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Msg  12065 of 12445  at  12/1/2023 6:37:18 PM  by

JBWIN


Building IP: BMY Patent Appl "ANTIBODIES AGAINST TIM3 AND USES THEREOF"

 

ANTIBODIES AGAINST TIM3 AND USES THEREOF

DOCUMENT ID

US 20230382992 A1

DATE PUBLISHED

2023-11-30

INVENTOR INFORMATION

NAME

CITY

STATE

ZIP CODE

COUNTRY

SCHEBYE; Xiao Min
San Carlos
CA
N/A
US
SELBY; Mark J.
San Francisco
CA
N/A
US
HAN; Michelle Minhua
Piedmont
CA
N/A
US
BEE; Christine
San Francisco
CA
N/A
US
DENG; Andy X.
San Mateo
CA
N/A
US
CHUNTHARAPAI; Anan
Daly City
CA
N/A
US
DEVAUX; Brigitte
Palo Alto
CA
N/A
US
LI; Huiming
Lexington
MA
N/A
US
SHEPPARD; Paul O.
Granite Falls
WA
N/A
US
KORMAN; Alan J.
Piedmont
CA
N/A
US
ARDOUREL; Daniel F.
Woodinville
WA
N/A
US
DEYANOVA; Ekaterina
Lawrenceville
NJ
N/A
US
HUANG; Richard
Bridgewater
NJ
N/A
US
CHEN; Guodong
East Brunswick
NJ
N/A
US
KUHNE; Michelle
San Francisco
CA
N/A
US
TRUONG; Hong-An
San Francisco
CA
N/A
US

APPLICANT INFORMATION

NAME
Bristol-Myers Squibb Company
CITY
Princeton
STATE
NJ
ZIP CODE
N/A
COUNTRY
US
AUTHORITY
N/A
TYPE
assignee

ASSIGNEE INFORMATION

NAME
Bristol-Myers Squibb Company
CITY
Princeton
STATE
NJ
ZIP CODE
N/A
COUNTRY
US
TYPE CODE
02

APPLICATION NO

18/175420

DATE FILED

2023-02-27

DOMESTIC PRIORITY (CONTINUITY DATA)

parent US continuation 16697653 20191127 parent-grant-document US 11591392 child US 18175420

parent US continuation 16017489 20180625 parent-grant-document US 10533052 child US 16697653

parent US continuation 15649380 20170713 parent-grant-document US 10077306 child US 16017489

us-provisional-application US 62459499 20170215

us-provisional-application US 62362541 20160714

US CLASS CURRENT:

1/1

CPC CURRENT

TYPE

CPC

DATE

CPCI
2018-01-01
CPCI
2013-01-01
CPCI
2017-08-01
CPCI
2013-01-01
CPCI
2013-01-01
CPCI
2013-01-01
CPCI
2013-01-01
CPCI
2013-01-01
CPCI
2013-01-01
CPCA
2013-01-01
CPCA
2013-01-01
CPCA
2013-01-01
CPCA
2013-01-01
CPCA
2013-01-01
CPCA
2013-01-01
CPCA
2013-01-01
CPCA
2013-01-01
CPCA
2013-01-01
CPCA
2013-01-01
CPCA
2013-01-01
CPCA
2013-01-01
CPCA
2013-01-01
CPCA
2013-01-01
CPCA
2013-01-01
CPCA
2013-01-01
CPCA
2013-01-01
CPCA
2013-01-01
CPCA
2013-01-01

Abstract

Provided herein are antibodies, or antigen-binding portions thereof, that bind to T-cell immunoglobulin and mucin-domain containing-3 (TIM3) protein. Also provided are uses of these antibodies, or antigen-binding portions thereof, in therapeutic applications, such as treatment of cancer. Further provided are cells that produce the antibodies, or antigen-binding portions thereof, polynucleotides encoding the heavy and/or light chain regions of the antibodies, or antigen-binding portions thereof, and vectors comprising the polynucleotides encoding the heavy and/or light chain regions of the antibodies, or antigen-binding portions thereof.

Background/Summary

CROSS-REFERENCE TO RELATED APPLICATIONS

[0001] This application is a continuation of U.S. application Ser. No. 16/697,653, filed Nov. 27, 2019, issued as U.S. Pat. No. 11,591,392 on Feb. 28, 2023, which is a continuation application of U.S. application Ser. No. 16/017,489, filed Jun. 25, 2018, issued as U.S. Pat. No. 10,533,052 on Jan. 14, 2020, which is a continuation of U.S. application Ser. No. 15/649,380, filed Jul. 13, 2017, issued as U.S. Pat. No. 10,077,306 on Sep. 18, 2018, which claims the benefit of U.S. Provisional Application Nos. 62/362,541, filed Jul. 14, 2016, and 62/459,499, filed Feb. 15, 2017, each of which is hereby incorporated by reference in its entirety.

REFERENCE TO SEQUENCE LISTING SUBMITTED ELECTRONICALLY

[0002] The content of the electronically submitted sequence listing submitted in this application (Name: 3338_0520006_Seqlisting_ST26.XML; Size: 666,858 Bytes; and Date of Creation: Jul. 7, 2023) is herein incorporated by reference in its entirety.

BACKGROUND OF THE DISCLOSURE

[0003] T-cell immunoglobulin and mucin-domain containing-3 (TIM3), also known as hepatitis A virus cellular receptor 2 (HAVCR2), is a type-I transmembrane protein that functions as a key regulator of immune responses. TIM3 was initially identified on activated IFN-γ producing T cells (e.g., type 1 helper CD4.sup.+ T cells and cytotoxic CD8.sup.+ T cells) and shown to induce T cell death or exhaustion after binding to galectin-9. More recent studies have indicated that TIM3 expression is also important in regulating the activities of many innate immune cells (e.g., macrophages, monocytes, dendritic cells, mast cells, and natural killer cells). See Han G et al., Front Immunol. 4: 449 (2013).

[0004] Like many inhibitory receptors (e.g., PD-1 and CTLA-4), TIM3 expression has been associated with many types of chronic diseases, including cancer. TIM3.sup.+ T cells have been detected in patients with advanced melanoma, non-small cell lung cancer, or follicular B-cell non-Hodgkin lymphoma. And the presence of TIM3.sup.+ regulatory T cells have been described as an effective indicator of lung cancer progression. See Anderson A C. Cancer Immunol Res. 2: 393-8 (2014).

[0005] Several potential ligands for TIM3 have been identified: Galectin-9, HMGB1, Semaphorin-4A, CEACAM-1, ILT-4 and phosphatidylserine (PtdSer or PS). PS is an important cell membrane component, and is normally localized to the inner leaflet of cell membranes. But as a cell undergoes apoptosis, PS is redistributed and exposed to the outer membrane. This redistribution is also observed in many tumor cell lines. See Riedl S et al., Biochim Biophys Acta. 1808: 2638-2645 (2011). Binding of TIM3 to PS may be critical for phagocytosis and cross-presentation. See Nakayama M et al., Blood. 113: 3821-30 (2009).

[0006] Studies have shown a close relationship between TIM3 and the inhibitory receptor PD-1. For example, many tumor-specific T cells express both PD-1 and TIM3, and these T cells have been shown to be more dysfunctional compared to T cells that express only PD-1 or TIM3. See Fourcade J et al., J Exp Med. 207: 2175-2186 (2010).

[0007] Accordingly, agents that target TIM3, and methods of using such agents, are highly desirable for designing new cancer immunotherapies and improving traditional cancer immunotherapies.

SUMMARY OF THE DISCLOSURE

[0008] Provided herein are isolated antibodies, such as monoclonal antibodies, in particular human (e.g., monoclonal) antibodies, that specifically bind TIM3 and have desirable functional properties. These properties include, e.g., high affinity binding to human TIM3, binding to monkey TIM3 (e.g., cynomolgus TIM3), and the ability to stimulate immune responses, e.g., antigen-specific T cell responses, such as in a tumor-bearing or virus-bearing (virus-infected) subject, and to detect TIM3 protein in a sample.

[0009] In one aspect, the isolated antibodies, or antigen binding portions thereof, which bind to TIM3, exhibit at least one of the following properties: (a) binding to soluble and/or membrane bound human TIM3; (b) binding to soluble and/or membrane bound cyno TIM3; (c) inducing or stimulating an immune response; (d) inducing or stimulating T cell activation, e.g., Th1 cell activation, (as evidenced, e.g., by enhanced cytokine secretion and/or proliferation); (e) inducing or stimulating T cell proliferation (e.g., CD4.sup.+, CD8.sup.+ T cells, Th1 cells or TILs), e.g., in a coculture assay, such as described in the Examples; (f) inducing or stimulating IFN-γ production by T cells, e.g., Th1 cells or tumor infiltrating lymphocytes (TILs), such as TILs from human renal, lung, pancreatic or breast cancer tumors, as determined, e.g., in the assay described in the Examples; (g) blocking or inhibiting the binding of human TIM3 to PtdSer, as determined, e.g., in the assay described in the Examples; (h) not internalizing or downregulating cell surface TIM3 when binding to TIM3 on cells; (i) binding to human TIM3 extracellular domain (a) CPVFECG (SEQ ID NO: 296); (b) RIQIPGIMND (SEQ ID NO: 298); (c) CPVFECG and RIQIPGIMND (SEQ ID NOs: 296 and 298, respectively); or (d) WTSRYWLNGDFR (SEQ ID NO: 297); (j) competing with, or cross-blocking, the binding to human TIM3 of an antibody binding to TIM3 described herein (e.g., 13A3, 3G4, 17C3, 17C8, 9F6, or any of TIM3.2 to TIM3.18), as determined, e.g., in the assay described in the Examples; (k) binding to human TIM3, but not to human TIM3 having an amino acid substitution of one or more of the following amino acid residues: L48, C58, P59, V60, F61, E62, C63, G64, W78, S80, R81, W83, L84, G86, D87, R89, D104, R111, Q113, G116, M118, and D120, as numbered in SEQ ID NO: 286 (FIG. 20); (l) binding to human TIM3 regions .sup.49VPVCWGKGACPVFE.sup.62 (SEQ ID NO: 367), .sup.111RIQIPGIMNDEKFNLKL.sup.127 (SEQ ID NO: 368), and .sup.119NDEKFNLKL.sup.127 (SEQ ID NO: 373) as determined by HDX-MS; (m) having the heavy chain and/or light chain variable regions interact with at least 5, 10, 15, 20 or all of the following amino acids of human TIM3: P50, V51, C52, P59, V60, F61, E62, C63, G64, N65, V66, V67, L68, R69, D71, E72, D74, R111, Q113, G116, 1117, M118, D120, and optionally T70 and/or I112, as determined by X-ray crystallography; and/or (n) competing with or cross-blocking with the binding to human TIM3 of 13A3 or TIM3.18.IgG1.3, e.g., as described in the Examples.

[0010] In certain embodiments, the anti-TIM3 antibodies, or antigen binding portion thereof, stimulate an anti-tumor immune response, e.g., an antigen-specific T cell response. In other embodiments, the anti-TIM3 antibodies, or antigen binding portions thereof, increase cytokine production (e.g., IFN-γ) in TIM3-expressing T cells and/or increase T cell proliferation. In some embodiments, the anti-TIM3 antibodies, or antigen binding portions thereof, do not bind to Fc receptors.

[0011] In certain embodiments, the anti-TIM3 antibodies, or antigen binding portions thereof, bind to soluble human TIM3 with a K.sub.D of 10 nM or less as measured by Biacore, bind to membrane bound human TIM3 with a K.sub.D of 1 nM or less as measured by Scatchard, bind to soluble cynomolgus TIM3 with a K.sub.D of 100 nM or less as measured by Biacore, bind to membrane bound human TIM3 with an EC.sub.50 of 1 μg/mL or less as measured by flow cytometry, bind to membrane bound human TIM3 with an EC.sub.50 of 0.1 lag/mL or less as measured by flow cytometry, bind to membrane bound cynomolgus TIM3 with an EC.sub.50 of 1 μg/mL or less as measured by flow cytometry, bind to membrane bound cyno TIM-3 with a K.sub.D of 1 nM or less as measured by Scatchard.

[0012] Provided herein are isolated antibodies, or antigen binding portions thereof, which bind to human TIM3 and comprise heavy chain CDR1, CDR2, and CDR3 and light chain CDR1, CDR2, and CDR3, wherein the heavy chain CDR3 comprises an amino acid sequence selected from the group consisting of: SEQ ID NO: 53, SEQ ID NO: 54, SEQ ID NO: 55, SEQ ID NO: 56, SEQ ID NO: 57, SEQ ID NO: 58, SEQ ID NO: 59, SEQ ID NO: 126, SEQ ID NO: 127, SEQ ID NO: 128, and SEQ ID NO: 129.

[0013] In certain embodiments, the heavy chain CDR1 comprises X1, X2, X3, X4, Y, X5, and X6, and wherein X1 is S or none, X2 is R or none, X3 is S, R, or D, X4 is Y or H, X5 is W or M, and X6 is G, N, S, or H. In other embodiments, the heavy chain CDR1 comprises X1, Y, Y, M, and X2, and wherein X1 is S or D and X2 is H or S. In some embodiments, the heavy chain CDR1 comprises R, X1, Y, W, and X2, and wherein X1 is H or Y and X2 is N or S.

[0014] In one embodiment, the heavy chain CDR2 comprises X1, I, X2, X3, X4, G, X5, X6, X7, X8, Y, X9, X10, X11, X12, X13, and X14, and wherein X1 is S, Y, I, or F, X2 is Y, H, N, or S, X3 is Y, P, G, T, or S, X4 is S, T, R, or G, X5 is F, S, or D, X6 is S, T, or I, X7 is I or none, X8 is Y, N, or I, X9 is N, Q, S, or A, X10 is P, S, Q, or D, X11 is S or K, X12 is L, F, or V, X13 is K or Q, and X14 is S or G. In another embodiment, the heavy chain CDR2 comprises Y, I, H, Y, X1, G, S, T, N, Y, N, X2, S, L, K, and S, and wherein X1 is S or T and X2 is S or P. In some embodiments, the heavy chain CDR2 comprises F, I, S, X1, X2, G, S, X3, I, Y, Y, A, D, S, V, K, and G, and wherein X1 is G, T or S, X2 is G or S, and X3 is T or I. In other embodiments, the heavy chain CDR2 comprises I, I, N, P, R, G, D, S, I, I, Y, A, Q, K, F, Q, and G.

[0015] In certain embodiments, the anti-TIM3 antibodies, or antigen binding portions thereof, comprise a light chain CDR1 comprising SEQ ID NO: 64 or SEQ ID NO: 65, a light chain CDR2 comprising SEQ ID NO: 66 or SEQ ID NO: 67, and/or a light chain CDR3 comprising SEQ ID NO: 68, SEQ ID NO: 69, SEQ ID NO: or SEQ ID NO: 71.

[0016] Provided herein are isolated antibodies, or antigen binding portions thereof, which bind human TIM3 and comprise heavy chain CDR1, CDR2, and CDR3 and light chain CDR1, CDR2, and CDR3, wherein (a) the heavy chain CDR1 is selected from the group consisting of SEQ ID NO: 41, SEQ ID NO: 42; SEQ ID NO: 43; SEQ ID NO: 44; and SEQ ID NO: 45; (b) the heavy chain CDR2 is selected from the group consisting of SEQ ID NO: 46, SEQ ID NO: 47; SEQ ID NO: 48; SEQ ID NO: 49; SEQ ID NO: 50; SEQ ID NO: 51; SEQ ID NO: 52; SEQ ID NO: 122; SEQ ID NO: 123; SEQ ID NO: 124 and SEQ ID NO: 125; (c) the heavy chain CDR3 is selected from the group consisting of SEQ ID NO: 53, SEQ ID NO: 54; SEQ ID NO: 55; SEQ ID NO: 56; SEQ ID NO: 57; SEQ ID NO: 58; SEQ ID NO: 59; SEQ ID NO: 126; SEQ ID NO: 127; SEQ ID NO:128 and SEQ ID NO: 129; (d) the light chain CDR1 comprises SEQ ID NO: 64 or SEQ ID NO: 65; (e) the light chain CDR2 comprises SEQ ID NO: 66 or SEQ ID NO: 67; and (f) the light chain CDR3 comprises SEQ ID NO: 68, SEQ ID NO: 69, SEQ ID NO: 70, or SEQ ID NO: 71.

[0017] Provided herein are isolated antibodies, or antigen binding portions thereof, which bind to human TIM3 and comprise: (a1) the heavy chain variable region CDR1, CDR2, and CDR3 comprises SEQ ID NOs: 41, 46, 53, respectively, and the light chain variable region CDR1, CDR2, and CDR3 comprises SEQ ID NOs: 64, 66, 68, respectively; (a2) the heavy chain variable region CDR1, CDR2, and CDR3 comprises SEQ ID NOs: 41, 122, 53, respectively, and the light chain variable region CDR1, CDR2, and CDR3 comprises SEQ ID NOs: 64, 66, 68, respectively; (a3) the heavy chain variable region CDR1, CDR2, and CDR3 comprises SEQ ID NOs: 41, 123, 53, respectively, and the light chain variable region CDR1, CDR2, and CDR3 comprises SEQ ID NOs: 64, 66, 68, respectively; (a4) the heavy chain variable region CDR1, CDR2, and CDR3 comprises SEQ ID NOs: 41, 124, 53, respectively, and the light chain variable region CDR1, CDR2, and CDR3 comprises SEQ ID NOs: 64, 66, 68, respectively; (a5) the heavy chain variable region CDR1, CDR2, and CDR3 comprises SEQ ID NOs: 41, 46, 126, respectively, and the light chain variable region CDR1, CDR2, and CDR3 comprises SEQ ID NOs: 64, 66, 68, respectively; (a6) the heavy chain variable region CDR1, CDR2, and CDR3 comprises SEQ ID NOs: 41, 46, 127, respectively, and the light chain variable region CDR1, CDR2, and CDR3 comprises SEQ ID NOs: 64, 66, 68, respectively; (a7) the heavy chain variable region CDR1, CDR2, and CDR3 comprises SEQ ID NOs: 41, 46, 128, respectively, and the light chain variable region CDR1, CDR2, and CDR3 comprises SEQ ID NOs: 64, 66, 68, respectively; (a8) the heavy chain variable region CDR1, CDR2, and CDR3 comprises SEQ ID NOs: 41, 46, 129, respectively, and the light chain variable region CDR1, CDR2, and CDR3 comprises SEQ ID NOs: 64, 66, 68, respectively; (a9) the heavy chain variable region CDR1, CDR2, and CDR3 comprises SEQ ID NOs: 41, 122, 128, respectively, and the light chain variable region CDR1, CDR2, and CDR3 comprises SEQ ID NOs: 64, 66, 68, respectively; (a10) the heavy chain variable region CDR1, CDR2, and CDR3 comprises SEQ ID NOs: 41, 122, 126, respectively, and the light chain variable region CDR1, CDR2, and CDR3 comprises SEQ ID NOs: 64, 66, 68, respectively; (b1) the heavy chain variable region CDR1, CDR2, and CDR3 comprises SEQ ID NOs: 42, 47, 54, respectively, and the light chain variable region CDR1, CDR2, and CDR3 comprises SEQ ID NOs: 64, 66, 69, respectively; (b2) the heavy chain variable region CDR1, CDR2, and CDR3 comprises SEQ ID NOs: 42, 125, 54, respectively, and the light chain variable region CDR1, CDR2, and CDR3 comprises SEQ ID NOs: 64, 66, 69, respectively; (c) heavy chain CDR1, CDR2, and CDR3 sequences comprising SEQ ID NOs: 43, 48, and 55, respectively, and/or light chain CDR1, CDR2, and CDR3 sequences comprising SEQ ID NOs: 64, 66, and 69, respectively; (d) heavy chain CDR1, CDR2, and CDR3 sequences comprising SEQ ID NOs: 44, 49, and 56, respectively, and/or light chain CDR1, CDR2, and CDR3 sequences comprising SEQ ID NOs: 64, 66, and 68, respectively; (e) heavy chain CDR1, CDR2, and CDR3 sequences comprising SEQ ID NOs: 45, 50, and 57, respectively, and/or light chain CDR1, CDR2, and CDR3 sequences comprising SEQ ID NOs: 64, 66, and 69, respectively; (f) heavy chain CDR1, CDR2, and CDR3 sequences comprising SEQ ID NOs: 45, 50, and 57, respectively, and/or light chain CDR1, CDR2, and CDR3 sequences comprising SEQ ID NOs: 64, 66, and 71, respectively; (g) heavy chain CDR1, CDR2, and CDR3 sequences comprising SEQ ID NOs: 45, 50, and 57, respectively, and/or light chain CDR1, CDR2, and CDR3 sequences comprising SEQ ID NOs: 65, 67, and 70, respectively; (h) heavy chain CDR1, CDR2, and CDR3 sequences comprising SEQ ID NOs: 45, 51, and 58, respectively, and/or light chain CDR1, CDR2, and CDR3 sequences comprising SEQ ID NOs: 64, 66, and 68, respectively; (i) heavy chain CDR1, CDR2, and CDR3 sequences comprising SEQ ID NOs: 45, 52, and 59, respectively, and/or light chain CDR1, CDR2, and CDR3 sequences comprising SEQ ID NOs: 64, 66, and 69, respectively.

[0018] Provided herein are isolated antibodies, or antigen binding portions thereof, which bind to human TIM3 and comprise heavy and light chain variable regions, wherein the heavy chain variable region comprises an amino acid sequence which is at least about 80%, at least about 85%, at least about 90%, at least about 95%, at least about 96%, at least about 97%, at least about 98%, at least about 99%, or about 100% identical to the amino acid sequence selected from the group consisting of SEQ ID NOs: 34, 35, 36, 37, 38, 39, 40, 112, 113, 114, 115, 116, 117, 118, 119, 120, 121, and 364 and/or wherein the light chain variable region comprises an amino acid sequence which is at least about 80%, at least about 85%, at least about 90%, at least about 95%, at least about 96%, at least about 97%, at least about 98%, at least about 99%, or about 100% identical to the amino acid sequence selected from the group consisting of SEQ ID NOs: 60, 61, 62, and 63.

[0019] Provided herein are isolated antibodies, or antigen binding portions thereof, which bind to human TIM3 and cross-compete for binding to human TIM3 with a reference antibody comprising a VH and a VL, wherein the VH and the VL are selected from the group consisting of: [0020] (a) a VH comprising the amino acid sequence set forth in SEQ ID NO: 34 and a VL comprising the amino acid sequence set forth in SEQ ID NO: 60; [0021] (b) a VH comprising the amino acid sequence set forth in SEQ ID NO: 35 and a VL comprising the amino acid sequence set forth in SEQ ID NO: 61; [0022] (c) a VH comprising the amino acid sequence set forth in SEQ ID NO: 36 and a VL comprising the amino acid sequence set forth in SEQ ID NO: 61; [0023] (d) a VH comprising the amino acid sequence set forth in SEQ ID NO: 37 and a VL comprising the amino acid sequence set forth in SEQ ID NO: 60; [0024] (e) a VH comprising the amino acid sequence set forth in SEQ ID NO: 38 and a VL comprising the amino acid sequence set forth in SEQ ID NO: 61; [0025] (f) a VH comprising the amino acid sequence set forth in SEQ ID NO: 38 and a VL comprising the amino acid sequence set forth in SEQ ID NO: 62; [0026] (g) a VH comprising the amino acid sequence set forth in SEQ ID NO: 38 and a VL comprising the amino acid sequence set forth in SEQ ID NO: 63; [0027] (h) a VH comprising the amino acid sequence set forth in SEQ ID NO: 39 and a VL comprising the amino acid sequence set forth in SEQ ID NO: 60; [0028] (i) a VH comprising the amino acid sequence set forth in SEQ ID NO: 40 and a VL comprising the amino acid sequence set forth in SEQ ID NO: 61; [0029] (j) a VH comprising the amino acid sequence set forth in SEQ ID NOs: 121 and a VL comprising the amino acid sequence set forth in 63, respectively; [0030] (k) a VH comprising the amino acid sequence set forth in SEQ ID NOs: 120 and a VL comprising the amino acid sequence set forth in 61, respectively; [0031] (1) a VH comprising the amino acid sequence set forth in SEQ ID NOs: 112 and a VL comprising the amino acid sequence set forth in 60, respectively; [0032] (m) a VH comprising the amino acid sequence set forth in SEQ ID NOs: 113 and a VL comprising the amino acid sequence set forth in 60, respectively; [0033] (n) a VH comprising the amino acid sequence set forth in SEQ ID NOs: 114 and a VL comprising the amino acid sequence set forth in 60, respectively; [0034] (o) a VH comprising the amino acid sequence set forth in SEQ ID NOs: 115 and a VL comprising the amino acid sequence set forth in 60, respectively; [0035] (p) a VH comprising the amino acid sequence set forth in SEQ ID NOs: 116 and a VL comprising the amino acid sequence set forth in 60, respectively; [0036] (q) a VH comprising the amino acid sequence set forth in SEQ ID NOs: 117 and a VL comprising the amino acid sequence set forth in 60, respectively; [0037] (r) a VH comprising the amino acid sequence set forth in SEQ ID NOs: 118 and a VL comprising the amino acid sequence set forth in 60, respectively; [0038] (s) a VH comprising the amino acid sequence set forth in SEQ ID NOs: 119 and a VL comprising the amino acid sequence set forth in 60, respectively; and [0039] (t) a VH comprising the amino acid sequence set forth in SEQ ID NOs: 364 and a VL comprising the amino acid sequence set forth in 60, respectively.

[0040] In one embodiment, the isolated anti-TIM3 antibodies, or antigen binding portions thereof, bind to TIM3 at the same epitope as the reference antibody.

[0041] In other embodiments, the isolated anti-TIM3 antibodies, or antigen binding portions thereof, comprise a VH and a VL, selected from the group consisting of: (a) a VH comprising the amino acid sequence set forth in SEQ ID NO: 34 and a VL comprising the amino acid sequence set forth in SEQ ID NO: 60; [0042] (b) a VH comprising the amino acid sequence set forth in SEQ ID NO: 35 and a VL comprising the amino acid sequence set forth in SEQ ID NO: 61; [0043] (c) a VH comprising the amino acid sequence set forth in SEQ ID NO: 36 and a VL comprising the amino acid sequence set forth in SEQ ID NO: 61; [0044] (d) a VH comprising the amino acid sequence set forth in SEQ ID NO: 37 and a VL comprising the amino acid sequence set forth in SEQ ID NO: 60; [0045] (e) a VH comprising the amino acid sequence set forth in SEQ ID NO: 38 and a VL comprising the amino acid sequence set forth in SEQ ID NO: 61; [0046] (f) a VH comprising the amino acid sequence set forth in SEQ ID NO: 38 and a VL comprising the amino acid sequence set forth in SEQ ID NO: 62; [0047] (g) a VH comprising the amino acid sequence set forth in SEQ ID NO: 38 and a VL comprising the amino acid sequence set forth in SEQ ID NO: 63; [0048] (h) a VH comprising the amino acid sequence set forth in SEQ ID NO: 39 and a VL comprising the amino acid sequence set forth in SEQ ID NO: 60; [0049] (i) a VH comprising the amino acid sequence set forth in SEQ ID NO: 40 and a VL comprising the amino acid sequence set forth in SEQ ID NO: 61; [0050] (j) a VH comprising the amino acid sequence set forth in SEQ ID NOs: 121 and a VL comprising the amino acid sequence set forth in 63, respectively; [0051] (k) a VH comprising the amino acid sequence set forth in SEQ ID NOs: 120 and a VL comprising the amino acid sequence set forth in 61, respectively; [0052] (l) a VH comprising the amino acid sequence set forth in SEQ ID NOs: 112 and a VL comprising the amino acid sequence set forth in 60, respectively; [0053] (m) a VH comprising the amino acid sequence set forth in SEQ ID NOs: 113 and a VL comprising the amino acid sequence set forth in 60, respectively; [0054] (n) a VH comprising the amino acid sequence set forth in SEQ ID NOs: 114 and a VL comprising the amino acid sequence set forth in 60, respectively; [0055] (o) a VH comprising the amino acid sequence set forth in SEQ ID NOs: 115 and a VL comprising the amino acid sequence set forth in 60, respectively; [0056] (p) a VH comprising the amino acid sequence set forth in SEQ ID NOs: 116 and a VL comprising the amino acid sequence set forth in 60, respectively; [0057] (q) a VH comprising the amino acid sequence set forth in SEQ ID NOs: 117 and a VL comprising the amino acid sequence set forth in 60, respectively; [0058] (r) a VH comprising the amino acid sequence set forth in SEQ ID NOs: 118 and a VL comprising the amino acid sequence set forth in 60, respectively; [0059] (s) a VH comprising the amino acid sequence set forth in SEQ ID NOs: 119 and a VL comprising the amino acid sequence set forth in 60, respectively; and [0060] (t) a VH comprising the amino acid sequence set forth in SEQ ID NOs: 364 and a VL comprising the amino acid sequence set forth in 60, respectively.

[0061] In certain embodiments, the anti-TIM3 antibodies, or antigen binding portions thereof, are selected from the group consisting of an IgG1, an IgG2, an IgG3, an IgG4 or a variant thereof. In some embodiments, the anti-TIM3 antibodies, or antigen binding portions thereof, comprise an effectorless IgG1 Fc that comprises the following mutations: L234A, L235E, G237A, and optionally A330S and P331S. In other embodiments, the anti-TIM3 antibodies, or antigen binding portions thereof, comprise a heavy chain constant region comprising an amino acid sequence selected from the group consisting of SEQ ID NOs: 130-133. In certain embodiments, the anti-TIM3 antibodies, or antigen binding portions thereof, are human or humanized antibody.

[0062] In certain embodiments, the anti-TIM3 antibodies, or antigen binding portions thereof, specifically bind to human TIM3 and comprise (a1) heavy and light chain sequences comprising SEQ ID NOs: 301 (or 302) and 29, respectively; [0063] (a2) heavy and light chain sequences comprising SEQ ID NOs: 1 (or 8) and 29, respectively; [0064] (a3) heavy and light chain sequences comprising SEQ ID NOs: 15 (or 22) and 29, respectively; [0065] (a4) heavy and light chain sequences comprising SEQ ID NOs: 303 (or 304) and 29, respectively; [0066] (a5) heavy and light chain sequences comprising SEQ ID NOs: 72 (or 82) and 29, respectively; [0067] (a6) heavy and light chain sequences comprising SEQ ID NOs: 92 (or 102) and 29, respectively; [0068] (a7) heavy and light chain sequences comprising SEQ ID NOs: 305 (or 306) and 29, respectively; [0069] (a8) heavy and light chain sequences comprising SEQ ID NOs: 73 (or 83) and 29, respectively; [0070] (a9) heavy and light chain sequences comprising SEQ ID NOs: 93 (or 103) and 29, respectively; [0071] (a10) heavy and light chain sequences comprising SEQ ID NOs: 307 (or 308) and 29, respectively; [0072] (a11) heavy and light chain sequences comprising SEQ ID NOs: 74 (or 84) and 29, respectively; [0073] (a12) heavy and light chain sequences comprising SEQ ID NOs: 94 (or 104) and 29, respectively; [0074] (a13) heavy and light chain sequences comprising SEQ ID NOs: 309 (or 310) and 29, respectively; [0075] (a14) heavy and light chain sequences comprising SEQ ID NOs: 75 (or 85) and 29, respectively; [0076] (a15) heavy and light chain sequences comprising SEQ ID NOs: 95 (or 105) and 29, respectively; [0077] (a16) heavy and light chain sequences comprising SEQ ID NOs: 311 (or 312) and 29, respectively; [0078] (a17) heavy and light chain sequences comprising SEQ ID NOs: 76 (or 86) and 29, respectively; [0079] (a18) heavy and light chain sequences comprising SEQ ID NOs: 96 (or 106) and 29, respectively; [0080] (a19) heavy and light chain sequences comprising SEQ ID NOs: 313 (or 314) and 29, respectively; [0081] (a20) heavy and light chain sequences comprising SEQ ID NOs: 77 (or 87) and 29, respectively; [0082] (a21) heavy and light chain sequences comprising SEQ ID NOs: 97 (or 107) and 29, respectively; [0083] (a22) heavy and light chain sequences comprising SEQ ID NOs: 315 (or 316) and 29, respectively; [0084] (a23) heavy and light chain sequences comprising SEQ ID NOs: 78 (or 88) and 29, respectively; [0085] (a24) heavy and light chain sequences comprising SEQ ID NOs: 98 (or 108) and 29, respectively; [0086] (a25) heavy and light chain sequences comprising SEQ ID NOs: 317 (or 318) and 29, respectively; [0087] (a26) heavy and light chain sequences comprising SEQ ID NOs: 79 (or 89) and 29, respectively; [0088] (a27) heavy and light chain sequences comprising SEQ ID NOs: 99 (or 109) and 29, respectively; [0089] (a28) heavy and light chain sequences comprising SEQ ID NOs: 319 (or 320) and 29, respectively; [0090] (a29) heavy and light chain sequences comprising SEQ ID NOs: 349 (or 350) and 29, respectively; [0091] (a30) heavy and light chain sequences comprising SEQ ID NOs: 351 (or 352) and 29, respectively; [0092] (a31) heavy and light chain sequences comprising SEQ ID NOs: 353 (or 354) and 29, respectively; [0093] (b1) heavy and light chain sequences comprising SEQ ID NOs: 321 (or 322) and 30, respectively; [0094] (b2) heavy and light chain sequences comprising SEQ ID NOs: 2 (or 9) and 30, respectively; [0095] (b3) heavy and light chain sequences comprising SEQ ID NOs: 16 (or 23) and 30, respectively; [0096] (b4) heavy and light chain sequences comprising SEQ ID NOs: 323 (or 324) and 30, respectively; [0097] (b5) heavy and light chain sequences comprising SEQ ID NOs: 80 (or 90) and 30, respectively; [0098] (b6) heavy and light chain sequences comprising SEQ ID NOs: 100 (or 110) and 30, respectively; [0099] (b7) heavy and light chain sequences comprising SEQ ID NOs: 325 (or 326) and 30, respectively; [0100] (c1) heavy and light chain sequences comprising SEQ ID NOs: 327 (or 328) and 30, respectively; [0101] (c2) heavy and light chain sequences comprising SEQ ID NOs: 3 (or 10) and 30, respectively; [0102] (c3) heavy and light chain sequences comprising SEQ ID NOs: 17 (or 24) and 30, respectively; [0103] (c4) heavy and light chain sequences comprising SEQ ID NOs: 329 (or 330) and 30, respectively; [0104] (d1) heavy and light chain sequences comprising SEQ ID NOs: 331 (or 332) and 29, respectively; [0105] (d2) heavy and light chain sequences comprising SEQ ID NOs: 4 (or 11) and 29, respectively; [0106] (d3) heavy and light chain sequences comprising SEQ ID NOs: 18 (or 25) and 29, respectively; [0107] (d4) heavy and light chain sequences comprising SEQ ID NOs: 333 (or 334) and 29, respectively; [0108] (ell) heavy and light chain sequences comprising SEQ ID NOs: 335 (or 336) and 32, respectively; [0109] (e12) heavy and light chain sequences comprising SEQ ID NOs: 335 (or 336) and 33, respectively; [0110] (e13) heavy and light chain sequences comprising SEQ ID NOs: 335 (or 336) and 33, respectively; [0111] (e2) heavy and light chain sequences comprising SEQ ID NOs: 5 (or 12) and 33, respectively; [0112] (e3) heavy and light chain sequences comprising SEQ ID NOs: 19 (or 26) and 33, respectively; [0113] (e4) heavy and light chain sequences comprising SEQ ID NOs: 337 (or 338) and 33, respectively; [0114] (e5) heavy and light chain sequences comprising SEQ ID NOs: 81 (or 91) and 33, respectively; [0115] (e6) heavy and light chain sequences comprising SEQ ID NOs: 101 (or 111) and 33, respectively; [0116] (e7) heavy and light chain sequences comprising SEQ ID NOs: 339 (or 340) and 33, respectively; [0117] (f1) heavy and light chain sequences comprising SEQ ID NOs: 341 (or 342) and 29, respectively; [0118] (f2) heavy and light chain sequences comprising SEQ ID NOs: 6 (or 13) and 29, respectively; [0119] (f3) heavy and light chain sequences comprising SEQ ID NOs: 20 (or 27) and 29, respectively; [0120] (f4) heavy and light chain sequences comprising SEQ ID NOs: 343 (or 344) and 29, respectively; [0121] (g1) heavy and light chain sequences comprising SEQ ID NOs: 345 (or 346) and 30, respectively; [0122] (g2) heavy and light chain sequences comprising SEQ ID NOs: 7 (or 14) and 30, respectively; [0123] (g3) heavy and light chain sequences comprising SEQ ID NOs: 21 (or 28) and 30, respectively; or [0124] (g4) heavy and light chain sequences comprising SEQ ID NOs: 347 (or 348) and 30, respectively.

[0125] In other embodiments, the anti-TIM3 antibodies, or antigen binding portions thereof, have one or more of the following properties: [0126] (1) binding to soluble human TIM3, e.g., with a K.sub.D of 10 nM or less (e.g., 0.01 nM to 10 nM), e.g., as measured by Biacore, e.g., as described in the Examples; [0127] (2) binding to soluble cynomolgus TIM3, e.g., with a K.sub.D of 100 nM or less (e.g., 0.01 nM to 100 nM), e.g., as measured by Biacore, e.g., as described in the Examples; [0128] (3) binding to membrane bound human TIM3, e.g., with an EC.sub.50 of 1 ug/mL or less (e.g., 0.01 ug/mL to 1 ug/mL), e.g., as measured by flow cytometry (e.g., as described in the Examples); [0129] (4) binding to membrane bound human TIM3, e.g., with a K.sub.D of 1 nM or less (e.g., 0.01 nM to 10 nM), e.g., as measured by Scatchard analysis, e.g., as described in the Examples; [0130] (5) binding to membrane bound cynomolgus TIM3, e.g., with an EC.sub.50 of 20 ug/mL or less (e.g., 0.01 ug/mL to 20 ug/mL), e.g., as measured by flow cytometry (e.g., as described in the Examples); [0131] (6) binding to membrane bound cynomolgus TIM3, e.g., with a K.sub.D of 1 nM or less (e.g., 0.01 nM to 10 nM), e.g., as measured by Scatchard analysis, e.g., as described in the Examples; [0132] (7) inducing or enhancing T cell activation (e.g., by blocking or reducing the inhibitory effect of TIM3), as evidenced by (i) increased IFN-γ production in TIM3-expressing T cells (e.g., Th1 cells or TILs) and/or (ii) enhanced proliferation of TIM3-expressing T cells (e.g., Th1 cells or TILs), e.g., as described in the Examples; [0133] (8) stimulating T cell proliferation in a mixed lymphocyte reaction (MLR) assay, e.g., as described in the Examples; [0134] (9) inhibiting the binding of phosphatidylserine to TIM3, e.g., as measured by PS-hTIM3 “in-tandem” blocking assay, e.g., as described in the Examples; [0135] (10) not internalizing or downregulating cell surface TIM3 when binding to TIM3 on cells; [0136] (11) binding to one of the following regions of human TIM3 extracellular domain (SEQ ID NO: 290): (a) CPVFECG (SEQ ID NO: 296); (b) RIQIPGIMND (SEQ ID NO: 298); (c) CPVFECG and RIQIPGIMND (SEQ ID NOs: 296 and 298, respectively); and (d) WTSRYWLNGDFR (SEQ ID NO: 297), e.g., as described in the Examples; [0137] (12) having reduced binding to human TIM3 in which one or more of amino acids L48, C58, P59, V60, F61, E62, C63, G64, W78, S80, R81, W83, L84, G86, D87, R89, D104, R111, Q113, G116, M118, and D120 (as numbered in SEQ ID NO: 286 (FIG. 20)) is substituted with another amino acid relative to binding to wild-type human TIM3, e.g., as described in the Examples; [0138] (13) competing in either direction or both directions for binding to human TIM3 with an antibody comprising VH and VL domains of any one of 13A3, 3G4, 17C3, 17C8, 9F6, 8B9, 8C4, or TIM3.7, TIM3.8, TIM3.10, TIM3.11, TIM3.12, TIM3.13, TIM3.14, TIM3.15, TIM3.16, TIM3.17, and TIM3.18, e.g., as described in the Examples; [0139] (14) binding to human TIM3 regions .sup.49VPVCWGKGACPVFE.sup.62 (SEQ ID NO: 367) and .sup.111RIQIPGIMNDEKFNLKL.sup.127 (SEQ ID NO: 368) as determined by HDX-MS, e.g., as described in the Examples; [0140] (15) having the heavy chain and/or light chain variable regions interact with at least 5, 10, 15, 20 or all of the following amino acids of human TIM3: P50, V51, C52, P59, V60, F61, E62, C63, G64, N65, V66, V67, L68, R69, D71, E72, D74, R111, Q113, G116, 1117, M118, D120, and optionally T70 and/or I112, as determined by X-ray crystallography (e.g., described in the Examples; numbering per SEQ ID NO: 286 (FIG. 20)); and/or [0141] (16) (a) having reduced binding to human TIM3 in which 1, 2, 3, 4, 5, 6, 7, 8 or 9 of amino acids C58, P59, F61, E62, C63, R111, D120, and optionally D104 and Q113 (numbering per SEQ ID NO: 286 (FIG. 20)) are substituted with another amino acid relative to binding to wildtype human TIM3; (b) binding to .sup.49VPVCWGKGACPVFE.sup.62 (SEQ ID NO: 367), .sup.111RIQIPGIMNDEKFNLKL.sup.127 (SEQ ID NO: 368), and .sup.119NDEKFNLKL.sup.127 (SEQ ID NO: 373), as determined by HDX-MS, as described in the Examples; and/or (c) competing with or cross-blocking with the binding to human TIM3 of 13A3 or TIM3.18.IgG1.3, e.g., as described in the Examples.

[0142] Provided herein are bispecific molecules comprising an anti-TIM3 antibody linked to a molecule having a second binding specificity.

[0143] Provided herein are nucleic acids encoding the heavy and/or light chain variable regions of the anti-TIM3 antibodies, or antigen binding portions thereof, expression vectors comprising the nucleic acid molecules, and cells transformed with the expression vectors.

[0144] Provided herein are immunoconjugates comprising the anti-TIM3 antibodies described herein, linked to an agent.

[0145] Provided herein are compositions comprising anti-TIM3 antibodies, or antigen binding portions thereof, bispecific molecules, or immunoconjugates described herein, and a carrier. Also provided herein are kits comprising the anti-TIM3 antibodies, or antigen binding portions thereof, bispecific molecules, or immunoconjugates described herein, and instructions for use.

[0146] Provided herein is a method of preparing anti-TIM3 antibodies, or antigen binding portions thereof, comprising expressing an anti-TIM3 antibody, or antigen binding portion thereof, in a cell and isolating the antibody, or antigen binding portion thereof, from the cell.

[0147] Provided herein is a method of stimulating an antigen-specific T cell response comprising contacting the T cell with an anti-TIM3 antibody, or antigen binding portion thereof, bispecific molecules, or immunoconjugates described herein such that an antigen-specific T cell response is stimulated (e.g., by inhibiting the negative effect of TIM3 on cells, e.g., T cells).

[0148] Provided herein is a method of activating or co-stimulating a T cell, e.g., an effector T cell (e.g., Th1 cell), comprising contacting a cell, e.g., an effector T cell, with an anti-TIM3 antibody, or antigen binding portion thereof, bispecific molecules, or immunoconjugates described herein, and CD3, wherein the effector T cell is activated or co-stimulated (e.g., by inhibiting the negative effect of TIM3 on cells, e.g., T cells).

[0149] Provided herein is a method of increasing IFN-γ production in and/or proliferation of a T cell, e.g., Th1 cell or TIL, comprising contacting the T cell with an effective amount of an anti-TIM3 antibody, or antigen binding portion thereof, bispecific molecules, or immunoconjugates described herein.

[0150] Provided herein is a method of increasing IFN-γ production in T cells in a subject comprising administering to the subject an effective amount of an anti-TIM3 antibody, or antigen binding portion thereof, bispecific molecule, or immunoconjugate described herein to increase IFN-γ production from the T cells.

[0151] Provided herein a method of stimulating TIL activity in a subject comprising administering to the subject a therapeutically effective amount of an anti-TIM3 antibody, or antigen binding portion thereof, described herein, such that the TILs proliferate or secrete a cytokine, e.g., IFN-γ.

[0152] Provided herein are methods for stimulating NK cells (e.g., by increasing NK cell cytotoxic activity) and/or macrophages or other antigen presenting cell in a subject, comprising administering to the subject an effective amount of an anti-TIM3 antibody, or antigen binding portion thereof, bispecific molecule, or immunoconjugate described herein. For example, an anti-TIM3 antibody described herein can increase IL-12 secretion by antigen presenting cells contacted with the TIM3 antibody.

[0153] Provided herein is a method of stimulating an immune response in a subject comprising administering to the subject an anti-TIM3 antibody, or antigen binding portion thereof, bispecific molecule or immunoconjugate described herein, such that an immune response in the subject is stimulated. In certain embodiments, the subject has a tumor and an immune response against the tumor is stimulated.

[0154] Provided herein is a method for inhibiting the growth of tumors or reducing the size of tumors in a subject comprising administering to the subject an anti-TIM3 antibody, or antigen binding portion thereof, bispecific molecule, or immunoconjugate described herein, such that growth of the tumor is inhibited in the subject.

[0155] Provided herein is a method of treating cancer, e.g., by immunotherapy, comprising administering to a subject in need thereof a therapeutically effective amount of an anti-TIM3 antibody, or antigen binding portion thereof, bispecific molecule, or immunoconjugate described herein to treat the cancer. In certain embodiments, the cancer is selected from the group consisting of: bladder cancer, breast cancer, uterine/cervical cancer, ovarian cancer, prostate cancer, testicular cancer, esophageal cancer, gastrointestinal cancer, pancreatic cancer, colorectal cancer, colon cancer, kidney cancer, head and neck cancer, lung cancer, stomach cancer, germ cell cancer, bone cancer, liver cancer, thyroid cancer, skin cancer, neoplasm of the central nervous system, lymphoma, leukemia, myeloma, sarcoma, virus-related cancer, and any combinations thereof. In some embodiments, the cancer is a metastatic cancer, refractory cancer, or recurrent cancer. In some embodiments, the cancer is a cold tumor.

[0156] In certain embodiments, the methods described herein further comprise one or more additional therapeutics with an anti-TIM3 antibody, e.g., an anti-PD-1 antibody, an anti-LAG-3 antibody, an anti-CTLA-4 antibody, an anti-GITR antibody, and/or an anti-PD-L1 antibody.

[0157] Provided herein is a method of detecting the presence of a TIM3 protein in a sample comprising contacting the sample with an anti-TIM3 antibody, or antigen binding portion thereof, under conditions that allow for formation of a complex between the antibody, or antigen binding portion thereof, and TIM3, and detecting the formation of a complex.



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