Multivalent, Soluble Nano-Self Peptides Increase Phagocytosis of Antibody-Opsonized Targets while Suppressing Self Signaling

Macrophages engulf foreign cells and particles, but phagocytosis of healthy cells and cancer cells is inhibited by expression of the ubiquitous membrane protein CD47 which binds SIRP alpha on macrophages to signal self. Motivated by some clinical efficacy of anti-CD47 against liquid tumors and based on past studies of CD47-derived polypeptides on particles that inhibited phagocytosis of the particles, here we design soluble, multivalent peptides to bind and block SIRP alpha. Bivalent and tetravalent nano-Self peptides prove more potent (K-eff similar to 10 nM) than monovalent 8-mers as agonists for phagocytosis of antibody opsonized cells, including cancer cells. Multivalent peptides also outcompete soluble CD47 binding to human macrophages, consistent with SIRP alpha binding, and the peptides suppress phosphotyrosine in macrophages, consistent with inhibition of SIRP alpha's self signaling. Peptides exhibit minimal folding, but functionality suggests an induced fit into SIRP alpha's binding pocket. Pre-clinical studies in mice indicate safety, with no anemia that typifies clinical infusions of anti-CD47. Multivalent nano-Self peptides thus constitute an alternative approach to promoting phagocytosis of self, including cancer cells targeted clinically.