Anti-lag-3 antibodies and methods of use thereof

Patent metadata

Field	Value
Publication number	US-11993651-B2
Application number	US-202017100038-A
Country	US
Kind code	B2
Filing date	Nov 20, 2020
Priority date	Oct 11, 2016
Publication date	May 28, 2024
Grant date	May 28, 2024

Abstract

The instant disclosure provides antibodies that specifically bind to LAG-3 (e.g., human LAG-3) and antagonize LAG-3 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.

First claim

What is claimed:

1. An isolated antibody that specifically binds to human LAG-3, the antibody comprising a heavy chain variable region comprising complementarity determining regions CDRH1, CDRH2 and CDRH3 and a light chain variable region comprising complementarity determining regions CDRL1, CDRL2 and CDRL3, wherein:
(a) CDRH1 comprises the amino acid sequence of DX 1 YX 2 X 3 (SEQ ID NO: 140), wherein
X 1 is T or N,
X 2 is I or M, and
X 3 is H, Y or D;

(b) CDRH2 comprises the amino acid sequence of X 1 IDPANX 2 X 3 X 4 X 5 X 6 X 7 PX 8 X 9 QX 10 (SEQ ID NO: 142), wherein
X 1 is E, R, S, or K,
X 2 is D or G,
X 3 is N or H,
X 4 is T or S,
X 5 is K or H,
X 6 is Y or F,
X 7 is D or A,
X 8 is K or R,
X 9 is F or L, and
X 10 is G or D;

(c) CDRH3 comprises the amino acid sequence of YX 1 X 2 X 3 YX 4 VGGX 5 DY (SEQ ID NO: 144), wherein
X 1 is Y, F, or S,
X 2 is Y or D,
X 3 is K or R,
X 4 is D or E, and
X 5 is F or C;

(d) CDRL1 comprises the amino acid sequence of SVSSX 1 ISSSX 2 LX 3 (SEQ ID NO: 147), wherein
X 1 is S or G,
X 2 is N or T, and
X 3 is H or Y;

(e) CDRL2 comprises the amino acid sequence of SEQ ID NO: 104; and
(f) CDRL3 comprises the amino acid sequence of QQWX 1 X 2 YPX 3 T (SEQ ID NO: 149), wherein
X 1 is S, N, or R,
X 2 is S, T or R, and
X 3 is F, L, H, or W,

wherein the CDRH1, CDRH2, CDRH3, CDRL1, CDRL2, and CDRL3 do not comprise the amino acid sequences of SEQ ID NOs: 79, 90, 98, 100, 104, and 105, respectively.

2. The isolated antibody of claim 1 , wherein:
(a) CDRH1 comprises the amino acid sequence of DX 1 YX 2 X 3 (SEQ ID NO: 141), wherein
X 1 is Tor N,
X 2 is I or M, and
X 3 is H or Y;

(b) CDRH2 comprises the amino acid sequence of X 1 IDPANX 2 X 3 X 4 KX 5 X 6 PX 7 FQX 8 (SEQ ID NO: 143), wherein
X 1 is E, R, or S,
X 2 is D or G,
X 3 is N or H,
X 4 is T or S,
X 5 is Y or F,
X 6 is D or A,
X 7 is K or R, and
X 8 is G or D;

(c) CDRH3 comprises the amino acid sequence of YX 1 X 2 X 3 YDVGGX 4 DY (SEQ ID NO: 145), wherein
X 1 is Y, F, or S,
X 2 is Y or D,
X 3 is K or R, and
X 4 is F or C;

(d) CDRH3 comprises the amino acid sequence of YYYX 1 YX 2 VGGFDY (SEQ ID NO: 146), wherein
X 1 is K or R, and
X 2 is D or E;

(e) CDRL1 comprises the amino acid sequence of SVSSSISSSNLX 1 (SEQ ID NO: 148), wherein X 1 is H or Y; and/or
(f) CDRL3 comprises the amino acid sequence of QQWX 1 SYPX 2 T (SEQ ID NO: 150), wherein
X 1 is S, N, or R, and
X 2 is F, L, or H.

3. The isolated antibody of claim 1 , wherein:
(a) CDRH1 comprises an amino acid sequence selected from the group consisting of SEQ ID NOs: 78-82;
(b) CDRH2 comprises an amino acid sequence selected from the group consisting of SEQ ID NOs: 83-93;
(c) CDRH3 comprises the amino acid sequence of YYYX 1 YX 2 VGGFDY (SEQ ID NO: 146), wherein
X 1 is K or R, and
X 2 is D or E;

(d) CDRH3 comprises an amino acid sequence selected from the group consisting of SEQ ID NOs: 94-99;
(e) CDRL1 comprises an amino acid sequence selected from the group consisting of SEQ ID NOs: 100-103; and/or
(f) CDRL3 comprises an amino acid sequence selected from the group consisting of SEQ ID NOs: 105-112.

4. The isolated antibody of claim 1 , wherein CDRH1, CDRH2 and CDRH3 comprise the CDRH1, CDRH2 and CDRH3 amino acid sequences, respectively, set forth in SEQ ID NOs: 78, 83, and 94; 78, 85, and 95; 78, 86, and 96; 78, 86, and 97; 78, 91, and 94; 78, 92, and 96; 79, 84, and 95; 79, 88, and 95; 79, 89, and 95; 79, 90, and 95; 79, 90, and 98; 79, 90, and 99; 80, 85, and 96; 81, 87, and 96; or, 82, 93, and 95, and/or CDRL1, CDRL2 and CDRL3 comprise the CDRL1, CDRL2 and CDRL3 amino acid sequences, respectively, set forth in SEQ ID NOs: 100, 104, and 105; 100, 104, and 106; 100, 104, and 107; 100, 104, and 109; 100, 104, and 110; 101, 104, and 108; 102, 104, and 105; 102, 104, and 112; or, 103, 104, and 111.

5. The isolated antibody of claim 1 , wherein:
CDRH1, CDRH2, CDRH3, CDRL1, CDRL2, and CDRL3 comprise the amino acid sequences set forth in SEQ ID NOs: 78, 83, 94, 100, 104, and 105; 78, 85, 95, 100, 104, and 105; 78, 86, 96, 100, 104, and 105; 78, 86, 96, 100, 104, and 109; 78, 86, 96, 100, 104, and 110; 78, 86, 96, 101, 104, and 108; 78, 86, 96, 103, 104, and 111; 78, 86, 97, 102, 104, and 112; 78, 91, 94, 100, 104, and 107; 78, 92, 96, 100, 104, and 105; 78, 92, 96, 100, 104, and 109; 79, 84, 95, 100, 104, and 105; 79, 84, 95, 100, 104, and 106; 79, 84, 95, 102, 104, and 105; 79, 88, 95, 100, 104, and 105; 79, 89, 95, 100, 104, and 105; 79, 90, 95, 100, 104, and 105; 79, 90, 99, 100, 104, and 105; 80, 85, 96, 100, 104, and 105; 81, 87, 96, 100, 104, and 105; 81, 87, 96, 100, 104, and 107; or 82, 93, 95, 100, 104, and 105, respectively.

6. The isolated antibody of claim 1 , wherein the antibody comprises a heavy chain variable region comprising the amino acid sequence of SEQ ID NO: 151, 222, 218, or 223, and/or a light chain variable region comprising the amino acid sequence of SEQ ID NO: 152 or 224.

7. The isolated antibody of claim 1 , wherein the antibody comprises a heavy chain variable region comprising an amino acid sequence selected from the group consisting of SEQ ID NOs: 56-72 and 220, and/or a light chain variable region comprising an amino acid sequence selected from the group consisting of SEQ ID NOs: 73-77 and 221.

8. The isolated antibody of claim 1 , wherein the antibody comprises a heavy chain comprising an amino acid sequence selected from the group consisting of SEQ ID NOs: 168-186 and 225-227, and/or a light chain comprising an amino acid sequence selected from the group consisting of SEQ ID NOs: 187-191 and 228.

9. The isolated antibody of claim 1 , wherein the antibody comprises:
(a) a heavy chain variable framework region that is or is derived from an amino acid sequence encoded by a human gene, optionally wherein said amino acid sequence is selected from the group consisting of IGHV1-46*01 (SEQ ID NO: 153), IGHV1-69-2*01 (SEQ ID NO: 154), IGHV1-3*01 (SEQ ID NO: 155), IGHV1-24*01 (SEQ ID NO: 156), IGHV1-2*01 (SEQ ID NO: 157), IGHV1-45*01 (SEQ ID NO: 158), and IGHV1-18*01 (SEQ ID NO: 159); and/or
(b) a light chain variable framework region that is or is derived from an amino acid sequence encoded by a human gene, optionally wherein said amino acid sequence is selected from the group consisting of IGKV3-20*01 (SEQ ID NO: 160), IGKV3D-15*01 (SEQ ID NO: 161), IGKV3-15*01 (SEQ ID NO: 161), IGKV3D-20*01 (SEQ ID NO: 162), IGKV3D-7*01 (SEQ ID NO: 163), IGKV1-9*01 (SEQ ID NO: 164), and IGKV3-11*01 (SEQ ID NO: 165).

10. The isolated antibody of claim 1 , wherein the heavy chain variable region and the light chain variable region, respectively, comprise the amino acid sequences set forth in SEQ ID NOs: 56 and 73; 56 and 74; 56 and 75; 56 and 76; 56 and 77; 57 and 73; 57 and 74; 57 and 75; 57 and 76; 57 and 77; 58 and 73; 58 and 74; 58 and 75; 58 and 76; 58 and 77; 59 and 73; 59 and 74; 59 and 75; 59 and 76; 59 and 77; 60 and 73; 60 and 74; 60 and 75; 60 and 76; 60 and 77; or 62 and 77.

11. The isolated antibody of claim 1 , wherein the antibody comprises:
(a) a heavy chain comprising the amino acid sequence of SEQ ID NO: 168 or 225, and a light chain comprising the amino acid sequence of SEQ ID NO: 187 or 228;
(b) a heavy chain comprising the amino acid sequence of SEQ ID NO: 169 or 226, and a light chain comprising the amino acid sequence of SEQ ID NO: 187 or 228; or
(c) a heavy chain comprising the amino acid sequence of SEQ ID NO: 169 or 226, and a light chain comprising the amino acid sequence of SEQ ID NO: 187 or 228.

12. The isolated antibody of claim 1 , where

Assignees

• Agenus Inc

Inventors

• Wilson Nicholas Stuart
• Savitsky David Adam
• Jennings Shawn Michael
• Van Dijk Marc
• Mundt Cornelia Anne

Classifications

• C07K2317/56

  variable (Fv) region, i.e. VH and/or VL · CPC title

• C07K2317/33

  Crossreactivity, e.g. for species or epitope, or lack of said crossreactivity · CPC title

• A61K2300/00

  Mixtures or combinations of active ingredients, wherein at least one active ingredient is fully defined in groups A61K31/00 - A61K41/00 · CPC title

• A61K47/6849

  the antibody targeting a receptor, a cell surface antigen or a cell surface determinant · CPC title

• A61K2039/507

  Comprising a combination of two or more separate antibodies · CPC title