METHODS OF USE OF ANTI-CD19/ANTI-CD38 COMMON LIGHT CHAIN BISPECIFIC ANTIBODIES
Provided are anti-CD19 and anti-CD38 common light chain bispecific antibodies. The anti-CD-19 and anti-CD38 bispecific antibodies described herein are useful in methods for treating a cancer or a tumor.
1 . A method of treating an individual afflicted with a cancer or a tumor comprising administering to the individual a common light chain bispecific antibody wherein the common light chain bispecific antibody comprises an anti-human-CD38 immunoglobulin heavy chain variable region paired with a common immunoglobulin light chain variable region and an anti-human-CD19 immunoglobulin heavy chain variable region paired with the common immunoglobulin light chain variable region, wherein the anti-human-CD38 immunoglobulin heavy chain variable region comprises:
(a) a heavy chain complementarity determining region 1 (HCDR1) comprising an amino acid sequence set forth in SEQ ID NO: 72;
(b) a heavy chain complementarity determining region 2 (HCDR2) comprising an amino acid sequence set forth in SEQ ID NO: 154; and
(c) a heavy chain complementarity determining region 3 (HCDR3) comprising an amino acid sequence set forth in SEQ ID NO: 93;
wherein the anti-human-CD19 immunoglobulin heavy chain variable region comprises:
(d) a heavy chain complementarity determining region 1 (HCDR1) comprising an amino acid sequence set forth in SEQ ID NO: 12;
(e) a heavy chain complementarity determining region 2 (HCDR2) comprising an amino acid sequence set forth in SEQ ID NO: 23; and
(f) a heavy chain complementarity determining region 3 (HCDR3) comprising an amino acid sequence set forth in SEQ ID NO: 33;
wherein the common immunoglobulin light chain variable region comprises:
(g) a light chain complementarity determining region 1 (LCDR1) comprising an amino acid sequence set forth in SEQ ID NO: 103;
(h) a light chain complementarity determining region 2 (LCDR2) comprising an amino acid sequence set forth in SEQ ID NO: 113; and
(i) a light chain complementarity determining region 3 (LCDR3) comprising an amino acid sequence set forth in SEQ ID NO: 123
thereby treating the individual afflicted with the cancer or tumor.
2 . The method of claim 1 , wherein the anti-human-CD38 immunoglobulin heavy chain variable region comprises an amino acid sequence having at least 90% identity to SEQ ID NO:
3 or 5, wherein the anti-human-CD38 immunoglobulin heavy chain variable region comprises (a), (b), and (c) of claim 1 .
3 . The method of claim 2 , wherein the anti-human-CD38 immunoglobulin heavy chain variable region comprises an amino acid sequence identical to SEQ ID NO: 3 or 5, wherein the phenylalanine at position 54 of SEQ ID NO: 3 or at position 54 of SEQ ID NO: 5 is substituted with glutamine.
4 . The method of claim 1 , wherein the anti-human-CD19 immunoglobulin heavy chain variable region comprises an amino acid sequence having at least 90% identity to SEQ ID NO:
1 or 6, wherein the anti-human-CD19 immunoglobulin heavy chain variable region comprises (d), (e), and (f) of claim 1 .
5 . The method of claim 4 , wherein the anti-human-CD19 immunoglobulin heavy chain variable region comprises an amino acid sequence identical to SEQ ID NO: 1 or 6.
6 . The method of claim 1 , wherein the common light chain bispecific antibody comprises an anti-human-CD38 immunoglobulin heavy chain constant region, comprising one or more amino acid substitutions that inhibit homodimerization of the anti-human-CD38 immunoglobulin heavy chain constant region and promote heterodimerization of the anti-human-CD38 immunoglobulin heavy chain constant region with a non-anti-human-CD38 immunoglobulin heavy chain constant region.
7 . The method of claim 6 , wherein the anti-human-CD38 immunoglobulin heavy chain constant region comprises a T366W substitution according to EU numbering or T366S/L368A/Y407V substitution according to EU numbering.
8 . The method of claim 1 , wherein the common light chain bispecific antibody comprises an anti-human-CD19 immunoglobulin heavy chain constant region comprising one or more amino acid substitutions that inhibit homodimerization of the anti-human-CD19 immunoglobulin heavy chain constant region and promote heterodimerization of the anti-human-CD19 immunoglobulin heavy chain constant region with a non-anti-human CD19 immunoglobulin heavy chain constant region.
9 . The method of claim 8 , wherein the anti-human-CD19 immunoglobulin heavy chain constant region comprises a T366W substitution according to EU numbering or a T366S/L368A/Y407V substitution according to EU numbering.
10 . The method of claim 1 , wherein the common immunoglobulin light chain variable region further comprises an immunoglobulin light chain constant region.
11 . The method of claim 1 , comprising an anti-human-CD19 immunoglobulin heavy chain comprising the amino acid sequence set forth in SEQ ID NO: 201, a common immunoglobulin light chain comprising the amino acid sequence set forth in SEQ ID NO: 213, and an anti-human-CD38 immunoglobulin heavy chain comprising the amino acid sequence set forth in SEQ ID NO: 202 or 215 wherein the phenylalanine at position 54 of SEQ ID NO: 202 or SEQ ID NO: 215 is substituted with glutamine.
12 . The method of claim 1 , wherein the anti-human-CD19 immunoglobulin heavy chain variable region comprises an A84S or an Al 08L substitution according to Kabat numbering.
13 . The method of claim 1 , wherein the common immunoglobulin light chain variable region comprises a W32H substitution according to Kabat numbering.
14 . The method of claim 1 , wherein the common light chain bispecific antibody is included in a composition further comprising a pharmaceutically acceptable diluent, carrier, or excipient.
15 . The method of claim 1 , wherein the common immunoglobulin light chain variable region comprises an amino acid sequence having at least 90% identity to SEQ ID NO: 4, wherein the common immunoglobulin light chain variable region comprises (g), (h), and (i) of claim 1 .
16 . The method of claim 1 , wherein the common immunoglobulin light chain variable region comprises the amino acid sequence of SEQ ID NO: 4.
17 . The method of claim 1 , wherein the common light chain antibody is administered intravenously
18 . The method of claim 1 , wherein the cancer or the tumor is a hematological cancer.
19 . The method of claim 18 , wherein the hematological cancer is a B cell malignancy.
20 . The method of claim 1 , wherein the cancer or the tumor is a solid-tissue cancer.
21 . The method of claim 20 , wherein the solid-tissue cancer comprises breast cancer, prostate cancer, pancreatic cancer, lung cancer, kidney cancer, stomach cancer, esophageal cancer, skin cancer, colorectal cancer, brain cancer, or head and neck cancer.