr Phe Cys Gln Gln Tyr Tyr Asp Tyr Pro Pro

85 90 95

Thr Phe Gly Gln Gly Thr Lys Val Glu Ile Lys

100 105

<210> 68

<211> 10

<212> PRT

<213> Artificial sequence

<220>

<221> source

<223> /note="Description of the artificial sequence:

Synthetic peptide"

<400> 68

Gly Asp Ser Val Ser Ser Asn Ser Ala Ala

1 5 10

<210> 69

<211> 9

<212> PRT

<213> Artificial sequence

<220>

<221> source

<223> /note="Description of the artificial sequence:

Synthetic peptide"

<400> 69

Thr Tyr Tyr Arg Ser Lys Trp Tyr Ser

15

<210> 70

<211> 16

<212> PRT

<213> Artificial sequence

<220>

<221> source

<223> /note="Description of the artificial sequence:

Synthetic peptide"

<400> 70

Cys Ala Arg Glu Gly Ser Ser Gly Trp Tyr Gly Tyr Val His His Trp

1 5 10 15

<210> 71

<211> 6

<212> PRT

<213> Artificial sequence

<220>

<221> source

<223> /note="Description of the artificial sequence:

Synthetic peptide"

<400> 71

Glu Asp Ile Tyr Asn Gly

15

<210> 72

<211> 3

<212> PRT

<213> Artificial sequence

<220>

<221> source

<223> /note="Description of the artificial sequence:

Synthetic peptide"

<400> 72

Asn Ala Asn

1

<210> 73

<211> 11

<212> PRT

<213> Artificial sequence

<220>

<221> source

<223> /note="Description of the artificial sequence:

Synthetic peptide"

<400> 73

Cys Gln Gln Tyr Tyr Asp Tyr Pro Pro Thr Phe

1 5 10

<210> 74

<211> 369

<212> DNA

<213> Artificial sequence

<220>

<221> source

<223> /note="Description of the artificial sequence:

Synthetic polynucleotide"

<400> 74

caggtgcagc tgcaggagtc gggcccagga ctggtgaagc cttcggagac cctgtccctc 60

acctgcactg tctctggtgg ctccttcagc agtagtagtt actactgggg ctggatccgc 120

cagccccctg ggaaggggct ggagtggatt gggatcttct attatagtgg gaccacctac 180

tacaacccgt ccctcaagag tcgagtcacc atatccgcac acacgtccaa gagccagttc 240

tccctgaagc tgagctctgt gaccgccgca gacacggctg tgtattactg tgcgagaggg 300

ggagaatatt ttgaccggtt actccccttt gactactggg gccagggaac cctggtcacc 360

gtctcgagt 369

<210> 75

<211> 321

<212> DNA

<213> Artificial sequence

<220>

<221> source

<223> /note="Description of the artificial sequence:

Synthetic polynucleotide"

<400> 75

gaaattgtga tgacgcagtc tccatccttc ctgtctgcat ctgtaggaga cagagtcacc 60

atcacttgcc gggccagtca gggcattagc agttatttag cctggtatca gcaaaaacca 120

gggaaagccc ctaagctcct gatctatgct gcatccactt tggaaagtgg ggtcccatca 180

aggttcagcg gcagtggatc tgggacagaa ttcactctca caatcagcag cctgcagcct 240

gaagattttg caacttatta ctgtcaacag cttaatagtt acccattcac tttcggccct 300

gggaccaaag tggatatcaa a 321

<210> 76

<211> 123

<212> PRT

<213> Artificial sequence

<220>

<221> source

<223> /note="Description of the artificial sequence:

Synthetic polypeptide"

<400> 76

Gln Val Gln Leu Gln Glu Ser Gly Pro Gly Leu Val Lys Pro Ser Glu

1 5 10 15

Thr Leu Ser Leu Thr Cys Thr Val Ser Gly Gly Ser Phe Ser Ser Ser

20 25 30

Ser Tyr Tyr Trp Gly Trp Ile Arg Gln Pro Pro Gly Lys Gly Leu Glu

35 40 45

Trp Ile Gly Ile Phe Tyr Tyr Ser Gly Thr Thr Tyr Tyr Asn Pro Ser

50 55 60

Leu Lys Ser Arg Val Thr Ile Ser Ala His Thr Ser Lys Ser Gln Phe

65 70 75 80

Ser Leu Lys Leu Ser Ser Val Thr Ala Ala Asp Thr Ala Val Tyr Tyr

85 90 95

Cys Ala Arg Gly Gly Glu Tyr Phe Asp Arg Leu Leu Pro Phe Asp Tyr

100 105 110

Trp Gly Gln Gly Thr Leu Val Thr Val Ser Ser

115 120

<210> 77

<211> 107

<212> PRT

<213> Artificial sequence

<220>

<221> source

<223> /note="Description of the artificial sequence:

Synthetic polypeptide"

<400> 77

Glu Ile Val Met Thr Gln Ser Pro Ser Phe 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 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 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 Leu Asn Ser Tyr Pro Phe

85 90 95

Thr Phe Gly Pro Gly Thr Lys Val Asp Ile Lys

100 105

<210> 78

<211> 10

<212> PRT

<213> Artificial sequence

<220>

<221> source

<223> /note="Description of the artificial sequence:

Synthetic peptide"

<400> 78

Gly Gly Ser Phe Ser Ser Ser Ser Tyr Tyr

1 5 10

<210> 79

<211> 7

<212> PRT

<213> Artificial sequence

<220>

<221> source

<223> /note="Description of the artificial sequence:

Synthetic peptide"

<400> 79

Phe Tyr Tyr Ser Gly Thr Thr

15

<210> 80

<211> 17

<212> PRT

<213> Artificial sequence

<220>

<221> source

<223> /note="Description of the artificial sequence:

Synthetic peptide"

<400> 80

Cys Ala Arg Gly Gly Glu Tyr Phe Asp Arg Leu Leu Pro Phe Asp Tyr

1 5 10 15

trp

<210> 81

<211> 6

<212> PRT

<213> Artificial sequence

<220>

<221> source

<223> /note="Description of the artificial sequence:

Synthetic peptide"

<400> 81

Gln Gly Ile Ser Ser Tyr

15

<210> 82

<211> 3

<212> PRT

<213> Artificial sequence

<220>

<221> source

<223> /note="Description of the artificial sequence:

Synthetic peptide"

<400> 82

Ala Ala Ser

1

<210> 83

<211> 11

<212> PRT

<213> Artificial sequence

<220>

<221> source

<223> /note="Description of the artificial sequence:

Synthetic peptide"

<400> 83

Cys Gln Gln Leu Asn Ser Tyr Pro Phe Thr Phe

1 5 10

<210> 84

<211> 351

<212> DNA

<213> Artificial sequence

<220>

<221> source

<223> /note="Description of the artificial sequence:

Synthetic polynucleotide"

<400> 84

caggtgcagc tggtggagtc tgggggaggc ttggtacagc cgggggggtc cctgagactc 60

tcctgtacag cctctggatt cacctttagc agctatgcca tgagctgggt ccgccaggct 120

ccagggaagg ggctggagtg ggtctcagct attggtggta gtggtggtag cacatactac 180

gcagactccg tgaagggccg gttcaccatc tccagagaca attccaagaa cacgctgtat 240

ctgcaaatga acagcctgag agccgaggac acggccgtat attactgtgt gaaagatggg 300

gcaggaggct ttgactactg gggccaggga accctggtca ccgtctcgag t 351

<210> 85

<211> 321

<212> DNA

<213> Artificial sequence

<220>

<221> source

<223> /note="Description of the artificial sequence:

Synthetic polynucleotide"

<400> 85

gatattgtga tgacgcagtc ttcatcctcc ctgtctgcat ctgtaggaga cagagtcacc 60

atcacttgcc gggcaagtca gggcattata aatcatttag gctggtatca gcataaacca 120

gggaaagccc ctaatcgcct aatctatgct gcatccagtt tgcaaagtgg ggtcccatca 180

aggttcagcg gcagtggatc tgggacagaa ttcactctca caatcagcag cctgcagcct 240

gaagattttg caacttatta ctgtctacgg cataatagtt accctccgac gttcggccaa 300

gggaccaagg tggaaatcaa g 321

<210> 86

<211> 117

<212> PRT

<213> Artificial sequence

<220>

<221> source

<223> /note="Description of the artificial sequence:

Synthetic polypeptide"

<400> 86

Gln 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 Thr Ala Ser Gly Phe Thr Phe Ser Ser Tyr

20 25 30

Ala Met Ser Trp Val Arg Gln Ala Pro Gly Lys Gly Leu Glu Trp Val

35 40 45

Ser Ala Ile Gly Gly Ser Gly Gly Ser Thr 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

Val Lys Asp Gly Ala Gly Gly Phe Asp Tyr Trp Gly Gln Gly Thr Leu

100 105 110

Val Thr Val Ser Ser

115

<210> 87

<211> 107

<212> PRT

<213> Artificial sequence

<220>

<221> source

<223> /note="Description of the artificial sequence:

Synthetic polypeptide"

<400> 87

Asp Ile Val Met Thr Gln Ser Ser 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 Ile Asn His

20 25 30

Leu Gly Trp Tyr Gln His Lys Pro Gly Lys Ala Pro Asn Arg 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 Glu Phe Thr Leu Thr Ile Ser Ser Leu Gln Pro

65 70 75 80

Glu Asp Phe Ala Thr Tyr Tyr Cys Leu Arg His Asn Ser Tyr Pro Pro

85 90 95

Thr Phe Gly Gln Gly Thr Lys Val Glu Ile Lys

100 105

<210> 88

<211> 8

<212> PRT

<213> Artificial sequence

<220>

<221> source

<223> /note="Description of the artificial sequence:

Synthetic peptide"

<400> 88

Gly Phe Thr Phe Ser Ser Tyr Ala

15

<210> 89

<211> 8

<212> PRT

<213> Artificial sequence

<220>

<221> source

<223> /note="Description of the artificial sequence:

Synthetic peptide"

<400> 89

Ile Gly Gly Ser Gly Gly Ser Thr

15

<210> 90

<211> 12

<212> PRT

<213> Artificial sequence

<220>

<221> source

<223> /note="Description of the artificial sequence:

Synthetic peptide"

<400> 90

Cys Val Lys Asp Gly Ala Gly Gly Phe Asp Tyr Trp

1 5 10

<210> 91

<211> 6

<212> PRT

<213> Artificial sequence

<220>

<221> source

<223> /note="Description of the artificial sequence:

Synthetic peptide"

<400> 91

Gln Gly Ile Ile Asn His

15

<210> 92

<211> 3

<212> PRT

<213> Artificial sequence

<220>

<221> source

<223> /note="Description of the artificial sequence:

Synthetic peptide"

<400> 92

Ala Ala Ser

1

<210> 93

<211> 5

<212> PRT

<213> Artificial sequence

<220>

<221> source

<223> /note="Description of the artificial sequence:

Synthetic peptide"

<400> 93

Tyr Pro Pro Thr Phe

15

<210> 94

<211> 366

<212> DNA

<213> Artificial sequence

<220>

<221> source

<223> /note="Description of the artificial sequence:

Synthetic polynucleotide"

<400> 94

60

acctgcactg tctctggtgg ctccatcaac agtggtggtc actactggag ctggatccgc 120

cagcacccag ggaggggcct ggagtggatt gggtacatct attacagtgg gagcatctac 180

tacaacccgt ccctcaagag tcgacttacc atatcagtag acacgtctaa gaaccagttc 240

tccctgaagc tgagctctgt gactgccgcg gacacggccg tgtattactg tgcgagttat 300

tactatgcca gtagtggtga tgcttttgat atctggggcc aagggacaat ggtcaccgtc 360

tcgagt 366

<210> 95

<211> 321

<212> DNA

<213> Artificial sequence

<220>

<221> source

<223> /note="Description of the artificial sequence:

Synthetic polynucleotide"

<400> 95

gaaacgacac tcacgcagtc tccagccacc ctgtctttgt ctccagggga aagagccacc 60

ctctcctgca gggccagtca gagtgttagc agctacttag cctggtacca acagaaacct 120

ggccaggctc ccaggctcct catctatgat gcatccaaca gggccactgg catcccagcc 180

aggttcagtg gcagtgggtc tgggacagac ttcactctca ccatcagcag cctagagcct 240

gaagattttg cagtttatta ctgtcagcag cgtagcaact ggcctccgac gttcggccaa 300

gggaccaagg tggaaatcaa a 321

<210> 96

<211> 122

<212> PRT

<213> Artificial sequence

<220>

<221> source

<223> /note="Description of the artificial sequence:

Synthetic polypeptide"

<400> 96

Gln 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 Thr Val Ser Gly Gly Ser Ile Asn Ser Gly

20 25 30

Gly His Tyr Trp Ser Trp Ile Arg Gln His Pro Gly Arg Gly Leu Glu

35 40 45

Trp Ile Gly Tyr Ile Tyr Tyr Ser Gly Ser Ile Tyr Tyr Asn Pro Ser

50 55 60

Leu Lys Ser Arg Leu Thr Ile Ser Val Asp Thr Ser Lys Asn Gln Phe

65 70 75 80

Ser Leu Lys Leu Ser Ser Val Thr Ala Ala Asp Thr Ala Val Tyr Tyr

85 90 95

Cys Ala Ser Tyr Tyr Tyr Ala Ser Ser Gly Asp Ala Phe Asp Ile Trp

100 105 110

Gly Gln Gly Thr Met Val Thr Val Ser Ser

115 120

<210> 97

<211> 107

<212> PRT

<213> Artificial sequence

<220>

<221> source

<223> /note="Description of the artificial sequence:

Synthetic polypeptide"

<400> 97

Glu Thr Thr 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 Ser Ser Tyr

20 25 30

Leu Ala Trp Tyr Gln Gln Lys Pro Gly Gln Ala Pro Arg Leu Leu Ile

35 40 45

Tyr Asp Ala Ser Asn Arg Ala Thr Gly Ile Pro Ala Arg Phe Ser Gly

50 55 60

Ser Gly Ser Gly Thr Asp Phe Thr Leu Thr Ile Ser Ser Leu Glu Pro

65 70 75 80

Glu Asp Phe Ala Val Tyr Tyr Cys Gln Gln Arg Ser Asn Trp Pro Pro

85 90 95

Thr Phe Gly Gln Gly Thr Lys Val Glu Ile Lys

100 105

<210> 98

<211> 10

<212> PRT

<213> Artificial sequence

<220>

<221> source

<223> /note="Description of the artificial sequence:

Synthetic peptide"

<400> 98

Gly Gly Ser Ile Asn Ser Gly Gly His Tyr

1 5 10

<210> 99

<211> 7

<212> PRT

<213> Artificial sequence

<220>

<221> source

<223> /note="Description of the artificial sequence:

Synthetic peptide"

<400> 99

Ile Tyr Tyr Ser Gly Ser Ile

15

<210> 100

<211> 16

<212> PRT

<213> Artificial sequence

<220>

<221> source

<223> /note="Description of the artificial sequence:

Synthetic peptide"

<400> 100

Cys Ala Ser Tyr Tyr Tyr Ala Ser Ser Gly Asp Ala Phe Asp Ile Trp

1 5 10 15

<210> 101

<211> 6

<212> PRT

<213> Artificial sequence

<220>

<221> source

<223> /note="Description of the artificial sequence:

Synthetic peptide"

<400> 101

Gln Ser Val Ser Ser Tyr

15

<210> 102

<211> 3

<212> PRT

<213> Artificial sequence

<220>

<221> source

<223> /note="Description of the artificial sequence:

Synthetic peptide"

<400> 102

Asp Ala Ser

1

<210> 103

<211> 11

<212> PRT

<213> Artificial sequence

<220>

<221> source

<223> /note="Description of the artificial sequence:

Synthetic peptide"

<400> 103

Cys Gln Gln Arg Ser Asn Trp Pro Pro Thr Phe

1 5 10

<210> 104

<211> 372

<212> DNA

<213> Artificial sequence

<220>

<221> source

<223> /note="Description of the artificial sequence:

Synthetic polynucleotide"

<400> 104

caggtgcagc tgcaggagtc tgggggaggc ttggtacagc cgggggggtc cctgagactc 60

tcctgtacag cctctggatt cacctttagt aattatgcca tgagctgggt ccgccaggct 120

ccagggaagg ggctggagtg ggtctcagct attagtggtc gtggtggtag cacattcttc 180

gcagactccg tgaagggccg gttcaccatc tccagagaca attccaagag cacgctgtat 240

ctgcaaacga acagcctgag agccgaggac acggccgtat attactgtgc gaaagggggc 300

ccgttgtata actggaacga cggtgatggt tttgatatct ggggccaagg gaccacggtc 360

acagtctcga gt 372

<210> 105

<211> 324

<212> DNA

<213> Artificial sequence

<220>

<221> source

<223> /note="Description of the artificial sequence:

Synthetic polynucleotide"

<400> 105

gaaattgtgt tgacgcagtc tccagccacc ctgtctgtgt ctccagggga aagagccacc 60

ctctcctgca gggccagtca gagtgttagc agcaacttag cctggtacca gcagaaacct 120

ggccaggctc ccaggctcct catctatggt gcatccacca gggccactgg tatcccagcc 180

aggttcagtg gcactgggtc tgggacagag ttcactctca ccatcagcag cctgcagtct 240

gaagattttg cactttatta ctgtcagcag tatgataact ggcctccgtg gacgttcggc 300

caagggacca aggtggaaat caaa 324

<210> 106

<211> 124

<212> PRT

<213> Artificial sequence

<220>

<221> source

<223> /note="Description of the artificial sequence:

Synthetic polypeptide"

<400> 106

Gln Val Gln Leu Gln Glu Ser Gly Gly Gly Leu Val Gln Pro Gly Gly

1 5 10 15

Ser Leu Arg Leu Ser Cys Thr Ala Ser Gly Phe Thr Phe Ser Asn Tyr

20 25 30

Ala Met Ser Trp Val Arg Gln Ala Pro Gly Lys Gly Leu Glu Trp Val

35 40 45

Ser Ala Ile Ser Gly Arg Gly Gly Ser Thr Phe Phe Ala Asp Ser Val

50 55 60

Lys Gly Arg Phe Thr Ile Ser Arg Asp Asn Ser Lys Ser Thr Leu Tyr

65 70 75 80

Leu Gln Thr Asn Ser Leu Arg Ala Glu Asp Thr Ala Val Tyr Tyr Cys

85 90 95

Ala Lys Gly Gly Pro Leu Tyr Asn Trp Asn Asp Gly Asp Gly Phe Asp

100 105 110

Ile Trp Gly Gln Gly Thr Thr Val Thr Val Ser Ser

115 120

<210> 107

<211> 108

<212> PRT

<213> Artificial sequence

<220>

<221> source

<223> /note="Description of the artificial sequence:

Synthetic polypeptide"

<400> 107

Glu Ile Val Leu Thr Gln Ser Pro Ala Thr Leu Ser Val Ser Pro Gly

1 5 10 15

Glu Arg Ala Thr Leu Ser Cys Arg Ala Ser Gln Ser Val Ser Ser Asn

20 25 30

Leu Ala Trp Tyr Gln Gln Lys Pro Gly Gln Ala Pro Arg Leu Leu Ile

35 40 45

Tyr Gly Ala Ser Thr Arg Ala Thr Gly Ile Pro Ala Arg Phe Ser Gly

50 55 60

Thr Gly Ser Gly Thr Glu Phe Thr Leu Thr Ile Ser Ser Leu Gln Ser

65 70 75 80

Glu Asp Phe Ala Leu Tyr Tyr Cys Gln Gln Tyr Asp Asn Trp Pro Pro

85 90 95

Trp Thr Phe Gly Gln Gly Thr Lys Val Glu Ile Lys

100 105

<210> 108

<211> 8

<212> PRT

<213> Artificial sequence

<220>

<221> source

<223> /note="Description of the artificial sequence:

Synthetic peptide"

<400> 108

Gly Phe Thr Phe Ser Asn Tyr Ala

15

<210> 109

<211> 8

<212> PRT

<213> Artificial sequence

<220>

<221> source

<223> /note="Description of the artificial sequence:

Synthetic peptide"

<400> 109

Ile Ser Gly Arg Gly Gly Ser Thr

15

<210> 110

<211> 19

<212> PRT

<213> Artificial sequence

<220>

<221> source

<223> /note="Description of the artificial sequence:

Synthetic peptide"

<400> 110

Cys Ala Lys Gly Gly Pro Leu Tyr Asn Trp Asn Asp Gly Asp Gly Phe

1 5 10 15

Asp Ile Trp

<210> 111

<211> 6

<212> PRT

<213> Artificial sequence

<220>

<221> source

<223> /note="Description of the artificial sequence:

Synthetic peptide"

<400> 111

Gln Ser Val Ser Ser Asn

15

<210> 112

<211> 3

<212> PRT

<213> Artificial sequence

<220>

<221> source

<223> /note="Description of the artificial sequence:

Synthetic peptide"

<400> 112

Gly Ala Ser

1

<210> 113

<211> 12

<212> PRT

<213> Artificial sequence

<220>

<221> source

<223> /note="Description of the artificial sequence:

Synthetic peptide"

<400> 113

Cys Gln Gln Tyr Asp Asn Trp Pro Pro Trp Thr Phe

1 5 10

<210> 114

<211> 357

<212> DNA

<213> Artificial sequence

<220>

<221> source

<223> /note="Description of the artificial sequence:

Synthetic polynucleotide"

<400> 114

caggtgcagc tgcaggagtc tgggggaggc ttggtcaagc ctggagggtc cctgagactc 60

tcctgtgcag cctctggatt caccttcagt gactactaca tgacctggat ccgccaggct 120

ccagggaagg ggctggagtg gatttcatac attagtggtg gtggtggttc catatactac 180

gcagactctg tgaagggccg attcaccatc tccagggaca acgccaagaa ctcactgtat 240

ctgcaaatga acagcctgag agccgaggac acggccgttt atttctgtgc gagagggaac 300

tggggatcgg cggctcttga tatctggggc caagggacaa tggtcacggt ctcgagt 357

<210> 115

<211> 321

<212> DNA

<213> Artificial sequence

<220>

<221> source

<223> /note="Description of the artificial sequence:

Synthetic polynucleotide"

<400> 115

gaaattgtgt tgacgcagtc tccatcctca ctgtctgcat ctgtaggaga cagagtcacc 60

atcacttgtc gggcgagtca gggcattaac aattatttag cctggtttca gcagaaacca 120

gggagagccc ctaagtccct gatctatgct gcatccagtt tgcaaagtgg ggtcccatcg 180

aagttcagcg gcagtggatc tgggacagat ttcactctca ccatcagcag cctgcagcct 240

gaagattttg caacttatta ctgccaacag tataatagtt accctccaac tctcggccct 300

gggaccaacg tggatatcaa a 321

<210> 116

<211> 119

<212> PRT

<213> Artificial sequence

<220>

<221> source

<223> /note="Description of the artificial sequence:

Synthetic polypeptide"

<400> 116

Gln Val Gln Leu Gln Glu Ser Gly Gly Gly Leu Val Lys 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

Tyr Met Thr Trp Ile Arg Gln Ala Pro Gly Lys Gly Leu Glu Trp Ile

35 40 45

Ser Tyr Ile Ser Gly Gly Gly Gly Ser 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 Val Tyr Phe Cys

85 90 95

Ala Arg Gly Asn Trp Gly Ser Ala Ala Leu Asp Ile Trp Gly Gln Gly

100 105 110

Thr Met Val Thr Val Ser Ser

115

<210> 117

<211> 107

<212> PRT

<213> Artificial sequence

<220>

<221> source

<223> /note="Description of the artificial sequence:

Synthetic polypeptide"

<400> 117

Glu Ile Val 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 Asn Asn Tyr

20 25 30

Leu Ala Trp Phe Gln Gln Lys Pro Gly Arg Ala Pro Lys Ser Leu Ile

35 40 45

Tyr Ala Ala Ser Ser Leu Gln Ser Gly Val Pro Ser Lys 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 Tyr Asn Ser Tyr Pro Pro

85 90 95

Thr Leu Gly Pro Gly Thr Asn Val Asp Ile Lys

100 105

<210> 118

<211> 8

<212> PRT

<213> Artificial sequence

<220>

<221> source

<223> /note="Description of the artificial sequence:

Synthetic peptide"

<400> 118

Gly Phe Thr Phe Ser Asp Tyr Tyr

15

<210> 119

<211> 11

<212> PRT

<213> Artificial sequence

<220>

<221> source

<223> /note="Description of the artificial sequence:

Synthetic peptide"

<400> 119

Ile Ser Tyr Ile Ser Gly Gly Gly Gly Ser Ile

1 5 10

<210> 120

<211> 14

<212> PRT

<213> Artificial sequence

<220>

<221> source

<223> /note="Description of the artificial sequence:

Synthetic peptide"

<400> 120

Cys Ala Arg Gly Asn Trp Gly Ser Ala Ala Leu Asp Ile Trp

1 5 10

<210> 121

<211> 6

<212> PRT

<213> Artificial sequence

<220>

<221> source

<223> /note="Description of the artificial sequence:

Synthetic peptide"

<400> 121

Gln Gly Ile Asn Asn Tyr

15

<210> 122

<211> 3

<212> PRT

<213> Artificial sequence

<220>

<221> source

<223> /note="Description of the artificial sequence:

Synthetic peptide"

<400> 122

Ala Ala Ser

1

<210> 123

<211> 11

<212> PRT

<213> Artificial sequence

<220>

<221> source

<223> /note="Description of the artificial sequence:

Synthetic peptide"

<400> 123

Cys Gln Gln Tyr Asn Ser Tyr Pro Pro Thr Leu

1 5 10

<210> 124

<211> 351

<212> DNA

<213> Artificial sequence

<220>

<221> source

<223> /note="Description of the artificial sequence:

Synthetic polynucleotide"

<400> 124

caggtgcagc tggtggagtc tgggggaggc ttggtacagc cgggggggtc cctgagactc 60

tcctgtacag cctctggatt cacctttagc agctatgcca tgagctgggt ccgccaggct 120

ccagggaagg ggctggagtg ggtctcagct attggtggta gtggtggtag cgcatactac 180

gcagactccg tgaagggccg gttcaccatc tccagagaca attccaagaa cacgctgtat 240

ctgcaaatga acagcctgag agccgaggac acggccgtat attactgtgt gaaagatggg 300

gcaggaggct ttgactactg gggccagggc accctggtca ccgtctcgag t 351

<210> 125

<211> 321

<212> DNA

<213> Artificial sequence

<220>

<221> source

<223> /note="Description of the artificial sequence:

Synthetic polynucleotide"

<400> 125

gacatccagt tgacccagtc cccatcctcc ctgtctgcat ctgtaggaga cagagtcacc 60

atcacttgcc gggcaagtca gggcattaga aatcatttag gctggtatca gcagaaacca 120

gggaaagccc ctaagcgcct aatctatgct gcatccagtt tgcaaagtgg ggtcccatca 180

aggttcagcg gcagtggatc tgggacagaa ttcactctca caatcagcag cctgcagcct 240

gaagattttg caacttatta ctgtctacag cataatagtt accctccgac gttcggccaa 300

gggaccaagg tggaaatcaa g 321

<210> 126

<211> 117

<212> PRT

<213> Artificial sequence

<220>

<221> source

<223> /note="Description of the artificial sequence:

Synthetic polypeptide"

<400> 126

Gln 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 Thr Ala Ser Gly Phe Thr Phe Ser Ser Tyr

20 25 30

Ala Met Ser Trp Val Arg Gln Ala Pro Gly Lys Gly Leu Glu Trp Val

35 40 45

Ser Ala Ile Gly Gly Ser Gly Gly Ser Ala 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

Val Lys Asp Gly Ala Gly Gly Phe Asp Tyr Trp Gly Gln Gly Thr Leu

100 105 110

Val Thr Val Ser Ser

115

<210> 127

<211> 107

<212> PRT

<213> Artificial sequence

<220>

<221> source

<223> /note="Description of the artificial sequence:

Synthetic polypeptide"

<400> 127

Asp 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 Arg Asn His

20 25 30

Leu Gly Trp Tyr Gln Gln Lys Pro Gly Lys Ala Pro Lys Arg 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 Glu Phe Thr Leu Thr Ile Ser Ser Leu Gln Pro

65 70 75 80

Glu Asp Phe Ala Thr Tyr Tyr Cys Leu Gln His Asn Ser Tyr Pro Pro

85 90 95

Thr Phe Gly Gln Gly Thr Lys Val Glu Ile Lys

100 105

<210> 128

<211> 8

<212> PRT

<213> Artificial sequence

<220>

<221> source

<223> /note="Description of the artificial sequence:

Synthetic peptide"

<400> 128

Gly Phe Thr Phe Ser Ser Tyr Ala

15

<210> 129

<211> 8

<212> PRT

<213> Artificial sequence

<220>

<221> source

<223> /note="Description of the artificial sequence:

Synthetic peptide"

<400> 129

Ile Gly Gly Ser Gly Gly Ser Ala

15

<210> 130

<211> 12

<212> PRT

<213> Artificial sequence

<220>

<221> source

<223> /note="Description of the artificial sequence:

Synthetic peptide"

<400> 130

Cys Val Lys Asp Gly Ala Gly Gly Phe Asp Tyr Trp

1 5 10

<210> 131

<211> 6

<212> PRT

<213> Artificial sequence

<220>

<221> source

<223> /note="Description of the artificial sequence:

Synthetic peptide"

<400> 131

Gln Gly Ile Arg Asn His

15

<210> 132

<211> 3

<212> PRT

<213> Artificial sequence

<220>

<221> source

<223> /note="Description of the artificial sequence:

Synthetic peptide"

<400> 132

Ala Ala Ser

1

<210> 133

<211> 11

<212> PRT

<213> Artificial sequence

<220>

<221> source

<223> /note="Description of the artificial sequence:

Synthetic peptide"

<400> 133

Cys Leu Gln His Asn Ser Tyr Pro Pro Thr Phe

1 5 10

<210> 134

<211> 354

<212> DNA

<213> Artificial sequence

<220>

<221> source

<223> /note="Description of the artificial sequence:

Synthetic polynucleotide"

<400> 134

cagatgcagc tacagcagtc tgggggaggc ttggtacagc cgggggggtc cctgagactc 60

tcctgtgcag cctctggatt caccgttagc agctatgcca tgagctgggt ccgccaggct 120

ctagggaagg ggctggagtg ggtctcaggt attagtggta gtggtggtag cacatactac 180

gcagactccg tgaagggccg gttcaccatc tccagagaca attccaagaa tacgctgtat 240

ctgcaaatga acagcctgag agccgaggac acggccgtat attactgtgc gaagatagtg 300

ggagctaccc actttgacta ctggggccag ggaaccctgg tcacggtctc gagt 354

<210> 135

<211> 339

<212> DNA

<213> Artificial sequence

<220>

<221> source

<223> /note="Description of the artificial sequence:

Synthetic polynucleotide"

<400> 135

gaaattgtga tgacacagtc tccagactcc ctggctgtgt ctctgggcga gagggccacc 60

atcaactgca agtccagcca gagtgtttta tacagctcca acaataagaa ctacttagct 120

tggtaccagc agaaaccagg acagcctcct aagctgctca tttactgggc atctacccgg 180

gaatccgggg tccctgaccg attcagtggc agcgggtctg ggacagattt cactctcacc 240

atcagcagcc tgcaggctga agatgtggca gtttattact gtcagcaata ttatagtggt 300

ccgatcacct tcggccaagg gacacgactg gagattaag 339

<210> 136

<211> 118

<212> PRT

<213> Artificial sequence

<220>

<221> source

<223> /note="Description of the artificial sequence:

Synthetic polypeptide"

<400> 136

Gln Met Gln Leu Gln 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 Val Ser Ser Tyr

20 25 30

Ala Met Ser Trp Val Arg Gln Ala Leu Gly Lys Gly Leu Glu Trp Val

35 40 45

Ser Gly Ile Ser Gly Ser Gly Gly Ser Thr 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 Lys Ile Val Gly Ala Thr His Phe Asp Tyr Trp Gly Gln Gly Thr

100 105 110

Leu Val Thr Val Ser Ser

115

<210> 137

<211> 113

<212> PRT

<213> Artificial sequence

<220>

<221> source

<223> /note="Description of the artificial sequence:

Synthetic polypeptide"

<400> 137

Glu Ile Val Met Thr Gln Ser Pro Asp Ser Leu Ala Val Ser Leu Gly

1 5 10 15

Glu Arg Ala Thr Ile Asn Cys Lys Ser Ser Gln Ser Val Leu Tyr Ser

20 25 30

Ser Asn Asn Lys Asn Tyr Leu Ala Trp Tyr Gln Gln Lys Pro Gly Gln

35 40 45

Pro Pro Lys Leu Leu Ile Tyr Trp Ala Ser Thr Arg Glu Ser Gly Val

50 55 60

Pro Asp Arg Phe Ser Gly Ser Gly Ser Gly Thr Asp Phe Thr Leu Thr

65 70 75 80

Ile Ser Ser Leu Gln Ala Glu Asp Val Ala Val Tyr Tyr Cys Gln Gln

85 90 95

Tyr Tyr Ser Gly Pro Ile Thr Phe Gly Gln Gly Thr Arg Leu Glu Ile

100 105 110

Lys

<210> 138

<211> 8

<212> PRT

<213> Artificial sequence

<220>

<221> source

<223> /note="Description of the artificial sequence:

Synthetic peptide"

<400> 138

Gly Phe Thr Val Ser Ser Tyr Ala

15

<210> 139

<211> 8

<212> PRT

<213> Artificial sequence

<220>

<221> source

<223> /note="Description of the artificial sequence:

Synthetic peptide"

<400> 139

Ile Ser Gly Ser Gly Gly Ser Thr

15

<210> 140

<211> 13

<212> PRT

<213> Artificial sequence

<220>

<221> source

<223> /note="Description of the artificial sequence:

Synthetic peptide"

<400> 140

Cys Ala Lys Ile Val Gly Ala Thr His Phe Asp Tyr Trp

1 5 10

<210> 141

<211> 12

<212> PRT

<213> Artificial sequence

<220>

<221> source

<223> /note="Description of the artificial sequence:

Synthetic peptide"

<400> 141

Gln Ser Val Leu Tyr Ser Ser Asn Asn Lys Asn Tyr

1 5 10

<210> 142

<211> 3

<212> PRT

<213> Artificial sequence

<220>

<221> source

<223> /note="Description of the artificial sequence:

Synthetic peptide"

<400> 142

Trp Ala Ser

1

<210> 143

<211> 11

<212> PRT

<213> Artificial sequence

<220>

<221> source

<223> /note="Description of the artificial sequence:

Synthetic peptide"

<400> 143

Cys Gln Gln Tyr Tyr Ser Gly Pro Ile Thr Phe

1 5 10

<210> 144

<211> 366

<212> DNA

<213> Artificial sequence

<220>

<221> source

<223> /note="Description of the artificial sequence:

Synthetic polynucleotide"

<400> 144

caggtgcagc tggtggagtc gggccgga ctggtgaagc cttcacagac cctgtccctc 60

acctgcactg tctctggtgg ctccatcaac agtggtggtt actactggag ctggatccgc 120

cagcacccag ggaagggcct ggagtggatt gggtacatct attacagtgg gagcatctac 180

tacaacccgt ccctcaggag tcgacttacc atatcagtag acacgtctaa gaaccagttc 240

tccctgaagc tgagctctgt gactgccgcg gacacggccg ttttattactg tgcgactcct 300

tattactatg gttcggggag ttatggggac tactggggcc agggcaccct ggtcactgtc 360

tcgagt 366

<210> 145

<211> 321

<212> DNA

<213> Artificial sequence

<220>

<221> source

<223> /note="Description of the artificial sequence:

Synthetic polynucleotide"

<400> 145

gacatccaga tgacccagtc tccagccacc ctgtctttgt ctccagggga aagagccacc 60

ctctcctgca gggccagtca gagtgttaac aactacttag cctggtacca acagaaacct 120

ggccaggctc ccaggctcct catctatgat gcatccaaca gggccactgg catcccagcc 180

aggttcagtg gcagtgggtc tgggacagac ttcactctca ccatcagcag cctagagcct 240

gaagattttg cagtttatta ctgtcagcag cgtagcaact ggcccatcac cttcggccaa 300

gggacacgac tggagattaa a 321

<210> 146

<211> 122

<212> PRT

<213> Artificial sequence

<220>

<221> source

<223> /note="Description of the artificial sequence:

Synthetic polypeptide"

<400> 146

Gln Val Gln Leu Val Glu Ser Gly Pro Gly Leu Val Lys Pro Ser Gln

1 5 10 15

Thr Leu Ser Leu Thr Cys Thr Val Ser Gly Gly Ser Ile Asn Ser Gly

20 25 30

Gly Tyr Tyr Trp Ser Trp Ile Arg Gln His Pro Gly Lys Gly Leu Glu

35 40 45

Trp Ile Gly Tyr Ile Tyr Tyr Ser Gly Ser Ile Tyr Tyr Asn Pro Ser

50 55 60

Leu Arg Ser Arg Leu Thr Ile Ser Val Asp Thr Ser Lys Asn Gln Phe

65 70 75 80

Ser Leu Lys Leu Ser Ser Val Thr Ala Ala Asp Thr Ala Val Tyr Tyr

85 90 95

Cys Ala Thr Pro Tyr Tyr Tyr Gly Ser Gly Ser Tyr Gly Asp Tyr Trp

100 105 110

Gly Gln Gly Thr Leu Val Thr Val Ser Ser

115 120

<210> 147

<211> 107

<212> PRT

<213> Artificial sequence

<220>

<221> source

<223> /note="Description of the artificial sequence:

Synthetic polypeptide"

<400> 147

Asp Ile Gln Met 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 Asn Asn Tyr

20 25 30

Leu Ala Trp Tyr Gln Gln Lys Pro Gly Gln Ala Pro Arg Leu Leu Ile

35 40 45

Tyr Asp Ala Ser Asn Arg Ala Thr Gly Ile Pro Ala Arg Phe Ser Gly

50 55 60

Ser Gly Ser Gly Thr Asp Phe Thr Leu Thr Ile Ser Ser Leu Glu Pro

65 70 75 80

Glu Asp Phe Ala Val Tyr Tyr Cys Gln Gln Arg Ser Asn Trp Pro Ile

85 90 95

Thr Phe Gly Gln Gly Thr Arg Leu Glu Ile Lys

100 105

<210> 148

<211> 10

<212> PRT

<213> Artificial sequence

<220>

<221> source

<223> /note="Description of the artificial sequence:

Synthetic peptide"

<400> 148

Gly Gly Ser Ile Asn Ser Gly Gly Tyr Tyr

1 5 10

<210> 149

<211> 7

<212> PRT

<213> Artificial sequence

<220>

<221> source

<223> /note="Description of the artificial sequence:

Synthetic peptide"

<400> 149

Ile Tyr Tyr Ser Gly Ser Ile

15

<210> 150

<211> 16

<212> PRT

<213> Artificial sequence

<220>

<221> source

<223> /note="Description of the artificial sequence:

Synthetic peptide"

<400> 150

Cys Ala Thr Pro Tyr Tyr Tyr Gly Ser Gly Ser Tyr Gly Asp Tyr Trp

1 5 10 15

<210> 151

<211> 6

<212> PRT

<213> Artificial sequence

<220>

<221> source

<223> /note="Description of the artificial sequence:

Synthetic peptide"

<400> 151

Gln Ser Val Asn Asn Tyr

15

<210> 152

<211> 3

<212> PRT

<213> Artificial sequence

<220>

<221> source

<223> /note="Description of the artificial sequence:

Synthetic peptide"

<400> 152

Asp Ala Ser

1

<210> 153

<211> 11

<212> PRT

<213> Artificial sequence

<220>

<221> source

<223> /note="Description of the artificial sequence:

Synthetic peptide"

<400> 153

Cys Gln Gln Arg Ser Asn Trp Pro Ile Thr Phe

1 5 10

<210> 154

<211> 363

<212> DNA

<213> Artificial sequence

<220>

<221> source

<223> /note="Description of the artificial sequence:

Synthetic polynucleotide"

<400> 154

cagatgcagc tgcaggagtc gggcccagga ctggtgaagc cttctcagac cctgtccctc 60

acctgcactg tgtctggtgg ctccatcagc agtgttggtt actactggaa ctggatccgc 120

cagcacccag ggaagggcct ggagttcatt gggtacatct attacagtgg gagcatctac 180

tacaatccgt ccctcaagag tcgagttacc atatccgtag acacgtctaa gaaccagttc 240

tccctgaagc tgagctctgt gactgccgcg gacacggccc tatattactg tgcgagcgtc 300

ggtatagtgg gagcctccta ctttgagtac tggggccagg gaaccctggt cacagtctcg 360

agt 363

<210> 155

<211> 321

<212> DNA

<213> Artificial sequence

<220>

<221> source

<223> /note="Description of the artificial sequence:

Synthetic polynucleotide"

<400> 155

gaaattgtga tgacacagtc tccagccacc ctgtctttgt ctccagggga aagagccacc 60

ctctcctgca gggccagtca gagtgttagc agctacttag cctggtacca acagaaacct 120

ggccaggctc ccaggctcct catctatgat gcatccaaca gggccactgg catcccagcc 180

aggttcagtg gcagtgggtc tgggacagac ttcactctca ccatcagcag cctagagcct 240

gaagattttg cagtttatta ctgtcagcag cgtagcaact ggcctatcac cttcggccaa 300

gggacacgac tggagatcaa g 321

<210> 156

<211> 121

<212> PRT

<213> Artificial sequence

<220>

<221> source

<223> /note="Description of the artificial sequence:

Synthetic polypeptide"

<400> 156

Gln Met Gln Leu Gln Glu Ser Gly Pro Gly Leu Val Lys Pro Ser Gln

1 5 10 15

Thr Leu Ser Leu Thr Cys Thr Val Ser Gly Gly Ser Ile Ser Ser Val

20 25 30

Gly Tyr Tyr Trp Asn Trp Ile Arg Gln His Pro Gly Lys Gly Leu Glu

35 40 45

Phe Ile Gly Tyr Ile Tyr Tyr Ser Gly Ser Ile Tyr Tyr Asn Pro Ser

50 55 60

Leu Lys Ser Arg Val Thr Ile Ser Val Asp Thr Ser Lys Asn Gln Phe

65 70 75 80

Ser Leu Lys Leu Ser Ser Val Thr Ala Ala Asp Thr Ala Leu Tyr Tyr

85 90 95

Cys Ala Ser Val Gly Ile Val Gly Ala Ser Tyr Phe Glu Tyr Trp Gly

100 105 110

Gln Gly Thr Leu Val Thr Val Ser Ser

115 120

<210> 157

<211> 107

<212> PRT

<213> Artificial sequence

<220>

<221> source

<223> /note="Description of the artificial sequence:

Synthetic polypeptide"

<400> 157

Glu Ile Val Met 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 Ser Ser Tyr

20 25 30

Leu Ala Trp Tyr Gln Gln Lys Pro Gly Gln Ala Pro Arg Leu Leu Ile

35 40 45

Tyr Asp Ala Ser Asn Arg Ala Thr Gly Ile Pro Ala Arg Phe Ser Gly

50 55 60

Ser Gly Ser Gly Thr Asp Phe Thr Leu Thr Ile Ser Ser Leu Glu Pro

65 70 75 80

Glu Asp Phe Ala Val Tyr Tyr Cys Gln Gln Arg Ser Asn Trp Pro Ile

85 90 95

Thr Phe Gly Gln Gly Thr Arg Leu Glu Ile Lys

100 105

<210> 158

<211> 10

<212> PRT

<213> Artificial sequence

<220>

<221> source

<223> /note="Description of the artificial sequence:

Synthetic peptide"

<400> 158

Gly Gly Ser Ile Ser Val Gly Tyr Tyr

1 5 10

<210> 159

<211> 7

<212> PRT

<213> Artificial sequence

<220>

<221> source

<223> /note="Description of the artificial sequence:

Synthetic peptide"

<400> 159

Ile Tyr Tyr Ser Gly Ser Ile

15

<210> 160

<211> 15

<212> PRT

<213> Artificial sequence

<220>

<221> source

<223> /note="Description of the artificial sequence:

Synthetic peptide"

<400> 160

Cys Ala Ser Val Gly Ile Val Gly Ala Ser Tyr Phe Glu Tyr Trp

1 5 10 15

<210> 161

<211> 6

<212> PRT

<213> Artificial sequence

<220>

<221> source

<223> /note="Description of the artificial sequence:

Synthetic peptide"

<400> 161

Gln Ser Val Ser Ser Tyr

15

<210> 162

<211> 3

<212> PRT

<213> Artificial sequence

<220>

<221> source

<223> /note="Description of the artificial sequence:

Synthetic peptide"

<400> 162

Asp Ala Ser

1

<210> 163

<211> 11

<212> PRT

<213> Artificial sequence

<220>

<221> source

<223> /note="Description of the artificial sequence:

Synthetic peptide"

<400> 163

Cys Gln Gln Arg Ser Asn Trp Pro Ile Thr Phe

1 5 10

<210> 164

<211> 354

<212> DNA

<213> Artificial sequence

<220>

<221> source

<223> /note="Description of the artificial sequence:

Synthetic polynucleotide"

<400> 164

caggtgcagc tacagcagtc tgggggaggc ttggtacagc ctggggggtc cctgagactc 60

tcctgtgcag cctctggatt caccttaagc agctatgcca tgagctgggt ccgccaggct 120

ccagggaagg ggctggagtg ggtctcaggt attagtggta gtggtggtag cacatacaac 180

gcagactccg tgaagggccg gttcaccatc tccagagaca attccaagaa cacgctgttt 240

ctgcaaatga acagcctgag agccgaggac acggccgtat attactgtgc gaaaattttt 300

gggtcctact actttgacta ctggggccag ggaaccctgg tcacagtctc gagt 354

<210> 165

<211> 339

<212> DNA

<213> Artificial sequence

<220>

<221> source

<223> /note="Description of the artificial sequence:

Synthetic polynucleotide"

<400> 165

gaaattgtga tgacacagtc tccagactcc ctggctgtgt ctctgggcga gagggccacc 60

atcaactgca agtccagcca gagtgtttta tacagctcca acaataagaa ctacttagct 120

tggtaccagc agaaaccagg acagcctcct aagctgctca tttactggac atctacccgg 180

gaatccgggg tccctaaccg attcagtggc agcgggtctg ggacagattt cactctcacc 240

atcagcagcc tgcaggctga agatgtggca gtttattact gtcagcaata ttatagtggt 300

cctccgacgt tcggccaagg gaccaaggtg gaaatcaaa 339

<210> 166

<211> 118

<212> PRT

<213> Artificial sequence

<220>

<221> source

<223> /note="Description of the artificial sequence:

Synthetic polypeptide"

<400> 166

Gln Val Gln Leu Gln 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 Leu Ser Ser Tyr

20 25 30

Ala Met Ser Trp Val Arg Gln Ala Pro Gly Lys Gly Leu Glu Trp Val

35 40 45

Ser Gly Ile Ser Gly Ser Gly Gly Ser Thr Tyr Asn Ala Asp Ser Val

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 Ile Phe Gly Ser Tyr Tyr Phe Asp Tyr Trp Gly Gln Gly Thr

100 105 110

Leu Val Thr Val Ser Ser

115

<210> 167

<211> 113

<212> PRT

<213> Artificial sequence

<220>

<221> source

<223> /note="Description of the artificial sequence:

Synthetic polypeptide"

<400> 167

Glu Ile Val Met Thr Gln Ser Pro Asp Ser Leu Ala Val Ser Leu Gly

1 5 10 15

Glu Arg Ala Thr Ile Asn Cys Lys Ser Ser Gln Ser Val Leu Tyr Ser

20 25 30

Ser Asn Asn Lys Asn Tyr Leu Ala Trp Tyr Gln Gln Lys Pro Gly Gln

35 40 45

Pro Pro Lys Leu Leu Ile Tyr Trp Thr Ser Thr Arg Glu Ser Gly Val

50 55 60

Pro Asn Arg Phe Ser Gly Ser Gly Ser Gly Thr Asp Phe Thr Leu Thr

65 70 75 80

Ile Ser Ser Leu Gln Ala Glu Asp Val Ala Val Tyr Tyr Cys Gln Gln

85 90 95

Tyr Tyr Ser Gly Pro Thr Phe Gly Glyn Gly Thr Lys Val Glu Ile

100 105 110

Lys

<210> 168

<211> 8

<212> PRT

<213> Artificial sequence

<220>

<221> source

<223> /note="Description of the artificial sequence:

Synthetic peptide"

<400> 168

Gly Phe Thr Leu Ser Ser Tyr Ala

15

<210> 169

<211> 8

<212> PRT

<213> Artificial sequence

<220>

<221> source

<223> /note="Description of the artificial sequence:

Synthetic peptide"

<400> 169

Ile Ser Gly Ser Gly Gly Ser Thr

15

<210> 170

<211> 13

<212> PRT

<213> Artificial sequence

<220>

<221> source

<223> /note="Description of the artificial sequence:

Synthetic peptide"

<400> 170

Cys Ala Lys Ile Phe Gly Ser Tyr Tyr Phe Asp Tyr Trp

1 5 10

<210> 171

<211> 12

<212> PRT

<213> Artificial sequence

<220>

<221> source

<223> /note="Description of the artificial sequence:

Synthetic peptide"

<400> 171

Gln Ser Val Leu Tyr Ser Ser Asn Asn Lys Asn Tyr

1 5 10

<210> 172

<211> 3

<212> PRT

<213> Artificial sequence

<220>

<221> source

<223> /note="Description of the artificial sequence:

Synthetic peptide"

<400> 172

Trp Thr Ser

1

<210> 173

<211> 11

<212> PRT

<213> Artificial sequence

<220>

<221> source

<223> /note="Description of the artificial sequence:

Synthetic peptide"

<400> 173

Cys Gln Gln Tyr Tyr Ser Gly Pro Pro Thr Phe

1 5 10

<210> 174

<211> 354

<212> DNA

<213> Artificial sequence

<220>

<221> source

<223> /note="Description of the artificial sequence:

Synthetic polynucleotide"

<400> 174

caggtgcagc tggtggagtc tgggggaggc ttggttcggc ctggggggtc cctgagactc 60

tcctgtgcag tctctggatt cacctttagc agctatgcca tgagctgggt ccgccaggct 120

ccagggaagg ggctggagtg ggtctcaggt attagtggta gtggtggtag cacatacaac 180

gcagactccg tgaagggccg gttcaccatc tccagagaca attccaagaa cacgctgtat 240

cttcaaatga acagcctgag agccgaggac acggccgtat attactgtgc gaaaattttt 300

gggtcctact actttgacta ctggggccag ggaaccctgg tcaccgtctc gagt 354

<210> 175

<211> 339

<212> DNA

<213> Artificial sequence

<220>

<221> source

<223> /note="Description of the artificial sequence:

Synthetic polynucleotide"

<400> 175

gaaattgtga tgacacagtc tccagactcc ctggctgtgt ctctgggcga gagggccacc 60

atcaactgca agtccagcca gagtgtttta tacagctcca ataataagaa ctacttagct 120

tggtaccagc agaaatcagg acagcctcct aagctgctca tttactgggc atctacccgg 180

gaatccgggg tccctgaccg attcagtggc agcgggtctg ggacagattt cactctcacc 240

atcagcagcc tgcaggctga agatgtggca gtttattact gtcagcaata ttatagtggt 300

ccaccgacgt tcggccaagg gaccaaggtg gaaatcaaa 339

<210> 176

<211> 118

<212> PRT

<213> Artificial sequence

<220>

<221> source

<223> /note="Description of the artificial sequence:

Synthetic polypeptide"

<400> 176

Gln Val Gln Leu Val Glu Ser Gly Gly Gly Leu Val Arg Pro Gly Gly

1 5 10 15

Ser Leu Arg Leu Ser Cys Ala Val Ser Gly Phe Thr Phe Ser Ser Tyr

20 25 30

Ala Met Ser Trp Val Arg Gln Ala Pro Gly Lys Gly Leu Glu Trp Val

35 40 45

Ser Gly Ile Ser Gly Ser Gly Gly Ser Thr Tyr Asn 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 Lys Ile Phe Gly Ser Tyr Tyr Phe Asp Tyr Trp Gly Gln Gly Thr

100 105 110

Leu Val Thr Val Ser Ser

115

<210> 177

<211> 113

<212> PRT

<213> Artificial sequence

<220>

<221> source

<223> /note="Description of the artificial sequence:

Synthetic polypeptide"

<400> 177

Glu Ile Val Met Thr Gln Ser Pro Asp Ser Leu Ala Val Ser Leu Gly

1 5 10 15

Glu Arg Ala Thr Ile Asn Cys Lys Ser Ser Gln Ser Val Leu Tyr Ser

20 25 30

Ser Asn Asn Lys Asn Tyr Leu Ala Trp Tyr Gln Gln Lys Ser Gly Gln

35 40 45

Pro Pro Lys Leu Leu Ile Tyr Trp Ala Ser Thr Arg Glu Ser Gly Val

50 55 60

Pro Asp Arg Phe Ser Gly Ser Gly Ser Gly Thr Asp Phe Thr Leu Thr

65 70 75 80

Ile Ser Ser Leu Gln Ala Glu Asp Val Ala Val Tyr Tyr Cys Gln Gln

85 90 95

Tyr Tyr Ser Gly Pro Thr Phe Gly Glyn Gly Thr Lys Val Glu Ile

100 105 110

Lys

<210> 178

<211> 8

<212> PRT

<213> Artificial sequence

<220>

<221> source

<223> /note="Description of the artificial sequence:

Synthetic peptide"

<400> 178

Gly Phe Thr Phe Ser Ser Tyr Ala

15

<210> 179

<211> 8

<212> PRT

<213> Artificial sequence

<220>

<221> source

<223> /note="Description of the artificial sequence:

Synthetic peptide"

<400> 179

Ile Ser Gly Ser Gly Gly Ser Thr

15

<210> 180

<211> 13

<212> PRT

<213> Artificial sequence

<220>

<221> source

<223> /note="Description of the artificial sequence:

Synthetic peptide"

<400> 180

Cys Ala Lys Ile Phe Gly Ser Tyr Tyr Phe Asp Tyr Trp

1 5 10

<210> 181

<211> 12

<212> PRT

<213> Artificial sequence

<220>

<221> source

<223> /note="Description of the artificial sequence:

Synthetic peptide"

<400> 181

Gln Ser Val Leu Tyr Ser Ser Asn Asn Lys Asn Tyr

1 5 10

<210> 182

<211> 3

<212> PRT

<213> Artificial sequence

<220>

<221> source

<223> /note="Description of the artificial sequence:

Synthetic peptide"

<400> 182

Trp Ala Ser

1

<210> 183

<211> 11

<212> PRT

<213> Artificial sequence

<220>

<221> source

<223> /note="Description of the artificial sequence:

Synthetic peptide"

<400> 183

Cys Gln Gln Tyr Tyr Ser Gly Pro Pro Thr Phe

1 5 10

<210> 184

<211> 377

<212> DNA

<213> Artificial sequence

<220>

<221> source

<223> /note="Description of the artificial sequence:

Synthetic polynucleotide"

<400> 184

acgtgacagg gcgcgcccag gtccagctgc aggagagcgg tcccggactg gtgaagccat 60

cccagacact gagcctgact tgtactgtga gcggcggtag catctccagc ggcggctact 120

attggtcctg gatcaggcag cacccaggca agggcctgga gtggatcggc tacatctact 180

atagcggctc tatctactat aacccttccc tgaagagccg ggtgaccatc tctgtggaca 240

catccaagaa tcagttctat ctgaagctgt cttccgtgac cgccgctgat acagccgtgt 300

actattgcgc ctcactgatg gtctgggggg tcatgggcga ttactggggg cagggcacac 360

tggtcacagt ctcgagt 377

<210> 185

<211> 321

<212> DNA

<213> Artificial sequence

<220>

<221> source

<223> /note="Description of the artificial sequence:

Synthetic polynucleotide"

<400> 185

gagattgtgc tgacccagtc tcccgccacc ctgtctctga gtcctggcga gagagccacc 60

ctgagctgca gagcctctca gtccgtgtcc agctatctgg cctggtatca gcagaagccc 120

ggccaggctc cccggctgct gatctacgat gcctccaata gagccaccgg catccctgcc 180

agattctccg gctctggctc tggcaccgac tttaccctga ccatctccag cctggaaccc 240

gaggacttcg ccgtgtacta ctgccagcag cggtccgact ggcctcctac atttggccaa 300

ggcaccaagg tggaaatcaa g 321

<210> 186

<211> 120

<212> PRT

<213> Artificial sequence

<220>

<221> source

<223> /note="Description of the artificial sequence:

Synthetic polypeptide"

<400> 186

Gln Val Gln Leu Gln Glu Ser Gly Pro Gly Leu Val Lys Pro Ser Gln

1 5 10 15

Thr Leu Ser Leu Thr Cys Thr Val Ser Gly Gly Ser Ile Ser Ser Gly

20 25 30

Gly Tyr Tyr Trp Ser Trp Ile Arg Gln His Pro Gly Lys Gly Leu Glu

35 40 45

Trp Ile Gly Tyr Ile Tyr Tyr Ser Gly Ser Ile Tyr Tyr Asn Pro Ser

50 55 60

Leu Lys Ser Arg Val Thr Ile Ser Val Asp Thr Ser Lys Asn Gln Phe

65 70 75 80

Tyr Leu Lys Leu Ser Ser Val Thr Ala Ala Asp Thr Ala Val Tyr Tyr

85 90 95

Cys Ala Ser Leu Met Val Trp Gly Val Met Gly Asp Tyr Trp Gly Gln

100 105 110

Gly Thr Leu Val Thr Val Ser Ser

115 120

<210> 187

<211> 107

<212> PRT

<213> Artificial sequence

<220>

<221> source

<223> /note="Description of the artificial sequence:

Synthetic polypeptide"

<400> 187

Glu Ile Val 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 Ser Ser Tyr

20 25 30

Leu Ala Trp Tyr Gln Gln Lys Pro Gly Gln Ala Pro Arg Leu Leu Ile

35 40 45

Tyr Asp Ala Ser Asn Arg Ala Thr Gly Ile Pro Ala Arg Phe Ser Gly

50 55 60

Ser Gly Ser Gly Thr Asp Phe Thr Leu Thr Ile Ser Ser Leu Glu Pro

65 70 75 80

Glu Asp Phe Ala Val Tyr Tyr Cys Gln Gln Arg Ser Asp Trp Pro Pro

85 90 95

Thr Phe Gly Gln Gly Thr Lys Val Glu Ile Lys

100 105

<210> 188

<211> 10

<212> PRT

<213> Artificial sequence

<220>

<221> source

<223> /note="Description of the artificial sequence:

Synthetic peptide"

<400> 188

Gly Gly Ser Ile Ser Ser Gly Gly Tyr Tyr

1 5 10

<210> 189

<211> 7

<212> PRT

<213> Artificial sequence

<220>

<221> source

<223> /note="Description of the artificial sequence:

Synthetic peptide"

<400> 189

Ile Tyr Tyr Ser Gly Ser Ile

15

<210> 190

<211> 14

<212> PRT

<213> Artificial sequence

<220>

<221> source

<223> /note="Description of the artificial sequence:

Synthetic peptide"

<400> 190

Cys Ala Ser Leu Met Val Trp Gly Val Met Gly Asp Tyr Trp

1 5 10

<210> 191

<211> 6

<212> PRT

<213> Artificial sequence

<220>

<221> source

<223> /note="Description of the artificial sequence:

Synthetic peptide"

<400> 191

Gln Ser Val Ser Ser Tyr

15

<210> 192

<211> 3

<212> PRT

<213> Artificial sequence

<220>

<221> source

<223> /note="Description of the artificial sequence:

Synthetic peptide"

<400> 192

Asp Ala Ser

1

<210> 193

<211> 11

<212> PRT

<213> Artificial sequence

<220>

<221> source

<223> /note="Description of the artificial sequence:

Synthetic peptide"

<400> 193

Cys Gln Gln Arg Ser Asp Trp Pro Pro Thr Phe

1 5 10

<210> 194

<211> 354

<212> DNA

<213> Artificial sequence

<220>

<221> source

<223> /note="Description of the artificial sequence:

Synthetic polynucleotide"

<400> 194

caggtccagc tacagcagtc tgggggaggc ttggttcatc ctggggggtc cctaagactc 60

tcctgtgcag cctctggatt caccgttgac acctatgcca tgacctgggt ccgccaggct 120

ccagggaagg ggctggagtg ggtctcaggt attagcggta gtggtggtag cacatactac 180

gcagactccg tgaagggccg gttcaccatc tccagagaca actccaagaa cacgctgtat 240

ctgcaaatga acagcctgag agacgaggac acggccgtat attactgtgc gaagatagtg 300

ggagttaccc actttgacta ctggggccag ggcaccctgg tcacggtctc gagt 354

<210> 195

<211> 339

<212> DNA

<213> Artificial sequence

<220>

<221> source

<223> /note="Description of the artificial sequence:

Synthetic polynucleotide"

<400> 195

gaaattgtga tgacgcagtc tccagactcc ctggctgtgt ctctgggcga gagggccacc 60

atcaactgca agtccagcca gagtgtttta tacaggtcca acaataagaa ctatttagct 120

tggtaccagc agaaaccagg acagcctcct aagctgctca tttactgggc atctacccgg 180

gaatccgggg tccctgaccg attcagtggc agcgggtctg ggacagattt cactctcacc 240

atcagcagcc tgcaggctga agatgtggca gtttattact gtcagcaata ttatagtggt 300

ccgatcacct tcggccaagg gacacgactg gagattaag 339

<210> 196

<211> 118

<212> PRT

<213> Artificial sequence

<220>

<221> source

<223> /note="Description of the artificial sequence:

Synthetic polypeptide"

<400> 196

Gln Val Gln Leu Gln Gln Ser Gly Gly Gly Leu Val His Pro Gly Gly

1 5 10 15

Ser Leu Arg Leu Ser Cys Ala Ala Ser Gly Phe Thr Val Asp Thr Tyr

20 25 30

Ala Met Thr Trp Val Arg Gln Ala Pro Gly Lys Gly Leu Glu Trp Val

35 40 45

Ser Gly Ile Ser Gly Ser Gly Gly Ser Thr 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 Asp Glu Asp Thr Ala Val Tyr Tyr Cys

85 90 95

Ala Lys Ile Val Gly Val Thr His Phe Asp Tyr Trp Gly Gln Gly Thr

100 105 110

Leu Val Thr Val Ser Ser

115

<210> 197

<211> 113

<212> PRT

<213> Artificial sequence

<220>

<221> source

<223> /note="Description of the artificial sequence:

Synthetic polypeptide"

<400> 197

Glu Ile Val Met Thr Gln Ser Pro Asp Ser Leu Ala Val Ser Leu Gly

1 5 10 15

Glu Arg Ala Thr Ile Asn Cys Lys Ser Ser Gln Ser Val Leu Tyr Arg

20 25 30

Ser Asn Asn Lys Asn Tyr Leu Ala Trp Tyr Gln Gln Lys Pro Gly Gln

35 40 45

Pro Pro Lys Leu Leu Ile Tyr Trp Ala Ser Thr Arg Glu Ser Gly Val

50 55 60

Pro Asp Arg Phe Ser Gly Ser Gly Ser Gly Thr Asp Phe Thr Leu Thr

65 70 75 80

Ile Ser Ser Leu Gln Ala Glu Asp Val Ala Val Tyr Tyr Cys Gln Gln

85 90 95

Tyr Tyr Ser Gly Pro Ile Thr Phe Gly Gln Gly Thr Arg Leu Glu Ile

100 105 110

Lys

<210> 198

<211> 8

<212> PRT

<213> Artificial sequence

<220>

<221> source

<223> /note="Description of the artificial sequence:

Synthetic peptide"

<400> 198

Gly Phe Thr Val Asp Thr Tyr Ala

15

<210> 199

<211> 8

<212> PRT

<213> Artificial sequence

<220>

<221> source

<223> /note="Description of the artificial sequence:

Synthetic peptide"

<400> 199

Ile Ser Gly Ser Gly Gly Ser Thr

15

<210> 200

<211> 13

<212> PRT

<213> Artificial sequence

<220>

<221> source

<223> /note="Description of the artificial sequence:

Synthetic peptide"

<400> 200

Cys Ala Lys Ile Val Gly Val Thr His Phe Asp Tyr Trp

1 5 10

<210> 201

<211> 12

<212> PRT

<213> Artificial sequence

<220>

<221> source

<223> /note="Description of the artificial sequence:

Synthetic peptide"

<400> 201

Gln Ser Val Leu Tyr Arg Ser Asn Asn Lys Asn Tyr

1 5 10

<210> 202

<211> 3

<212> PRT

<213> Artificial sequence

<220>

<221> source

<223> /note="Description of the artificial sequence:

Synthetic peptide"

<400> 202

Trp Ala Ser

1

<210> 203

<211> 11

<212> PRT

<213> Artificial sequence

<220>

<221> source

<223> /note="Description of the artificial sequence:

Synthetic peptide"

<400> 203

Cys Gln Gln Tyr Tyr Ser Gly Pro Ile Thr Phe

1 5 10

<210> 204

<211> 369

<212> DNA

<213> Artificial sequence

<220>

<221> source

<223> /note="Description of the artificial sequence:

Synthetic polynucleotide"

<400> 204

caggtcacct tgaaggagtc gggcccagga ctggtgaagc cttcacagac cctgtccctc 60

acctgcactg tctctggtgg ctccatcagc agtggtggtc attactggag ctggatccgc 120

cagcacccag ggaagggcct ggagtggatt gggtacatct cttacagtgg gagcacctac 180

tacaacccgt ccctcaagag tcgacttacc atatcagtag acacgtctaa gaaccagttc 240

tccctgaagc tgagctctgt gactgccgcg gacacggccg tgtattactg tgcgaccgcg 300

tattacgata ttttgactgg ttaccctttt gactactggg gccagggaac cctggtcacg 360

gtctcgagt 369

<210> 205

<211> 321

<212> DNA

<213> Artificial sequence

<220>

<221> source

<223> /note="Description of the artificial sequence:

Synthetic polynucleotide"

<400> 205

gaaattgtga tgacacagtc tccagccacc ctgtctttgt ctccagggga aagagccacc 60

ctctcctgca gggccagtca gagtgttagc agctacttag cctggtacca acagaaacct 120

ggccaggctc ccaggctcct catctatgat gcatccgaca gggccactgg catcccagcc 180

aggttcagtg gcagtgggtc tgggacagac ttcactctca ccatcagcag cctagagcct 240

gaagattttg cagtttatta ctgtcagcag cgtagcaact ggccgatcac cttcggccaa 300

gggacacgac tggagatcaa g 321

<210> 206

<211> 123

<212> PRT

<213> Artificial sequence

<220>

<221> source

<223> /note="Description of the artificial sequence:

Synthetic polypeptide"

<400> 206

Gln Val Thr Leu Lys Glu Ser Gly Pro Gly Leu Val Lys Pro Ser Gln

1 5 10 15

Thr Leu Ser Leu Thr Cys Thr Val Ser Gly Gly Ser Ile Ser Ser Gly

20 25 30

Gly His Tyr Trp Ser Trp Ile Arg Gln His Pro Gly Lys Gly Leu Glu

35 40 45

Trp Ile Gly Tyr Ile Ser Tyr Ser Gly Ser Thr Tyr Tyr Asn Pro Ser

50 55 60

Leu Lys Ser Arg Leu Thr Ile Ser Val Asp Thr Ser Lys Asn Gln Phe

65 70 75 80

Ser Leu Lys Leu Ser Ser Val Thr Ala Ala Asp Thr Ala Val Tyr Tyr

85 90 95

Cys Ala Thr Ala Tyr Tyr Asp Ile Leu Thr Gly Tyr Pro Phe Asp Tyr

100 105 110

Trp Gly Gln Gly Thr Leu Val Thr Val Ser Ser

115 120

<210> 207

<211> 107

<212> PRT

<213> Artificial sequence

<220>

<221> source

<223> /note="Description of the artificial sequence:

Synthetic polypeptide"

<400> 207

Glu Ile Val Met 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 Ser Ser Tyr

20 25 30

Leu Ala Trp Tyr Gln Gln Lys Pro Gly Gln Ala Pro Arg Leu Leu Ile

35 40 45

Tyr Asp Ala Ser Asp Arg Ala Thr Gly Ile Pro Ala Arg Phe Ser Gly

50 55 60

Ser Gly Ser Gly Thr Asp Phe Thr Leu Thr Ile Ser Ser Leu Glu Pro

65 70 75 80

Glu Asp Phe Ala Val Tyr Tyr Cys Gln Gln Arg Ser Asn Trp Pro Ile

85 90 95

Thr Phe Gly Gln Gly Thr Arg Leu Glu Ile Lys

100 105

<210> 208

<211> 10

<212> PRT

<213> Artificial sequence

<220>

<221> source

<223> /note="Description of the artificial sequence:

Synthetic peptide"

<400> 208

Gly Gly Ser Ile Ser Ser Gly Gly His Tyr

1 5 10

<210> 209

<211> 7

<212> PRT

<213> Artificial sequence

<220>

<221> source

<223> /note="Description of the artificial sequence:

Synthetic peptide"

<400> 209

Ile Ser Tyr Ser Gly Ser Thr

15

<210> 210

<211> 17

<212> PRT

<213> Artificial sequence

<220>

<221> source

<223> /note="Description of the artificial sequence:

Synthetic peptide"

<400> 210

Cys Ala Thr Ala Tyr Tyr Asp Ile Leu Thr Gly Tyr Pro Phe Asp Tyr

1 5 10 15

trp

<210> 211

<211> 6

<212> PRT

<213> Artificial sequence

<220>

<221> source

<223> /note="Description of the artificial sequence:

Synthetic peptide"

<400> 211

Gln Ser Val Ser Ser Tyr

15

<210> 212

<211> 3

<212> PRT

<213> Artificial sequence

<220>

<221> source

<223> /note="Description of the artificial sequence:

Synthetic peptide"

<400> 212

Asp Ala Ser

1

<210> 213

<211> 11

<212> PRT

<213> Artificial sequence

<220>

<221> source

<223> /note="Description of the artificial sequence:

Synthetic peptide"

<400> 213

Cys Gln Gln Arg Ser Asn Trp Pro Ile Thr Phe

1 5 10

<210> 214

<211> 369

<212> DNA

<213> Artificial sequence

<220>

<221> source

<223> /note="Description of the artificial sequence:

Synthetic polynucleotide"

<400> 214

60

acctgcactg tctctggtgg ctccatcagc agtggtggtt actactggag ctggatccgc 120

cagcacccag ggaagggcct ggagtggatt gggtacatct cttatagtgg gagtatctac 180

tacaacccgt ccctcaagag tcgagttacc atatcagtag acacgtctaa gaaccagttc 240

tccctgaagc tgagctctgt gactgccacg gacacggccg tgtattactg tgcgaccgcg 300

tattacgatc ttttgactgg ttaccctttt gactactggg gccagggaac cctggtcacg 360

gtctcgagt 369

<210> 215

<211> 321

<212> DNA

<213> Artificial sequence

<220>

<221> source

<223> /note="Description of the artificial sequence:

Synthetic polynucleotide"

<400> 215

gaaattgtga tgacgcagtc tccagccacc ctgtctttgt ctccagggga aagagccacc 60

ctctcctgca gggccagtca gagtgttagc agctacttag cctggtacca acagaaacct 120

ggccaggctc ccaggctcct catctatgat gcatccaaca gggccactgg catcccagcc 180

aggttcagtg gcagtgggtc tgggacagac ttcactctca ccatcagcag cctagagcct 240

gaagattttg cagtttatta ctgtcagcag cgtagcaact ggccgatcac cttcggccaa 300

gggacacgac tggagattaa g 321

<210> 216

<211> 123

<212> PRT

<213> Artificial sequence

<220>

<221> source

<223> /note="Description of the artificial sequence:

Synthetic polypeptide"

<400> 216

Gln 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 Thr Val Ser Gly Gly Ser Ile Ser Ser Gly

20 25 30

Gly Tyr Tyr Trp Ser Trp Ile Arg Gln His Pro Gly Lys Gly Leu Glu

35 40 45

Trp Ile Gly Tyr Ile Ser Tyr Ser Gly Ser Ile Tyr Tyr Asn Pro Ser

50 55 60

Leu Lys Ser Arg Val Thr Ile Ser Val Asp Thr Ser Lys Asn Gln Phe

65 70 75 80

Ser Leu Lys Leu Ser Ser Val Thr Ala Thr Asp Thr Ala Val Tyr Tyr

85 90 95

Cys Ala Thr Ala Tyr Tyr Asp Leu Leu Thr Gly Tyr Pro Phe Asp Tyr

100 105 110

Trp Gly Gln Gly Thr Leu Val Thr Val Ser Ser

115 120

<210> 217

<211> 107

<212> PRT

<213> Artificial sequence

<220>

<221> source

<223> /note="Description of the artificial sequence:

Synthetic polypeptide"

<400> 217

Glu Ile Val Met 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 Ser Ser Tyr

20 25 30

Leu Ala Trp Tyr Gln Gln Lys Pro Gly Gln Ala Pro Arg Leu Leu Ile

35 40 45

Tyr Asp Ala Ser Asn Arg Ala Thr Gly Ile Pro Ala Arg Phe Ser Gly

50 55 60

Ser Gly Ser Gly Thr Asp Phe Thr Leu Thr Ile Ser Ser Leu Glu Pro

65 70 75 80

Glu Asp Phe Ala Val Tyr Tyr Cys Gln Gln Arg Ser Asn Trp Pro Ile

85 90 95

Thr Phe Gly Gln Gly Thr Arg Leu Glu Ile Lys

100 105

<210> 218

<211> 10

<212> PRT

<213> Artificial sequence

<220>

<221> source

<223> /note="Description of the artificial sequence:

Synthetic peptide"

<400> 218

Gly Gly Ser Ile Ser Ser Gly Gly Tyr Tyr

1 5 10

<210> 219

<211> 7

<212> PRT

<213> Artificial sequence

<220>

<221> source

<223> /note="Description of the artificial sequence:

Synthetic peptide"

<400> 219

Ile Ser Tyr Ser Gly Ser Ile

15

<210> 220

<211> 17

<212> PRT

<213> Artificial sequence

<220>

<221> source

<223> /note="Description of the artificial sequence:

Synthetic peptide"

<400> 220

Cys Ala Thr Ala Tyr Tyr Asp Leu Leu Thr Gly Tyr Pro Phe Asp Tyr

1 5 10 15

trp

<210> 221

<211> 6

<212> PRT

<213> Artificial sequence

<220>

<221> source

<223> /note="Description of the artificial sequence:

Synthetic peptide"

<400> 221

Gln Ser Val Ser Ser Tyr

15

<210> 222

<211> 3

<212> PRT

<213> Artificial sequence

<220>

<221> source

<223> /note="Description of the artificial sequence:

Synthetic peptide"

<400> 222

Asp Ala Ser

1

<210> 223

<211> 11

<212> PRT

<213> Artificial sequence

<220>

<221> source

<223> /note="Description of the artificial sequence:

Synthetic peptide"

<400> 223

Cys Gln Gln Arg Ser Asn Trp Pro Ile Thr Phe

1 5 10

<210> 224

<211> 379

<212> DNA

<213> Artificial sequence

<220>

<221> source

<223> /note="Description of the artificial sequence:

Synthetic polynucleotide"

<400> 224

ggcgcgccga ggtgcagctg ctggaatctg gaggaggact ggtccagcca ggtggatccc 60

tgcgactgag ctgcgccgct tctggattca cctttacaag atacgacatg gtgtgggtcc 120

gccaggcacc aggaaaggga ctggagtggg tggctggtat cggcgatagt aacaagatga 180

cccgctacgc acctgccgtc aaagggaggg caacaattag tcgggacaac tcaaagaata 240

ctctgtatct gcagatgaat tccctgcgag ctgaggatac agcagtgtac tattgtgcca 300

aaggtagctg catcgcctgt tgggacgaag ctggccgtat tgatgcatgg ggacagggga 360

ctctggtgac cgtctcgag 379

<210> 225

<211> 351

<212> DNA

<213> Artificial sequence

<220>

<221> source

<223> /note="Description of the artificial sequence:

Synthetic polynucleotide"

<400> 225

gctagcctct tacgagctga ctcaggaccc tgcagtgagt gtcgccctgg gccagacagt 60

gagaatcact tgctccggcg gagggagcta cgatggttcc agctactatg gctggtatca 120

gcagaagcca ggacaggcac ctgtgaccgt catctataac aataacaata ggccatctga 180

cattcccgat cggttcagtg gatctagttc agggaacaca gcttctctga ccattacagg 240

agcccaggct gaggacgaag cagattacta ttgtgggtca tacgacaggc cagaaaacaaa 300

ttccgattat gtgggaatgt ttggtagcgg cactaaagtc accgtcctag g 351

<210> 226

<211> 124

<212> PRT

<213> Artificial sequence

<220>

<221> source

<223> /note="Description of the artificial sequence:

Synthetic polypeptide"

<400> 226

Glu Val Gln Leu Leu 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 Thr Arg Tyr

20 25 30

Asp Met Val Trp Val Arg Gln Ala Pro Gly Lys Gly Leu Glu Glu Trp Val

35 40 45

Ala Gly Ile Gly Asp Ser Asn Lys Met Thr Arg Tyr Ala Pro Ala Val

50 55 60

Lys Gly Arg Ala 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 Gly Ser Cys Ile Ala Cys Trp Asp Glu Ala Gly Arg Ile Asp

100 105 110

Ala Trp Gly Gln Gly Thr Leu Val Thr Val Ser Ser

115 120

<210> 227

<211> 114

<212> PRT

<213> Artificial sequence

<220>

<221> source

<223> /note="Description of the artificial sequence:

Synthetic polypeptide"

<400> 227

Ser Tyr Glu Leu Thr Gln Asp Pro Ala Val Ser Val Ala Leu Gly Gln

1 5 10 15

Thr Val Arg Ile Thr Cys Ser Gly Gly Gly Ser Tyr Asp Gly Ser Ser

20 25 30

Tyr Tyr Gly Trp Tyr Gln Gln Lys Pro Gly Gln Ala Pro Val Thr Val

35 40 45

Ile Tyr Asn Asn Asn Asn Arg Pro Ser Asp Ile Pro Asp Arg Phe Ser

50 55 60

Gly Ser Ser Ser Gly Asn Thr Ala Ser Leu Thr Ile Thr Gly Ala Gln

65 70 75 80

Ala Glu Asp Glu Ala Asp Tyr Tyr Cys Gly Ser Tyr Asp Arg Pro Glu

85 90 95

Thr Asn Ser Asp Tyr Val Gly Met Phe Gly Ser Gly Thr Lys Val Thr

100 105 110

Val Leu

<210> 228

<211> 8

<212> PRT

<213> Artificial sequence

<220>

<221> source

<223> /note="Description of the artificial sequence:

Synthetic peptide"

<400> 228

Gly Phe Thr Phe Thr Arg Tyr Asp

15

<210> 229

<211> 8

<212> PRT

<213> Artificial sequence

<220>

<221> source

<223> /note="Description of the artificial sequence:

Synthetic peptide"

<400> 229

Ile Gly Asp Ser Asn Lys Met Thr

15

<210> 230

<211> 19

<212> PRT

<213> Artificial sequence

<220>

<221> source

<223> /note="Description of the artificial sequence:

Synthetic peptide"

<400> 230

Cys Ala Lys Gly Ser Cys Ile Ala Cys Trp Asp Glu Ala Gly Arg Ile

1 5 10 15

Asp Ala Trp

<210> 231

<211> 8

<212> PRT

<213> Artificial sequence

<220>

<221> source

<223> /note="Description of the artificial sequence:

Synthetic peptide"

<400> 231

Gly Ser Tyr Asp Gly Ser Ser Tyr

15

<210> 232

<211> 3

<212> PRT

<213> Artificial sequence

<220>

<221> source

<223> /note="Description of the artificial sequence:

Synthetic peptide"

<400> 232

Asn Asn Asn

1

<210> 233

<211> 17

<212> PRT

<213> Artificial sequence

<220>

<221> source

<223> /note="Description of the artificial sequence:

Synthetic peptide"

<400> 233

Cys Gly Ser Tyr Asp Arg Pro Glu Thr Asn Ser Asp Tyr Val Gly Met

1 5 10 15

Phe

<210> 234

<211> 400

<212> DNA

<213> Artificial sequence

<220>

<221> source

<223> /note="Description of the artificial sequence:

Synthetic polynucleotide"

<400> 234

ggcgcgccga ggtgcagctg ctggaaagcg gaggaggact ggtccagcca ggtggatctc 60

tgcgactgag ttgcgccgct tcaggcttca cattttctga ctacgccatg aactgggtga 120

ggcaggctcc tggcaaggga ctggagtggg tcgcaggaat cgggaacgat ggaagttaca 180

ctaattatgg agcagccgtg aaggggagag ctactatttc ccgcgacaac agcaaaaata 240

ccctgtacct gcagatgaac tcactgagag ctgaagatac cgcagtgtac tattgtgcct 300

ctgacatcag gagtcggaat gattgctcct atttcctggg agggtgttcc agcggcttta 360

ttgacgtgtg gggtcaggggc accctggtca cagtctcgag 400

<210> 235

<211> 321

<212> DNA

<213> Artificial sequence

<220>

<221> source

<223> /note="Description of the artificial sequence:

Synthetic polynucleotide"

<400> 235

gctagcctct tacgagctga cccaggaccc agcagtgtcc gtcgccctgg gccagacagt 60

gagaatcact tgctccggcg gatccagcta cagctatgggg tggttccagc agaagcccgg 120

tcaggcccct gtgaccgtca tctatgaaag taacaatagg ccatcagaca ttcccgatcg 180

gttttctggc tctagttcag gaaacacagc tagtctgacc atcacagggg cccaggctga 240

ggacgaagct gattactatt gtggcaatgc agattccagc tctggaattt tcgggtccgg 300

tactaaagtc accgtcctag g 321

<210> 236

<211> 131

<212> PRT

<213> Artificial sequence

<220>

<221> source

<223> /note="Description of the artificial sequence:

Synthetic polypeptide"

<400> 236

Glu Val Gln Leu Leu 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 Asp Tyr

20 25 30

Ala Met Asn Trp Val Arg Gln Ala Pro Gly Lys Gly Leu Glu Trp Val

35 40 45

Ala Gly Ile Gly Asn Asp Gly Ser Tyr Thr Asn Tyr Gly Ala Ala Val

50 55 60

Lys Gly Arg Ala 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 Ser Asp Ile Arg Ser Arg Asn Asp Cys Ser Tyr Phe Leu Gly Gly

100 105 110

Cys Ser Ser Gly Phe Ile Asp Val Trp Gly Gln Gly Thr Leu Val Thr

115 120 125

Val Ser Ser

130

<210> 237

<211> 104

<212> PRT

<213> Artificial sequence

<220>

<221> source

<223> /note="Description of the artificial sequence:

Synthetic polypeptide"

<400> 237

Ser Tyr Glu Leu Thr Gln Asp Pro Ala Val Ser Val Ala Leu Gly Gln

1 5 10 15

Thr Val Arg Ile Thr Cys Ser Gly Gly Ser Ser Tyr Ser Tyr Gly Trp

20 25 30

Phe Gln Gln Lys Pro Gly Gln Ala Pro Val Thr Val Ile Tyr Glu Ser

35 40 45

Asn Asn Arg Pro Ser Asp Ile Pro Asp Arg Phe Ser Gly Ser Ser Ser

50 55 60

Gly Asn Thr Ala Ser Leu Thr Ile Thr Gly Ala Gln Ala Glu Asp Glu

65 70 75 80

Ala Asp Tyr Tyr Cys Gly Asn Ala Asp Ser Ser Ser Gly Ile Phe Gly

85 90 95

Ser Gly Thr Lys Val Thr Val Leu

100

<210> 238

<211> 8

<212> PRT

<213> Artificial sequence

<220>

<221> source

<223> /note="Description of the artificial sequence:

Synthetic peptide"

<400> 238

Gly Phe Thr Phe Ser Asp Tyr Ala

15

<210> 239

<211> 8

<212> PRT

<213> Artificial sequence

<220>

<221> source

<223> /note="Description of the artificial sequence:

Synthetic peptide"

<400> 239

Ile Gly Asn Asp Gly Ser Tyr Thr

15

<210> 240

<211> 26

<212> PRT

<213> Artificial sequence

<220>

<221> source

<223> /note="Description of the artificial sequence:

Synthetic peptide"

<400> 240

Cys Ala Ser Asp Ile Arg Ser Arg Asn Asp Cys Ser Tyr Phe Leu Gly

1 5 10 15

Gly Cys Ser Ser Gly Phe Ile Asp Val Trp

20 25

<210> 241

<211> 4

<212> PRT

<213> Artificial sequence

<220>

<221> source

<223> /note="Description of the artificial sequence:

Synthetic peptide"

<400> 241

Ser Ser Tyr Ser

1

<210> 242

<211> 3

<212> PRT

<213> Artificial sequence

<220>

<221> source

<223> /note="Description of the artificial sequence:

Synthetic peptide"

<400> 242

Glu Ser Asn

1

<210> 243

<211> 11

<212> PRT

<213> Artificial sequence

<220>

<221> source

<223> /note="Description of the artificial sequence:

Synthetic peptide"

<400> 243

Cys Gly Asn Ala Asp Ser Ser Ser Gly Ile Phe

1 5 10

<210> 244

<211> 385

<212> DNA

<213> Artificial sequence

<220>

<221> source

<223> /note="Description of the artificial sequence:

Synthetic polynucleotide"

<400> 244

ggcgcgccga ggtgcagctg ctggaatccg gaggaggact ggtccagcca ggtggatccc 60

tgcgactgag ctgcgccgct tctggattcg actttagcga tcacgggatg cagtggggtga 120

gacaggcacc aggcaaggga ctggagtacg tgggtgtcat cgacaccaca ggccgctata 180

catactatgc acctgccgtc aagggcaggg ctaccattag tcgggacaac tcaaaaaata 240

cactgtacct gcagatgaac tctctgaggg ctgaagatac tgcagtgtac tattgcgcca 300

aaactacctg cgtgggggg tacctgtgca ataccgtcgg aagtatcgat gcttggggac 360

aggggacact ggtgactgtc tcgag 385

<210> 245

<211> 330

<212> DNA

<213> Artificial sequence

<220>

<221> source

<223> /note="Description of the artificial sequence:

Synthetic polynucleotide"

<400> 245

gctagcctcc tacgagctga ctcaggaccc agcagtgagc gtcgccctgg gccagacagt 60

gagaatcact tgctctggcg gagggtccag ctcttactat ggttggtacc agcagaagcc 120

cggccaggct cctgtgaccg tcatctatga cgatacaaac aggccaagtg gaattcccga 180

tcggttctca ggtagttcat ccggcaatac agcttctctg accatcacag gggcccaggc 240

tgaggacgaa gcagattact attgtggtgg ctatgaagga agctctcacg ccgggatttt 300

tggaagtggg actaaagtca ccgtcctaggg 330

<210> 246

<211> 126

<212> PRT

<213> Artificial sequence

<220>

<221> source

<223> /note="Description of the artificial sequence:

Synthetic polypeptide"

<400> 246

Glu Val Gln Leu Leu 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 Asp Phe Ser Asp His

20 25 30

Gly Met Gln Trp Val Arg Gln Ala Pro Gly Lys Gly Leu Glu Tyr Val

35 40 45

Gly Val Ile Asp Thr Thr Gly Arg Tyr Thr Tyr Tyr Ala Pro Ala Val

50 55 60

Lys Gly Arg Ala 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 Thr Thr Cys Val Gly Gly Tyr Leu Cys Asn Thr Val Gly Ser

100 105 110

Ile Asp Ala Trp Gly Gln Gly Thr Leu Val Thr Val Ser Ser

115 120 125

<210> 247

<211> 107

<212> PRT

<213> Artificial sequence

<220>

<221> source

<223> /note="Description of the artificial sequence:

Synthetic polypeptide"

<400> 247

Ser Tyr Glu Leu Thr Gln Asp Pro Ala Val Ser Val Ala Leu Gly Gln

1 5 10 15

Thr Val Arg Ile Thr Cys Ser Gly Gly Gly Ser Ser Ser Tyr Tyr Gly

20 25 30

Trp Tyr Gln Gln Lys Pro Gly Gln Ala Pro Val Thr Val Ile Tyr Asp

35 40 45

Asp Thr Asn Arg Pro Ser Gly Ile Pro Asp Arg Phe Ser Gly Ser Ser

50 55 60

Ser Gly Asn Thr Ala Ser Leu Thr Ile Thr Gly Ala Gln Ala Glu Asp

65 70 75 80

Glu Ala Asp Tyr Tyr Cys Gly Gly Tyr Glu Gly Ser Ser His Ala Gly

85 90 95

Ile Phe Gly Ser Gly Thr Lys Val Thr Val Leu

100 105

<210> 248

<211> 8

<212> PRT

<213> Artificial sequence

<220>

<221> source

<223> /note="Description of the artificial sequence:

Synthetic peptide"

<400> 248

Gly Phe Asp Phe Ser Asp His Gly

15

<210> 249

<211> 8

<212> PRT

<213> Artificial sequence

<220>

<221> source

<223> /note="Description of the artificial sequence:

Synthetic peptide"

<400> 249

Ile Asp Thr Thr Gly Arg Tyr Thr

15

<210> 250

<211> 21

<212> PRT

<213> Artificial sequence

<220>

<221> source

<223> /note="Description of the artificial sequence:

Synthetic peptide"

<400> 250

Cys Ala Lys Thr Thr Cys Val Gly Gly Tyr Leu Cys Asn Thr Val Gly

1 5 10 15

Ser Ile Asp Ala Trp

20

<210> 251

<211> 5

<212> PRT

<213> Artificial sequence

<220>

<221> source

<223> /note="Description of the artificial sequence:

Synthetic peptide"

<400> 251

Gly Ser Ser Ser Tyr

15

<210> 252

<211> 3

<212> PRT

<213> Artificial sequence

<220>

<221> source

<223> /note="Description of the artificial sequence:

Synthetic peptide"

<400> 252

Asp Asp Thr

1

<210> 253

<211> 13

<212> PRT

<213> Artificial sequence

<220>

<221> source

<223> /note="Description of the artificial sequence:

Synthetic peptide"

<400> 253

Cys Gly Gly Tyr Glu Gly Ser Ser His Ala Gly Ile Phe

1 5 10

<210> 254

<211> 376

<212> DNA

<213> Artificial sequence

<220>

<221> source

<223> /note="Description of the artificial sequence:

Synthetic polynucleotide"

<400> 254

ggcgcgccga ggtgcagctg ctggaaagtg gaggaggact ggtccagcca ggtggaagcc 60

tgagactgtc ttgcgccgct agtggcttcg acttttccag ctacaccatg cagtgggtga 120

ggcaggcacc aggcaaggga ctggagtggg tgggcgtcat ctctagtact ggagggtcta 180

ccggatacgg gcctgctgtg aagggaaggg caacaatttc acgggataac tccaaaaata 240

ctctgtatct gcagatgaac agcctgaggg cagaagacac agccgtgtac tattgcgtga 300

aatcaatctc cggagatgcc tggtctgtgg acgggctgga tgcttggggt cagggcaccc 360

tggtcacagt ctcgag 376

<210> 255

<211> 321

<212> DNA

<213> Artificial sequence

<220>

<221> source

<223> /note="Description of the artificial sequence:

Synthetic polynucleotide"

<400> 255

gctagcctca tacgagctga cccaggaccc agcagtgtcc gtcgccctgg gacagacagt 60

gagaatcact tgctccggag gaggatccgc ctacggttgg tatcagcaga agcccggcca 120

ggcacctgtg accgtcatct actataacaa tcagaggcca tctggcattc ccgaccggtt 180

cagtggatcc agctctggga acacagcaag tctgaccatc acaggcgccc aggctgagga 240

cgaagccgat tactattgtg gaagctatga tagttcagct gtggggattt ttggttctgg 300

cactaaagtc accgtcctag g 321

<210> 256

<211> 123

<212> PRT

<213> Artificial sequence

<220>

<221> source

<223> /note="Description of the artificial sequence:

Synthetic polypeptide"

<400> 256

Glu Val Gln Leu Leu 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 Asp Phe Ser Ser Tyr

20 25 30

Thr Met Gln Trp Val Arg Gln Ala Pro Gly Lys Gly Leu Glu Trp Val

35 40 45

Gly Val Ile Ser Ser Thr Gly Gly Ser Thr Gly Tyr Gly Pro Ala Val

50 55 60

Lys Gly Arg Ala 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

Val Lys Ser Ile Ser Gly Asp Ala Trp Ser Val Asp Gly Leu Asp Ala

100 105 110

Trp Gly Gln Gly Thr Leu Val Thr Val Ser Ser

115 120

<210> 257

<211> 104

<212> PRT

<213> Artificial sequence

<220>

<221> source

<223> /note="Description of the artificial sequence:

Synthetic polypeptide"

<400> 257

Ser Tyr Glu Leu Thr Gln Asp Pro Ala Val Ser Val Ala Leu Gly Gln

1 5 10 15

Thr Val Arg Ile Thr Cys Ser Gly Gly Gly Ser Ala Tyr Gly Trp Tyr

20 25 30

Gln Gln Lys Pro Gly Gln Ala Pro Val Thr Val Ile Tyr Tyr Asn Asn

35 40 45

Gln Arg Pro Ser Gly Ile Pro Asp Arg Phe Ser Gly Ser Ser Ser Gly

50 55 60

Asn Thr Ala Ser Leu Thr Ile Thr Gly Ala Gln Ala Glu Asp Glu Ala

65 70 75 80

Asp Tyr Tyr Cys Gly Ser Tyr Asp Ser Ser Ala Val Gly Ile Phe Gly

85 90 95

Ser Gly Thr Lys Val Thr Val Leu

100

<210> 258

<211> 8

<212> PRT

<213> Artificial sequence

<220>

<221> source

<223> /note="Description of the artificial sequence:

Synthetic peptide"

<400> 258

Gly Phe Asp Phe Ser Ser Tyr Thr

15

<210> 259

<211> 8

<212> PRT

<213> Artificial sequence

<220>

<221> source

<223> /note="Description of the artificial sequence:

Synthetic peptide"

<400> 259

Ile Ser Ser Thr Gly Gly Ser Thr

15

<210> 260

<211> 18

<212> PRT

<213> Artificial sequence

<220>

<221> source

<223> /note="Description of the artificial sequence:

Synthetic peptide"

<400> 260

Cys Val Lys Ser Ile Ser Gly Asp Ala Trp Ser Val Asp Gly Leu Asp

1 5 10 15

Ala Trp

<210> 261

<211> 3

<212> PRT

<213> Artificial sequence

<220>

<221> source

<223> /note="Description of the artificial sequence:

Synthetic peptide"

<400> 261

Gly Ser Ala

1

<210> 262

<211> 3

<212> PRT

<213> Artificial sequence

<220>

<221> source

<223> /note="Description of the artificial sequence:

Synthetic peptide"

<400> 262

Tyr Asn Asn

1

<210> 263

<211> 12

<212> PRT

<213> Artificial sequence

<220>

<221> source

<223> /note="Description of the artificial sequence:

Synthetic peptide"

<400> 263

Cys Gly Ser Tyr Asp Ser Ser Ala Val Gly Ile Phe

1 5 10

<210> 264

<211> 376

<212> DNA

<213> Artificial sequence

<220>

<221> source

<223> /note="Description of the artificial sequence:

Synthetic polynucleotide"

<400> 264

ggcgcgccga ggtgcagctg ctggaaagtg gaggaggact ggtccagcca ggtggaagcc 60

tgagactgtc ttgcgccgct agtggcttcg acttttccag ctacaccatg cagtgggtga 120

ggcaggcacc aggcaaggga ctggagtggg tgggcgtcat ctctagtact ggagggtcta 180

ccggatacgg gcctgctgtg aagggaaggg caacaatttc acgggataac tccaaaaata 240

ctctgtatct gcagatgaac agcctgaggg cagaagacac agccgtgtac tattgcgtga 300

aatcagtctc cggagatgcc tggtctgtgg acgggctgga tgcttggggt cagggcaccc 360

tggtcacagt ctcgag 376

<210> 265

<211> 321

<212> DNA

<213> Artificial sequence

<220>

<221> source

<223> /note="Description of the artificial sequence:

Synthetic polynucleotide"

<400> 265

gctagcctca tacgagctga cccaggaccc agcagtgtcc gtcgccctgg gccagacagt 60

gagaatcact tgctccggag gaggatccgc ctacggttgg tatcagcaga agcccggcca 120

ggcacctgtg accgtcatct actataacaa tcagaggcca tctgacattc ccgatcggtt 180

cagtggatcc agctctggga acacagcaag tctgaccatc acaggcgccc aggctgagga 240

cgaagccgat tactattgtg gaagctatga tagttcagct gtggggattt ttggttctgg 300

cactaaagtc accgtcctag g 321

<210> 266

<211> 123

<212> PRT

<213> Artificial sequence

<220>

<221> source

<223> /note="Description of the artificial sequence:

Synthetic polypeptide"

<400> 266

Glu Val Gln Leu Leu 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 Asp Phe Ser Ser Tyr

20 25 30

Thr Met Gln Trp Val Arg Gln Ala Pro Gly Lys Gly Leu Glu Trp Val

35 40 45

Gly Val Ile Ser Ser Thr Gly Gly Ser Thr Gly Tyr Gly Pro Ala Val

50 55 60

Lys Gly Arg Ala 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

Val Lys Ser Val Ser Gly Asp Ala Trp Ser Val Asp Gly Leu Asp Ala

100 105 110

Trp Gly Gln Gly Thr Leu Val Thr Val Ser Ser

115 120

<210> 267

<211> 104

<212> PRT

<213> Artificial sequence

<220>

<221> source

<223> /note="Description of the artificial sequence:

Synthetic polypeptide"

<400> 267

Ser Tyr Glu Leu Thr Gln Asp Pro Ala Val Ser Val Ala Leu Gly Gln

1 5 10 15

Thr Val Arg Ile Thr Cys Ser Gly Gly Gly Ser Ala Tyr Gly Trp Tyr

20 25 30

Gln Gln Lys Pro Gly Gln Ala Pro Val Thr Val Ile Tyr Tyr Asn Asn

35 40 45

Gln Arg Pro Ser Asp Ile Pro Asp Arg Phe Ser Gly Ser Ser Ser Gly

50 55 60

Asn Thr Ala Ser Leu Thr Ile Thr Gly Ala Gln Ala Glu Asp Glu Ala

65 70 75 80

Asp Tyr Tyr Cys Gly Ser Tyr Asp Ser Ser Ala Val Gly Ile Phe Gly

85 90 95

Ser Gly Thr Lys Val Thr Val Leu

100

<210> 268

<211> 8

<212> PRT

<213> Artificial sequence

<220>

<221> source

<223> /note="Description of the artificial sequence:

Synthetic peptide"

<400> 268

Gly Phe Asp Phe Ser Ser Tyr Thr

15

<210> 269

<211> 8

<212> PRT

<213> Artificial sequence

<220>

<221> source

<223> /note="Description of the artificial sequence:

Synthetic peptide"

<400> 269

Ile Ser Ser Thr Gly Gly Ser Thr

15

<210> 270

<211> 18

<212> PRT

<213> Artificial sequence

<220>

<221> source

<223> /note="Description of the artificial sequence:

Synthetic peptide"

<400> 270

Cys Val Lys Ser Val Ser Gly Asp Ala Trp Ser Val Asp Gly Leu Asp

1 5 10 15

Ala Trp

<210> 271

<211> 3

<212> PRT

<213> Artificial sequence

<220>

<221> source

<223> /note="Description of the artificial sequence:

Synthetic peptide"

<400> 271

Gly Ser Ala

1

<210> 272

<211> 3

<212> PRT

<213> Artificial sequence

<220>

<221> source

<223> /note="Description of the artificial sequence:

Synthetic peptide"

<400> 272

Tyr Asn Asn

1

<210> 273

<211> 12

<212> PRT

<213> Artificial sequence

<220>

<221> source

<223> /note="Description of the artificial sequence:

Synthetic peptide"

<400> 273

Cys Gly Ser Tyr Asp Ser Ser Ala Val Gly Ile Phe

1 5 10

<210> 274

<211> 385

<212> DNA

<213> Artificial sequence

<220>

<221> source

<223> /note="Description of the artificial sequence:

Synthetic polynucleotide"

<400> 274

ggcgcgccga ggtgcagctg ctggaatccg gaggaggact ggtccagcca ggtggaagcc 60

tgcgactgtc ttgcgccgct agtggattcg acttttccag ctacggaatg cagtggggtga 120

ggcaggcacc aggcaaggga ctggagtggg tgggcgtcat ctctggaagt gggattacca 180

cactgtacgc acctgccgtc aagggaaggg ctactatctc acgggacaac tctaaaaata 240

cagtgtatct gcagatgaac tccctgagag ctgaagatac cgcagtctac tattgtacac 300

gctcaccctc catcacagac ggctggactt atggaggggc ctggattgat gcttggggtc 360

agggcactct ggtgaccgtc tcgag 385

<210> 275

<211> 318

<212> DNA

<213> Artificial sequence

<220>

<221> source

<223> /note="Description of the artificial sequence:

Synthetic polynucleotide"

<400> 275

gctagccagc tacgagctga cccaggaccc agcagtgtcc gtcgccctgg gccagacagt 60

gagaatcact tgcagtggcg gagatgggtc atacggttgg ttccagcaga agcccggaca 120

ggcccctgtg accgtcatct atgacaacga taataggcca tctgacattc ccgatcggtt 180

tagtggctcc agctctggaa acacagcttc tctgaccatc acaggggccc aggctgagga 240

cgaagctgat tactattgtg gcaatgcaga cctgtccggg ggtattttcg gcagcggaac 300

taaagtcacc gtctaggg 318

<210> 276

<211> 126

<212> PRT

<213> Artificial sequence

<220>

<221> source

<223> /note="Description of the artificial sequence:

Synthetic polypeptide"

<400> 276

Glu Val Gln Leu Leu 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 Asp Phe Ser Ser Tyr

20 25 30

Gly Met Gln Trp Val Arg Gln Ala Pro Gly Lys Gly Leu Glu Trp Val

35 40 45

Gly Val Ile Ser Gly Ser Gly Ile Thr Thr Leu Tyr Ala Pro Ala Val

50 55 60

Lys Gly Arg Ala Thr Ile Ser Arg Asp Asn Ser Lys Asn Thr Val Tyr

65 70 75 80

Leu Gln Met Asn Ser Leu Arg Ala Glu Asp Thr Ala Val Tyr Tyr Cys

85 90 95

Thr Arg Ser Pro Ser Ile Thr Asp Gly Trp Thr Tyr Gly Gly Ala Trp

100 105 110

Ile Asp Ala Trp Gly Gln Gly Thr Leu Val Thr Val Ser Ser

115 120 125

<210> 277

<211> 103

<212> PRT

<213> Artificial sequence

<220>

<221> source

<223> /note="Description of the artificial sequence:

Synthetic polypeptide"

<400> 277

Ser Tyr Glu Leu Thr Gln Asp Pro Ala Val Ser Val Ala Leu Gly Gln

1 5 10 15

Thr Val Arg Ile Thr Cys Ser Gly Gly Asp Gly Ser Tyr Gly Trp Phe

20 25 30

Gln Gln Lys Pro Gly Gln Ala Pro Val Thr Val Ile Tyr Asp Asn Asp

35 40 45

Asn Arg Pro Ser Asp Ile Pro Asp Arg Phe Ser Gly Ser Ser Ser Gly

50 55 60

Asn Thr Ala Ser Leu Thr Ile Thr Gly Ala Gln Ala Glu Asp Glu Ala

65 70 75 80

Asp Tyr Tyr Cys Gly Asn Ala Asp Leu Ser Gly Gly Ile Phe Gly Ser

85 90 95

Gly Thr Lys Val Thr Val Leu

100

<210> 278

<211> 8

<212> PRT

<213> Artificial sequence

<220>

<221> source

<223> /note="Description of the artificial sequence:

Synthetic peptide"

<400> 278

Gly Phe Asp Phe Ser Ser Tyr Gly

15

<210> 279

<211> 8

<212> PRT

<213> Artificial sequence

<220>

<221> source

<223> /note="Description of the artificial sequence:

Synthetic peptide"

<400> 279

Ile Ser Gly Ser Gly Ile Thr Thr

15

<210> 280

<211> 21

<212> PRT

<213> Artificial sequence

<220>

<221> source

<223> /note="Description of the artificial sequence:

Synthetic peptide"

<400> 280

Cys Thr Arg Ser Pro Ser Ile Thr Asp Gly Trp Thr Tyr Gly Gly Ala

1 5 10 15

Trp Ile Asp Ala Trp

20

<210> 281

<211> 3

<212> PRT

<213> Artificial sequence

<220>

<221> source

<223> /note="Description of the artificial sequence:

Synthetic peptide"

<400> 281

Asp Gly Ser

1

<210> 282

<211> 3

<212> PRT

<213> Artificial sequence

<220>

<221> source

<223> /note="Description of the artificial sequence:

Synthetic peptide"

<400> 282

Asp Asn Asp

1

<210> 283

<211> 11

<212> PRT

<213> Artificial sequence

<220>

<221> source

<223> /note="Description of the artificial sequence:

Synthetic peptide"

<400> 283

Cys Gly Asn Ala Asp Leu Ser Gly Gly Ile Phe

1 5 10

<210> 284

<211> 388

<212> DNA

<213> Artificial sequence

<220>

<221> source

<223> /note="Description of the artificial sequence:

Synthetic polynucleotide"

<400> 284

ggcgcgccga ggtgcagctg ctggaatctg gaggaggact ggtccagcca ggtggatccc 60

tgagactgag ctgcgccgct tctggattca cctttagtac attcaacatg gtgtggggtca 120

ggcaggcacc tggaaaggga ctggagtacg tggctgaaat ctccagcgac ggctctttta 180

catggtatgc aactgccgtc aagggcaggg ccaccattag tcgggataac tcaaaaaata 240

cagtgtacct gcagatgaat tccctgaggg ctgaggacac cgcagtctac tattgcgcaa 300

aatccgattg ttctagttca tactatggat atagctgtat cgggatcatt gacgcttggg 360

gtcagggcac tctggtgacc gtctcgag 388

<210> 285

<211> 339

<212> DNA

<213> Artificial sequence

<220>

<221> source

<223> /note="Description of the artificial sequence:

Synthetic polynucleotide"

<400> 285

gctagcctcc tatgagctga cccaggaccc agcagtgagc gtcgccctgg gccagacagt 60

gagaatcact tgctccggcg gaattagcga cgatggctct tactattacg gatggttcca 120

gcagaagccc ggacaggccc ctgtgaccgt catctatatt aacgacaggc ggccaagtaa 180

tatccccgat aggttttcag ggtccagctc tggtaacaca gcttctctga ccattacagg 240

ggcccaggct gaggacgaag ctgattatta ctgtggctct tacgatagtt cagcaggggt 300

gggtatcttc ggcagtggaa ctaaagtcac cgtcctaggg 339

<210> 286

<211> 127

<212> PRT

<213> Artificial sequence

<220>

<221> source

<223> /note="Description of the artificial sequence:

Synthetic polypeptide"

<400> 286

Glu Val Gln Leu Leu 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 Thr Phe

20 25 30

Asn Met Val Trp Val Arg Gln Ala Pro Gly Lys Gly Leu Glu Tyr Val

35 40 45

Ala Glu Ile Ser Ser Asp Gly Ser Phe Thr Trp Tyr Ala Thr Ala Val

50 55 60

Lys Gly Arg Ala Thr Ile Ser Arg Asp Asn Ser Lys Asn Thr Val 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 Ser Asp Cys Ser Ser Tyr Tyr Gly Tyr Ser Cys Ile Gly

100 105 110

Ile Ile Asp Ala Trp Gly Gln Gly Thr Leu Val Thr Val Ser Ser

115 120 125

<210> 287

<211> 110

<212> PRT

<213> Artificial sequence

<220>

<221> source

<223> /note="Description of the artificial sequence:

Synthetic polypeptide"

<400> 287

Ser Tyr Glu Leu Thr Gln Asp Pro Ala Val Ser Val Ala Leu Gly Gln

1 5 10 15

Thr Val Arg Ile Thr Cys Ser Gly Gly Ile Ser Asp Asp Gly Ser Tyr

20 25 30

Tyr Tyr Gly Trp Phe Gln Gln Lys Pro Gly Gln Ala Pro Val Thr Val

35 40 45

Ile Tyr Ile Asn Asp Arg Arg Pro Ser Asn Ile Pro Asp Arg Phe Ser

50 55 60

Gly Ser Ser Ser Gly Asn Thr Ala Ser Leu Thr Ile Thr Gly Ala Gln

65 70 75 80

Ala Glu Asp Glu Ala Asp Tyr Tyr Cys Gly Ser Tyr Asp Ser Ser Ala

85 90 95

Gly Val Gly Ile Phe Gly Ser Gly Thr Lys Val Thr Val Leu

100 105 110

<210> 288

<211> 8

<212> PRT

<213> Artificial sequence

<220>

<221> source

<223> /note="Description of the artificial sequence:

Synthetic peptide"

<400> 288

Gly Phe Thr Phe Ser Thr Phe Asn

15

<210> 289

<211> 8

<212> PRT

<213> Artificial sequence

<220>

<221> source

<223> /note="Description of the artificial sequence:

Synthetic peptide"

<400> 289

Ile Ser Ser Asp Gly Ser Phe Thr

15

<210> 290

<211> 22

<212> PRT

<213> Artificial sequence

<220>

<221> source

<223> /note="Description of the artificial sequence:

Synthetic peptide"

<400> 290

Cys Ala Lys Ser Asp Cys Ser Ser Ser Tyr Tyr Gly Tyr Ser Cys Ile

1 5 10 15

Gly Ile Ile Asp Ala Trp

20

<210> 291

<211> 8

<212> PRT

<213> Artificial sequence

<220>

<221> source

<223> /note="Description of the artificial sequence:

Synthetic peptide"

<400> 291

Ile Ser Asp Asp Gly Ser Tyr Tyr

15

<210> 292

<211> 3

<212> PRT

<213> Artificial sequence

<220>

<221> source

<223> /note="Description of the artificial sequence:

Synthetic peptide"

<400> 292

Ile Asn Asp

1

<210> 293

<211> 13

<212> PRT

<213> Artificial sequence

<220>

<221> source

<223> /note="Description of the artificial sequence:

Synthetic peptide"

<400> 293

Cys Gly Ser Tyr Asp Ser Ser Ala Gly Val Gly Ile Phe

1 5 10

<210> 294

<211> 400

<212> DNA

<213> Artificial sequence

<220>

<221> source

<223> /note="Description of the artificial sequence:

Synthetic polynucleotide"

<400> 294

ggcgcgccga ggtgcagctg ctggaaagtg gaggaggact ggtccagcca ggtggatcac 60

tgagactgtc ctgcgccgcc tccggcttca ccttttccag ctacaacatg ttctgggtgc 120

gccaggcacc aggaaaggga ctggagtttg tcgctgaaat ctctggtagt aatactggaa 180

gccgaacctg gtacgcacct gccgtgaagg gcagggctac aatttctcgg gacaacagta 240

aaaatactct gtatctgcag atgaactctc tgagggctga ggatacagca gtgtactatt 300

gtgcaaaatc aatctacgga gggtattgcg ccggtggcta ttcctgtggt gtgggcctga 360

ttgacgcatg gggacagggg accctggtca cagtctcgag 400

<210> 295

<211> 321

<212> DNA

<213> Artificial sequence

<220>

<221> source

<223> /note="Description of the artificial sequence:

Synthetic polynucleotide"

<400> 295

gctagcctca tacgagctga cccaggaccc agcagtgtcc gtcgccctgg gccagacagt 60

gagaatcact tgcagtggcg gatccagcga ttactatgggg tggttccagc agaagcccgg 120

tcaggcccct gtgaccgtca tctactataa caacaagagg ccatctgaca ttcccgatcg 180

gtttagtggc tctagttcag gaaacacagc ctccctgacc attacagggg cccaggctga 240

ggacgaagct gattactatt gtggcaatgc agactccagc gtgggagtct tcgggtctgg 300

tactaaggtg accgtcctag g 321

<210> 296

<211> 131

<212> PRT

<213> Artificial sequence

<220>

<221> source

<223> /note="Description of the artificial sequence:

Synthetic polypeptide"

<400> 296

Glu Val Gln Leu Leu 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

Asn Met Phe Trp Val Arg Gln Ala Pro Gly Lys Gly Leu Glu Phe Val

35 40 45

Ala Glu Ile Ser Gly Ser Asn Thr Gly Ser Arg Thr Trp Tyr Ala Pro

50 55 60

Ala Val Lys Gly Arg Ala Thr Ile Ser Arg Asp Asn Ser Lys Asn Thr

65 70 75 80

Leu Tyr Leu Gln Met Asn Ser Leu Arg Ala Glu Asp Thr Ala Val Tyr

85 90 95

Tyr Cys Ala Lys Ser Ile Tyr Gly Gly Tyr Cys Ala Gly Gly Tyr Ser

100 105 110

Cys Gly Val Gly Leu Ile Asp Ala Trp Gly Gln Gly Thr Leu Val Thr

115 120 125

Val Ser Ser

130

<210> 297

<211> 104

<212> PRT

<213> Artificial sequence

<220>

<221> source

<223> /note="Description of the artificial sequence:

Synthetic polypeptide"

<400> 297

Ser Tyr Glu Leu Thr Gln Asp Pro Ala Val Ser Val Ala Leu Gly Gln

1 5 10 15

Thr Val Arg Ile Thr Cys Ser Gly Gly Ser Ser Asp Tyr Tyr Gly Trp

20 25 30

Phe Gln Gln Lys Pro Gly Gln Ala Pro Val Thr Val Ile Tyr Tyr Asn

35 40 45

Asn Lys Arg Pro Ser Asp Ile Pro Asp Arg Phe Ser Gly Ser Ser Ser

50 55 60

Gly Asn Thr Ala Ser Leu Thr Ile Thr Gly Ala Gln Ala Glu Asp Glu

65 70 75 80

Ala Asp Tyr Tyr Cys Gly Asn Ala Asp Ser Ser Val Gly Val Phe Gly

85 90 95

Ser Gly Thr Lys Val Thr Val Leu

100

<210> 298

<211> 8

<212> PRT

<213> Artificial sequence

<220>

<221> source

<223> /note="Description of the artificial sequence:

Synthetic peptide"

<400> 298

Gly Phe Thr Phe Ser Ser Tyr Asn

15

<210> 299

<211> 10

<212> PRT

<213> Artificial sequence

<220>

<221> source

<223> /note="Description of the artificial sequence:

Synthetic peptide"

<400> 299

Ile Ser Gly Ser Asn Thr Gly Ser Arg Thr

1 5 10

<210> 300

<211> 24

<212> PRT

<213> Artificial sequence

<220>

<221> source

<223> /note="Description of the artificial sequence:

Synthetic peptide"

<400> 300

Cys Ala Lys Ser Ile Tyr Gly Gly Tyr Cys Ala Gly Gly Tyr Ser Cys

1 5 10 15

Gly Val Gly Leu Ile Asp Ala Trp

20

<210> 301

<211> 4

<212> PRT

<213> Artificial sequence

<220>

<221> source

<223> /note="Description of the artificial sequence:

Synthetic peptide"

<400> 301

Ser Ser Asp Tyr

1

<210> 302

<211> 3

<212> PRT

<213> Artificial sequence

<220>

<221> source

<223> /note="Description of the artificial sequence:

Synthetic peptide"

<400> 302

Tyr Asn Asn

1

<210> 303

<211> 11

<212> PRT

<213> Artificial sequence

<220>

<221> source

<223> /note="Description of the artificial sequence:

Synthetic peptide"

<400> 303

Cys Gly Asn Ala Asp Ser Ser Val Gly Val Phe

1 5 10

<210> 304

<211> 357

<212> DNA

<213> Artificial sequence

<220>

<221> source

<223> /note="Description of the artificial sequence:

Synthetic polynucleotide"

<400> 304

caggtgcagc tgcagcagtg gggtgccggt ctgctgaagc cttctgaaac tctgtctctg 60

acttgtgccg tctatggtgg atcattcagc ggctactatt ggtcctggat caggcagccc 120

cctggcaagg gcctggagtg gatcggcgag atcaaccacc ggggctctac caactacaat 180

ccctctctga agagcagggt gaccatctcc gtggacacat ctaagaatca gttcagcctg 240

aagctgagct ccgtgaccgc cgctgataca gccgtgtact attgcacaag gggggaggaa 300

tgggagtcac tgttctttga ttactggggg caggggacac tggtcacagt ctcgagt 357

<210> 305

<211> 321

<212> DNA

<213> Artificial sequence

<220>

<221> source

<223> /note="Description of the artificial sequence:

Synthetic polynucleotide"

<400> 305

gaaatcgtcc tgacccagtc ccccgccacc ctgagcctga gccccggaga aagagccacc 60

ctgtcctgcc gagcaagcca gtccatcagc tcctatctcg cctggtatca gcagaaacca 120

ggccaggctc cccggctgct gatctacggc gcctccaaca gagctacagg aatcccagcc 180

cgcttcagcg gctccggctc tggcacagac tttaccctga caatctctag cctggagcct 240

gaggatttcg ccgtgtacta ttgccagcag agatctaatt ggccactgac attcggcggc 300

ggcacacgggg tggagatcaa g 321

<210> 306

<211> 119

<212> PRT

<213> Artificial sequence

<220>

<221> source

<223> /note="Description of the artificial sequence:

Synthetic polypeptide"

<400> 306

Gln Val Gln Leu Gln Gln Trp Gly Ala Gly Leu Leu Lys Pro Ser Glu

1 5 10 15

Thr Leu Ser Leu Thr Cys Ala Val Tyr Gly Gly Ser Phe Ser Gly Tyr

20 25 30

Tyr Trp Ser Trp Ile Arg Gln Pro Pro Gly Lys Gly Leu Glu Trp Ile

35 40 45

Gly Glu Ile Asn His Arg Gly Ser Thr Asn Tyr Asn Pro Ser Leu Lys

50 55 60

Ser Arg Val Thr Ile Ser Val Asp Thr Ser Lys Asn Gln Phe Ser Leu

65 70 75 80

Lys Leu Ser Ser Val Thr Ala Ala Asp Thr Ala Val Tyr Tyr Cys Thr

85 90 95

Arg Gly Glu Glu Trp Glu Ser Leu Phe Phe Asp Tyr Trp Gly Gln Gly

100 105 110

Thr Leu Val Thr Val Ser Ser

115

<210> 307

<211> 107

<212> PRT

<213> Artificial sequence

<220>

<221> source

<223> /note="Description of the artificial sequence:

Synthetic polypeptide"

<400> 307

Glu Ile Val 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 Ile Ser Ser Tyr

20 25 30

Leu Ala Trp Tyr Gln Gln Lys Pro Gly Gln Ala Pro Arg Leu Leu Ile

35 40 45

Tyr Gly Ala Ser Asn Arg Ala Thr Gly Ile Pro Ala Arg Phe Ser Gly

50 55 60

Ser Gly Ser Gly Thr Asp Phe Thr Leu Thr Ile Ser Ser Leu Glu Pro

65 70 75 80

Glu Asp Phe Ala Val Tyr Tyr Cys Gln Gln Arg Ser Asn Trp Pro Leu

85 90 95

Thr Phe Gly Gly Gly Thr Arg Val Glu Ile Lys

100 105

<210> 308

<211> 8

<212> PRT

<213> Artificial sequence

<220>

<221> source

<223> /note="Description of the artificial sequence:

Synthetic peptide"

<400> 308

Gly Gly Ser Phe Ser Gly Tyr Tyr

15

<210> 309

<211> 7

<212> PRT

<213> Artificial sequence

<220>

<221> source

<223> /note="Description of the artificial sequence:

Synthetic peptide"

<400> 309

Ile Asn His Arg Gly Ser Thr

15

<210> 310

<211> 15

<212> PRT

<213> Artificial sequence

<220>

<221> source

<223> /note="Description of the artificial sequence:

Synthetic peptide"

<400> 310

Cys Thr Arg Gly Glu Glu Trp Glu Ser Leu Phe Phe Asp Tyr Trp

1 5 10 15

<210> 311

<211> 6

<212> PRT

<213> Artificial sequence

<220>

<221> source

<223> /note="Description of the artificial sequence:

Synthetic peptide"

<400> 311

Gln Ser Ile Ser Ser Tyr

15

<210> 312

<211> 3

<212> PRT

<213> Artificial sequence

<220>

<221> source

<223> /note="Description of the artificial sequence:

Synthetic peptide"

<400> 312

Gly Ala Ser

1

<210> 313

<211> 11

<212> PRT

<213> Artificial sequence

<220>

<221> source

<223> /note="Description of the artificial sequence:

Synthetic peptide"

<400> 313

Cys Gln Gln Arg Ser Asn Trp Pro Leu Thr Phe

1 5 10

<210> 314

<211> 366

<212> DNA

<213> Artificial sequence

<220>

<221> source

<223> /note="Description of the artificial sequence:

Synthetic polynucleotide"

<400> 314

caggttcagc tgcagcagtg gggcgccggc ctgctgagac caagcgagac cctgtccctg 60

acatgcgccg tgtatggcga gagcttctcc ggctattact ggaactggat ccggcagcct 120

cccggcaagg gcctggagtg gatcggcgag atcaatcact ccggctccac caattacaac 180

ccatccctga agtctcgggt gacaatcagc gtggatacaa gcaagaccca gttcagcctg 240

aagctgagct ccgtgacagc tgccgatacc gccgtgtatt actgcgccag aggctgggac 300

ctgctggatt ggaatgacta ctggaatgag tactggggcc aggggaccct ggtgaccgtc 360

tcgagt 366

<210> 315

<211> 321

<212> DNA

<213> Artificial sequence

<220>

<221> source

<223> /note="Description of the artificial sequence:

Synthetic polynucleotide"

<400> 315

gagatcgtgc tgacccagtc ccctgccacc ctgtctctgt cccctggcga gcgggccacc 60

ctgtcctgta gagcttctca gtccgtgtct tcctacctgg cttggtacca gcagaagcca 120

ggacaggccc caagactgct gatctatgac gcttccaatc gggctaccgg catcccagct 180

cgctttagcg gctccggctc cggcaccgac ttcaccctga caatcagctc cctggagcca 240

gaggattttg ccgtgtatta ctgtcagcag aggtccaatt ggccactgac atttggcggc 300

ggcacaaagg ttgagatcaa g 321

<210> 316

<211> 122

<212> PRT

<213> Artificial sequence

<220>

<221> source

<223> /note="Description of the artificial sequence:

Synthetic polypeptide"

<400> 316

Gln Val Gln Leu Gln Gln Trp Gly Ala Gly Leu Leu Arg Pro Ser Glu

1 5 10 15

Thr Leu Ser Leu Thr Cys Ala Val Tyr Gly Glu Ser Phe Ser Gly Tyr

20 25 30

Tyr Trp Asn Trp Ile Arg Gln Pro Pro Gly Lys Gly Leu Glu Trp Ile

35 40 45

Gly Glu Ile Asn His Ser Gly Ser Thr Asn Tyr Asn Pro Ser Leu Lys

50 55 60

Ser Arg Val Thr Ile Ser Val Asp Thr Ser Lys Thr Gln Phe Ser Leu

65 70 75 80

Lys Leu Ser Ser Val Thr Ala Ala Asp Thr Ala Val Tyr Tyr Cys Ala

85 90 95

Arg Gly Trp Asp Leu Leu Asp Trp Asn Asp Tyr Trp Asn Glu Tyr Trp

100 105 110

Gly Gln Gly Thr Leu Val Thr Val Ser Ser

115 120

<210> 317

<211> 107

<212> PRT

<213> Artificial sequence

<220>

<221> source

<223> /note="Description of the artificial sequence:

Synthetic polypeptide"

<400> 317

Glu Ile Val 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 Ser Ser Tyr

20 25 30

Leu Ala Trp Tyr Gln Gln Lys Pro Gly Gln Ala Pro Arg Leu Leu Ile

35 40 45

Tyr Asp Ala Ser Asn Arg Ala Thr Gly Ile Pro Ala Arg Phe Ser Gly

50 55 60

Ser Gly Ser Gly Thr Asp Phe Thr Leu Thr Ile Ser Ser Leu Glu Pro

65 70 75 80

Glu Asp Phe Ala Val Tyr Tyr Cys Gln Gln Arg Ser Asn Trp Pro Leu

85 90 95

Thr Phe Gly Gly Gly Thr Lys Val Glu Ile Lys

100 105

<210> 318

<211> 8

<212> PRT

<213> Artificial sequence

<220>

<221> source

<223> /note="Description of the artificial sequence:

Synthetic peptide"

<400> 318

Gly Glu Ser Phe Ser Gly Tyr Tyr

15

<210> 319

<211> 7

<212> PRT

<213> Artificial sequence

<220>

<221> source

<223> /note="Description of the artificial sequence:

Synthetic peptide"

<400> 319

Ile Asn His Ser Gly Ser Thr

15

<210> 320

<211> 18

<212> PRT

<213> Artificial sequence

<220>

<221> source

<223> /note="Description of the artificial sequence:

Synthetic peptide"

<400> 320

Cys Ala Arg Gly Trp Asp Leu Leu Asp Trp Asn Asp Tyr Trp Asn Glu

1 5 10 15

Tyr Trp

<210> 321

<211> 6

<212> PRT

<213> Artificial sequence

<220>

<221> source

<223> /note="Description of the artificial sequence:

Synthetic peptide"

<400> 321

Gln Ser Val Ser Ser Tyr

15

<210> 322

<211> 3

<212> PRT

<213> Artificial sequence

<220>

<221> source

<223> /note="Description of the artificial sequence:

Synthetic peptide"

<400> 322

Asp Ala Ser

1

<210> 323

<211> 11

<212> PRT

<213> Artificial sequence

<220>

<221> source

<223> /note="Description of the artificial sequence:

Synthetic peptide"

<400> 323

Cys Gln Gln Arg Ser Asn Trp Pro Leu Thr Phe

1 5 10

<210> 324

<211> 357

<212> DNA

<213> Artificial sequence

<220>

<221> source

<223> /note="Description of the artificial sequence:

Synthetic polynucleotide"

<400> 324

caggttcagc tgcagcagtg gggcgctggc ctgctgaagc cctctgagac cctgtctctg 60

acctgtgccg tgtatggcgg cagcttctcc ggctattact ggaactggat ccgccagccc 120

cccggcaagg gcctggagtg gatcggcgag atcaaccact ccggctctac caactacaat 180

ccttctctga agtccagggt gacaatcagc gtggacacca gcaagaacca gtttagcctg 240

aagctgtcca gcgtgacagc tgccgataca gccgtgtatt actgcgccag aggcgaggat 300

tggggcgaga gcttctttga ttactggggc caggggaccc tggtgaccgt ctcgagt 357

<210> 325

<211> 321

<212> DNA

<213> Artificial sequence

<220>

<221> source

<223> /note="Description of the artificial sequence:

Synthetic polynucleotide"

<400> 325

gagatcgtgc tgacccagtc ccctgccacc ctgtctctgt cccctggcga gcgggccacc 60

ctgagctgtc gggcctccca gtccgtgagc tcctacctgg cttggtatca gcagaagcca 120

ggacaggccc caagactgct gatctacgcc gcttccaatc gggccaccgg catccccgcc 180

agattttccg gctctggctc cggcaccgat ttcaccctga caatcagctc cctggagcca 240

gaggacttcg ccgtgtacta ctgccagcag aggtctaatt ggccactgac atttggcggc 300

ggcaccaagg ttgagatcaa g 321

<210> 326

<211> 119

<212> PRT

<213> Artificial sequence

<220>

<221> source

<223> /note="Description of the artificial sequence:

Synthetic polypeptide"

<400> 326

Gln Val Gln Leu Gln Gln Trp Gly Ala Gly Leu Leu Lys Pro Ser Glu

1 5 10 15

Thr Leu Ser Leu Thr Cys Ala Val Tyr Gly Gly Ser Phe Ser Gly Tyr

20 25 30

Tyr Trp Asn Trp Ile Arg Gln Pro Pro Gly Lys Gly Leu Glu Trp Ile

35 40 45

Gly Glu Ile Asn His Ser Gly Ser Thr Asn Tyr Asn Pro Ser Leu Lys

50 55 60

Ser Arg Val Thr Ile Ser Val Asp Thr Ser Lys Asn Gln Phe Ser Leu

65 70 75 80

Lys Leu Ser Ser Val Thr Ala Ala Asp Thr Ala Val Tyr Tyr Cys Ala

85 90 95

Arg Gly Glu Asp Trp Gly Glu Ser Phe Phe Asp Tyr Trp Gly Gln Gly

100 105 110

Thr Leu Val Thr Val Ser Ser

115

<210> 327

<211> 107

<212> PRT

<213> Artificial sequence

<220>

<221> source

<223> /note="Description of the artificial sequence:

Synthetic polypeptide"

<400> 327

Glu Ile Val 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 Ser Ser Tyr

20 25 30

Leu Ala Trp Tyr Gln Gln Lys Pro Gly Gln Ala Pro Arg Leu Leu Ile

35 40 45

Tyr Ala Ala Ser Asn Arg Ala Thr Gly Ile Pro Ala Arg Phe Ser Gly

50 55 60

Ser Gly Ser Gly Thr Asp Phe Thr Leu Thr Ile Ser Ser Leu Glu Pro

65 70 75 80

Glu Asp Phe Ala Val Tyr Tyr Cys Gln Gln Arg Ser Asn Trp Pro Leu

85 90 95

Thr Phe Gly Gly Gly Thr Lys Val Glu Ile Lys

100 105

<210> 328

<211> 8

<212> PRT

<213> Artificial sequence

<220>

<221> source

<223> /note="Description of the artificial sequence:

Synthetic peptide"

<400> 328

Gly Gly Ser Phe Ser Gly Tyr Tyr

15

<210> 329

<211> 7

<212> PRT

<213> Artificial sequence

<220>

<221> source

<223> /note="Description of the artificial sequence:

Synthetic peptide"

<400> 329

Ile Asn His Ser Gly Ser Thr

15

<210> 330

<211> 15

<212> PRT

<213> Artificial sequence

<220>

<221> source

<223> /note="Description of the artificial sequence:

Synthetic peptide"

<400> 330

Cys Ala Arg Gly Glu Asp Trp Gly Glu Ser Phe Phe Asp Tyr Trp

1 5 10 15

<210> 331

<211> 6

<212> PRT

<213> Artificial sequence

<220>

<221> source

<223> /note="Description of the artificial sequence:

Synthetic peptide"

<400> 331

Gln Ser Val Ser Ser Tyr

15

<210> 332

<211> 3

<212> PRT

<213> Artificial sequence

<220>

<221> source

<223> /note="Description of the artificial sequence:

Synthetic peptide"

<400> 332

Ala Ala Ser

1

<210> 333

<211> 11

<212> PRT

<213> Artificial sequence

<220>

<221> source

<223> /note="Description of the artificial sequence:

Synthetic peptide"

<400> 333

Cys Gln Gln Arg Ser Asn Trp Pro Leu Thr Phe

1 5 10

<210> 334

<211> 357

<212> DNA

<213> Artificial sequence

<220>

<221> source

<223> /note="Description of the artificial sequence:

Synthetic polynucleotide"

<400> 334

caggttcagc tggtgcagtc cggcgctgag gtgaagaagc ctggagcttc tgtgaaggtt 60

tcctgtaagg tttccggcta tagcctgacc gagatctcta tgcactgggt acggcaagcc 120

cccggcaagg gcctggagtg gatgggcggc tttgacccag aggatggcga gaccatctac 180

gctcagaggt ttcaggggcg cgtgatcatg accgaggata ccagcaccga taccgcctac 240

atggagctgt ccagcctgag atccgaggat accgccgtgt attactgcgc tactggtggc 300

tggggcccca attggttcga tccttggggc caggggaccc tggtgaccgt ctcgagt 357

<210> 335

<211> 321

<212> DNA

<213> Artificial sequence

<220>

<221> source

<223> /note="Description of the artificial sequence:

Synthetic polynucleotide"

<400> 335

gacatccaga tgacacagtc tccttcctct gtgagcgcct ctgtgggcga ccgcgtgacc 60

atcacatgcc gcgcttccca ggggatctct tcctggctgg cttggtacca gcagaagccc 120

ggcaaggccc ccaagctgct gatctatgct gccagcagcc tgcagtccgg cgtgccttcc 180

aggtttagcg gctccggctc cggcaccgac tttacactga caatcagctc cctgcagccc 240

gaggattttg ccacctatta ctgtcagcag gcgaattcct tcccttttac attcggccct 300

ggcaccaagg ttgatatcaa g 321

<210> 336

<211> 119

<212> PRT

<213> Artificial sequence

<220>

<221> source

<223> /note="Description of the artificial sequence:

Synthetic polypeptide"

<400> 336

Gln 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 Val Ser Gly Tyr Ser Leu Thr Glu Ile

20 25 30

Ser Met His Trp Val Arg Gln Ala Pro Gly Lys Gly Leu Glu Trp Met

35 40 45

Gly Gly Phe Asp Pro Glu Asp Gly Glu Thr Ile Tyr Ala Gln Arg Phe

50 55 60

Gln Gly Arg Val Ile Met Thr Glu Asp Thr Ser Thr Asp 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 Gly Gly Trp Gly Pro Asn Trp Phe Asp Pro Trp Gly Gln Gly

100 105 110

Thr Leu Val Thr Val Ser Ser

115

<210> 337

<211> 107

<212> PRT

<213> Artificial sequence

<220>

<221> source

<223> /note="Description of the artificial sequence:

Synthetic polypeptide"

<400> 337

Asp 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 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 Phe

85 90 95

Thr Phe Gly Pro Gly Thr Lys Val Asp Ile Lys

100 105

<210> 338

<211> 8

<212> PRT

<213> Artificial sequence

<220>

<221> source

<223> /note="Description of the artificial sequence:

Synthetic peptide"

<400> 338

Gly Tyr Ser Leu Thr Glu Ile Ser

15

<210> 339

<211> 8

<212> PRT

<213> Artificial sequence

<220>

<221> source

<223> /note="Description of the artificial sequence:

Synthetic peptide"

<400> 339

Phe Asp Pro Glu Asp Gly Glu Thr

15

<210> 340

<211> 14

<212> PRT

<213> Artificial sequence

<220>

<221> source

<223> /note="Description of the artificial sequence:

Synthetic peptide"

<400> 340

Cys Ala Thr Gly Gly Trp Gly Pro Asn Trp Phe Asp Pro Trp

1 5 10

<210> 341

<211> 6

<212> PRT

<213> Artificial sequence

<220>

<221> source

<223> /note="Description of the artificial sequence:

Synthetic peptide"

<400> 341

Gln Gly Ile Ser Ser Trp

15

<210> 342

<211> 3

<212> PRT

<213> Artificial sequence

<220>

<221> source

<223> /note="Description of the artificial sequence:

Synthetic peptide"

<400> 342

Ala Ala Ser

1

<210> 343

<211> 11

<212> PRT

<213> Artificial sequence

<220>

<221> source

<223> /note="Description of the artificial sequence:

Synthetic peptide"

<400> 343

Cys Gln Gln Ala Asn Ser Phe Pro Phe Thr Phe

1 5 10

<210> 344

<211> 363

<212> DNA

<213> Artificial sequence

<220>

<221> source

<223> /note="Description of the artificial sequence:

Synthetic polynucleotide"

<400> 344

caggttcagc tgcagcagtc cggccccggc ctggtgaagc caagccagac cctgtctctg 60

acatgcgcca tctccggcga cagcgtgtcc tctaactccg ccgcttggaa ttggatccgg 120

cagtctccat ccagaggcct ggagtggctg ggcagaacct attaccggtc caagtggtac 180

aacgattatg ccgtgtccgt gaagagcaga atcaccatca accctgatac cagcaagaac 240

cagttcagcc tgcagctgaa ttccgtgacc ccagaggata cagccgtgta ttactgtgct 300

agggacgatg attggaatga cttcgattac tggggccagg ggaccctggt gacagtctcg 360

agt 363

<210> 345

<211> 321

<212> DNA

<213> Artificial sequence

<220>

<221> source

<223> /note="Artificial sequence description: Synthetic polynucleotide"

<400> 345

gagatcgtgc tgacccagtc cccagctaca ctgtccctgt ctcccggcga gcgggccacc 60

ctgagctgta gagcttccca gtccgtgtct tcctatctgg cttggtatca gcagaagcca 120

ggacaggccc caaggctgct gatctacgac gcctccaata gagccaccgg catcccagct 180

agattttctg gctccggctc cggcaccgat ttcacactga ccatctctag cctggagcca 240

gaggattttg ctgtatatta ctgccagcag cgcagcaact ggcccctgac atttggcggc 300

ggcaccaagg ttgagatcaa g 321

<210> 346

<211> 121

<212> PRT

<213> Artificial sequence

<220>

<221> source

<223> /note="Description of the artificial sequence:

Synthetic polypeptide"

<400> 346

Gln 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 Asp Asp Trp Asn Asp Phe Asp Tyr Trp Gly

100 105 110

Gln Gly Thr Leu Val Thr Val Ser Ser

115 120

<210> 347

<211> 107

<212> PRT

<213> Artificial sequence

<220>

<221> source

<223> /note="Description of the artificial sequence:

Synthetic polypeptide"

<400> 347

Glu Ile Val 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 Ser Ser Tyr

20 25 30

Leu Ala Trp Tyr Gln Gln Lys Pro Gly Gln Ala Pro Arg Leu Leu Ile

35 40 45

Tyr Asp Ala Ser Asn Arg Ala Thr Gly Ile Pro Ala Arg Phe Ser Gly

50 55 60

Ser Gly Ser Gly Thr Asp Phe Thr Leu Thr Ile Ser Ser Leu Glu Pro

65 70 75 80

Glu Asp Phe Ala Val Tyr Tyr Cys Gln Gln Arg Ser Asn Trp Pro Leu

85 90 95

Thr Phe Gly Gly Gly Thr Lys Val Glu Ile Lys

100 105

<210> 348

<211> 9

<212> PRT

<213> Artificial sequence

<220>

<221> source

<223> /note="Description of the artificial sequence:

Synthetic peptide"

<400> 348

Gly Asp Ser Val Ser Ser Asn Ser Ala

15

<210> 349

<211> 7

<212> PRT

<213> Artificial sequence

<220>

<221> source

<223> /note="Description of the artificial sequence:

Synthetic peptide"

<400> 349

Thr Tyr Tyr Arg Ser Lys Trp

15

<210> 350

<211> 13

<212> PRT

<213> Artificial sequence

<220>

<221> source

<223> /note="Description of the artificial sequence:

Synthetic peptide"

<400> 350

Cys Ala Arg Asp Asp Asp Trp Asn Asp Phe Asp Tyr Trp

1 5 10

<210> 351

<211> 6

<212> PRT

<213> Artificial sequence

<220>

<221> source

<223> /note="Description of the artificial sequence:

Synthetic peptide"

<400> 351

Gln Ser Val Ser Ser Tyr

15

<210> 352

<211> 3

<212> PRT

<213> Artificial sequence

<220>

<221> source

<223> /note="Description of the artificial sequence:

Synthetic peptide"

<400> 352

Asp Ala Ser

1

<210> 353

<211> 11

<212> PRT

<213> Artificial sequence

<220>

<221> source

<223> /note="Description of the artificial sequence:

Synthetic peptide"

<400> 353

Cys Gln Gln Arg Ser Asn Trp Pro Leu Thr Phe

1 5 10

<210> 354

<211> 372

<212> DNA

<213> Artificial sequence

<220>

<221> source

<223> /note="Description of the artificial sequence:

Synthetic polynucleotide"

<400> 354

cagctgcagc tgcaggaaag cggccccggc ctggtgaagc cctctgagac cctgtccctg 60

acatgcaccg tgagcggcga ttccatcagc tcttccagct attactgggg ctggatccgg 120

cagccccccg gcaagggcct ggagtggatc ggcagcatct tctactccgg caatacatat 180

tataatcctt ctctgaagag cagggtgaca atcagcgtgg atacctccaa gaatcagttt 240

agcctgaagc tgagctccgt gacagctgcc gatacagccg tgtattactg cgctagggag 300

gacgattttc tgaccgatta ttacggcgct ttcgacatct ggggccaggg gacaatggtg 360

acagtctcga gt 372

<210> 355

<211> 318

<212> DNA

<213> Artificial sequence

<220>

<221> source

<223> /note="Description of the artificial sequence:

Synthetic polynucleotide"

<400> 355

gatatccaga tgacccagtc tccaagcacc ctgagcgcct ctgtgggcga tcgggtgacc 60

atcacatgtc gggcttctca gtccatcagc agctggctgg cttggtatca gcagaagccc 120

ggcaaggccc caaagctgct gatctacaag gcctcttcca gcgagagcgg cgtgccatcc 180

aggtttagcg gctccggctc cggcaccgag tttaccctga ccatctcttc cctgcagccc 240

gatgactttg ccacctacta ctgtcagcag tacaattcct atctgacatt cggcggcggc 300

accaaggttg agatcaag 318

<210> 356

<211> 124

<212> PRT

<213> Artificial sequence

<220>

<221> source

<223> /note="Description of the artificial sequence:

Synthetic polypeptide"

<400> 356

Gln Leu Gln Leu Gln Glu Ser Gly Pro Gly Leu Val Lys Pro Ser Glu

1 5 10 15

Thr Leu Ser Leu Thr Cys Thr Val Ser Gly Asp Ser Ile Ser Ser Ser

20 25 30

Ser Tyr Tyr Trp Gly Trp Ile Arg Gln Pro Pro Gly Lys Gly Leu Glu

35 40 45

Trp Ile Gly Ser Ile Phe Tyr Ser Gly Asn Thr Tyr Tyr Asn Pro Ser

50 55 60

Leu Lys Ser Arg Val Thr Ile Ser Val Asp Thr Ser Lys Asn Gln Phe

65 70 75 80

Ser Leu Lys Leu Ser Ser Val Thr Ala Ala Asp Thr Ala Val Tyr Tyr

85 90 95

Cys Ala Arg Glu Asp Asp Phe Leu Thr Asp Tyr Tyr Gly Ala Phe Asp

100 105 110

Ile Trp Gly Gln Gly Thr Met Val Thr Val Ser Ser

115 120

<210> 357

<211> 106

<212> PRT

<213> Artificial sequence

<220>

<221> source

<223> /note="Description of the artificial sequence:

Synthetic polypeptide"

<400> 357

Asp Ile Gln 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 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 Lys Ala Ser Ser Ser 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 Asn Ser Tyr Leu Thr

85 90 95

Phe Gly Gly Gly Thr Lys Val Glu Ile Lys

100 105

<210> 358

<211> 10

<212> PRT

<213> Artificial sequence

<220>

<221> source

<223> /note="Description of the artificial sequence:

Synthetic peptide"

<400> 358

Gly Asp Ser Ile Ser Ser Ser Ser Tyr Tyr

1 5 10

<210> 359

<211> 7

<212> PRT

<213> Artificial sequence

<220>

<221> source

<223> /note="Description of the artificial sequence:

Synthetic peptide"

<400> 359

Ile Phe Tyr Ser Gly Asn Thr

15

<210> 360

<211> 18

<212> PRT

<213> Artificial sequence

<220>

<221> source

<223> /note="Description of the artificial sequence:

Synthetic peptide"

<400> 360

Cys Ala Arg Glu Asp Asp Phe Leu Thr Asp Tyr Tyr Gly Ala Phe Asp

1 5 10 15

Ile Trp

<210> 361

<211> 6

<212> PRT

<213> Artificial sequence

<220>

<221> source

<223> /note="Description of the artificial sequence:

Synthetic peptide"

<400> 361

Gln Ser Ile Ser Ser Trp

15

<210> 362

<211> 3

<212> PRT

<213> Artificial sequence

<220>

<221> source

<223> /note="Description of the artificial sequence:

Synthetic peptide"

<400> 362

Lys Ala Ser

1

<210> 363

<211> 10

<212> PRT

<213> Artificial sequence

<220>

<221> source

<223> /note="Description of the artificial sequence:

Synthetic peptide"

<400> 363

Cys Gln Gln Tyr Asn Ser Tyr Leu Thr Phe

1 5 10

<210> 364

<211> 375

<212> DNA

<213> Artificial sequence

<220>

<221> source

<223> /note="Description of the artificial sequence:

Synthetic polynucleotide"

<400> 364

gaggtgcagc tgctggaatc cggaggagga ctggtccagc caggtggatc cctgcgactg 60

agctgcgccg cttctggctt cgactttaga agctacgcaa tgatgtgggt ccgccaggca 120

cggaaagg gactggagtg ggtgggaggg atcaacggtg aagtcggtgg ctctaataca 180

tactatgcac ctgccgtcaa gggaagggct actattagtc gggacaactc aaaaaatacc 240

ctgtatctgc aaatgaacag tctgagggcc gaggataccg ccgtgtacta ttgcgtgaaa 300

ggtgctggcg catgcggcat ctgtaatgac gatattgatg catggggaca ggggaccctg 360

gtgacagtct cgagt 375

<210> 365

<211> 330

<212> DNA

<213> Artificial sequence

<220>

<221> source

<223> /note="Description of the artificial sequence:

Synthetic polynucleotide"

<400> 365

agttatgagc tgactcagga cccagcagtg tcagtcgccc tgggccagac agtgagaatc 60

acttgcagtg gggctggttc atatgcaggc tcctactatt acggatggca ccagcagaag 120

ccgggacagg cacctgtgac agtcatctac gacaacgata aaaggccaag caatattccc 180

gaccggttct ctgggtccag ctctggtaac accgcctccc tgaccattac tggggcccag 240

gctgaggacg aagctgatta ttactgtggc tctacaaacg ataatgacga tggcggactg 300

tttggctccg gaactaaggt caccgtccta 330

<210> 366

<211> 125

<212> PRT

<213> Artificial sequence

<220>

<221> source

<223> /note="Description of the artificial sequence:

Synthetic polypeptide"

<400> 366

Glu Val Gln Leu Leu 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 Asp Phe Arg Ser Tyr

20 25 30

Ala Met Met Trp Val Arg Gln Ala Pro Gly Lys Gly Leu Glu Trp Val

35 40 45

Gly Gly Ile Asn Gly Glu Val Gly Gly Ser Asn Thr Tyr Tyr Ala Pro

50 55 60

Ala Val Lys Gly Arg Ala Thr Ile Ser Arg Asp Asn Ser Lys Asn Thr

65 70 75 80

Leu Tyr Leu Gln Met Asn Ser Leu Arg Ala Glu Asp Thr Ala Val Tyr

85 90 95

Tyr Cys Val Lys Gly Ala Gly Ala Cys Gly Ile Cys Asn Asp Asp Ile

100 105 110

Asp Ala Trp Gly Gln Gly Thr Leu Val Thr Val Ser Ser

115 120 125

<210> 367

<211> 110

<212> PRT

<213> Artificial sequence

<220>

<221> source

<223> /note="Description of the artificial sequence:

Synthetic polypeptide"

<400> 367

Ser Tyr Glu Leu Thr Gln Asp Pro Ala Val Ser Val Ala Leu Gly Gln

1 5 10 15

Thr Val Arg Ile Thr Cys Ser Gly Ala Gly Ser Tyr Ala Gly Ser Tyr

20 25 30

Tyr Tyr Gly Trp His Gln Gln Lys Pro Gly Gln Ala Pro Val Thr Val

35 40 45

Ile Tyr Asp Asn Asp Lys Arg Pro Ser Asn Ile Pro Asp Arg Phe Ser

50 55 60

Gly Ser Ser Ser Gly Asn Thr Ala Ser Leu Thr Ile Thr Gly Ala Gln

65 70 75 80

Ala Glu Asp Glu Ala Asp Tyr Tyr Cys Gly Ser Thr Asn Asp Asn Asp

85 90 95

Asp Gly Gly Leu Phe Gly Ser Gly Thr Lys Val Thr Val Leu

100 105 110

<210> 368

<211> 8

<212> PRT

<213> Artificial sequence

<220>

<221> source

<223> /note="Description of the artificial sequence:

Synthetic peptide"

<400> 368

Gly Phe Asp Phe Arg Ser Tyr Ala

15

<210> 369

<211> 10

<212> PRT

<213> Artificial sequence

<220>

<221> source

<223> /note="Description of the artificial sequence:

Synthetic peptide"

<400> 369

Ile Asn Gly Glu Val Gly Gly Ser Asn Thr

1 5 10

<210> 370

<211> 18

<212> PRT

<213> Artificial sequence

<220>

<221> source

<223> /note="Description of the artificial sequence:

Synthetic peptide"

<400> 370

Cys Val Lys Gly Ala Gly Ala Cys Gly Ile Cys Asn Asp Asp Ile Asp

1 5 10 15

Ala Trp

<210> 371

<211> 7

<212> PRT

<213> Artificial sequence

<220>

<221> source

<223> /note="Description of the artificial sequence:

Synthetic peptide"

<400> 371

Gly Ser Tyr Ala Gly Ser Tyr

15

<210> 372

<211> 3

<212> PRT

<213> Artificial sequence

<220>

<221> source

<223> /note="Description of the artificial sequence:

Synthetic peptide"

<400> 372

Asp Asn Asp

1

<210> 373

<211> 13

<212> PRT

<213> Artificial sequence

<220>

<221> source

<223> /note="Description of the artificial sequence:

Synthetic peptide"

<400> 373

Cys Gly Ser Thr Asn Asp Asn Asp Asp Gly Gly Leu Phe

1 5 10

<210> 374

<211> 330

<212> PRT

<213> Artificial sequence

<220>

<221> source

<223> /note="Description of the artificial sequence:

Synthetic polypeptide"

<400> 374

Ala Ser Thr Lys Gly Pro Ser Val Phe Pro Leu Ala Pro Ser Ser Lys

1 5 10 15

Ser Thr Ser Gly Gly Thr Ala Ala Leu Gly Cys Leu Val Lys Asp Tyr

20 25 30

Phe Pro Glu Pro Val Thr Val Ser Trp Asn Ser Gly Ala Leu Thr Ser

35 40 45

Gly Val His Thr Phe Pro Ala Val Leu Gln Ser Ser Gly Leu Tyr Ser

50 55 60

Leu Ser Ser Val Val Thr Val Pro Ser Ser Ser Leu Gly Thr Gln Thr

65 70 75 80

Tyr Ile Cys Asn Val Asn His Lys Pro Ser Asn Thr Lys Val Asp Lys

85 90 95

Arg Val Glu Pro Lys Ser Cys Asp Lys Thr His Thr Cys Pro Pro Cys

100 105 110

Pro Ala Pro Glu Leu Leu Gly Gly Pro Ser Val Phe Leu Phe Pro Pro

115 120 125

Lys Pro Lys Asp Thr Leu Met Ile Ser Arg Thr Pro Glu Val Thr Cys

130 135 140

Val Val Val Asp Val Ser His Glu Asp Pro Glu Val Lys Phe Asn Trp

145 150 155 160

Tyr Val Asp Gly Val Glu Val His Asn Ala Lys Thr Lys Pro Arg Glu

165 170 175

Glu Gln Tyr Asn Ser Thr Tyr Arg Val Val Ser Val Leu Thr Val Leu

180 185 190

His Gln Asp Trp Leu Asn Gly Lys Glu Tyr Lys Cys Lys Val Ser Asn

195 200 205

Lys Ala Leu Pro Ala Pro Ile Glu Lys Thr Ile Ser Lys Ala Lys Gly

210 215 220

Gln Pro Arg Glu Pro Gln Val Tyr Thr Leu Pro Pro Ser Arg Glu Glu

225 230 235 240

Met Thr Lys Asn Gln Val Ser Leu Thr Cys Leu Val Lys Gly Phe Tyr

245 250 255

Pro Ser Asp Ile Ala Val Glu Trp Glu Ser Asn Gly Gln Pro Glu Asn

260 265 270

Asn Tyr Lys Thr Thr Pro Pro Val Leu Asp Ser Asp Gly Ser Phe Phe

275 280 285

Leu Tyr Ser Lys Leu Thr Val Asp Lys Ser Arg Trp Gln Gln Gly Asn

290 295 300

Val Phe Ser Cys Ser Val Met His Glu Ala Leu His Asn His Tyr Thr

305 310 315 320

Gln Lys Ser Leu Ser Leu Ser Pro Gly Lys

325 330

<210> 375

<211> 330

<212> PRT

<213> Artificial sequence

<220>

<221> source

<223> /note="Description of the artificial sequence:

Synthetic polypeptide"

<400> 375

Ala Ser Thr Lys Gly Pro Ser Val Phe Pro Leu Ala Pro Ser Ser Lys

1 5 10 15

Ser Thr Ser Gly Gly Thr Ala Ala Leu Gly Cys Leu Val Lys Asp Tyr

20 25 30

Phe Pro Glu Pro Val Thr Val Ser Trp Asn Ser Gly Ala Leu Thr Ser

35 40 45

Gly Val His Thr Phe Pro Ala Val Leu Gln Ser Ser Gly Leu Tyr Ser

50 55 60

Leu Ser Ser Val Val Thr Val Pro Ser Ser Ser Leu Gly Thr Gln Thr

65 70 75 80

Tyr Ile Cys Asn Val Asn His Lys Pro Ser Asn Thr Lys Val Asp Lys

85 90 95

Arg Val Glu Pro Lys Ser Cys Asp Lys Thr His Thr Cys Pro Pro Cys

100 105 110

Pro Ala Pro Glu Ala Ala Gly Gly Pro Ser Val Phe Leu Phe Pro Pro

115 120 125

Lys Pro Lys Asp Thr Leu Met Ile Ser Arg Thr Pro Glu Val Thr Cys

130 135 140

Val Val Val Asp Val Ser His Glu Asp Pro Glu Val Lys Phe Asn Trp

145 150 155 160

Tyr Val Asp Gly Val Glu Val His Asn Ala Lys Thr Lys Pro Arg Glu

165 170 175

Glu Gln Tyr Asn Ser Thr Tyr Arg Val Val Ser Val Leu Thr Val Leu

180 185 190

His Gln Asp Trp Leu Asn Gly Lys Glu Tyr Lys Cys Lys Val Ser Asn

195 200 205

Lys Ala Leu Pro Ala Pro Ile Glu Lys Thr Ile Ser Lys Ala Lys Gly

210 215 220

Gln Pro Arg Glu Pro Gln Val Tyr Thr Leu Pro Pro Ser Arg Glu Glu

225 230 235 240

Met Thr Lys Asn Gln Val Ser Leu Thr Cys Leu Val Lys Gly Phe Tyr

245 250 255

Pro Ser Asp Ile Ala Val Glu Trp Glu Ser Asn Gly Gln Pro Glu Asn

260 265 270

Asn Tyr Lys Thr Thr Pro Pro Val Leu Asp Ser Asp Gly Ser Phe Phe

275 280 285

Leu Tyr Ser Lys Leu Thr Val Asp Lys Ser Arg Trp Gln Gln Gly Asn

290 295 300

Val Phe Ser Cys Ser Val Met His Glu Ala Leu His Asn His Tyr Thr

305 310 315 320

Gln Lys Ser Leu Ser Leu Ser Pro Gly Lys

325 330

<210> 376

<211> 327

<212> PRT

<213> Artificial sequence

<220>

<221> source

<223> /note="Description of the artificial sequence:

Synthetic polypeptide"

<400> 376

Ala Ser Thr Lys Gly Pro Ser Val Phe Pro Leu Ala Pro Cys Ser Arg

1 5 10 15

Ser Thr Ser Glu Ser Thr Ala Ala Leu Gly Cys Leu Val Lys Asp Tyr

20 25 30

Phe Pro Glu Pro Val Thr Val Ser Trp Asn Ser Gly Ala Leu Thr Ser

35 40 45

Gly Val His Thr Phe Pro Ala Val Leu Gln Ser Ser Gly Leu Tyr Ser

50 55 60

Leu Ser Ser Val Val Thr Val Pro Ser Ser Ser Leu Gly Thr Lys Thr

65 70 75 80

Tyr Thr Cys Asn Val Asp His Lys Pro Ser Asn Thr Lys Val Asp Lys

85 90 95

Arg Val Glu Ser Lys Tyr Gly Pro Pro Cys Pro Pro Cys Pro Ala Pro

100 105 110

Glu Phe Leu Gly Gly Pro Ser Val Phe Leu Phe Pro Pro Lys Pro Lys

115 120 125

Asp Thr Leu Met Ile Ser Arg Thr Pro Glu Val Thr Cys Val Val Val

130 135 140

Asp Val Ser Gln Glu Asp Pro Glu Val Gln Phe Asn Trp Tyr Val Asp

145 150 155 160

Gly Val Glu Val His Asn Ala Lys Thr Lys Pro Arg Glu Glu Gln Phe

165 170 175

Asn Ser Thr Tyr Arg Val Val Ser Val Leu Thr Val Leu His Gln Asp

180 185 190

Trp Leu Asn Gly Lys Glu Tyr Lys Cys Lys Val Ser Asn Lys Gly Leu

195 200 205

Pro Ser Ser Ile Glu Lys Thr Ile Ser Lys Ala Lys Gly Gln Pro Arg

210 215 220

Glu Pro Gln Val Tyr Thr Leu Pro Ser Gln Glu Glu Met Thr Lys

225 230 235 240

Asn Gln Val Ser Leu Thr Cys Leu Val Lys Gly Phe Tyr Pro Ser Asp

245 250 255

Ile Ala Val Glu Trp Glu Ser Asn Gly Gln Pro Glu Asn Asn Tyr Lys

260 265 270

Thr Thr Pro Pro Val Leu Asp Ser Asp Gly Ser Phe Phe Leu Tyr Ser

275 280 285

Arg Leu Thr Val Asp Lys Ser Arg Trp Gln Glu Gly Asn Val Phe Ser

290 295 300

Cys Ser Val Met His Glu Ala Leu His Asn His Tyr Thr Gln Lys Ser

305 310 315 320

Leu Ser Leu Ser Leu Gly Lys

325

<210> 377

<211> 326

<212> PRT

<213> Artificial sequence

<220>

<221> source

<223> /note="Description of the artificial sequence:

Synthetic polypeptide"

<400> 377

Ala Ser Thr Lys Gly Pro Ser Val Phe Pro Leu Ala Pro Cys Ser Arg

1 5 10 15

Ser Thr Ser Glu Ser Thr Ala Ala Leu Gly Cys Leu Val Lys Asp Tyr

20 25 30

Phe Pro Glu Pro Val Thr Val Ser Trp Asn Ser Gly Ala Leu Thr Ser

35 40 45

Gly Val His Thr Phe Pro Ala Val Leu Gln Ser Ser Gly Leu Tyr Ser

50 55 60

Leu Ser Ser Val Val Thr Val Pro Ser Ser Asn Phe Gly Thr Gln Thr

65 70 75 80

Tyr Thr Cys Asn Val Asp His Lys Pro Ser Asn Thr Lys Val Asp Lys

85 90 95

Thr Val Glu Arg Lys Cys Cys Val Glu Cys Pro Pro Cys Pro Ala Pro

100 105 110

Pro Val Ala Gly Pro Ser Val Phe Leu Phe Pro Pro Lys Pro Lys Asp

115 120 125

Thr Leu Met Ile Ser Arg Thr Pro Glu Val Thr Cys Val Val Val Asp

130 135 140

Val Ser His Glu Asp Pro Glu Val Gln Phe Asn Trp Tyr Val Asp Gly

145 150 155 160

Val Glu Val His Asn Ala Lys Thr Lys Pro Arg Glu Glu Gln Phe Asn

165 170 175

Ser Thr Phe Arg Val Val Ser Val Leu Thr Val Val His Gln Asp Trp

180 185 190

Leu Asn Gly Lys Glu Tyr Lys Cys Lys Val Ser Asn Lys Gly Leu Pro

195 200 205

Ala Pro Ile Glu Lys Thr Ile Ser Lys Thr Lys Gly Gln Pro Arg Glu

210 215 220

Pro Gln Val Tyr Thr Leu Pro Ser Arg Glu Glu Met Thr Lys Asn

225 230 235 240

Gln Val Ser Leu Thr Cys Leu Val Lys Gly Phe Tyr Pro Ser Asp Ile

245 250 255

Ala Val Glu Trp Glu Ser Asn Gly Gln Pro Glu Asn Asn Tyr Lys Thr

260 265 270

Thr Pro Pro Met Leu Asp Ser Asp Gly Ser Phe Phe Leu Tyr Ser Lys

275 280 285

Leu Thr Val Asp Lys Ser Arg Trp Gln Gln Gly Asn Val Phe Ser Cys

290 295 300

Ser Val Met His Glu Ala Leu His Asn His Tyr Thr Gln Lys Ser Leu

305 310 315 320

Ser Leu Ser Pro Gly Lys

325

<210> 378

<211> 107

<212> PRT

<213> Artificial sequence

<220>

<221> source

<223> /note="Description of the artificial sequence:

Synthetic polypeptide"

<400> 378

Arg Thr Val Ala Ala Pro Ser Val Phe Ile Phe Pro Pro Ser Asp Glu

1 5 10 15

Gln Leu Lys Ser Gly Thr Ala Ser Val Val Cys Leu Leu Asn Asn Phe

20 25 30

Tyr Pro Arg Glu Ala Lys Val Gln Trp Lys Val Asp Asn Ala Leu Gln

35 40 45

Ser Gly Asn Ser Gln Glu Ser Val Thr Glu Gln Asp Ser Lys Asp Ser

50 55 60

Thr Tyr Ser Leu Ser Ser Thr Leu Thr Leu Ser Lys Ala Asp Tyr Glu

65 70 75 80

Lys His Lys Val Tyr Ala Cys Glu Val Thr His Gln Gly Leu Ser Ser

85 90 95

Pro Val Thr Lys Ser Phe Asn Arg Gly Glu Cys

100 105

<210> 379

<211> 106

<212> PRT

<213> Artificial sequence

<220>

<221> source

<223> /note="Description of the artificial sequence:

Synthetic polypeptide"

<400> 379

Gly Gln Pro Lys Ala Asn Pro Thr Val Thr Leu Phe Pro Pro Ser Ser

1 5 10 15

Glu Glu Leu Gln Ala Asn Lys Ala Thr Leu Val Cys Leu Ile Ser Asp

20 25 30

Phe Tyr Pro Gly Ala Val Thr Val Ala Trp Lys Ala Asp Gly Ser Pro

35 40 45

Val Lys Ala Gly Val Glu Thr Thr Lys Pro Ser Lys Gln Ser Asn Asn

50 55 60

Lys Tyr Ala Ala Ser Ser Tyr Leu Ser Leu Thr Pro Glu Gln Trp Lys

65 70 75 80

Ser His Arg Ser Tyr Ser Cys Gln Val Thr His Glu Gly Ser Thr Val

85 90 95

Glu Lys Thr Val Ala Pro Thr Glu Cys Ser

100 105

<210> 380

<211> 990

<212> DNA

<213> Artificial sequence

<220>

<221> source

<223> /note="Description of the artificial sequence:

Synthetic polynucleotide"

<400> 380

gcctccacca agggcccatc ggtcttcccc ctggcaccct cctccaagag caccctctggg 60

ggcacagcgg ccctgggctg cctggtcaag gactacttcc ccgaaccggt gacggtgtcg 120

tggaactcag gcgccctgac cagcggcgtg cacaccttcc cggctgtcct acagtcctca 180

ggactctact ccctcagcag cgtggtgacc gtgccctcca gcagcttggg cacccagacc 240

tacatctgca acgtgaatca caagcccagc aacaccaagg tggacaagag agttgagccc 300

aaatcttgtg acaaaactca cacatgccca ccgtgcccag cacctgaagc cgccggggga 360

ccgtcagtct tcctcttccc cccaaaaccc aaggacaccc tcatgatctc ccggacccct 420

gaggtcacat gcgtggtggt ggacgtgagc cacgaagacc ctgaggtcaa gttcaactgg 480

tacgtggacg gcgtggaggt gcataatgcc aagacaaagc cgcgggagga gcagtacaac 540

agcacgtacc gtgtggtcag cgtcctcacc gtcctgcacc aggactggct gaatggcaag 600

gagtacaagt gcaaggtctc caacaaagcc ctcccagccc ccatcgagaa aaccatctcc 660

aaagccaaag ggcagccccg agaaccacag gtgtacaccc tgcccccatc ccgggaggag 720

atgaccaaga accaggtcag cctgacctgc ctggtcaaag gcttctatcc cagcgacatc 780

gccgtggagt gggagagcaa tgggcagccg gagaacaact acaagaccac gcctcccgtg 840

ctggactccg acggctcctt cttcctctat agcaagctca ccgtggacaa gagcaggtgg 900

cagcagggga acgtcttctc atgctccgtg atgcatgagg ctctgcacaa ccactacacg 960

cagaagagcc tctccctgtc ccggggtaaa 990

<210> 381

<211> 1596

<212> DNA

<213> Artificial sequence

<220>

<221> source

<223> /note="Description of the artificial sequence:

Synthetic polynucleotide"

<400> 381

gcctccacca agggcccatc ggtcttcccc ctggcaccct cctccaagag caccctctggg 60

ggcacagcgg ccctgggctg cctggtcaag gactacttcc ccgaaccggt gacggtgtcg 120

tggaactcag gcgccctgac cagcggcgtg cacaccttcc cggctgtcct acagtcctca 180

ggactctact ccctcagcag cgtggtgacc gtgccctcca gcagcttggg cacccagacc 240

tacatctgca acgtgaatca caagcccagc aacaccaagg tggacaagag agttggtgag 300

aggccagcac agggagggag ggtgtctgct ggaagccagg ctcagcgctc ctgcctggac 360

gcatcccggc tatgcagtcc cagtccaggg cagcaaggca ggccccgtct gcctcttcac 420

ccggaggcct ctgcccgccc cactcatgct cagggagagg gtcttctggc tttttcccca 480

ggctctggggc aggcacaggc taggtgcccc taacccaggc cctgcacaca aaggggcagg 540

tgctgggctc agacctgcca agagccatat ccgggaggac cctgcccctg acctaagccc 600

accccaaagg ccaaactctc cactccctca gctcggacac cttctctcct cccagattcc 660

agtaactccc aatcttctct ctgcagagcc caaatcttgt gacaaaactc acacatgccc 720

accgtgccca ggtaagccag cccaggcctc gccctccagc tcaaggcggg acaggtgccc 780

tagagtagcc tgcatccagg gacaggcccc agccgggtgc tgacacgtcc acctccatct 840

cttcctcagc acctgaagcc gccgggggac cgtcagtctt cctcttcccc ccaaaaccca 900

aggacaccct catgatctcc cggacccctg aggtcacatg cgtggtggtg gacgtgagcc 960

acgaagaccc tgaggtcaag ttcaactggt acgtggacgg cgtggaggtg cataatgcca 1020

agacaaagcc gcgggaggag cagtacaaca gcacgtaccg tgtggtcagc gtcctcaccg 1080

tcctgcacca ggactggctg aatggcaagg agtacaagtg caaggtctcc aacaaagccc 1140

tcccagcccc catcgagaaa accatctcca aagccaaagg tgggacccgt ggggtgcgag 1200

ggccacatgg acagaggccg gctcggccca ccctctgccc tgagagtgac cgctgtacca 1260

acctctgtcc ctacagggca gccccgagaa ccacaggtgt acaccctgcc cccatcccgg 1320

gaggagatga ccaagaacca ggtcagcctg acctgcctgg tcaaaggctt ctatcccagc 1380

gacatcgccg tggagtggga gagcaatggg cagccggaga acaactacaa gaccacgcct 1440

cccgtgctgg actccgacgg ctccttcttc ctctatagca agctcaccgt ggacaagagc 1500

aggtggcagc aggggaacgt cttctcatgc tccgtgatgc atgaggctct gcacaaccac 1560

tacacgcaga agagcctctc cctgtccccg ggtaaa 1596

<210> 382

<211> 981

<212> DNA

<213> Artificial sequence

<220>

<221> source

<223> /note="Description of the artificial sequence:

Synthetic polynucleotide"

<400> 382

gcttccacca agggcccatc ggtcttcccc ctggcgccct gctccaggag cacctccgag 60

agcacagccg ccctgggctg cctggtcaag gactacttcc ccgaaccggt gacggtgtcg 120

tggaactcag gcgccctgac cagcggcgtg cacaccttcc cggctgtcct acagtcctca 180

ggactctact ccctcagcag cgtggtgacc gtgccctcca gcagcttggg cacgaagacc 240

tacacctgca acgtagatca caagcccagc aacaccaagg tggacaagag agttgagtcc 300

aaatatggtc cccatgccc accatgccca gcacctgagt tcctgggggg accatcagtc 360

ttcctgttcc ccccaaaacc caaggacact ctcatgatct cccggacccc tgaggtcacg 420

tgcgtggtgg tggacgtgag cggaagac cccgaggtcc agttcaactg gtacgtggat 480

ggcgtggagg tgcataatgc caagacaaag ccgcgggagg agcagttcaa cagcacgtac 540

cgtgtggtca gcgtcctcac cgtcctgcac caggactggc tgaacggcaa ggagtacaag 600

tgcaaggtct ccaacaaagg cctcccgtcc tccatcgaga aaaccatctc caaagccaaa 660

gggcagcccc gagagccaca ggtgtacacc ctgcccccat cccaggagga gatgaccaag 720

aaccaggtca gcctgacctg cctggtcaaa ggcttctacc ccagcgacat cgccgtggag 780

tgggagagca atgggcagcc ggagaacaac tacaagacca cgcctcccgt gctggactcc 840

gacggctcct tcttcctcta cagcaggctc accgtggaca agagcaggtg gcaggagggg 900

aatgtcttct catgctccgt gatgcatgag gctctgcaca accactacac acagaagagc 960

ctctccctgt ctctgggtaa a 981

<210> 383

<211> 1588

<212> DNA

<213> Artificial sequence

<220>

<221> source

<223> /note="Description of the artificial sequence:

Synthetic polynucleotide"

<400> 383

gcttccacca agggcccatc ggtcttcccc ctggcgccct gctccaggag cacctccgag 60

agcacagccg ccctgggctg cctggtcaag gactacttcc ccgaaccggt gacggtgtcg 120

tggaactcag gcgccctgac cagcggcgtg cacaccttcc cggctgtcct acagtcctca 180

ggactctact ccctcagcag cgtggtgacc gtgccctcca gcagcttggg cacgaagacc 240

tacacctgca acgtagatca caagcccagc aacaccaagg tggacaagag agttggtgag 300

aggccagcac agggagggag ggtgtctgct ggaagccagg ctcagccctc ctgcctggac 360

gcaccccggc tgtgcagccc cagcccaggg cagcaaggca ggccccatct gtctcctcac 420

cgggaggcct ctgaccaccc cactcatgct cagggagagg gtcttctggga tttttccacc 480

aggctccggg cagccacagg ctggatgccc ctaccccagg ccctgagcat acaggggcag 540

gtgctgcgct cagacctgcc aagagccata tccgggagga ccctgcccct gacctaagcc 600

caccccaaag gccaaactct ccactccctc agctcagaca ccttctctcc tccagatct 660

gagtaactcc caatcttctc tctgcagagt ccaaatatgg tcccccatgc ccaccatgcc 720

caggtaagcc aacccaggcc tcgccctcca gctcaaggcg ggacaggtgc cctagagtag 780

cctgcatcca gggacaggcc ccagccgggt gctgacgcat ccacctccat ctcttcctca 840

gcacctgagt tcctgggggg accatcagtc ttcctgttcc ccccaaaacc caaggacact 900

ctcatgatct cccggacccc tgaggtcacg tgcgtggtgg tggacgtgag cggaagac 960

cccgaggtcc agttcaactg gtacgtggat ggcgtggagg tgcataatgc caagacaaag 1020

ccgcgggagg agcagttcaa cagcacgtac cgtgtggtca gcgtcctcac cgtcctgcac 1080

caggactggc tgaacggcaa ggagtacaag tgcaaggtct ccaacaaagg cctcccgtcc 1140

tccatcgaga aaaccatctc caaagccaaa ggtgggaccc acggggtgcg agggccacat 1200

ggacagaggt cagctcggcc caccctctgc cctgggagtg accgctgtgc caacctctgt 1260

ccctacaggg cagccccgag agccacaggt gtacaccctg cccccatccc aggaggagat 1320

gaccaagaac caggtcagcc tgacctgcct ggtcaaaggc ttctacccca gcgacatcgc 1380

1440

ggactccgac ggctccttct tcctctacag caggctcacc gtggacaaga gcaggtggca 1500

ggaggggaat gtcttctcat gctccgtgat gcatgaggct ctgcacaacc actacacaca 1560

gaagagcctc tccctgtctc tgggtaaa 1588

<210> 384

<211> 978

<212> DNA

<213> Artificial sequence

<220>

<221> source

<223> /note="Description of the artificial sequence:

Synthetic polynucleotide"

<400> 384

gcctccacca agggcccatc ggtcttcccc ctggcgccct gctccaggag cacctccgag 60

agcacagccg ccctgggctg cctggtcaag gactacttcc ccgaaccggt gacggtgtcg 120

tggaactcag gcgctctgac cagcggcgtg cacaccttcc cagctgtcct acagtcctca 180

ggactctact ccctcagcag cgtggtgacc gtgccctcca gcaacttcgg cacccagacc 240

tacacctgca acgtagatca caagcccagc aacaccaagg tggacaagac agttgagcgc 300

aaatgttgtg tcgagtgccc accgtgccca gcaccacctg tggcaggacc gtcagtcttc 360

ctcttcccc caaaacccaa ggacaccctc atgatctccc ggacccctga ggtcacgtgc 420

gtggtggtgg acgtgagcca cgaagacccc gaggtccagt tcaactggta cgtggacggc 480

gtggaggtgc ataatgccaa gacaaagcca cgggaggagc agttcaacag cacgttccgt 540

gtggtcagcg tcctcaccgt tgtgcaccag gactggctga acggcaagga gtacaagtgc 600

aaggtctcca acaaaggcct cccagccccc atcgagaaaa ccatctccaa aaccaaaggg 660

cagccccgag aaccacaggt gtacaccctg cccccatccc gggaggagat gaccaagaac 720

caggtcagcc tgacctgcct ggtcaaaggc ttctacccca gcgacatcgc cgtggagtgg 780

gagagcaatg ggcagccgga gaacaactac aagaccacac ctcccatgct ggactccgac 840

ggctccttct tcctctacag caagctcacc gtggacaaga gcaggtggca gcaggggaac 900

gtcttctcat gctccgtgat gcatgaggct ctgcacaacc actacacgca gaagagcctc 960

tccctgtctc cgggtaaa 978

<210> 385

<211> 1585

<212> DNA

<213> Artificial sequence

<220>

<221> source

<223> /note="Description of the artificial sequence:

Synthetic polynucleotide"

<400> 385

gcctccacca agggcccatc ggtcttcccc ctggcgccct gctccaggag cacctccgag 60

agcacagccg ccctgggctg cctggtcaag gactacttcc ccgaaccggt gacggtgtcg 120

tggaactcag gcgctctgac cagcggcgtg cacaccttcc cagctgtcct acagtcctca 180

ggactctact ccctcagcag cgtggtgacc gtgccctcca gcaacttcgg cacccagacc 240

tacacctgca acgtagatca caagcccagc aacaccaagg tggacaagac agttggtgag 300

aggccagctc agggagggag ggtgtctgct ggaagccagg ctcagccctc ctgcctggac 360

gcaccccggc tgtgcagccc cagcccaggg cagcaaggca ggccccatct gtctcctcac 420

ccggaggcct ctgcccgccc cactcatgct cagggagagg gtcttctggc tttttccacc 480

aggctccagg caggcacagg ctgggtgccc ctaccccagg cccttcacac acaggggcag 540

gtgcttggct cagacctgcc aaaagccata tccgggagga ccctgcccct gacctaagcc 600

gaccccaaag gccaaactgt ccactccctc agctcggaca ccttctctcc tccagatcc 660

gagtaactcc caatcttctc tctgcagagc gcaaatgttg tgtcgagtgc ccaccgtgcc 720

caggtaagcc agcccaggcc tcgccctcca gctcaaggcg ggacaggtgc cctagagtag 780

cctgcatcca gggacaggcc ccagctgggt gctgacacgt ccacctccat ctcttcctca 840

gcaccacctg tggcaggacc gtcagtcttc ctcttccccc caaaacccaa ggacaccctc 900

atgatctccc ggacccctga ggtcacgtgc gtggtggtgg acgtgagcca cgaagacccc 960

gaggtccagt tcaactggta cgtggacggc gtggaggtgc ataatgccaa gacaaagcca 1020

cgggaggagc agttcaacag cacgttccgt gtggtcagcg tcctcaccgt tgtgcaccag 1080

gactggctga acggcaagga gtacaagtgc aaggtctcca acaaaggcct cccagccccc 1140

atcgagaaaa ccatctccaa aaccaaaggt gggacccgcg gggtatgagg gccacatgga 1200

cagaggccgg ctcggcccac cctctgccct gggagtgacc gctgtgccaa cctctgtccc 1260

tacaggggcag ccccgagaac cacaggtgta caccctgccc ccatcccggg aggagatgac 1320

caagaaccag gtcagcctga cctgcctggt caaaggcttc taccccagcg acatcgccgt 1380

ggagtgggag agcaatggggc agccggagaa caactacaag accacacctc ccatgctgga 1440

ctccgacggc tccttcttcc tctacagcaa gctcaccgtg gacaagagca ggtggcagca 1500

ggggaacgtc ttctcatgct ccgtgatgca tgaggctctg cacaaccact acacgcagaa 1560

gagcctctcc ctgtctccgg gtaaa 1585

<210> 386

<211> 321

<212> DNA

<213> Artificial sequence

<220>

<221> source

<223> /note="Description of the artificial sequence:

Synthetic polynucleotide"

<400> 386

cgtacggtgg ctgcaccatc tgtcttcatc ttcccgccat ctgatgagca gttgaaatct 60

ggaactgcct ctgttgtgtg cctgctgaat aacttctatc ccagagaggc caaagtacag 120

tggaaggtgg ataacgccct ccaatcgggt aactcccagg agagtgtcac agagcaggac 180

agcaaggaca gcacctacag cctcagcagc accctgacgc tgagcaaagc agactacgag 240

aaacacaaag tctacgcctg cgaagtcacc catcagggcc tgagctcgcc cgtcacaaag 300

agcttcaaca ggggagagtg t 321

<210> 387

<211> 325

<212> DNA

<213> Artificial sequence

<220>

<221> source

<223> /note="Description of the artificial sequence:

Synthetic polynucleotide"

<400> 387

cctaggtcag cccaaggcca accccactgt cactctgttc ccgccctcct ctgaggagct 60

ccaagccaac aaggccacac tagtgtgtct gatcagtgac ttctacccgg gagctgtgac 120

agtggcctgg aaggcagatg gcagccccgt caaggcggga gtggagacca ccaaaccctc 180

caaacagagc aacaacaagt acgcggccag cagctacctg agcctgacgc ccgagcagtg 240

gaagtcccac agaagctaca gctgccaggt cacgcatgaa gggagcaccg tggagaagac 300

agtggcccct acagaatgtt cataa 325

<210> 388

<211> 288

<212> PRT

<213> Homo sapiens

<400> 388

Met Gln Ile Pro Gln Ala Pro Trp Pro Val Val Trp Ala Val Leu Gln

1 5 10 15

Leu Gly Trp Arg Pro Gly Trp Phe Leu Asp Ser Pro Asp Arg Pro Trp

20 25 30

Asn Pro Pro Thr Phe Ser Pro Ala Leu Leu Val Val Thr Glu Gly Asp

35 40 45

Asn Ala Thr Phe Thr Cys Ser Phe Ser Asn Thr Ser Glu Ser Phe Val

50 55 60

Leu Asn Trp Tyr Arg Met Ser Pro Ser Asn Gln Thr Asp Lys Leu Ala

65 70 75 80

Ala Phe Pro Glu Asp Arg Ser Gln Pro Gly Gln Asp Cys Arg Phe Arg

85 90 95

Val Thr Gln Leu Pro Asn Gly Arg Asp Phe His Met Ser Val Val Arg

100 105 110

Ala Arg Arg Asn Asp Ser Gly Thr Tyr Leu Cys Gly Ala Ile Ser Leu

115 120 125

Ala Pro Lys Ala Gln Ile Lys Glu Ser Leu Arg Ala Glu Leu Arg Val

130 135 140

Thr Glu Arg Arg Ala Glu Val Pro Thr Ala His Pro Ser Pro Ser Pro

145 150 155 160

Arg Pro Ala Gly Gln Phe Gln Thr Leu Val Val Gly Val Val Gly Gly

165 170 175

Leu Leu Gly Ser Leu Val Leu Leu Val Trp Val Leu Ala Val Ile Cys

180 185 190

Ser Arg Ala Ala Arg Gly Thr Ile Gly Ala Arg Arg Thr Gly Gln Pro

195 200 205

Leu Lys Glu Asp Pro Ser Ala Val Pro Val Phe Ser Val Asp Tyr Gly

210 215 220

Glu Leu Asp Phe Gln Trp Arg Glu Lys Thr Pro Glu Pro Pro Val Pro

225 230 235 240

Cys Val Pro Glu Gln Thr Glu Tyr Ala Thr Ile Val Phe Pro Ser Gly

245 250 255

Met Gly Thr Ser Ser Pro Ala Arg Arg Gly Ser Ala Asp Gly Pro Arg

260 265 270

Ser Ala Gln Pro Leu Arg Pro Glu Asp Gly His Cys Ser Trp Pro Leu

275 280 285

<210> 389

<211> 301

<212> PRT

<213> Homo sapiens

<400> 389

Met Phe Ser His Leu Pro Phe Asp Cys Val Leu Leu Leu Leu Leu Leu

1 5 10 15

Leu Leu Thr Arg Ser Ser Glu Val Glu Tyr Arg Ala Glu Val Gly Gln

20 25 30

Asn Ala Tyr Leu Pro Cys Phe Tyr Thr Pro Ala Ala Pro Gly Asn Leu

35 40 45

Val Pro Val Cys Trp Gly Lys Gly Ala Cys Pro Val Phe Glu Cys Gly

50 55 60

Asn Val Val Leu Arg Thr Asp Glu Arg Asp Val Asn Tyr Trp Thr Ser

65 70 75 80

Arg Tyr Trp Leu Asn Gly Asp Phe Arg Lys Gly Asp Val Ser Leu Thr

85 90 95

Ile Glu Asn Val Thr Leu Ala Asp Ser Gly Ile Tyr Cys Cys Arg Ile

100 105 110

Gln Ile Pro Gly Ile Met Asn Asp Glu Lys Phe Asn Leu Lys Leu Val

115 120 125

Ile Lys Pro Ala Lys Val Thr Pro Ala Pro Thr Arg Gln Arg Asp Phe

130 135 140

Thr Ala Ala Phe Pro Arg Met Leu Thr Thr Arg Gly His Gly Pro Ala

145 150 155 160

Glu Thr Gln Thr Leu Gly Ser Leu Pro Asp Ile Asn Leu Thr Gln Ile

165 170 175

Ser Thr Leu Ala Asn Glu Leu Arg Asp Ser Arg Leu Ala Asn Asp Leu

180 185 190

Arg Asp Ser Gly Ala Thr Ile Arg Ile Gly Ile Tyr Ile Gly Ala Gly

195 200 205

Ile Cys Ala Gly Leu Ala Leu Ala Leu Ile Phe Gly Ala Leu Ile Phe

210 215 220

Lys Trp Tyr Ser His Ser Lys Glu Lys Ile Gln Asn Leu Ser Leu Ile

225 230 235 240

Ser Leu Ala Asn Leu Pro Ser Gly Leu Ala Asn Ala Val Ala Glu

245 250 255

Gly Ile Arg Ser Glu Glu Asn Ile Tyr Thr Ile Glu Glu Asn Val Tyr

260 265 270

Glu Val Glu Glu Pro Asn Glu Tyr Tyr Cys Tyr Val Ser Ser Arg Gln

275 280 285

Gln Pro Ser Gln Pro Leu Gly Cys Arg Phe Ala Met Pro

290 295 300

<210> 390

<211> 525

<212> PRT

<213> Homo sapiens

<400> 390

Met Trp Glu Ala Gln Phe Leu Gly Leu Leu Phe Leu Gln Pro Leu Trp

1 5 10 15

Val Ala Pro Val Lys Pro Leu Gln Pro Gly Ala Glu Val Pro Val Val

20 25 30

Trp Ala Gln Glu Gly Ala Pro Ala Gln Leu Pro Cys Ser Pro Thr Ile

35 40 45

Pro Leu Gln Asp Leu Ser Leu Leu Arg Arg Ala Gly Val Thr Trp Gln

50 55 60

His Gln Pro Asp Ser Gly Pro Pro Ala Ala Ala Pro Gly His Pro Leu

65 70 75 80

Ala Pro Gly Pro His Pro Ala Ala Pro Ser Ser Trp Gly Pro Arg Pro

85 90 95

Arg Arg Tyr Thr Val Leu Ser Val Gly Pro Gly Gly Leu Arg Ser Gly

100 105 110

Arg Leu Pro Leu Gln Pro Arg Val Gln Leu Asp Glu Arg Gly Arg Gln

115 120 125

Arg Gly Asp Phe Ser Leu Trp Leu Arg Pro Ala Arg Arg Ala Asp Ala

130 135 140

Gly Glu Tyr Arg Ala Ala Val His Leu Arg Asp Arg Ala Leu Ser Cys

145 150 155 160

Arg Leu Arg Leu Arg Leu Gly Gln Ala Ser Met Thr Ala Ser Pro Pro

165 170 175

Gly Ser Leu Arg Ala Ser Asp Trp Val Ile Leu Asn Cys Ser Phe Ser

180 185 190

Arg Pro Asp Arg Pro Ala Ser Val His Trp Phe Arg Asn Arg Gly Gln

195 200 205

Gly Arg Val Pro Val Arg Glu Ser Pro His His His Leu Ala Glu Ser

210 215 220

Phe Leu Phe Leu Pro Gln Val Ser Pro Met Asp Ser Gly Pro Trp Gly

225 230 235 240

Cys Ile Leu Thr Tyr Arg Asp Gly Phe Asn Val Ser Ile Met Tyr Asn

245 250 255

Leu Thr Val Leu Gly Leu Glu Pro Pro Thr Pro Leu Thr Val Tyr Ala

260 265 270

Gly Ala Gly Ser Arg Val Gly Leu Pro Cys Arg Leu Pro Ala Gly Val

275 280 285

Gly Thr Arg Ser Phe Leu Thr Ala Lys Trp Thr Pro Pro Gly Gly Gly

290 295 300

Pro Asp Leu Leu Val Thr Gly Asp Asn Gly Asp Phe Thr Leu Arg Leu

305 310 315 320

Glu Asp Val Ser Gln Ala Gln Ala Gly Thr Tyr Thr Cys His Ile His

325 330 335

Leu Gln Glu Gln Gln Leu Asn Ala Thr Val Thr Leu Ala Ile Ile Thr

340 345 350

Val Thr Pro Lys Ser Phe Gly Ser Pro Gly Ser Leu Gly Lys Leu Leu

355 360 365

Cys Glu Val Thr Pro Val Ser Gly Gln Glu Arg Phe Val Trp Ser Ser

370 375 380

Leu Asp Thr Pro Ser Gln Arg Ser Phe Ser Gly Pro Trp Leu Glu Ala

385 390 395 400

Gln Glu Ala Gln Leu Leu Ser Gln Pro Trp Gln Cys Gln Leu Tyr Gln

405 410 415

Gly Glu Arg Leu Leu Gly Ala Ala Val Tyr Phe Thr Glu Leu Ser Ser

420 425 430

Pro Gly Ala Gln Arg Ser Gly Arg Ala Pro Gly Ala Leu Pro Ala Gly

435 440 445

His Leu Leu Leu Phe Leu Ile Leu Gly Val Leu Ser Leu Leu Leu Leu

450 455 460

Val Thr Gly Ala Phe Gly Phe His Leu Trp Arg Arg Gln Trp Arg Pro

465 470 475 480

Arg Arg Phe Ser Ala Leu Glu Gln Gly Ile His Pro Pro Gln Ala Gln

485 490 495

Ser Lys Ile Glu Glu Leu Glu Gln Glu Pro Glu Pro Glu Pro Glu Pro

500 505 510

Glu Pro Glu Pro Glu Pro Glu Pro Glu Pro Glu Gln Leu

515 520 525

<210> 391

<211> 321

<212> DNA

<213> Artificial sequence

<220>

<221> source

<223> /note="Description of the artificial sequence:

Synthetic polynucleotide"

<400> 391

gctagcctct tacgagctga ctcagccacc ttccgtgtcc gtgtccccag gacagaccgc 60

aagaatcaca tgcagtggcg gatccagcta ctcatatggg tggttccagc agaagcctgg 120

tcaggccccc gtgacagtca tctatgagag caacaatagg ccttctgaca ttccagaacg 180

gtttagtggc tctagttcag gaaccacagt gactctgacc atcagcgggg tccaggccga 240

ggacgaagct gattactatt gtggcaacgc tgattccagc tctggaattt tcgggtccgg 300

tacaaaagtg actgtcctag g 321

<210> 392

<211> 104

<212> PRT

<213> Artificial sequence

<220>

<221> source

<223> /note="Description of the artificial sequence:

Synthetic polypeptide"

<400> 392

Ser Tyr Glu Leu Thr Gln Pro Ser Val Ser Val Ser Pro Gly Gln

1 5 10 15

Thr Ala Arg Ile Thr Cys Ser Gly Gly Ser Ser Tyr Ser Tyr Gly Trp

20 25 30

Phe Gln Gln Lys Pro Gly Gln Ala Pro Val Thr Val Ile Tyr Glu Ser

35 40 45

Asn Asn Arg Pro Ser Asp Ile Pro Glu Arg Phe Ser Gly Ser Ser Ser

50 55 60

Gly Thr Thr Val Thr Leu Thr Ile Ser Gly Val Gln Ala Glu Asp Glu

65 70 75 80

Ala Asp Tyr Tyr Cys Gly Asn Ala Asp Ser Ser Ser Gly Ile Phe Gly

85 90 95

Ser Gly Thr Lys Val Thr Val Leu

100

<210> 393

<211> 4

<212> PRT

<213> Artificial sequence

<220>

<221> source

<223> /note="Description of the artificial sequence:

Synthetic peptide"

<400> 393

Ser Ser Tyr Ser

1

<210> 394

<211> 3

<212> PRT

<213> Artificial sequence

<220>

<221> source

<223> /note="Description of the artificial sequence:

Synthetic peptide"

<400> 394

Glu Ser Asn

1

<210> 395

<211> 11

<212> PRT

<213> Artificial sequence

<220>

<221> source

<223> /note="Description of the artificial sequence:

Synthetic peptide"

<400> 395

Cys Gly Asn Ala Asp Ser Ser Ser Gly Ile Phe

1 5 10

<210> 396

<211> 15

<212> PRT

<213> Artificial sequence

<220>

<221> source

<223> /note="Description of the artificial sequence:

Synthetic peptide"

<400> 396

Gly Gly Gly Gly Ser Gly Gly Gly Gly Ser Gly Gly Gly Gly Ser

1 5 10 15

<210> 397

<211> 6

<212> PRT

<213> Homo sapiens

<400> 397

Lys Ile Glu Glu Leu Glu

15

<---

Claims (41)

1. A method for enhancing immunity in a human patient in need thereof, comprising administering to the patient antibodies against TIM-3 or an antigen-binding portion thereof, and an anti-PD-1 antibody, or an antigen-binding portion thereof, wherein the anti-TIM-3 antibody has H-CDR1-3 and L-CDR1-3, which comprise the amino acid sequences from SEQ ID NOs: 8-13, respectively, and the anti-PD-1 antibody a) has H-CDR1-3 and L-CDR1-3 which contain the amino acid sequences of SEQ ID NOs: 228-233, respectively; b) is pembrolizumab; or c) nivolumab. 2. The method of claim 1, wherein the anti-TIM-3 antibody has a heavy chain variable domain (VH) and a light chain variable domain (VL) that contain the amino acid sequences of: a) SEQ ID NO: 7 and 4, respectively, and the anti-PD-1 antibody has VH and VL, which contain the amino acid sequences of SEQ ID NO: 226 and 227, respectively. 3. The method of claim 1, wherein the anti-TIM-3 antibody has: a heavy chain (HC) containing the amino acid sequences of SEQ ID NOs: 7 and 377, and a light chain (LC) containing the amino acid sequences of SEQ ID NOs: 4 and 378, and the anti-PD-1 antibody has a HC containing the amino acid sequences of SEQ ID NOs: 226 and 375 and an LC containing the amino acid sequences of SEQ ID NOs: 227 and 379. 4. The method of claim 1, wherein the anti-TIM-3 antibody has VH and VL that contain the amino acid sequences of SEQ ID NOs: 7 and 4, respectively, and the anti-PD-1 antibody is pembrolizumab or nivolumab. 5. A method for enhancing immunity in a human patient in need, comprising administering an anti-TIM-3 antibody and an anti-PD-1 antibody to the patient, wherein the anti-TIM-3 antibody has a heavy chain (HC) that contains the amino acid sequences of SEQ ID NOS: 7 and 377 and a light chain (LC) that contains the amino acid sequences of SEQ ID NOS: 4 and 378, and the anti-PD-1 antibody is pembrolizumab. 6. A method for enhancing immunity in a human patient in need thereof, comprising administering an anti-TIM-3 antibody and an anti-PD-1 antibody to the patient, wherein the anti-TIM-3 antibody has a heavy chain (HC) that contains the amino acid sequences of SEQ ID NOS: 7 and 377 and a light chain (LC) that contains the amino acid sequences of SEQ ID NOS: 4 and 378, and the anti-PD-1 antibody is nivolumab. 7. The method according to any one of paragraphs. 1-6, wherein the antibodies or antigen-binding portions are administered to the patient at the same time. 8. The method of claim 7 wherein the antibodies or antigen-binding portions thereof are administered in a single pharmaceutical composition. 9. The method according to any one of paragraphs. 1-6, wherein the antibodies or antigen-binding portions are administered sequentially to the patient. 10. The method according to any one of paragraphs. 1-9 in which the patient has cancer. 11. The method of claim 10, wherein the cancer is a hematological malignancy. 12. The method of claim 11, wherein the hematological malignancy is leukemia, Hodgkin's lymphoma, non-Hodgkin's lymphoma, or myeloma. 13. The method of claim 10 wherein the cancer is a solid tumor. 14. The method of claim 10, wherein the cancer is melanoma, non-small cell lung cancer, bladder cancer, gallbladder cancer, head and neck squamous cell cancer, esophageal cancer, esophagogastric junction cancer, gastric cancer, ovarian cancer, colon cancer , renal cell carcinoma, pancreatic cancer, Merkel cell carcinoma, fibrosarcoma, gliosarcoma, mesothelioma, bile duct cancer, or glioblastoma. 15. The method according to any one of paragraphs. 1-14 further comprising administering radiation therapy to the patient or administering at least one of a chemotherapeutic agent, an anticancer agent, and an antiangiogenic agent. 16. The method of claim 15 wherein said chemotherapeutic agent is irinotecan. 17. A pharmaceutical composition for enhancing immunity and treating cancer, comprising an antibody to TIM-3 or an antigen-binding portion thereof and an antibody to PD-1 or an antigen-binding portion thereof, wherein a) anti-TIM-3 antibody i) has H-CDR1-3 and L-CDR1-3 which contain the amino acid sequences of SEQ ID NOs: 8-13, respectively; ii) has a heavy chain variable domain (VH) and a light chain variable domain (VL), which contain the amino acid sequences of SEQ ID NOs: 7 and 4, respectively; or iii) has a heavy chain (HC) that contains the amino acid sequences of SEQ ID NOs: 7 and 377 and a light chain (LC) that contains the amino acid sequences of SEQ ID NOs: 4 and 378; And b) anti-PD-1 antibody i) has H-CDR1-3 and L-CDR1-3 which contain the amino acid sequences of SEQ ID NOs: 228-233, respectively; ii) has a VH and VL that contain the amino acid sequences of SEQ ID NOs: 226 and 227, respectively; iii) has a HC that contains the amino acid sequences of SEQ ID NOs: 226 and 375 and an LC that contains the amino acid sequences of SEQ ID NOs: 227 and 379; iv) is pembrolizumab; or v) nivolumab. 18. A pharmaceutical composition according to claim 17, further comprising a chemotherapeutic agent, an antitumor agent, or an antiangiogenic agent. 19. The pharmaceutical composition of claim 18, wherein said chemotherapeutic agent is irinotecan.

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