Abstract 3239: CTX-5861 mediated SIRPα blockade combines with tumor targeting antibodies, checkpoint blockade and/or CD137 agonism to elicit curative anti-tumor activity in syngeneic mouse models

Abstract

Blockade of inhibitory checkpoint pathways, such as PD-1/PD-L1 and CTLA-4, has provided significant benefit to subsets of patients and changed the cancer therapy landscape. These checkpoint inhibitors promote adaptive T cell-mediated anti-tumor immunity while signaling regulatory protein alpha (SIRPα)/CD47 axis represents an innate specific checkpoint that has become an attractive target for immunotherapy. CD47 is expressed by virtually all cells, providing an anti-phagocytic “don’t eat me” signal through its interaction with the inhibitory immune receptor SIRPα which is expressed on myeloid cells. Blockade of the CD47-SIRPα interaction has been shown to promote phagocytosis and antigen presentation. Bispecific antibodies are emerging as an attractive therapeutic modality capable of simultaneously engaging two targets with a single drug to improve efficacy. Here we describe the discovery and characterization of a series of fully human, tetravalent common light chain SIRPαxPD-L1 bispecific antibodies. CTX-5861 was identified based on epitope binning and functional studies. The CD47 binding domain of SIRPα is known to be highly polymorphic, with allelic variants differing by as many as 13 amino acids. CTX-5861 bound to all tested polymorphic variants with higher specificity towards SIRPα expressed on myeloid cells as opposed SIRPγ expressed on T cells. In vitro studies showed that, CTX-5861 enhanced antibody-dependent cell mediated phagocytosis by macrophages and increased antigen presentation by dendritic cells. In vivo, CTX-5861 combination with tumor targeting antibodies significantly reduced tumor burden in the B16F10 lung metastasis and subcutaneous MC38 models without inducing hematological toxicities commonly associated with anti-CD47 antibodies. In the MC38 model, the addition of either PD-L1 blockade or CD137 agonism to the combination regimen led to curative anti-tumor activity in 40-60% of the mice. Quadruple combination of tumor targeting antibody, CTX-5861, PD-L1 blockade, and CD137 agonism achieved a 100% cure rate. These results suggest that SIRPα blockade, as mediated by CTX-5861, could be of central importance in rationally-designed, multi-agent immunotherapy combinations. Through its ability to enhance tumor antigen processing and presentation without incurring hematological toxicity, CTX-5861 represents a highly promising novel agent for cancer immunotherapy. Note: This abstract was not presented at the meeting. Citation Format: Ugur Eskiocak, Wilson Guzman, Thomas Daly, Allison Nelson, Pearl Bakhru, Jason Lajoie, Sara Haserlat, Samantha Ottinger, Lucy Liu, Amanda Oliphant, Alan Leung, Girish Hemashettar, Rachel Rennard, Benjamin Wolf, Monia Draghi, Michael Schmidt, Robert Tighe. CTX-5861 mediated SIRPα blockade combines with tumor targeting antibodies, checkpoint blockade and/or CD137 agonism to elicit curative anti-tumor activity in syngeneic mouse models [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 3239.

Therapeutic modulation of the CD47-SIRPα axis in the pediatric tumor microenvironment: working up an appetite

“…Next-generation CD47 blockade has resulted in bispecific antibody platforms that can also target CD19 or CD20 in a mouse lymphoma model [80][81][82] , CD33 or CD123 in AML [83][84][85] , CD40 in colon carcinoma [86] , tumor-associated antigens such as mesothelin [87] and VEGFR1 [60] in non-small cell lung cancer, and even dual blockade of CD47 and SIRPα [88,89] or SIRPα and PD-L1 [90] ; however, trials in humans have yet to be conducted. CD96, like CD123, has been suggested as a leukemic stem cell-specific molecule that also engages Fc receptors on phagocytes [26] , and might be an effective target in combination with anti-CD47.…”

SIRPα: A key player in innate immunity

“…It has shown no hematological toxicity as a monotherapy and has led to full recovery when used in combination with other tumor-targeting antibodies. This makes CTX-5861 a promising candidate for multiagent immunotherapy combinations [87]. Selective SIRPα blockade may stimulate T-cell recruitment to tumor nests by enhancing macrophage chemokine secretion and activating antitumor T-cell responses by promoting tumor antigen cross-presentation by dendritic cells in mice [88].…”