IP Library › Granted Patent US 12,492,257
Granted Patent B2
US 12,492,257 · App. 17/582,839 · Granted Dec 9, 2025

Anti-CTLA-4 antibodies and methods of use thereof

Inventors: Marc Van Dijk (Bosch en Duin, NL); Cornelia Anne Mundt (Lörrach, DE); Gerd Ritter (New York, NY); David Schaer (Mamaroneck, NY); Jedd David Wolchok (New York, NY); Taha Merghoub (Jersey City, NJ); David Adam Savitsky (Boxford, MA); Nicholas Stuart Wilson (San Carlos, CA)
Assignees: AGENUS INC.; LUDWIG INSTITUTE FOR CANCER RESEARCH LTD.; MEMORIAL SLOAN-KETTERING CANCER CENTER
C07K16/2818A61K47/6849A61K51/1027A61P35/00A61P37/04C07K16/283A61K2039/505C07K2317/21C07K2317/33C07K2317/34C07K2317/41C07K2317/52C07K2317/56C07K2317/565C07K2317/567C07K2317/73C07K2317/76C07K2317/92
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Quick Facts
Patent No.
US 12,492,257
App. No.
17/582,839
Granted
Dec 9, 2025
Kind
B2
Abstract

The instant disclosure provides antibodies that specifically bind to human CTLA-4 and antagonize CTLA-4 function. Also provided are pharmaceutical compositions comprising these antibodies, nucleic acids encoding these antibodies, expression vectors and host cells for making these antibodies, and methods of treating a subject using these antibodies.

Claims (93)

1 . A host cell comprising:

(a) a first isolated polynucleotide encoding an antibody heavy chain variable region of an antibody that specifically binds human CTLA-4 protein, wherein the antibody heavy chain variable region comprises complementarity determining regions CDRH1, CDRH2, and CDRH3, wherein

(i) CDRH1 comprises the amino acid sequence of SYX 1 MX 2 (SEQ ID NO: 22), wherein

X 1 is S or A; and

X 2 is N or S;

(ii) CDRH2 comprises the amino acid sequence of SISSSSSYIYYADSVKG (SEQ ID NO: 2); and

(iii) CDRH3 comprises the amino acid sequence of VGLMGPFXI (SEQ ID NO: 23),

wherein

X is D or N; and

(b) a second isolated polynucleotide encoding an antibody light chain variable region of an antibody that specifically binds human CTLA-4 protein, wherein the antibody light chain variable region comprises complementarity determining regions CDRL1, CDRL2, and CDRL3, wherein

(i) CDRL1 comprises the amino acid sequence of RASQSVX 1 X 2 YLX 3 (SEQ ID NO: 24),

wherein:

X 1 is S or G;

X 2 is R, S, or T; and

X 3 is G or A;

(ii) CDRL2 comprises the amino acid sequence of X 1 X 2 SX 3 RAT (SEQ ID NO: 25),

wherein:

X 1 is G or A;

X 2 is A or T; and

X 3 is T, S, R, or N; and

(iii) CDRL3 comprises the amino acid sequence of QQYGX 1 SPX 2 T (SEQ ID NO: 26),

wherein:

X 1 is S or T; and

X 2 is W or F.

2 . The host cell of claim 1 , wherein the first isolated polynucleotide encodes an antibody heavy chain variable region comprising CDRH1, CDRH2, and CDRH3 amino acid sequences selected from the group consisting of SEQ ID NOs 1, 2 and 3; 27, 2 and 3; and 27, 2 and 28, respectively.

3 . The host cell of claim 1 , wherein the second isolated polynucleotide encodes an antibody light chain variable region comprising CDRL1, CDRL2, and CDRL3 amino acid sequences selected from the group consisting of SEQ ID NOs: 4, 5, and 6; 29, 32, and 36; 29, 33, and 37; 30, 31, and 6; 29, 34, and 6; and 29, 35, and 37, respectively.

4 . The host cell of claim 1 , wherein:

(a) the first isolated polynucleotide encodes an antibody heavy chain variable region comprising CDRH1, CDRH2, and CDRH3 amino acid sequences selected from the group consisting of SEQ ID NOs 1, 2 and 3; 27, 2 and 3; and 27, 2 and 28, respectively; and

(b) the second isolated polynucleotide encodes an antibody light chain variable region comprising CDRL1, CDRL2, and CDRL3 amino acid sequences selected from the group consisting of SEQ ID NOs: 4, 5, and 6; 29, 32, and 36; 29, 33, and 37; 30, 31, and 6; 29, 34, and 6; and 29, 35, and 37, respectively.

5 . The host cell of claim 1 , wherein:

(i) the first isolated polynucleotide encodes an antibody heavy chain variable region comprising the CDRH1, CDRH2, and CDRH3 amino acid sequences of SEQ ID NOs: 1, 2, and 3, respectively; and the second isolated polynucleotide encodes an antibody light chain variable region comprising the CDRL1, CDRL2, and CDRL3 amino acid sequences of SEQ ID NOs: 4, 5, and 6, respectively;

(ii) the first isolated polynucleotide encodes an antibody heavy chain variable region comprising the CDRH1, CDRH2, and CDRH3 amino acid sequences of SEQ ID NOs: 1, 2, and 3, respectively; and the second isolated polynucleotide encodes an antibody light chain variable region comprising the CDRL1, CDRL2, and CDRL3 amino acid sequences of SEQ ID NOs: 29, 32, and 36, respectively;

(iii) the first isolated polynucleotide encodes an antibody heavy chain variable region comprising the CDRH1, CDRH2, and CDRH3 amino acid sequences of SEQ ID NOs: 1, 2, and 3, respectively; and the second isolated polynucleotide encodes an antibody light chain variable region comprising the CDRL1, CDRL2, and CDRL3 amino acid sequences of SEQ ID NOs: 29, 33, and 37, respectively;

(iv) the first isolated polynucleotide encodes an antibody heavy chain variable region comprising the CDRH1, CDRH2, and CDRH3 amino acid sequences of SEQ ID NOs: 27, 2, and 3, respectively; and the second isolated polynucleotide encodes an antibody light chain variable region comprising the CDRL1, CDRL2, and CDRL3 amino acid sequences of SEQ ID NOs: 4, 5, and 6, respectively;

(v) the first isolated polynucleotide encodes an antibody heavy chain variable region comprising the CDRH1, CDRH2, and CDRH3 amino acid sequences of SEQ ID NOs: 27, 2, and 3, respectively; and the second isolated polynucleotide encodes an antibody light chain variable region comprising the CDRL1, CDRL2, and CDRL3 amino acid sequences of SEQ ID NOs: 29, 33, and 37, respectively;

(vi) the first isolated polynucleotide encodes an antibody heavy chain variable region comprising the CDRH1, CDRH2, and CDRH3 amino acid sequences of SEQ ID NOs: 1, 2, and 3, respectively; and the second isolated polynucleotide encodes an antibody light chain variable region comprising the CDRL1, CDRL2, and CDRL3 amino acid sequences of SEQ ID NOs: 30, 31, and 6, respectively;

(vii) the first isolated polynucleotide encodes an antibody heavy chain variable region comprising the CDRH1, CDRH2, and CDRH3 amino acid sequences of SEQ ID NOs: 1, 2, and 3, respectively; and the second isolated polynucleotide encodes an antibody light chain variable region comprising the CDRL1, CDRL2, and CDRL3 amino acid sequences of SEQ ID NOs: 29, 34, and 6, respectively;

(viii) the first isolated polynucleotide encodes an antibody heavy chain variable region comprising the CDRH1, CDRH2, and CDRH3 amino acid sequences of SEQ ID NOs: 1, 2, and 3, respectively; and the second isolated polynucleotide encodes an antibody light chain variable region comprising the CDRL1, CDRL2, and CDRL3 amino acid sequences of SEQ ID NOs: 29, 35, and 37, respectively;

(ix) the first isolated polynucleotide encodes an antibody heavy chain variable region comprising the CDRH1, CDRH2, and CDRH3 amino acid sequences of SEQ ID NOs: 27, 2, and 28, respectively; and the second isolated polynucleotide encodes an antibody light chain variable region comprising the CDRL1, CDRL2, and CDRL3 amino acid sequences of SEQ ID NOs: 4, 5, and 6, respectively;

(x) the first isolated polynucleotide encodes an antibody heavy chain variable region comprising the CDRH1, CDRH2, and CDRH3 amino acid sequences of SEQ ID NOs: 27, 2, and 28, respectively; and the second isolated polynucleotide encodes an antibody light chain variable region comprising the CDRL1, CDRL2, and CDRL3 amino acid sequences of SEQ ID NOs: 29, 32, and 36, respectively;

(xi) the first isolated polynucleotide encodes an antibody heavy chain variable region comprising the CDRH1, CDRH2, and CDRH3 amino acid sequences of SEQ ID NOs: 27, 2, and 28, respectively; and the second isolated polynucleotide encodes an antibody light chain variable region comprising the CDRL1, CDRL2, and CDRL3 amino acid sequences of SEQ ID NOs: 29, 33, and 37, respectively; or

(xii) the first isolated polynucleotide encodes an antibody heavy chain variable region comprising the CDRH1, CDRH2, and CDRH3 amino acid sequences of SEQ ID NOs: 27, 2, and 28, respectively; and the second isolated polynucleotide encodes an antibody light chain variable region comprising the CDRL1, CDRL2, and CDRL3 amino acid sequences of SEQ ID NOs: 29, 35, and 37, respectively.

6 . The host cell of claim 1 , wherein:

(a) the first isolated polynucleotide encodes an antibody heavy chain variable region comprising CDRH1, CDRH2, and CDRH3 amino acid sequences selected from the group consisting of SEQ ID NOs 1, 2 and 3, respectively; and

(b) the second isolated polynucleotide encodes an antibody light chain variable region comprising CDRL1, CDRL2, and CDRL3 amino acid sequences selected from the group consisting of SEQ ID NOs: 4, 5, and 6, respectively.

7 . The host cell of claim 1 , wherein the first isolated polynucleotide encodes a heavy chain variable region comprising an amino acid sequence selected from the group consisting of SEQ ID NOs: 7, 38-42, and 72.

8 . The host cell of claim 1 , wherein the second isolated polynucleotide encodes a light chain variable region comprising an amino acid sequence selected from the group consisting of SEQ ID NOs: 8, 43-47, and 73.

9 . The host cell of claim 1 , wherein:

(a) the first isolated polynucleotide encodes an antibody heavy chain variable region comprising an amino acid sequence selected from the group consisting of SEQ ID NOs: 7, 38-42, and 72; and

(b) the second isolated polynucleotide encodes an antibody light chain variable region comprising an amino acid sequence selected from the group consisting of SEQ ID NOs: 8, 43-47, and 73.

10 . The host cell of claim 1 , wherein:

(i) the first isolated polynucleotide encodes an antibody heavy chain variable region comprising the amino acid sequence of SEQ ID NO: 7; and the second isolated polynucleotide encodes an antibody light chain variable region comprising the amino acid sequence of SEQ ID NO: 8;

(ii) the first isolated polynucleotide encodes an antibody heavy chain variable region comprising the amino acid sequence of SEQ ID NO: 7; and the second isolated polynucleotide encodes an antibody light chain variable region comprising the amino acid sequence of SEQ ID NO: 44;

(iii) the first isolated polynucleotide encodes an antibody heavy chain variable region comprising the amino acid sequence of SEQ ID NO: 7; and the second isolated polynucleotide encodes an antibody light chain variable region comprising the amino acid sequence of SEQ ID NO: 45;

(iv) the first isolated polynucleotide encodes an antibody heavy chain variable region comprising the amino acid sequence of SEQ ID NO: 38; and the second isolated polynucleotide encodes an antibody light chain variable region comprising the amino acid sequence of SEQ ID NO: 8;

(v) the first isolated polynucleotide encodes an antibody heavy chain variable region comprising the amino acid sequence of SEQ ID NO: 38; and the second isolated polynucleotide encodes an antibody light chain variable region comprising the amino acid sequence of SEQ ID NO: 45;

(vi) the first isolated polynucleotide encodes an antibody heavy chain variable region comprising the amino acid sequence of SEQ ID NO: 39; and the second isolated polynucleotide encodes an antibody light chain variable region comprising the amino acid sequence of SEQ ID NO: 43;

(vii) the first isolated polynucleotide encodes an antibody heavy chain variable region comprising the amino acid sequence of SEQ ID NO: 39; and the second isolated polynucleotide encodes an antibody light chain variable region comprising the amino acid sequence of SEQ ID NO: 45;

(viii) the first isolated polynucleotide encodes an antibody heavy chain variable region comprising the amino acid sequence of SEQ ID NO: 39; and the second isolated polynucleotide encodes an antibody light chain variable region comprising the amino acid sequence of SEQ ID NO: 46;

(ix) the first isolated polynucleotide encodes an antibody heavy chain variable region comprising the amino acid sequence of SEQ ID NO: 39; and the second isolated polynucleotide encodes an antibody light chain variable region comprising the amino acid sequence of SEQ ID NO: 47;

(x) the first isolated polynucleotide encodes an antibody heavy chain variable region comprising the amino acid sequence of SEQ ID NO: 40; and the second isolated polynucleotide encodes an antibody light chain variable region comprising the amino acid sequence of SEQ ID NO: 43;

(xi) the first isolated polynucleotide encodes an antibody heavy chain variable region comprising the amino acid sequence of SEQ ID NO: 40; and the second isolated polynucleotide encodes an antibody light chain variable region comprising the amino acid sequence of SEQ ID NO: 8;

(xii) the first isolated polynucleotide encodes an antibody heavy chain variable region comprising the amino acid sequence of SEQ ID NO: 40; and the second isolated polynucleotide encodes an antibody light chain variable region comprising the amino acid sequence of SEQ ID NO: 44;

(xiii) the first isolated polynucleotide encodes an antibody heavy chain variable region comprising the amino acid sequence of SEQ ID NO: 40; and the second isolated polynucleotide encodes an antibody light chain variable region comprising the amino acid sequence of SEQ ID NO: 45;

(xiv) the first isolated polynucleotide encodes an antibody heavy chain variable region comprising the amino acid sequence of SEQ ID NO: 41; and the second isolated polynucleotide encodes an antibody light chain variable region comprising the amino acid sequence of SEQ ID NO: 8;

(Xv) the first isolated polynucleotide encodes an antibody heavy chain variable region comprising the amino acid sequence of SEQ ID NO: 41; and the second isolated polynucleotide encodes an antibody light chain variable region comprising the amino acid sequence of SEQ ID NO: 44;

(xvi) the first isolated polynucleotide encodes an antibody heavy chain variable region comprising the amino acid sequence of SEQ ID NO: 41; and the second isolated polynucleotide encodes an antibody light chain variable region comprising the amino acid sequence of SEQ ID NO: 45;

(xvii) the first isolated polynucleotide encodes an antibody heavy chain variable region comprising the amino acid sequence of SEQ ID NO: 41; and the second isolated polynucleotide encodes an antibody light chain variable region comprising the amino acid sequence of SEQ ID NO: 47;

(xviii) the first isolated polynucleotide encodes an antibody heavy chain variable region comprising the amino acid sequence of SEQ ID NO: 42; and the second isolated polynucleotide encodes an antibody light chain variable region comprising the amino acid sequence of SEQ ID NO: 43; or

(xix) the first isolated polynucleotide encodes an antibody heavy chain variable region comprising the amino acid sequence of SEQ ID NO: 42; and the second isolated polynucleotide encodes an antibody light chain variable region comprising the amino acid sequence of SEQ ID NO: 45.

11 . The host cell of claim 1 , wherein:

(a) the first isolated polynucleotide encodes an antibody heavy chain variable region comprising the amino acid of SEQ ID NO: 7; and

(b) the second isolated polynucleotide encodes an antibody light chain variable region comprising the amino acid sequence of SEQ ID NO: 8.

12 . The host cell of claim 1 , wherein the first isolated polynucleotide encodes an antibody heavy chain of an antibody that specifically binds human CTLA-4 protein, wherein the antibody heavy chain comprises an amino acid sequence selected from the group consisting of SEQ ID NOs: 12, 14, 93, and 94.

13 . The host cell of claim 1 , wherein the second isolated polynucleotide encodes an antibody light chain of an antibody that specifically binds human CTLA-4 protein, wherein the antibody light chain comprises an amino acid sequence selected from the group consisting of SEQ ID NOs: 13 and 15.

14 . The host cell of claim 1 , wherein:

(i) the first isolated polynucleotide encodes an antibody heavy chain comprising the amino acid sequence of SEQ ID NO: 93; and the second isolated polynucleotide encodes an antibody light chain comprising the amino acid sequence of SEQ ID NO: 13;

(ii) the first isolated polynucleotide encodes an antibody heavy chain comprising the amino acid sequence of SEQ ID NO: 12; and the second isolated polynucleotide encodes an antibody light chain comprising the amino acid sequence of SEQ ID NO: 15;

(iii) the first isolated polynucleotide encodes an antibody heavy chain comprising the amino acid sequence of SEQ ID NO: 93; and the second isolated polynucleotide encodes an antibody light chain comprising the amino acid sequence of SEQ ID NO: 15;

(iv) the first isolated polynucleotide encodes an antibody heavy chain comprising the amino acid sequence of SEQ ID NO: 14; and the second isolated polynucleotide encodes an antibody light chain comprising the amino acid sequence of SEQ ID NO: 13;

(v) the first isolated polynucleotide encodes an antibody heavy chain comprising the amino acid sequence of SEQ ID NO: 14; and the second isolated polynucleotide encodes an antibody light chain comprising the amino acid sequence of SEQ ID NO: 15

(vi) the first isolated polynucleotide encodes an antibody heavy chain comprising the amino acid sequence of SEQ ID NO: 94; and the second isolated polynucleotide encodes an antibody light chain comprising the amino acid sequence of SEQ ID NO: 13; or

(vii) the first isolated polynucleotide encodes an antibody heavy chain comprising the amino acid sequence of SEQ ID NO: 94; and the second isolated polynucleotide encodes an antibody light chain comprising the amino acid sequence of SEQ ID NO: 15.

15 . The host cell of claim 1 , wherein:

(a) the first isolated polynucleotide encodes an antibody heavy chain comprising an amino acid sequence selected from the group consisting of SEQ ID NOs: 12, 14, 93, and 94; and

(b) the second isolated polynucleotide encodes an antibody light chain comprising an amino acid sequence selected from the group consisting of SEQ ID NOs: 13 and 15.

16 . The host cell of claim 1 , wherein:

(a) the first isolated polynucleotide encodes an antibody heavy chain comprising the amino acid sequence of SEQ ID NO: 93; and

(b) the second isolated polynucleotide encodes an antibody light chain comprising the amino acid sequence of SEQ ID NOs: 13.

17 . A method of producing an antibody that specifically binds to human CTLA-4 protein, the method comprising culturing the host cell of claim 1 so that the first and second polynucleotides are expressed and the antibody is produced.

18 . A method of producing an antibody that specifically binds to human CTLA-4 protein, the method comprising culturing the host cell of claim 6 so that the first and second polynucleotides are expressed and the antibody is produced.

19 . A method of producing an antibody that specifically binds to human CTLA-4 protein, the method comprising culturing the host cell of claim 11 so that the first and second polynucleotides are expressed and the antibody is produced.

20 . A method of producing an antibody that specifically binds to human CTLA-4 protein, the method comprising culturing the host cell of claim 16 so that the first and second polynucleotides are expressed and the antibody is produced.

Assignments (8)
SECURITY INTEREST Recorded Mar 31, 2025
From: AGENUS, INC.
To: LIGAND PHARMACEUTICALS INCORPORATED
Reel/Frame 070680/0634 →
AMENDED AND RESTATED PATENT SECURITY AGREEMENT Recorded Mar 6, 2025
From: UROGEN PHARMA LTD.
To: BIOPHARMA CREDIT PLC [COLLATERAL AGENT]
Reel/Frame 070434/0319 →
ASSIGNMENT OF ASSIGNOR'S INTEREST Recorded May 17, 2022
From: 4-ANTIBODY AG
To: AGENUS INC.
Reel/Frame 059935/0855 →
ASSIGNMENT OF ASSIGNOR'S INTEREST Recorded May 17, 2022
From: RITTER, GERD
To: LUDWIG INSTITUTE FOR CANCER RESEARCH LTD
Reel/Frame 059935/0884 →
ASSIGNMENT OF ASSIGNOR'S INTEREST Recorded May 17, 2022
From: WILSON, NICHOLAS STUART; SAVITSKY, DAVID ADAM; FINDEIS, MARK ARTHUR
To: AGENUS INC.
Reel/Frame 059935/0825 →
ASSIGNMENT OF ASSIGNOR'S INTEREST Recorded May 17, 2022
From: WOLCHOK, JEDD DAVID; MERGHOUB, TAHA; SCHAER, DAVID
To: MEMORIAL SLOAN KETTERING CANCER CENTER
Reel/Frame 059935/0889 →
ASSIGNMENT OF ASSIGNOR'S INTEREST Recorded May 17, 2022
From: VAN DIJK, MARC; MUNDT, CORNELIA ANNE
To: 4-ANTIBODY AG
Reel/Frame 059935/0837 →
SECURITY INTEREST Recorded Mar 18, 2022
From: UROGEN PHARMA LTD.
To: BIOPHARMA CREDIT PLC
Reel/Frame 059302/0501 →
Continuity (13)
Continuation 16858195 · Apr 24, 2020
Continuation 16572216 · Sep 16, 2019
Continuation 16165833 · Oct 19, 2018
Continuation 15166305 · May 27, 2016
Provisional Application 62323226 · Apr 15, 2016
Provisional Application 62294558 · Feb 12, 2016
Provisional Application 62292500 · Feb 8, 2016
Provisional Application 62280263 · Jan 19, 2016
Provisional Application 62257202 · Nov 18, 2015
Provisional Application 62190653 · Jul 9, 2015
Provisional Application 62182363 · Jun 19, 2015
Provisional Application 62168391 · May 29, 2015
Related Publication 20220267443A1 · Aug 25, 2022
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