PD-L1 and OX40 binding proteins for cancer Regulation
Provided are monospecific and bispecific proteins that bind specifically to OX40 and/or PD-L1. Exemplary proteins release the inhibition through PD-L1 and stimulate T cell through OX40. Exemplary polyvalent proteins comprise at least one OX40 binding site and at least one PD-L1 binding site. In certain embodiments, the binding sites may be linked through an immunoglobulin constant region. Anti-OX40 and anti-PD-L1 antibodies are also provided.
1. An antibody or an antigen-binding portion thereof binding to OX40 (CD134), comprising:
a heavy chain variable region and a light chain variable region respectively comprising an amino acid sequence of
SEQ ID NO: 6 and amino acid 1-108 of SEQ ID NO: 5.
2. The antibody or the antigen-binding portion thereof of claim 1 , wherein the antibody or the antigen-binding portion thereof is a single chain variable fragment (scFv), wherein the sequence of the scFv is SEQ ID NO: 11.
3. The antibody or the antigen-binding portion thereof of claim 1 , wherein the antibody or the antigen-binding portion thereof is a bispecific antibody.
4. The antibody or the antigen-binding portion thereof of claim 3 , wherein the bispecific antibody comprises an immune checkpoint protein binding site.
5. The antibody or the antigen-binding portion thereof of claim 4 , wherein the immune checkpoint protein binding site comprises a programmed cell death protein 1 ligand (PD-L1) binding site, PD-1 binding site, epidermal growth factor receptor (EGFR) binding site, human epidermal growth factor receptor 2 (HER2) binding site, cytotoxic T-lymphocyte-associated antigen 4 (CTLA-4) binding site, or lymphocyte activation gene 3 (LAG3) binding site.
6. An antibody or an antigen-binding portion thereof binding to PD-L1, comprising:
a heavy chain variable region and a light chain variable region respectively comprising an amino acid sequence of
SEQ ID NO: 2 and amino acid 1-111 of SEQ ID NO: 1.
7. A bispecific antibody comprising at least one of polypeptide chain, wherein the polypeptide chain comprises:
an OX40 binding site, comprising:
a heavy chain variable region and a light chain variable region respectively comprising an amino acid sequence of
SEQ ID NO: 6 and amino acid 1-108 of SEQ ID NO: 5; and
a PD-L1 binding site, comprising:
a heavy chain variable region and a light chain variable region respectively comprising an amino acid sequence of
SEQ ID NO: 2 and amino acid 1-111 of SEQ ID NO: 1.
8. The bispecific antibody of claim 7 , wherein the polypeptide chain comprises:
a Fc domain;
a Fab fragment connected to the N-terminus of the Fc domain, and the Fab fragment comprising the PD-L1 binding site; and
a scFv connected to the C-terminus of the Fc domain, and the scFv comprising the OX40 binding site.
9. The bispecific antibody of claim 8 , wherein the polypeptide chain further comprises a linker between the Fc domain and the scFv.
10. The bispecific antibody of claim 9 , wherein the scFv comprises an amino acid sequence selected from the group consisting of amino acid 455-707 of SEQ ID NO: 18, 455-708 of SEQ ID NO: 19, 455-701 of SEQ ID NO: 20, 455-706 of SEQ ID NO: 21, 455-706 of SEQ ID NO: 22, 455-706 of SEQ ID NO: 23, 455-706 of SEQ ID NO: 24, 455-706 of SEQ ID NO: 25, 455-706 of SEQ ID NO: 26, 455-706 of SEQ ID NO: 27, 455-706 of SEQ ID NO: 28, and 455-706 of SEQ ID NO: 29.
11. The bispecific antibody of claim 7 , wherein the bispecific antibody comprises one pair of polypeptide chains.
12. The bispecific antibody of claim 11 , wherein the bispecific antibody is an IgG, IgE, IgM, IgD, IgA, or IgY antibody.
13. The bispecific antibody of claim 12 , wherein the bispecific antibody is an IgG antibody.
14. The bispecific antibody of claim 13 , wherein the IgG antibody is an IgG1, IgG2, IgG3, or IgG4 antibody.
15. An antibody-drug conjugate comprising:
a therapeutic agent; and
an antibody or an antigen-binding portion thereof binding PD-L1 and/or OX40, wherein the therapeutic agent is covalently conjugated to the antibody or the antigen-binding portion thereof by a linker;
wherein the antibody or the antigen-binding portion thereof is:
a) an antibody or an antigen-binding portion thereof binding to OX40, comprising:
a heavy chain variable region and a light chain variable region respectively comprising an amino acid sequence of
SEQ ID NO: 6 and amino acid 1-108 of SEQ ID NO: 5;
b) an antibody or an antigen-binding portion thereof binding to PD-L1, comprising:
a heavy chain variable region and a light chain variable region respectively comprising an amino acid sequence of
SEQ ID NO: 2 and amino acid 1-111 of SEQ ID NO: 1; or
c) a bispecific antibody comprising at least one polypeptide chain, wherein the polypeptide chain comprises:
an OX40 binding site, comprising:
a heavy chain variable region and a light chain variable region respectively comprising an amino acid sequence of
SEQ ID NO: 6 and amino acid 1-108 of SEQ ID NO: 5; and
a PD-L1 binding site, comprising:
a heavy chain variable region and a light chain variable region respectively comprising an amino acid sequence of
SEQ ID NO: 2 and amino acid 1-111 of SEQ ID NO: 1.
16. A pharmaceutical composition comprising the antibody or the antigen-binding portion thereof according to claim 1 , and at least one pharmaceutically acceptable carrier.
17. A pharmaceutical composition comprising the antibody or the antigen-binding portion thereof as claimed in claim 6 , and at least one pharmaceutically acceptable carrier.
18. A pharmaceutical composition comprising the bispecific antibody according to claim 7 , and at least one pharmaceutically acceptable carrier.
19. A method of treating cancer comprising administering to the subject in need thereof an effective amount of the antibody or antigen-binding portion thereof according to claim 1 .
20. The method of claim 19 , wherein the cancer is selected from the group consisting of prostate cancer, lung cancer, Non-Small Cell Lung Cancer (NSCLC), melanoma, lymphoma, breast cancer, head and neck cancer, renal cell carcinoma (RCC), and ovarian cancer.
21. A method of treating cancer comprising administering to the subject in need thereof an effective amount of the antibody or antigen-binding portion thereof as claimed in claim 6 .
22. The method of claim 21 , wherein the cancer is selected from the group consisting of prostate cancer, lung cancer, Non-Small Cell Lung Cancer (NSCLC), melanoma, lymphoma, breast cancer, head and neck cancer, renal cell carcinoma (RCC), and ovarian cancer.
23. A method of treating cancer comprising administering to the subject in need thereof an effective amount of the bispecific antibody according to claim 7 .
24. The method of claim 23 , wherein the cancer is selected from the group consisting of prostate cancer, lung cancer, Non-Small Cell Lung Cancer (NSCLC), melanoma, lymphoma, breast cancer, head and neck cancer, renal cell carcinoma (RCC), and ovarian cancer.
25. A nucleic acid molecule encoding the antibody or the antigen-binding portion thereof according to claim 1 .
26. A nucleic acid molecule encoding the antibody or the antigen-binding portion thereof as claimed in claim 6 .
27. A nucleic acid molecule encoding the bispecific antibody according to claim 7 .