Vista regulatory T cell mediator protein, vista binding agents and use thereof
The present invention relates to a novel regulatory T cell protein. This protein, designated PD-L3 OR VISTA resembles members of the PD-L1 family, identified a novel and structurally-distinct, Ig-superfamily inhibitory ligand, whose extracellular domain bears homology to the B7 family ligand PD-L1. This molecule is designated as PD-L3 OR VISTA or V-domain Immunoglobulin Suppressor of T cell Activation (VISTA). Expression of VISTA is primarily within the hematopoietic compartment and is highly regulated on myeloid APCs and T cells. Therapeutic intervention of the VISTA inhibitory pathway represents a novel approach to modulate T cell-mediated immunity for the treatment of a wide variety of cancers, e.g., ovarian, bladder cancer and melanomas. Also, VISTA proteins, especially multimeric VISTA proteins and antibodies may be used to suppress T cell immunity in autoimmune disease, allergy, infection and inflammatory conditions, e.g. multiple sclerosis and arthritic conditions such as RA.
1. A method of treating ovarian cancer in a patient in need thereof by administering an effective amount of an anti-human V-region Immunoglobulin-containing Suppressor of T Cell Activation (“VISTA”) protein antibody or antigen-binding antibody fragment, wherein such antibody or antigen-binding antibody fragment, inhibits the immunosuppressive effects of VISTA protein.
2. The method of claim 1 , wherein said cancer is in early (non-metastatic) form.
3. The method of claim 1 , wherein said cancer is metastatic.
4. The method of claim 1 , wherein the anti-human VISTA antibody is an intact antibody.
5. The method of claim 1 , wherein the anti-human VISTA antibody or antigen-binding fragment is polyclonal or monoclonal.
6. The method of claim 1 , wherein the anti-human VISTA antibody or antigen-binding fragment is a human or humanized antibody or antigen-binding fragment thereof.
7. The method of claim 1 , wherein the anti-human VISTA antibody or antigen-binding fragment is a chimeric antibody.
8. The method of claim 1 wherein the patient prior to treatment is found to express elevated levels of VISTA protein on immune cells.
9. The method of claim 1 , wherein the patient is further receiving radiotherapy, chemotherapy or another anti-cancer biologic.
10. The method of claim 9 wherein the patient prior to treatment has an ovarian cancer that does not respond to said radiotherapy, chemotherapy or said anti-cancer biologic.
11. The method of claim 1 , wherein the anti-VISTA antibody or antigen-binding antibody fragment specifically binds to an epitope comprised in the IgV or stalk region of human VISTA protein.
12. The method of claim 1 , wherein the anti-VISTA antibody or antigen-binding antibody fragment elicits one of the following activities: (i) upregulates cytokine production by T cells; (ii) induces expansion of T cells, (iii) promotes antigen specific T cell immunity; or (iv) promotes CD4 + and/or CD8 + T cell activation.