Ligufalimab, a novel anti-CD47 antibody with no hemagglutination demonstrates both monotherapy and combo antitumor activity

Abstract

BackgroundCD47 is a widely expressed transmembrane glycoprotein that delivers an antiphagocytic signal on macrophages through its interaction with SIRPα. CD47 is highly expressed in cancer cells and its overexpression is correlated with poor prognosis. CD47 blocking antibodies are actively being developed worldwide for cancer therapy, and the most challenging concern is associated with hematotoxicity. Ligufalimab (AK117) is a novel humanized IgG4 anti-CD47 antibody without hemagglutination effect. Blockade of CD47-SIRPα pathway by AK117 leads to a promising therapeutic strategy for cancer treatment with unique safety features.MethodsAK117 was discovered through a screening hierarchy excluding hemagglutination. AK117 was characterized by detecting CD47-SIRPα blocking potential. Its effect on human red blood cells was examined and the mechanism of its binding with erythrocytes was studied. The abilities of AK117 and its combination with various opsonizing antibodies to promote macrophage-dependent phagocytosis of multiple human tumor cells were determined using fluorescence microscopy and flow cytometry. In vivo, the antitumor efficacy of AK117 monotherapy and combination with AK112 (an anti-PD-1/VEGF-A bispecific antibody) was assessed in a variety of xenograft models. Toxicologic studies were evaluated in non-human primates.ResultsAK117 bound to CD47 with high affinity and blocked the CD47-SIRPα interaction. AK117 did not induce hemagglutination and showed significantly lower degree of erythrophagocytosis compared with Hu5F9-G4, and this mechanism of hemagglutination resistance might be related to the binding conformation. AK117 enhanced macrophage-mediated phagocytosis in both hematologic cancer and solid tumor cell lines as a single agent or in combination with cetuximab and rituximab in vitro, respectively. The antitumor effects of AK117 as a single agent or in combination with AK112 were also encouraging in various xenograft models. In non-human primates, AK117 showed less hematotoxicity compared with Hu5F9-G4.ConclusionsAK117 eliminated hemagglutination and also enabled to maintain full effectiveness of CD47 blockade on tumor cells, which resulted in excellent antitumor efficacy and favorable safety profile of AK117. A series of clinical trials of AK117 as a therapeutic agent in combination with various agents such as AK112 are in progress for the treatment of multiple hematologic malignancies and solid tumors.