A pan-allelic human SIRPα blocking antibody, ES004-B5 promotes tumor killing by enhancing macrophage phagocytosis and subsequently inducing an effective T-cell response

Abstract

Abstract Background As a major immune cell type in the tumor microenvironment, tumor-associated macrophages (TAMs) secrete suppressive factors that can inhibit anti-tumor immunity and promote tumor progression. One approach trying to utilize macrophages for immunotherapy has been to block the CD47-SIRPα axis, which mediates inhibitory signaling, to promote phagocytosis of tumor cells. Many CD47-targeted agents, namely anti-CD47 antibodies and SIRPα fusion proteins, were associated with a diverse spectrum of toxicities which limit their use in clinical settings. Universal expression of CD47 also leads to a severe ‘antigen sink’ effect of CD47-targeted agents. Given that the CD47 receptor, SIRPα, has a more restricted expression profile and may have CD47-independent functions, targeting SIRPα is considered to have distinct advantages in improving clinical efficacy with a better safety profile. Methods We have developed ES004-B5, a potentially best-in-class pan-allelic human SIRPα blocking antibody using hybridoma technology. Results ES004-B5 binds to major human SIRPα variants through a unique epitope with high affinity. By blocking CD47-induced inhibitory “don’t eat me” signaling, ES004-B5 exerts superior anti-tumor activity in combination with anti-TAA antibodies in vitro and in vivo. Unlike CD47-targeted agents, ES004-B5 exhibits an excellent safety profile in non-human primates. Conclusions ES004-B5 has potential to be an important backbone for SIRPα-based combination therapy and/or bispecific antibodies, which will likely overcome the limitations of CD47-targeted agents encountered in clinical settings. Statement of significance SIRPα-targeted therapy will likely overcome the limitations of anti-CD47 antibodies or SIRPα fusion proteins encountered in clinical settings. We have developed ES004-B5, a potentially best-in-class pan-allelic human SIRPα blocking antibody, which has potential to be an important backbone of SIRPα-based combination therapies or bispecific antibodies.