A method to combine two or three monoclonal antibodies (mABs) into one treatment to successfully bind to multiple cancer cell surface epitopes and promote targeted degradation by phagocytosis. Problem: Phagocytosis of ‘self’ cells is generally inhibited by a key macrophage checkpoint interaction between SIRPα on the macrophage and CD47 on all cells including cancer cells. Tumor cell engulfment can nonetheless be driven by anti-tumor monoclonal antibodies that bind Fc-receptors on macrophages (e.g., anti-CD20 in lymphoma). While the mAB-based therapies address critical aspects of cancer cell survival mechanisms, they often engage only one anti-cancer mechanism, increasing the probability of treatment-resistance disease. Further challenges for macrophage checkpoint blockade in solid tumors include low permeation of anti-CD4721 relative to the potency of inhibitory signaling as well as on-target, off-tumor binding of antibodies to ubiquitously expressed CD47. Solution: To overcome the challenge of the one anti-cancer mechanism of mAB-based therapies, the inventors have shown how macrophage cells can be promoted to engulf otherwise resistant cancers when a combination of macrophage checkpoint blockade strategies is engaged with opsonizing antibody subtypes. mABs are a beneficial therapy in treating specific cancer types and as general immune checkpoint inhibitors that help improve the host-immune response against invasion. The results provide the first evidence for cooperative phagocytosis by macrophages engulfing solid tumor targets and for an immune memory from macrophage checkpoint blockade that includes cancer-opsonizing IgG’s that drive macrophage clustering and tumor cell engulfment. Technology: To produce mAB’s that can promote cancer defense mechanisms, the inventors purified and filtered IgG subtypes from the serum of immunocompetent animals that have successfully eliminated syngeneic tumors. As a proof of concept for immune checkpoint blockade, initial assays employed tumors with no expression of the surface protein CD47, which is utilized by cancer as a self-cell labeling mechanism to protect them from phagocytosis by host macrophages. Recognition of CD47 surface protein on cancer is a two-part process also facilitated by the macrophage surface protein SIRPα and thus targeting either is a method to control macrophage detection and engulfment of cancer cells. In-vitro assays showed that bone-marrow derived macrophages can assemble and engulf B16 cells in the presence of mABs acting against the melanin-granule synthesis pathway member Tyrp1 (Figure B). This allows for specific reactivity against melanomas. In addition to in-vitro assays, pivotal in-vivo experiments induced wild-type tumors in mice by injection. Without intervention, 100% of mice did not survive. However, when anti-SIRPα, anti-CD47 and anti-Tyrp1 mABs are injected, 40% survival increases were demonstrated in treated mice, with complete recovery seen over a period of 80 days in this fraction. Advantages:
Stage of Development:
(A) SIRPα & CD47 blocking, with anti-Tyrp1 facilitated identification of melanoma, allows macrophages to identify and engulf cancer. (B) In the presence of B16 (CD47 KO) mouse melanoma cells, and anti-Tyrp1 antibodies, macrophages (Purple) fully engulf and degrade cancers. Intellectual Property:
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Docket #22-9941