TTI-622 (SIRP alpha-IgG4 Fc), a CD47-blocking innate immune checkpoint inhibitor, suppresses tumor growth and demonstrates enhanced efficacy in combination with antitumor antibodies in both hematologic and solid tumor models

Tumor cells frequently evade macrophage-mediated destruction by increasing cell surface expression of CD47, which delivers an anti-phagocytic (“do-not-eat”) signal by binding the inhibitory signal regulatory protein α (SIRPα) receptor on macrophages. Previous studies have shown that blockade of the CD47-SIRPα pathway using TTI-621, a soluble SIRPα-IgG1 Fc fusion protein, triggers macrophage phagocytosis of tumor cells in vitro, and potently inhibits tumor growth in vivo. In the current study, the in vitro and in vivo efficacy of TTI-622, a soluble SIRPα-Fc variant protein containing an IgG4 Fc tail, was evaluated in multiple model systems. Unlike CD47-blocking antibodies, TTI-622 binds minimally to human erythrocytes, and does not induce hemagglutination in vitro. Therefore, it avoids a large circulating antigen sink, and is less likely to cause anemia in patients. Additionally, TTI-622 potently induces phagocytosis of a broad panel of tumor cells derived from patients with both hematological and solid tumors. Although in vitro phagocytosis of human platelets is also observed, TTI-622 preferentially induces phagocytosis of tumor cells over platelets in a competitive phagocytosis assay. The in vivo efficacy of TTI-622 monotherapy and/or combination therapy was evaluated in different tumor models. In a DLBCL (Toledo) xenograft tumor model, both early and delayed treatments resulted in statistically significant decreases in tumor growth, and improved survival relative to treatment with control Fc. In the Burkitt lymphoma (Daudi) and multiple myeloma (MM.1S) xenograft tumor models, the potential of combining TTI-622 with daratumumab (anti-CD38 antibody) was also explored. In both models, TTI-622 monotherapy demonstrated partial tumor growth inhibition. However, the therapeutic efficacy was further enhanced when TTI-622 was combined with daratumumab. Intriguingly, a TTI-622 non-responsive head and neck cancer (FaDu) xenograft tumor model became responsive by combining TTI-622 with suboptimal doses of cetuximab (anti-EGFR antibody). The combination of TTI-622 with cetuximab resulted in a statistically significant decrease in tumor growth, and improved survival relative to monotherapy treatments. Collectively, these results demonstrate that TTI-622 induces potent, tumor-specific macrophage phagocytosis across a range of hematological and solid tumors, and is efficacious as a monotherapy agent in a DLBCL xenograft tumor model. Furthermore, TTI-622 potentiates the efficacy of daratumumab and cetuximab in hematological and solid xenograft tumor models, respectively. These data support the clinical evaluation of TTI-622 in combination with anti-tumor antibodies in cancer patients with both solid and hematological malignancies. Citation Format: Gloria H. Y. Lin, Natasja N. Viller, Marilyse Chabonneau, Laura Brinen, Tapfuma Mutukura, Karen Dodge, Simone Helke, Vien Chai, Violetta House, Vivian Lee, Hui Chen, Alison O9Connor, Debbie Jin, Rene Figueredo, Saman Maleki Vareki, Mark Wong, Emma Linderoth, Lisa D. Johnson, Xinli Pang, James Koropatnick, Jeff Winston, Penka S. Petrova, Robert A. Uger. TTI-622 (SIRPα-IgG4 Fc), a CD47-blocking innate immune checkpoint inhibitor, suppresses tumor growth and demonstrates enhanced efficacy in combination with antitumor antibodies in both hematologic and solid tumor models [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2018; 2018 Apr 14-18; Chicago, IL. Philadelphia (PA): AACR; Cancer Res 2018;78(13 Suppl):Abstract nr 2709.