Engineered SIRPα Variants as Immunotherapeutic Adjuvants to Anticancer Antibodies

Abstract

During oncogenesis, tumors develop mechanisms to avoid rejection by the immune system. Recent studies have identified CD47 as an anti-phagocytic “don't eat me” signal tat cancer cells employ to inhibit macrophage-mediated destruction. Here, we modified the 14 kDa binding domain of human SIRPα, the receptor for CD47, for use as a CD47 antagonist. Using in vitro evolution via yeast surface display, we engineered high-affinity SIRPα variants with up to a 50,000-fold increase in affinity for human CD47 relative to wild-type SIRPα. As high-affinity SIRPα monomers, the variants potently antagonized CD47 on cancer cells, but to our surprise, they did not induce macrophage phagocytosis on their own. Instead, the high-affinity SIRPα monomers exhibited remarkable synergy with all tumor-specific monoclonal antibodies tested by increasing phagocytosis in vitro and enhancing anti-tumor responses in vivo. This novel “one-two punch” directs immune responses against tumor cells while lowering the threshold for macrophage activation, thereby providing a universal method for augmenting the efficacy of therapeutic anti-cancer antibodies.

Identification of tumorigenic cells and therapeutic targets in pancreatic neuroendocrine tumors

“…Blocking the CD47-SIRPα interaction allows phagocytes to effectively destroy cancer cells in vitro and in vivo, leading to inhibition or elimination of primary tumors and metastases in human cancer xenotransplantation models (12). Furthermore, we have shown that blocking CD47 with monoclonal antibodies and other agents can dramatically enhance the efficacy of cancer-targeting monoclonal antibodies, including rituximab (anti-CD20) for lymphoma and trastuzumab (anti-her2) for breast cancer (13,14). In addition, we have shown that the anti-CD47 antibody treatment selectively increases the ability of macrophages to prime and activate cytotoxic T lymphocytes, which may limit tumor growth beyond the time of anti-CD47 monoclonal antibody treatment (15).…”

Antibody-mediated phagocytosis contributes to the anti-tumor activity of the therapeutic antibody daratumumab in lymphoma and multiple myeloma

“…41 Moreover, targeting the CD47-SIRP a axis has now been shown to increase efficacy of several therapeutic antibodies. 42,43 CD47 is described to be highly expressed on CD38 C MM cells, 44 suggesting that inhibition of the CD47-SIRP a axis might be an interesting therapeutic approach in combination with DARA.…”

Extracellular vesicles as a platform for membrane‐associated therapeutic protein delivery

“…Because CD47 is expressed on most cancer cell types, it represents a potentially tractable and widely applicable target for therapeutic blockade in cancer patients. Recently, recombinant SIRPα proteins were developed as a competitive antagonist to human CD47; they showed blocking activity in vitro , but the higher-affinity variants did not eliminate tumours in vivo when applied as a mono-treatment [123]. To address these issues, an exosome-based platform was developed to provide high avidity to CD47.…”