Srf231, A Fully Human Cd47 Antibody, Potentiates The Effects Of Opsonizing Antibodies And Cytotoxic Chemotherapies In Preclinical Cancer Models

CD47 is widely expressed on tumor cells and is an important checkpoint of the innate immune response. SRF231, an investigational fully human IgG4 anti-CD47 antibody, blocks CD47-SIRPα interaction and exerts anti-tumor activity via phagocytosis and cell death in a manner dependent on Fc-engagement with CD32a, leading to enhanced myeloid activity. Human IgG1 Fc-containing antibodies that target cancer antigens (opsonizing antibodies) can stimulate macrophage-mediated antibody-dependent cellular phagocytosis (ADCP) in addition to NK cell-mediated antibody-dependent cellular cytotoxicity (ADCC). Also, several chemotherapies trigger cell death response pathways that generate additional “eat-me” signals on tumor cells, rendering them more susceptible to SRF231. Given the dual mechanism of action of SRF231, combination therapies that induce ADCP or cell death were evaluated for their ability to potentiate SRF231-mediated anti-tumor responses in hematologic and solid tumor models. The effect of SRF231 alone and in combination with opsonizing antibodies was evaluated in multiple myeloma (MM) models. In vitro, SRF231 induced phagocytosis of MM cells by human monocyte-derived macrophages. Enhanced ADCP was observed with SRF231 in combination with opsonizing antibodies elotuzumab (anti-SLAMF7) and daratumumab (anti-CD38). In vivo, SRF231 monotherapy following single- and repeat-dosing regimens resulted in 50-80% tumor growth inhibition and significantly increased median survival time in the preclinical MM xenograft models OPM2 and MM1.S. Furthermore, SRF231 strongly synergized with a sub-optimal dose of elotuzumab leading to increased complete response (CR) rates in both models. The effect of SRF231 alone and in combination with chemotherapies was also assessed in non-small cell lung cancer (NSCLC) models. In vivo, SRF231 monotherapy induced anti-tumor activity and significantly increased median survival time in preclinical EGFR mutant (H1975) and EGFR wildtype (A549) NSCLC xenograft models. Cisplatin monotherapy induced modest H1975 anti-tumor activity; however, combination with SRF231 potentiated the effect of cisplatin in this model. Additionally, combination of SRF231 with docetaxel resulted in a 45% CR rate and a significant delay in H1975 tumor regrowth, as compared to a 100% regrowth rate with docetaxel monotherapy. In summary, SRF231 demonstrated significant anti-tumor activity in combination with the anti-SLAMF7 opsonizing antibody, elotuzumab, in preclinical MM xenograft models. Moreover, SRF231 potentiated the effects of taxane and platinum-based standard of care chemotherapies in preclinical NSCLC xenograft models. These results offer further guidance on the clinical development of anti-CD47 modalities in cancer treatment. Citation Format: Kshama A. Doshi, Matthew Rausch, Caroline M. Armet, Li Zhang, Alison M. Paterson, Benjamin H. Lee, Vito J. Palombella, Pamela Holland, Marisa O. Peluso. SRF231, a fully human CD47 antibody, potentiates the effects of opsonizing antibodies and cytotoxic chemotherapies in preclinical cancer models [abstract]. In: Proceedings of the Annual Meeting of the American Association for Cancer Research 2020; 2020 Apr 27-28 and Jun 22-24. Philadelphia (PA): AACR; Cancer Res 2020;80(16 Suppl):Abstract nr 2196.