Composite binding molecules targeting immunosuppressive B cells
Provided are anti-CD19 and anti-CD38 common light chain bispecific antibodies. The anti-CD19 and anti-CD38 bispecific antibodies described herein are useful in methods for treating a cancer or a tumor.
1. 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.
2. The common light chain bispecific antibody 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 common light chain bispecific antibody 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 common light chain bispecific antibody 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 common light chain bispecific antibody 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 common light chain bispecific antibody 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 common light chain bispecific antibody 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 common light chain bispecific antibody 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 common light chain bispecific antibody 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 common light chain bispecific antibody of claim 1 , wherein the common immunoglobulin light chain variable region further comprises an immunoglobulin light chain constant region.
11. The common light chain bispecific antibody 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 common light chain bispecific antibody of claim 1 , wherein the anti-human-CD19 immunoglobulin heavy chain variable region comprises an A84S or an A108L substitution according to Kabat numbering.
13. The common light chain bispecific antibody of claim 1 , wherein the common immunoglobulin light chain variable region comprises a W32H substitution according to Kabat numbering.
14. The common light chain bispecific antibody 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 .
15. The common light chain bispecific antibody of claim 1 , wherein the common immunoglobulin light chain variable region comprises the amino acid sequence of SEQ ID NO: 4.
16. A composition comprising the common light chain bispecific antibody of claim 1 and a pharmaceutically acceptable diluent, carrier, or excipient.
17. A nucleic acid or plurality of nucleic acids comprising a polynucleotide sequence encoding the common light chain bispecific antibody of claim 1 .