Killer cell lectin-like receptor subfamily g member 1 (klrg1) depleting antibodies

A method of treating a disorder associated with excess or unwanted KLRG1 expressing T cells in a subject in need thereof, comprising:

• delivering to a subject a therapeutically effective amount of an antibody, or a fragment thereof, that specifically binds to an extracellular domain of KLRG1 without interfering with binding by E-cadherin, N-cadherin, or R-cadherin to the extracellular domain of KLRG1 and comprises a heavy chain variable region comprising three heavy chain complementarity determining regions (CDR-H1, CDR-H2 and CDR-H3) and a light chain variable region comprising three light chain complementary determining regions (CDR-L1, CDR-L2 and CDR-L3),
• wherein said antibody, or fragment thereof, comprises
• i) SEQ ID NO:16 (CDR-H1), SEQ ID NO:17 (CDR-H2), SEQ ID NO:18 (CDR-H3), SEQ ID NO:19 (CRD-L1), SEQ ID NO:20 (CDR-L2), and SEQ ID NO:21 (CDR-L3);
• ii) SEQ ID NO:22 (CDR-H1), SEQ ID NO:23 (CDR-H2), SEQ ID NO:24 (CDR-H3), SEQ ID NO:25 (CRD-L1), SEQ ID NO:26 (CDR-L2), and SEQ ID NO:27 (CDR-L3);
• iii) SEQ ID NO:28 (CDR-H1), SEQ ID NO:29 (CDR-H2), SEQ ID NO:30 (CDR-H3), SEQ ID NO:31 (CRD-L1), SEQ ID NO:32 (CDR-L2), and SEQ ID NO:33 (CDR-L3);
• iv) SEQ ID NO:34 (CDR-H1), SEQ ID NO:35 (CDR-H2), SEQ ID NO:36 (CDR-H3), SEQ ID NO:37 (CRD-L1), SEQ ID NO:38 (CDR-L2), and SEQ ID NO:39 (CDR-L3);
• v) SEQ ID NO:40 (CDR-H1), SEQ ID NO:41 (CDR-H2), SEQ ID NO:42 (CDR-H3), SEQ ID NO:43 (CRD-L1), SEQ ID NO:44 (CDR-L2), and SEQ ID NO:45 (CDR-L3);
• or
• vi) SEQ ID NO:46 (CDR-H1), SEQ ID NO:47 (CDR-H2), SEQ ID NO:48 (CDR-H3), SEQ ID NO:49 (CRD-L1), SEQ ID NO:50 (CDR-L2), and SEQ ID NO:51 (CDR-L3).

A method of treating cancer in a subject, wherein the cancer comprises cancer cells that express KLRG1, the method comprising:

• delivering to a subject a therapeutically effective amount of an antibody, or a fragment thereof, that specifically binds to an extracellular domain of KLRG1 without interfering with binding by E-cadherin, N-cadherin, or R-cadherin to the extracellular domain of KLRG1,
• wherein the delivery to the subject depletes the cancer cells expressing KLRG1, and
• wherein said antibody, or fragment thereof, comprises a heavy chain variable region comprising three heavy chain complementarity determining regions (CDR-H1, CDR-H2 and CDR-H3) and a light chain variable region comprising three light chain complementary determining regions (CDR-L1, CDR-L2 and CDR-L3) comprising:
• i) SEQ ID NO:16 (CDR-H1), SEQ ID NO:17 (CDR-H2), SEQ ID NO:18 (CDR-H3), SEQ ID NO:19 (CRD-L1), SEQ ID NO:20 (CDR-L2), and SEQ ID NO:21 (CDR-L3);
• ii) SEQ ID NO:22 (CDR-H1), SEQ ID NO:23 (CDR-H2), SEQ ID NO:24 (CDR-H3), SEQ ID NO:25 (CRD-L1), SEQ ID NO:26 (CDR-L2), and SEQ ID NO:27 (CDR-L3);
• iii) SEQ ID NO:28 (CDR-H1), SEQ ID NO:29 (CDR-H2), SEQ ID NO:30 (CDR-H3), SEQ ID NO:31 (CRD-L1), SEQ ID NO:32 (CDR-L2), and SEQ ID NO:33 (CDR-L3);
• iv) SEQ ID NO:34 (CDR-H1), SEQ ID NO:35 (CDR-H2), SEQ ID NO:36 (CDR-H3), SEQ ID NO:37 (CRD-L1), SEQ ID NO:38 (CDR-L2), and SEQ ID NO:39 (CDR-L3);
• v) SEQ ID NO:40 (CDR-H1), SEQ ID NO:41 (CDR-H2), SEQ ID NO:42 (CDR-H3), SEQ ID NO:43 (CRD-L1), SEQ ID NO:44 (CDR-L2), and SEQ ID NO:45 (CDR-L3);
• or
• vi) SEQ ID NO:46 (CDR-H1), SEQ ID NO:47 (CDR-H2), SEQ ID NO:48 (CDR-H3), SEQ ID NO:49 (CRD-L1), SEQ ID NO:50 (CDR-L2), and SEQ ID NO:51 (CDR-L3).

An adjunct therapy for treatment of cancer in a subject, wherein the subject is undergoing checkpoint therapy, regardless of whether the cancer expresses KLRG1, the adjunct therapy comprising:

• delivering to a subject a therapeutically effective amount of an antibody, or a fragment thereof, that specifically binds to an extracellular domain of KLRG1 without interfering with binding by E-cadherin, N-cadherin, or R-cadherin to the extracellular domain of KLRG1,
• wherein the delivery depletes KLRG1 expressing pathogenic T cells and/or NK cells attacking self-tissues in the subject,
• wherein the antibody, or a fragment thereof, comprises:
• a heavy chain variable region comprising three heavy chain complementarity determining regions (CDR-H1, CDR-H2 and CDR-H3) and a light chain variable region comprising three light chain complementary determining regions (CDR-L1, CDR-L2 and CDR-L3) comprising:
• i) SEQ ID NO:16 (CDR-H1), SEQ ID NO:17 (CDR-H2), SEQ ID NO:18 (CDR-H3), SEQ ID NO:19 (CRD-L1), SEQ ID NO:20 (CDR-L2), and SEQ ID NO:21 (CDR-L3);
• ii) SEQ ID NO:22 (CDR-H1), SEQ ID NO:23 (CDR-H2), SEQ ID NO:24 (CDR-H3), SEQ ID NO:25 (CRD-L1), SEQ ID NO:26 (CDR-L2), and SEQ ID NO:27 (CDR-L3);
• iii) SEQ ID NO:28 (CDR-H1), SEQ ID NO:29 (CDR-H2), SEQ ID NO:30 (CDR-H3), SEQ ID NO:31 (CRD-L1), SEQ ID NO:32 (CDR-L2), and SEQ ID NO:33 (CDR-L3);
• iv) SEQ ID NO:34 (CDR-H1), SEQ ID NO:35 (CDR-H2), SEQ ID NO:36 (CDR-H3), SEQ ID NO:37 (CRD-L1), SEQ ID NO:38 (CDR-L2), and SEQ ID NO:39 (CDR-L3);
• v) SEQ ID NO:40 (CDR-H1), SEQ ID NO:41 (CDR-H2), SEQ ID NO:42 (CDR-H3), SEQ ID NO:43 (CRD-L1), SEQ ID NO:44 (CDR-L2), and SEQ ID NO:45 (CDR-L3);
• or
• vi) SEQ ID NO:46 (CDR-H1), SEQ ID NO:47 (CDR-H2), SEQ ID NO:48 (CDR-H3), SEQ ID NO:49 (CRD-L1), SEQ ID NO:50 (CDR-L2), and SEQ ID NO:51 (CDR-L3).

A method of depleting KLRG1 expressing cells in a mixed population of cells, wherein the KLRG1 expressing cells comprise one or more cells selected from the group consisting of T cells and/or NK cells and/or cancer cells, the method comprising:

• delivering to a mixed population of cells an effective amount of an antibody, or a fragment thereof, that specifically binds to KLRG1 and depletes KLRG1 expressing T cells and/or NK cells and/or cancer cells, thereby depleting KLRG1 expressing T cells and/or NK cells and/or cancer cells in the mixed population of cells,
• wherein the antibody, or a fragment thereof, comprises:
• a heavy chain variable region comprising three heavy chain complementarity determining regions (CDR-H1, CDR-H2 and CDR-H3) and a light chain variable region comprising three light chain complementary determining regions (CDR-L1, CDR-L2 and CDR-L3) comprising:
• i) SEQ ID NO:16 (CDR-H1), SEQ ID NO:17 (CDR-H2), SEQ ID NO:18 (CDR-H3), SEQ ID NO:19 (CRD-L1), SEQ ID NO:20 (CDR-L2), and SEQ ID NO:21 (CDR-L3);
• ii) SEQ ID NO:22 (CDR-H1), SEQ ID NO:23 (CDR-H2), SEQ ID NO:24 (CDR-H3), SEQ ID NO:25 (CRD-L1), SEQ ID NO:26 (CDR-L2), and SEQ ID NO:27 (CDR-L3);
• iii) SEQ ID NO:28 (CDR-H1), SEQ ID NO:29 (CDR-H2), SEQ ID NO:30 (CDR-H3), SEQ ID NO:31 (CRD-L1), SEQ ID NO:32 (CDR-L2), and SEQ ID NO:33 (CDR-L3);
• iv) SEQ ID NO:34 (CDR-H1), SEQ ID NO:35 (CDR-H2), SEQ ID NO:36 (CDR-H3), SEQ ID NO:37 (CRD-L1), SEQ ID NO:38 (CDR-L2), and SEQ ID NO:39 (CDR-L3);
• v) SEQ ID NO:40 (CDR-H1), SEQ ID NO:41 (CDR-H2), SEQ ID NO:42 (CDR-H3), SEQ ID NO:43 (CRD-L1), SEQ ID NO:44 (CDR-L2), and SEQ ID NO:45 (CDR-L3);
• or
• vi) SEQ ID NO:46 (CDR-H1), SEQ ID NO:47 (CDR-H2), SEQ ID NO:48 (CDR-H3), SEQ ID NO:49 (CRD-L1), SEQ ID NO:50 (CDR-L2), and SEQ ID NO:51 (CDR-L3).