Abstract 562: Antibodies to Sirpα enhance innate and adaptive immune responses to promote anti-tumor activity
Authors: Kuo Tracy C. , Chen Amy , Harrabi Ons , Kauder Steven E. , Sangalang Emma R. , Doyle Laura , Bollini Sangeetha , Han Bora , Sim Janet , Pons Jaume , Wan Hong I. 
Published: August 2019

Targeting the CD47-SIRPα myeloid checkpoint pathway represents a novel therapeutic approach to enhance anti-cancer immunity. CD47 is a widely expressed cell surface protein that functions as a marker of self. Signal regulatory protein-α (SIRPα) is an ITIM-containing inhibitory receptor of CD47 on myeloid cells. Tumor cells up-regulate CD47 expression to evade immune surveillance. Clinical trials targeting CD47 to inhibit SIRPα interaction have shown promising results (N Lakhani et al, 2018 SITC #P335). Unlike CD47, which is expressed ubiquitously, SIRPα has limited expression, mainly on myeloid cells including macrophages, dendritic cells, and neutrophils, and neurons. Targeting SIRPα circumvents the need to overcome the CD47 sink that is necessary for CD47 targeting molecules. Antibodies to SIRPα that bind mouse, human and cynomolgus monkey SIRPα with high affinity, were evaluated for their effects on macrophage function, anti-tumor activity and normal blood cells.

Humanized antibody to SIRPα was generated to bind both human SIRPα allele V1 and V2 with high affinity (pM) and cross-react with cynomolgus and mouse SIRPα. Anti-SIRPα antibody in combination with targeted anti-cancer antibodies enhanced antibody-dependent cellular phagocytosis (ADCP) of tumor cell lines by human monocyte derived macrophages. In preclinical xenograft models of SIRPα positive and negative malignant cell lines, administration of anti-SIRPα antibody enhanced anti-tumor activity of rituximab and cetuximab via ADCP.

The impact of SIRPα blockade on anti-tumor immunity was assessed in immunocompetent tumor mouse models. SIRPα antibodies enhanced anti-tumor activity of checkpoint inhibitors in syngeneic tumor models. Combination therapy with SIRPα antibodies and checkpoint inhibitors in tumor models showed eradication of tumors, acquired memory immune response upon tumor rechallenge and decreased lung metastasis. The cellular mechanisms driving efficacy include dendritic cell activation, reduction of myeloid suppression and enhancement of T cell effector profile.

Exploratory safety and PK/PD profiles of anti-SIRPα antibodies were assessed in cynomolgus monkeys. Antibodies to SIRPα demonstrated a typical antibody PK and complete SIRPα target occupancy. There were no adverse clinical observations, no changes in hematological parameters and no impact on serum chemistries.

In summary, anti-SIRPα antibodies combined with targeted anti-cancer antibodies or checkpoint inhibitors integrate innate and adaptive immune responses to promote anti-tumor activity in preclinical models. Together with the favorable safety profile in cynomolgus monkeys, these data support the development of SIRPα antibodies for solid tumors and hematological malignancies.

Citation Format: Tracy C. Kuo, Amy Chen, Ons Harrabi, Steven E. Kauder, Emma R. Sangalang, Laura Doyle, Sangeetha Bollini, Bora Han, Janet Sim, Jaume Pons, Hong I. Wan. Antibodies to Sirpα enhance innate and adaptive immune responses to promote anti-tumor activity [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2019; 2019 Mar 29-Apr 3; Atlanta, GA. Philadelphia (PA): AACR; Cancer Res 2019;79(13 Suppl):Abstract nr 562.