METHODS AND COMPOSITIONS FOR ENHANCING THE POTENCY OF SUPERANTIGEN MEDIATED CANCER IMMUNOTHERAPY
The invention provides methods or compositions for enhancing the potency of a targeted cancer immunotherapy in a subject by using a superantigen in combination with a PD-1 inhibitor.
1 . A method of treating a cancer in a subject in need thereof, the method comprising:
administering to the subject (i) an effective amount of a superantigen conjugate comprising a superantigen covalently linked to a targeting moiety that binds a first antigen expressed by cancerous cells within the subject and (ii) an effective amount of an immunopotentiator capable of one or more of the following activities (a) stimulating activating T-cell signaling, (b) repressing T-cell inhibitory signaling between the cancerous cells and a T-cell, and/or (c) repressing inhibitory signaling that leads to T-cell expansion, activation and/or activity via a human IgG4 immunoglobulin-mediated pathway, thereby to potentiate an immune response in the subject against the cancerous cells to treat the cancer.
2 . The method of claim 1 , wherein the superantigen is administered to the subject before, at the same time as, or after the immunopotentiator.
3 . The method of claim 1 , wherein the superantigen binds to a T-cell receptor on a surface of a T-cell.
4 . The method of claim 1 , wherein the superantigen comprises Staphylococcal enterotoxin A or an immunologically variant and/or fragment thereof.
5 . The method of claim 1 , wherein the first antigen is a cell surface antigen.
6 . The method of claim 5 , wherein the cell surface antigen is a 5T4 cancer antigen.
7 . The method of claim 1 , wherein the targeting moiety is an antibody.
8 . The method of claim 7 , wherein the antibody is an anti-5T4 antibody.
9 . The method of claim 8 , wherein the anti-5T4 antibody comprises a Fab fragment that binds a 5T4 cancer antigen.
10 . The method of claim 1 , wherein the superantigen comprises amino acid residues 226 to 458 of SEQ ID NO: 7 or an immunologically reactive variant and/or fragment thereof.
11 . The method of claim 1 , wherein a Programmed Cell Death-Ligand (PD-L) is expressed on the surface of the cancerous cells that binds to Programmed Cell Death-1 protein (PD-1) expressed by the T-cell.
12 . The method of claim 11 , wherein the immunopotentiator is an anti-PD-1 antibody that prevents PD-L from binding PD-1 expressed on the surface of the T-cell.
13 . The method of claim 12 , wherein the anti-PD-1 antibody has or is based on a human IgG4 isotype.
14 . The method of claim 12 , wherein the anti-PD-1 antibody is selected from the group consisting of nivolumab and pembrolizumab.
15 . The method of claim 1 , wherein the cancer is selected from the group consisting of breast cancer, cervical cancer, colorectal cancer, gastric cancer, non-small cell lung cancer, ovarian cancer, pancreatic cancer, prostate cancer, renal cell cancer, and skin cancer.
16 .- 28 . (canceled)