Antibodies targeting a complex comprising non-classical HLA-I and neoantigen and their methods of use
Provided herein are antibodies that selectively bind to complex comprising a non-classical HLA-I (e.g. HLA-E) and a neoantigen having variable heavy chain domains (VH), variable light chain domains (VL), and complementarity determining regions (CDRs) as disclosed herein, as well as methods and uses thereof.
1. A monoclonal antibody, or an antigen-binding fragment thereof, that selectively binds to a complex comprising an HLA-E and a peptide comprising the sequence according to SEQ ID NO: 18 (VMAPRTLFL), said antibody or antigen-binding fragment thereof comprising:
(i) a light chain variable domain (VL) comprising an amino acid sequence at least 90% identical to the sequence of SEQ ID NO: 7, wherein the VL amino acid sequence comprises a CDR1 having the amino acid sequence set forth as SEQ ID NO: 1, a CDR2 having the amino acid sequence set forth as SEQ ID NO: 2, and a CDR3 having the amino acid sequence set forth as SEQ ID NO: 3; and
(ii) a heavy chain variable domain (VH) comprising an amino acid sequence at least 90% identical to the sequence of SEQ ID NO: 8, wherein the VH amino acid sequence comprises a CDR1 having the amino acid sequence set forth as SEQ ID NO: 4, a CDR2 having the amino acid sequence set forth as SEQ ID NO: 5, and a CDR3 having the amino acid sequence set forth as SEQ ID NO: 6.
2. The monoclonal antibody of claim 1 , wherein the VL comprises the amino acid sequence of SEQ ID NO: 7 and the VH comprises the amino acid sequence of SEQ ID NO: 8.
3. The monoclonal antibody of claim 1 , wherein the monoclonal antibody or antigen-binding fragment thereof does not have a binding affinity to (i) the HLA-E alone; or (ii) the peptide alone.
4. A pharmaceutical composition, comprising (a) the monoclonal antibody or antigen-binding fragment thereof of claim 1 ; and (b) a pharmaceutically acceptable excipient.
5. A bispecific T cell engager, comprising the monoclonal antibody or antigen binding-fragment thereof of claim 1 .
6. The bispecific T cell engager of claim 5 , wherein the bispecific T cell engager binds to a CD3 protein associated with a T cell receptor.
7. A pharmaceutical composition, comprising (a) the bispecific T cell engager of claim 5 ; and (b) a pharmaceutically acceptable excipient.
8. A method of treating a cancer that expresses both HLA-E and HLA-G in an individual in need thereof, comprising administering to the individual an effective amount of the monoclonal antibody or antigen-binding fragment thereof of claim 1 , to thereby treat the cancer.
9. The method of claim 8 , wherein the cancer is breast cancer, kidney cancer, lung cancer, ovarian cancer, colorectal cancer, pancreatic cancer, choriocarcinoma, non-small cell lung carcinoma (NSCLC), gastric cancer, cervical cancer, head and neck cancer, leukemia, lymphoma, myeloma, multiple myeloma (MM), acute myeloid leukemia (AML), myelodysplastic syndrome, a B-cell malignancy, or mantel cell lymphoma.
10. A method of treating a cancer that expresses both HLA-E and HLA-G in an individual in need thereof, comprising administering to the individual an effective amount of the bispecific T cell engager of claim 5 , to thereby treat the cancer.
11. The method of claim 10 , wherein the cancer is breast cancer, kidney cancer, lung cancer, ovarian cancer, colorectal cancer, pancreatic cancer, choriocarcinoma, non-small cell lung carcinoma (NSCLC), gastric cancer, cervical cancer, head and neck cancer, leukemia, lymphoma, myeloma, multiple myeloma (MM), acute myeloid leukemia (AML), myelodysplastic syndrome, a B-cell malignancy, or mantel cell lymphoma.