CCR8 antibodies, antibody conjugates, and uses thereof
Disclosed herein are antibodies that bind to CCR8 (e.g., human CCR8) and anti-CCR8 antibody drug conjugates (ADC).
1 . An antibody that binds to CCR8 wherein the antibody comprises:
a heavy chain variable domain (VH) comprising a heavy chain complementary determining region 1 (CDR-H1) comprising the amino acid sequence FQFNAYAMN (SEQ ID NO: 88); a heavy chain complementary determining region 2 (CDR-H2) comprising the amino acid sequence RIRSKSNNYATYYADSVKD (SEQ ID NO: 26); a heavy chain complementary determining region 3 (CDR-H3) comprising the amino acid sequence VRQSYGNSNYAMDH (SEQ ID NO: 90); and
a light chain variable domain (VL) comprising a light chain complementary determining region 1 (CDR-L1) comprising the amino acid sequence RSSKSLLHSNGNTYLY (SEQ ID NO: 28); a light chain complementary determining region 2 (CDR-L2) comprising the amino acid sequence RVSNLAS (SEQ ID NO: 92); a light chain complementary determining region 3 (CDR-L3) comprising the amino acid sequence MQHFEYPFT (SEQ ID NO: 96).
2 . The antibody of claim 1 , wherein the VH comprises the amino acid sequence SEQ ID NO: 99, and the VL comprises the amino acid sequence SEQ ID NO: 100.
3 . The antibody of claim 1 , wherein the antibody is a full-length IgG.
4 . The antibody of claim 3 , wherein the full-length IgG comprises a heavy chain constant region of isotype IgG1.
5 . The antibody of claim 4 , wherein the heavy chain constant region comprises the amino acid sequence SEQ ID NO: 133.
6 . The antibody of claim 4 , wherein the heavy chain constant region comprises an L235A (EU numbering) and a G237A (EU numbering) mutation relative to the heavy chain constant region as set forth in SEQ ID NO: 133.
7 . The antibody of claim 6 , wherein the heavy chain constant region further comprises a D265C (EU numbering) mutation relative to the heavy chain constant region as set forth in SEQ ID NO: 133.
8 . The antibody of claim 1 , wherein the antibody comprises a light chain constant region comprising the amino acid sequence SEQ ID NO: 135.
9 . An antibody-drug conjugate (ADC) having the structure of Formula (A):
or a pharmaceutically acceptable salt, solvate, hydrate, tautomer, stereoisomer, diastereomer, or enantiomer thereof, wherein:
R is H, —OH, or —O-L-Z-Ab;
Y is —S—, —S(═O)—, or —SO 2 —;
X is H or -L-Z-Ab, wherein:
L is a linker of the formula: —(CH 2 ) n — or -Q L1 -Q 1 -Q L2 -,
wherein:
n is 2, 3, 4, 5, 6, 7, 8, 9, or 10; or
each of Q L1 and Q L2 is optionally substituted alkylene and Q 1 is a dipeptide;
Z is
provided that:
if X is H then R is —O-L-Z-Ab, and
if X is -L-Z-Ab then R is H or —OH; and
wherein Ab is an antibody comprising:
a heavy chain variable domain (VH) comprising a heavy chain complementary determining region 1 (CDR-H1) comprising the amino acid sequence FQFNAYAMN (SEQ ID NO: 88); a heavy chain complementary determining region 2 (CDR-H2) comprising the amino acid sequence RIRSKSNNYATYYADSVKD (SEQ ID NO: 26); a heavy chain complementary determining region 3 (CDR-H3) comprising the amino acid sequence VRQSYGNSNYAMDH (SEQ ID NO: 90); and
a light chain variable domain (VL) comprising a light chain complementary determining region 1 (CDR-L1) comprising the amino acid sequence RSSKSLLHSNGNTYLY (SEQ ID NO: 28); a light chain complementary determining region 2 (CDR-L2) comprising the amino acid sequence RVSNLAS (SEQ ID NO: 92); a light chain complementary determining region 3 (CDR-L3) comprising the amino acid sequence MQHFEYPFT (SEQ ID NO: 96).
10 . The ADC of claim 9 , wherein the ADC is of the Formula (A-I-c):
or a pharmaceutically acceptable salt, solvate, hydrate, tautomer, stereoisomer, diastereomer, or enantiomer thereof.
11 . The ADC of claim 9 , wherein the ADC is of the Formula (A-I-e):
or a pharmaceutically acceptable salt, solvate, hydrate, tautomer, stereoisomer, diastereomer, or enantiomer thereof.
12 . The ADC of claim 9 , wherein the ADC is of Formula (A-II-b):
or a pharmaceutically acceptable salt, solvate, hydrate, tautomer, stereoisomer, diastereomer, or enantiomer thereof, wherein n is 1, 2, 3, 4, 5, 6, 7, 8, 9, or 10.
13 . The ADC of claim 12 , or a pharmaceutically acceptable salt, solvate, hydrate, tautomer, stereoisomer, diastereomer, or enantiomer thereof, wherein n is 5.
14 . The ADC of claim 10 , wherein the VH comprises the amino acid sequence SEQ ID NO: 99, and the VL comprises the amino acid sequence SEQ ID NO: 100.
15 . The ADC of claim 11 , wherein the antibody comprises a heavy chain comprising the amino acid sequence of SEQ ID NO: 145 and a light chain comprising the amino acid sequence of SEQ ID NO: 146.
16 . The ADC of claim 12 , wherein n is 5 and the antibody comprises a heavy chain comprising the amino acid sequence of SEQ ID NO: 145 and a light chain comprising the amino acid sequence of SEQ ID NO: 146.
17 . A method comprising administering to a subject the ADC of claim 9 , or a pharmaceutically acceptable salt, solvate, hydrate, tautomer, stereoisomer, diastereomer, or enantiomer thereof, wherein the subject has cancer.
18 . The method of claim 17 wherein the cancer is microsatellite stable colorectal cancer, non-small cell lung cancer, triple negative breast cancer, or renal cell carcinoma.
19 . A method of treating a subject having non-small cell lung cancer, the method comprising administering to the subject the ADC of claim 9 , or a pharmaceutically acceptable salt, solvate, hydrate, tautomer, stereoisomer, diastereomer, or enantiomer thereof.
20 . An antibody-drug conjugate (ADC) having the structure of Formula (A-I-c):
or a pharmaceutically acceptable salt, solvate, hydrate, tautomer, stereoisomer, diastereomer, or enantiomer thereof,
wherein the antibody comprises a heavy chain comprising the amino acid sequence of SEQ ID NO: 145 and a light chain comprising the amino acid sequence of SEQ ID NO: 146.