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01-02-2022 | Multiple Myeloma | Original Article

Modulation of CD47-SIRPα innate immune checkpoint axis with Fc-function detuned anti-CD47 therapeutic antibody

Authors: Rama Krishna Narla, Hardik Modi, Daniel Bauer, Mahan Abbasian, Jim Leisten, Joseph R. Piccotti, Stephan Kopytek, Brendan P. Eckelman, Quinn Deveraux, John Timmer, Dan Zhu, Lilly Wong, Laure Escoubet, Heather K. Raymon, Kandasamy Hariharan

Published in: Cancer Immunology, Immunotherapy | Issue 2/2022

Abstract

Cluster of differentiation 47 (CD47) is a transmembrane protein ubiquitously expressed on human cells but overexpressed on many different tumor cells. The interaction of CD47 with signal-regulatory protein alpha (SIRPα) triggers a “don’t eat me” signal to the macrophage, inhibiting phagocytosis. Thus, overexpression of CD47 enables tumor cells to escape from immune surveillance via the blockade of phagocytic mechanisms. We report here the development and characterization of CC-90002, a humanized anti-CD47 antibody. CC-90002 is unique among previously reported anti-CD47 bivalent antibodies that it does not promote hemagglutination while maintaining high-affinity binding to CD47 and inhibition of the CD47–SIRPα interaction. Studies in a panel of hematological cancer cell lines showed concentration-dependent CC-90002-mediated phagocytosis in acute lymphoblastic leukemia, acute myeloid leukemia (AML), lenalidomide-resistant multiple myeloma (MM) cell lines and AML cells from patients. In vivo studies with MM cell line-derived xenograft models established in immunodeficient mice demonstrated significant dose-dependent antitumor activity of CC-90002. Treatment with CC-90002 significantly prolonged survival in an HL-60-disseminated AML model. Mechanistic studies confirmed the binding of CC-90002 to tumor cells and concomitant recruitment of F4-80 positive macrophages into the tumor and an increase in expression of select chemokines and cytokines of murine origin. Furthermore, the role of macrophages in the CC-90002-mediated antitumor activity was demonstrated by transient depletion of macrophages with liposome-clodronate treatment. In non-human primates, CC-90002 displayed acceptable pharmacokinetic properties and a favorable toxicity profile. These data demonstrate the potential activity of CC-90002 across hematological malignancies and provided basis for clinical studies CC-90002-ST-001 (NCT02367196) and CC-90002-AML-001 (NCT02641002).

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Title: Modulation of CD47-SIRPα innate immune checkpoint axis with Fc-function detuned anti-CD47 therapeutic antibody
Authors: Rama Krishna Narla
Hardik Modi
Daniel Bauer
Mahan Abbasian
Jim Leisten
Joseph R. Piccotti
Stephan Kopytek
Brendan P. Eckelman
Quinn Deveraux
John Timmer
Dan Zhu
Lilly Wong
Laure Escoubet
Heather K. Raymon
Kandasamy Hariharan
Publication date: 01-02-2022
Publisher: Springer Berlin Heidelberg
Keywords: Multiple Myeloma
Acute Myeloid Leukemia
Published in: Cancer Immunology, Immunotherapy / Issue 2/2022
Print ISSN: 0340-7004
Electronic ISSN: 1432-0851
DOI: https://doi.org/10.1007/s00262-021-03010-6

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