Abstract 2653: The anti-myeloma activity of TTI-621 (SIRPαFc), a CD47-blocking immunotherapeutic, is enhanced when combined with a proteasome inhibitor
Authors: Linderoth Emma , Helke Simone , Lee Vivian , Mutukura Tapfuma , Wong Mark , Lin Gloria H. , Johnson Lisa D. , Pang Xinli , Winston Jeff , Petrova Penka S. , Uger Robert A. , Viller Natasja N. 
Published: July 2017

Abstract
CD47 is transmembrane glycoprotein that delivers an anti-phagocytic (“do not eat”) signal by binding to its receptor, signal-regulatory protein α (SIRPα), on the surface of macrophages. Many tumors, including multiple myeloma (MM), express high levels of CD47 as a means to exploit the CD47-SIRPα pathway and escape macrophage-mediated immune surveillance. TTI-621 (SIRPαFc) is a soluble recombinant fusion protein consisting of the CD47-binding domain of human SIRPα linked to the Fc region of human IgG1. It is designed to promote anti-tumor responses by blocking the CD47 “do not eat” signal and engaging activating Fcγ receptors on macrophages. We have previously shown that TTI-621 enhances phagocytosis of malignant cells in vitro and exhibits anti-tumor activity in acute myeloid leukemia and B lymphoma xenograft models. In this study we investigated the anti-myeloma activity of TTI-621 as both a single agent and in combination with bortezomib or carfilzomib, two proteasome inhibitors that are approved for use in MM patients. The ability of TTI-621 to trigger macrophage phagocytosis of MM cells was assessed using a flow cytometry-based phagocytosis assay. Blockade of CD47 using TTI-621 effectively triggered macrophage-mediated phagocytosis of MM cells, and this anti-tumor effect was significantly enhanced by pre-treatment of MM cells with bortezomib or carfilzomib. In order to understand the molecular mechanism behind this enhanced phagocytic effect, we performed immunophenotyping of the tumor cells and observed an upregulation of pro-phagocytic “eat” signals on the tumor cell surface that potentially augment the phagocytic response. To investigate whether CD47 blockade in the context of proteasome inhibition translates to enhanced anti-tumor activity in vivo, we employed a MM xenograft model. NOD.SCID mice were subcutaneously engrafted with human MM cells followed by treatment with TTI-621, in the absence or presence of concurrent administration of a proteasome inhibitor. As monotherapies, both TTI-621 and the proteasome inhibitor reduced tumor burden relative to vehicle controls. Moreover, the combination of CD47 blockade and proteasome inhibition resulted in a greater reduction in tumor growth as compared to the two drugs alone. In conclusion, these data demonstrate that TTI-621 exhibits anti-myeloma activity that is further enhanced by combination with bortezomib or carfilzomib. TTI-621 monotherapy is currently being evaluated in a Phase 1b study in patients with MM and other hematological malignancies (NCT02663518). These data provide a rationale to evaluate a combination study of TTI-621 and a proteasome inhibitor in MM patients.
Citation Format: Emma Linderoth, Simone Helke, Vivian Lee, Tapfuma Mutukura, Mark Wong, Gloria H. Lin, Lisa D. Johnson, Xinli Pang, Jeff Winston, Penka S. Petrova, Robert A. Uger, Natasja N. Viller. The anti-myeloma activity of TTI-621 (SIRPαFc), a CD47-blocking immunotherapeutic, is enhanced when combined with a proteasome inhibitor [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2017; 2017 Apr 1-5; Washington, DC. Philadelphia (PA): AACR; Cancer Res 2017;77(13 Suppl):Abstract nr 2653. doi:10.1158/1538-7445.AM2017-2653