Anti-CD24 antibodies and their use

Abstract

Antibodies or fragments thereof having binding specificity to the human CD24 protein are provided. In various examples, the antibodies or fragments include the VH and VL CDRs disclosed herein, or variants thereof. Methods of using antibodies or fragments thereof to treat cancer are also provided. This disclosure provides antibodies or fragments thereof having binding specificity to the human CD24 protein. These antibodies and fragments are useful for treating cancer and infectious diseases.

Claims

1. An antibody or antigen-binding fragment having specificity for the human CD24 protein, wherein the antibody or antigen-binding fragment comprises a heavy chain variable region including heavy chain complementarity-determining regions HCDR1, HCDR2, and HCDR3, and a light chain variable region including light chain complementarity-determining regions LCDR1, LCDR2, and LCDR3, wherein each of the HCDR1, HCDR2, HCDR3, LCDR1, LCDR2, and LCDR3 is, HCDR1: GYHMN (SEQ ID NO: 1) or GYHMG (SEQ ID NO: 112), HCDR2: EINPITSDKTFNQKFKS (Sequence ID 2) or EINPITSDKYFNQKFKS (Sequence ID 113), HCDR3:RDYGTSLDY (Sequence ID 3), LCDR1: RASKSISKYLA (SEQ ID NO: 4), RASASISKYLA (SEQ ID NO: 114), RASKSISKYLA (SEQ ID NO: 115), or RASKSISKYGA (SEQ ID NO: 116), LCDR2:AGSTLHS (SEQ ID NO: 5), and LCDR3: QQHNEYPIT (Sequence ID 6) or QQHNEYPII (Sequence ID 117) An antibody or its antigen-binding fragment, including an antibody.

2. The antibody or its antigen-binding fragment according to claim 1, wherein the antibody is a chimeric antibody or a humanized antibody.

3. The antibody or antigen-binding fragment according to claim 1, wherein HCDR1, HCDR2, HCDR3, LCDR1, LCDR2, and LCDR3 are HCDR1: GYHMG (SEQ ID NO: 112), HCDR2: EINPITSDKYFNQKFKS (SEQ ID NO: 113), HCDR3: RDYGTSLDY (SEQ ID NO: 3), LCDR1: RASASISKYLA (SEQ ID NO: 114), LCDR2: AGSTLHS (SEQ ID NO: 5), and LCDR3: QQHNEYPIT (SEQ ID NO: 6).

4. The antibody or antigen-binding fragment according to claim 3, which is humanized and the heavy chain variable region comprises one or more revertant mutations selected from the group consisting of 38K, 48I, 68A, 72V, and 74R by Kabat numbering, and combinations thereof.

5. The antibody or antigen-binding fragment according to claim 3 or 4, wherein the antibody or antigen-binding fragment is humanized and the light chain variable region comprises one or more revertant mutations selected from the group consisting of 45R, 58I, and 63R by Kabat numbering and combinations thereof.

6. The antibody or antigen-binding fragment according to claim 3, comprising a heavy chain variable region containing an amino acid sequence selected from the group consisting of SEQ ID NOs. 60, 94-97, 102, 110, and 111, or a peptide having at least 90% sequence identity with an amino acid sequence selected from the group consisting of SEQ ID NOs. 60, 94-97, 102, 110, and 111.

7. The antibody or antigen-binding fragment according to claim 3 or 6, comprising a light chain variable region containing an amino acid sequence selected from the group consisting of SEQ ID NOs. 61, 98-101, and 103-109, or a peptide having at least 90% sequence identity with an amino acid sequence selected from the group consisting of SEQ ID NOs. 61, 98-101, and 103-109.

8. The antibody or antigen-binding fragment according to claim 3, comprising a heavy chain variable region containing the amino acid sequence of SEQ ID NO: 111, or a peptide having at least 90% sequence identity with SEQ ID NO: 111, and a light chain variable region containing the amino acid sequence of SEQ ID NO: 106, or a peptide having at least 90% sequence identity with SEQ ID NO:

106.

9. The antibody or antigen-binding fragment according to claim 8, comprising a heavy chain variable region containing the amino acid sequence of SEQ ID NO: 111 and a light chain variable region containing the amino acid sequence of SEQ ID NO:

106.

10. An antibody or antigen-binding fragment having specificity for the human CD24 protein, wherein the antibody or antigen-binding fragment comprises a heavy chain variable region including heavy chain complementarity-determining regions HCDR1, HCDR2, and HCDR3, and a light chain variable region including light chain complementarity-determining regions LCDR1, LCDR2, and LCDR3, Here, The sets of HCDR1, HCDR2, and HCDR3 are selected from Table 1, or from a set of CDRs derived from Table 1 or Table 5, which include the addition, deletion, and / or substitution of one, two, or three amino acids in one or more of the CDRs. The sets of LCDR1, LCDR2, and LCDR3 are selected from Table 1, or from sets of CDRs derived from Table 1 or Table 5, which include the addition, deletion, and / or substitution of one, two, or three amino acids in one or more of the CDRs. An antibody or its antigen-binding fragment.

11. An antibody or antigen-binding fragment having specificity for the human CD24 protein, wherein the antibody or antigen-binding fragment competes with the antibody or antigen-binding fragment described in any one of the preceding claims for binding to the CD24 protein.

12. An antibody or antigen-binding fragment according to any one of claims 1 to 11, further comprising a heavy chain constant region, a light chain constant region, an Fc region, or a combination thereof.

13. The antibody or antigen-binding fragment according to any one of claims 1 to 11, wherein the light chain constant region is a kappa chain constant region or a lambda chain constant region.

14. An antibody or antigen-binding fragment according to any one of claims 1 to 11, wherein the antibody is an isotype of IgG, IgM, IgA, IgE, or IgD.

15. The antibody or antigen-binding fragment according to claim 14, wherein the isotype is IgG1, IgG2, IgG3, or IgG4.

16. The antibody or antigen-binding fragment according to claim 12, wherein the Fc region is designed to enhance effector function.

17. The antibody or antigen-binding fragment according to claim 16, wherein the effector function includes antibody-mediated cytotoxicity (ADCC), complement-dependent cytotoxicity (CDC), or antibody-dependent cytophagia (ADCP).

18. The antibody or antigen-binding fragment according to claim 17, wherein the Fc region is designed to contain the S298A / E333A / K334A mutation in IgG1.

19. A bifunctional molecule comprising a first antigen-binding portion having specificity for human CD24 protein and a second portion having specificity for a second protein, wherein the first antigen-binding portion comprises an antibody or antigen-binding fragment according to any one of claims 1 to 18.

20. A composition comprising an antibody or its antigen-binding fragment according to any one of claims 1 to 18 or a bifunctional molecule according to claim 19, and a pharmaceutically acceptable carrier.

21. An isolated cell comprising one or more polynucleotides encoding an antibody or antigen-binding fragment thereof according to any one of claims 1 to 18, or a bifunctional molecule according to claim 19.

22. A polynucleotide encoding one or more chains of an antibody or its antigen-binding fragment according to any one of claims 1 to 18 or a bifunctional molecule according to claim 19.

23. A method for treating cancer in a patient requiring treatment for cancer, comprising administering to the patient an antibody or antigen-binding fragment thereof according to any one of claims 1 to 18 or a bifunctional molecule according to claim 19.

24. The method according to claim 23, wherein the cancer is selected from the group consisting of bladder cancer, breast cancer, colorectal cancer, endometrial cancer, esophageal cancer, head and neck cancer, kidney cancer, leukemia, liver cancer, lung cancer, lymphoma, melanoma, pancreatic cancer, prostate cancer, and thyroid cancer.

25. The method according to claim 23 or 24, further comprising administering a second therapy for treating the cancer to the patient.

26. The method according to claim 25, wherein the therapy is selected from the group consisting of immunotherapy, chemotherapy, and radiotherapy.

27. A method for treating an autoimmune disease or inflammatory condition in a patient requiring treatment of such condition, comprising administering to the patient an antibody or antigen-binding fragment thereof according to any one of claims 1 to 18 or a bifunctional molecule according to claim 19.

28. A method for detecting the expression of CD24 in a sample, comprising: contacting the sample with an antibody or antigen-binding fragment thereof according to any one of claims 1 to 18 or a bifunctional molecule according to claim 19 under conditions in which the antibody or antigen-binding fragment binds to the CD24; and detecting the binding that indicates the expression of CD24 in the sample.

Images