CD40 Enhances Type I Interferon Responses Downstream of CD47 Blockade, Bridging Innate and Adaptive Immunity

Abstract

Disrupting the binding of CD47 to SIRPa has emerged as a promising immunotherapeutic strategy for advanced cancers by potentiating antibody-dependent cellular phagocytosis (ADCP) of targeted antibodies. Preclinically, CD47/SIRPa blockade induces antitumor activity by increasing the phagocytosis of tumor cells by macrophages and enhancing the cross-presentation of tumor antigens to CD8 þ T cells by dendritic cells; both of these processes are potentiated by CD40 signaling. Here we generated a novel, two-sided fusion protein incorporating the extracellular domains of SIRPa and CD40L, adjoined by a central Fc domain, termed SIRPa-Fc-CD40L. SIRPa-Fc-CD40L bound CD47 and CD40 with high affinity and activated CD40 signaling in the absence of Fc receptor cross-linking. No evidence of hemolysis, hemagglutination, or thrombocytopenia was observed in vitro or in cynomolgus macaques. Murine SIRPa-Fc-CD40L outperformed CD47 blocking and CD40 agonist antibodies in murine CT26 tumor models and synergized with immune checkpoint blockade of PD-1 and CTLA4. SIRPa-Fc-CD40L activated a type I interferon response in macrophages and potentiated the activity of ADCP-competent targeted antibodies both in vitro and in vivo. These data illustrated that whereas CD47/SIRPa inhibition could potentiate tumor cell phagocytosis, CD40-mediated activation of a type I interferon response provided a bridge between macrophage-and T-cell-mediated immunity that significantly enhanced durable tumor control and rejection.

Cancer Therapy Targeting CD47/SIRPα

“…CD40/CD40L interaction partakes in both innate and adaptive anti-tumor immunity via stimulating pro-inflammatory cytokine production, including IL12 and TNF- α, the induction of ADCC, and T cell-mediated immunity and antibody production. It is also currently an active area of investigation for drug development in immune-oncology [ 111 , 112 , 113 ]. In vivo studies of SL-172154 have demonstrated superior anti-tumor activity with the fusion protein over either CD47 antagonist, CD40 agonist antibody as monotherapy or the combination of the two, suggesting a synergistic role [ 110 ].…”

Potential Role of CD47-Directed Bispecific Antibodies in Cancer Immunotherapy

“…Previous studies found that SL-172154 significantly improved rejection of both primary and secondary tumors, as compared with individual antibodies targeting CD40 and CD47 used alone or in combination, similar to PD-1-Fc-OX40L ( 56 ). Notably, the safety and efficacy of the bsAb in nonhuman primates in vivo that, the bsAb stimulated dose-dependent elevation in multiple serum cytokines and CD40 + B-cell margination in cynomolgus macaques, without causing hemolysis or thrombocytopenia, provides justification to further explore this strategy in patients with cancers ( 47 ).…”

Approaches of the Innate Immune System to Ameliorate Adaptive Immunotherapy for B-Cell Non-Hodgkin Lymphoma in Their Microenvironment

“…Both these processes are potentiated by CD40 signaling. Accordingly, Schreiber et al developed a SIRPα-Fc-CD40L agonist redirected checkpoint fusion protein to address these distinct pathways with a single biological agent SIRPα-Fc-CD40L is a novel, bifacial fusion protein that combines the extracellular domains of SIRPα and CD40L, adjacent to a fundamental Fc domain [ 70 ]. SIRPα-Fc-CD40L binds CD47 and CD40 with high affinity and activates CD40 signaling without FcR cross-linking.…”