Antigen-binding molecules that bind CD38 and/or CD28, and uses thereof

Patent metadata

Field	Value
Publication number	US-12590168-B2
Application number	US-202418420588-A
Country	US
Kind code	B2
Filing date	Jan 23, 2024
Priority date	Sep 18, 2020
Publication date	Mar 31, 2026
Grant date	Mar 31, 2026

Abstract

CD38 is expressed on malignant plasma cells. CD28 is a costimulatory molecule required for T-cell activation and survival. Provided herein are novel anti-CD38 antibodies, anti-CD28 antibodies, and bispecific antibodies (bsAbs) that bind to both CD38 and CD28 and act as costimulatory agents to activate T cells via binding CD80 and/or CD86. In certain embodiments, the bispecific antigen-binding molecules of the present invention are capable of inhibiting the growth of tumors expressing CD38. The bispecific antigen-binding molecules of the invention are useful for the treatment of diseases and disorders in which an upregulated or induced CD38-targeted immune response is desired and/or therapeutically beneficial. For example, the bispecific antibodies of the invention are useful for the treatment of various cancers, including multiple myeloma, lymphoma, and leukemia.

First claim

What it claimed is:

1 . A nucleic acid molecule comprising a polynucleotide sequence that encodes a heavy chain variable region (HCVR) and/or a polynucleotide sequence that encodes a light chain variable region (LCVR) of an isolated antibody or antigen-binding fragment thereof that binds to human CD38, wherein the antibody or antigen-binding fragment thereof comprises:
(a) three heavy chain complementarity determining regions (CDRs) (HCDR1, HCDR2 and HCDR3) contained within the HCVR amino acid sequence set forth in SEQ ID NO: 2; and three light chain CDRs (LCDR1, LCDR2 and LCDR3) contained within the LCVR amino acid sequence set forth in SEQ ID NO: 18; or (b) three heavy chain CDRs (HCDR1, HCDR2, and HCDR3) contained within the HCVR amino acid sequence set forth in SEQ ID NO: 32 and three light chain CDRs (LCDR1, LCDR2, and LCDR3) contained within the LCVR amino acid sequence set forth in SEQ ID NO: 48.

2 . The nucleic acid molecule of claim 1 comprising:
a polynucleotide sequence that encodes an HCVR comprising an HCDR1 comprising the amino acid sequence of SEQ ID NO: 4; an HCDR2 comprising the amino acid sequence of SEQ ID NO: 6; and an HCDR3 comprising the amino acid sequence of SEQ ID NO: 8; or
a polynucleotide sequence that encodes an HCVR comprising an HCDR1 comprising the amino acid sequence of SEQ ID NO: 34; an HCDR2 comprising the amino acid sequence of SEQ ID NO: 36; and an HCDR3 comprising the amino acid sequence of SEQ ID NO: 38.

3 . The nucleic acid molecule of claim 2 , wherein the polynucleotide encodes an HCVR comprising the amino acid sequence of SEQ ID NO: 2.

4 . The nucleic acid molecule of claim 3 comprising a nucleotide sequence as set forth in SEQ ID NO: 1 or a substantially identical sequence having at least 95% homology thereto.

5 . The nucleic acid molecule of claim 3 , wherein the polynucleotide encodes a heavy chain comprising the amino acid sequence of SEQ ID NO: 26.

6 . The nucleic acid molecule of claim 5 comprising a nucleotide sequence as set forth in SEQ ID NO: 25 or a substantially identical sequence having at least 95% homology thereto.

7 . The nucleic acid molecule of claim 2 , wherein the polynucleotide encodes an HCVR comprising the amino acid sequence of SEQ ID NO: 32.

8 . The nucleic acid molecule of claim 7 comprising a nucleotide sequence as set forth in SEQ ID NO: 31 or a substantially identical sequence having at least 95% homology thereto.

9 . The nucleic acid molecule of claim 2 , wherein the polynucleotide encodes a heavy chain comprising the amino acid sequence of SEQ ID NO: 56.

10 . The nucleic acid molecule of claim 9 comprising a nucleotide sequence as set forth in SEQ ID NO: 55 or a substantially identical sequence having at least 95% homology thereto.

11 . The nucleic acid molecule of claim 1 comprising:
a polynucleotide sequence that encodes an LCVR comprising an LCDR1 comprising the amino acid sequence of SEQ ID NO: 20; an LCDR2 comprising the amino acid sequence of AAS; and an LCDR3 comprising the amino acid sequence of SEQ ID NO: 24; or
a polynucleotide sequence that encodes an LCVR comprising an LCDR1 comprising the amino acid sequence of SEQ ID NO: 50; an LCDR2 comprising the amino acid sequence of GAS; and an LCDR3 comprising the amino acid sequence of SEQ ID NO: 54.

12 . The nucleic acid molecule of claim 11 , wherein the polynucleotide encodes an LCVR comprising the amino acid sequence of SEQ ID NO: 18.

13 . The nucleic acid molecule of claim 12 comprising a nucleotide sequence as set forth in SEQ ID NO: 17 or a substantially identical sequence having at least 95% homology thereto.

14 . The nucleic acid molecule of claim 12 , wherein the polynucleotide encodes a light chain comprising the amino acid sequence of SEQ ID NO: 30.

15 . The nucleic acid molecule of claim 14 comprising a nucleotide sequence as set forth in SEQ ID NO: 29 or a substantially identical sequence having at least 95% homology thereto.

16 . The nucleic acid molecule of claim 11 , wherein the polynucleotide encodes an LCVR comprising the amino acid sequence of SEQ ID NO: 48.

17 . The nucleic acid molecule of claim 16 comprising a nucleotide sequence as set forth in SEQ ID NO: 47 or a substantially identical sequence having at least 95% homology thereto.

18 . The nucleic acid molecule of claim 16 , wherein the polynucleotide encodes a light chain comprising the amino acid sequence of SEQ ID NO: 60.

19 . The nucleic acid molecule of claim 18 comprising a nucleotide sequence as set forth in SEQ ID NO: 59 or a substantially identical sequence having at least 95% homology thereto.

20 . The nucleic acid molecule of claim 1 comprising a polynucleotide sequence that encodes (i) an HCVR comprising an HCDR1 comprising the amino acid sequence of SEQ ID NO: 4, an HCDR2 comprising the amino acid sequence of SEQ ID NO: 6, and an HCDR3 comprising the amino acid sequence of SEQ ID NO: 8; and (ii) an LCVR comprising an LCDR1 comprising the amino acid sequence of SEQ ID NO: 20, an LCDR2 comprising the amino acid sequence of AAS, and an LCDR3 comprising the amino acid sequence of SEQ ID NO: 24.

21 . The nucleic acid molecule of claim 1 comprising a polynucleotide sequence that encodes (i) an HCVR comprising an HCDR1 comprising the amino acid sequence of SEQ ID NO: 34, an HCDR2 comprising the amino acid sequence of SEQ ID NO: 36, and an HCDR3 comprising the amino acid sequence of SEQ ID NO: 38; and (ii) an LCVR comprising an LCDR 1 comprising the amino acid sequence of SEQ ID NO: 50, an LCDR2 comprising the amino acid sequence of GAS, and an LCDR3 comprising the amino acid sequence of SEQ ID NO: 54.

22 . A composition comprising a first nucleic acid molecule and a second nucleic acid molecule, wherein:
a) the first nucleic acid molecule comprises a polynucleotide sequence encoding an HCVR of an isolated antibody or antigen-binding fragment thereof that binds to human CD38, wherein the HCVR comprises an HCDR1 comprising the amino acid sequence of SEQ ID NO: 4, an HCDR2 comprising the amino acid sequence of SEQ ID NO: 6, and an HCDR3 comprising the amino acid sequence of SEQ ID NO: 8; and the second nucleic acid molecule comprises a polynucleotide sequence encoding an LCVR of the antibody or antigen-binding fragment thereof that binds to human CD38, wherein the LCVR comprises an LCDR1 comprising the amino acid sequence of SEQ ID NO: 20, an LCDR2 comprising the amino acid sequence of AAS, and an LCDR3 comprising the amino acid sequence of SEQ ID NO: 24; or b) the first nucleic acid molecule comprises a polynucleotide sequence encoding an HCVR of an isolated antibody or antigen-binding fragment thereof that binds to human CD38, wherein the HCVR comprises an HCDR1 comprising the amino acid sequence of SEQ ID NO: 34, an HCDR2 comprising the amino acid sequence of SEQ ID NO: 36, and an HCDR3 comprising the amino acid sequence of SEQ ID NO: 38; and the second nucleic acid molecule comprises a polynucleotide sequence encoding an LCVR of the antibody or antigen-binding fragment thereof that binds to human CD38, wherein the LCVR comprises an LCDR1 comprising the amino acid sequence of SEQ ID NO: 50, an LCDR2 comprising the amino acid sequence of GAS, and an LCDR3 comprising the amino acid sequence of SEQ ID NO: 54.

23 . An expression vector comprising the nucleic acid molecule of claim 1 .

24 . An isolated host cell comprising the expression vector of claim 23 .

2

Assignees

• Regeneron Pharma

Inventors

• Dilillo David
• Hermann Aynur
• Kirshner Jessica
• Olson Kara
• Sineshchekova Olga
• Smith Eric
• Ullman Erica

Classifications

• C07K2317/92

  Affinity (KD), association rate (Ka), dissociation rate (Kd) or EC50 value · CPC title

• C07K2317/73

  Inducing cell death, e.g. apoptosis, necrosis or inhibition of cell proliferation · CPC title

• C07K2317/565

  Complementarity determining region [CDR] · CPC title

• C07K2317/33

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

• C07K2317/31

  multispecific · CPC title