Compositions and methods for targeted immunomodulatory antibodies and fusion proteins
The present invention is based on the seminal discovery that targeted immunomodulatory antibodies and fusion proteins can counter act or reverse immune tolerance of cancer cells. Cancer cells are able to escape elimination by chemotherapeutic agents or tumor-targeted antibodies via specific immunosuppressive mechanisms in the tumor microenvironment and such ability of cancer cells is recognized as immune tolerance. Such immune suppressive mechanisms include immunosuppressive cytokines (for example, Transforming growth factor beta (TGF-β) and regulatory T cells and/or immunosuppressive myeloid dendritic cells (DCs). By counteracting tumor-induced immune tolerance, the present invention provides effective compositions and methods for cancer treatment, optional in combination with another existing cancer treatment. The present invention provides strategies to counteract tumor-induced immune tolerance and enhance the antitumor efficacy of chemotherapy by activating and leveraging T cell-mediated adaptive antitumor immunity against resistant or disseminated cancer cells.
1. An isolated molecule comprising a targeting moiety fused with an immunomodulatory moiety, wherein:
(a) the targeting moiety specifically binds Cytotoxic T-lymphocyte associated antigen-4 (CTLA-4); and
(b) the immunomodulatory moiety comprises an amino acid sequence of the extracellular domain of Transforming growth factor-beta receptor (TGF-βR).
2. The molecule of claim 1 , wherein the targeting moiety comprises an antibody, antibody fragment, scFv, or Fc-containing polypeptide that specifically binds CTLA-4.
3. The molecule of claim 1 , wherein the immunomodulatory moiety comprises an amino acid sequence of the extracellular domain of Transforming growth factor-beta receptor selected from the group consisting of SEQ ID NO: 79-91.
4. The molecule of claim 3 , wherein the immunomodulatory moiety comprises an amino acid sequence of the extracellular domain of Transforming growth factor-beta receptor II (TGF-βRII).
5. The molecule of claim 4 , wherein the immunomodulatory moiety comprises the amino acid sequence corresponding to SEQ ID NO: 87 or a binding fragment thereof.
6. The molecule of claim 5 , wherein the molecule comprises the amino acid sequence corresponding to SEQ ID NO: 5 or a binding fragment thereof.
7. The molecule of claim 6 , wherein the molecule comprises the amino acid sequence corresponding to SEQ ID NO: 5 or a binding fragment thereof and the amino acid sequence corresponding to SEQ ID NO: 74 or a binding fragment thereof.
8. A method of treating a neoplastic disease comprising: administration to a subject in need thereof one or more molecules of claim 1 , wherein the neoplastic disease is bladder cancer or melanoma.
9. The method of claim 8 , wherein the subject is administered in combination with another anticancer therapy.
10. The method of claim 8 , wherein the anticancer therapy comprises a chemotherapeutic molecule, antibody, small molecule kinase inhibitor, hormonal agent, ionizing radiation, ultraviolet radiation, cryoablation, thermal ablation, or radiofrequency ablation.
11. The method of claim 8 , wherein the subject is administered in combination with a vaccine.
12. The method of claim 8 , wherein the subject is human.
13. The isolated molecule of claim 1 , further comprising a linker at the C H 3 region of the Fc.
14. The isolated molecule of claim 13 , wherein the linker is (GGGGS)n (SEQ ID NO:104), and wherein n is 1, 2, 3, 4, 5, 6, 7 or 8.
15. The isolated molecule of claim 13 , wherein the linker comprises the amino acid sequence GGGGSGGGGSGGGGS (SEQ ID NO:104).