title: Engineered SIRPα variants as immunotherapeutic adjuvants to anticancer antibodies.
abstract: CD47 is an antiphagocytic signal that cancer cells employ to inhibit macrophage-mediated destruction. Here, we modified the binding domain of human SIRPα, the receptor for CD47, for use as a CD47 antagonist. We engineered high-affinity SIRPα variants with about a 50,000-fold increased affinity for human CD47 relative to wild-type SIRPα. As high-affinity SIRPα monomers, they potently antagonized CD47 on cancer cells but did not induce macrophage phagocytosis on their own. Instead, they exhibited remarkable synergy with all tumor-specific monoclonal antibodies tested by increasing phagocytosis in vitro and enhancing antitumor responses in vivo. This "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 anticancer antibodies.
authors.affiliation: Institute for Stem Cell Biology and Regenerative Medicine, Stanford University School of Medicine, Stanford, CA 94305, USA.
authors.forename: Kipp
authors.initials: K
authors.lastname: Weiskopf
authors.forename: Aaron M
authors.initials: AM
authors.lastname: Ring
authors.forename: Chia Chi M
authors.initials: CC
authors.lastname: Ho
authors.forename: Jens-Peter
authors.initials: JP
authors.lastname: Volkmer
authors.forename: Aron M
authors.initials: AM
authors.lastname: Levin
authors.forename: Anne Kathrin
authors.initials: AK
authors.lastname: Volkmer
authors.forename: Engin
authors.initials: E
authors.lastname: Ozkan
authors.forename: Nathaniel B
authors.initials: NB
authors.lastname: Fernhoff
authors.forename: Matt
authors.initials: M
authors.lastname: van de Rijn
authors.forename: Irving L
authors.initials: IL
authors.lastname: Weissman
authors.forename: K Christopher
authors.initials: KC
authors.lastname: Garcia
mesh_terms: D000276:Adjuvants, Immunologic; D000818:Animals; D000911:Antibodies, Monoclonal / Q000627:therapeutic use*; D058846:Antibodies, Monoclonal, Murine-Derived / Q000627:therapeutic use; D000912:Antibodies, Neoplasm / Q000627:therapeutic use*; D000943:Antigens, Differentiation / Q000737:chemistry / Q000235:genetics / Q000627:therapeutic use*; D051928:CD47 Antigen / Q000276:immunology*; D045744:Cell Line, Tumor; D019020:Directed Molecular Evolution; D006801:Humans; D007167:Immunotherapy; D008262:Macrophage Activation; D051379:Mice; D009369:Neoplasms / Q000276:immunology / Q000628:therapy*; D010587:Phagocytosis; D011971:Receptors, Immunologic / Q000737:chemistry / Q000235:genetics / Q000627:therapeutic use*; D000069283:Rituximab
chemical_list: D000276:Adjuvants, Immunologic; D000911:Antibodies, Monoclonal; D058846:Antibodies, Monoclonal, Murine-Derived; D000912:Antibodies, Neoplasm; D000943:Antigens, Differentiation; D051928:CD47 Antigen; D011971:Receptors, Immunologic; C501920:SIRPA protein, human; D000069283:Rituximab