title: A bispecific antibody targeting CD47 and CD20 selectively binds and eliminates dual antigen expressing lymphoma cells.
abstract: Agents that block the anti-phagocytic signal CD47 can synergize with pro-phagocytic anti-tumor antigen antibodies to potently eliminate tumors. While CD47 is overexpressed on cancer cells, its expression in many normal tissues may create an 'antigen sink' that could minimize the therapeutic efficacy of CD47 blocking agents. Here, we report development of bispecific antibodies (BsAbs) that co-target CD47 and CD20, a therapeutic target for non-Hodgkin lymphoma (NHL), that have reduced affinity for CD47 relative to the parental antibody, but retain strong binding to CD20. These characteristics facilitate selective binding of BsAbs to tumor cells, leading to phagocytosis. Treatment of human NHL-engrafted mice with BsAbs reduced lymphoma burden and extended survival while recapitulating the synergistic efficacy of anti-CD47 and anti-CD20 combination therapy. These findings serve as proof of principle for BsAb targeting of CD47 with tumor-associated antigens as a viable strategy to induce selective phagocytosis of tumor cells and recapitulate the synergy of combination antibody therapy. This approach may be broadly applied to cancer to add a CD47 blocking component to existing antibody therapies.
authors.affiliation: a Department of Medicine; Division of Hematology, Cancer Institute; and Institute for Stem Cell Biology and Regenerative Medicine, Stanford University , Stanford , CA , USA.
authors.forename: Emily C
authors.initials: EC
authors.lastname: Piccione
authors.forename: Silvia
authors.initials: S
authors.lastname: Juarez
authors.forename: Jie
authors.initials: J
authors.lastname: Liu
authors.forename: Serena
authors.initials: S
authors.lastname: Tseng
authors.forename: Christine E
authors.initials: CE
authors.lastname: Ryan
authors.forename: Cyndhavi
authors.initials: C
authors.lastname: Narayanan
authors.forename: Lijuan
authors.initials: L
authors.lastname: Wang
authors.forename: Kipp
authors.initials: K
authors.lastname: Weiskopf
authors.forename: Ravindra
authors.initials: R
authors.lastname: Majeti
mesh_terms: D000818:Animals; D018033:Antibodies, Bispecific / Q000276:immunology / Q000494:pharmacology*; D000911:Antibodies, Monoclonal / Q000276:immunology / Q000494:pharmacology*; D000915:Antibody Affinity; D018951:Antigens, CD20 / Q000276:immunology*; D051928:CD47 Antigen / Q000276:immunology*; D006801:Humans; D007074:Immunoglobulin G / Q000276:immunology / Q000494:pharmacology; D008228:Lymphoma, Non-Hodgkin / Q000276:immunology*; D051379:Mice; D016133:Polymerase Chain Reaction; D020349:Surface Plasmon Resonance; D023041:Xenograft Model Antitumor Assays
chemical_list: D018033:Antibodies, Bispecific; D000911:Antibodies, Monoclonal; D018951:Antigens, CD20; D051928:CD47 Antigen; D007074:Immunoglobulin G
keywords: CD47; bispecific antibody; lymphoma; phagocytosis; synergy