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

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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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Fig. 1
Fig. 2

source of CD47. Data were normalized to a no antibody control. E. CC-90002 does not promote hemagglutination of human RBCs. Human RBCs were treated with a titration of CD47 antibodies. Evidence of hemagglutination was demonstrated by the presence of non-settled RBCs, appearing as a haze compared to a punctate red dot of non-hemagglutinated RBCs. The anti-CD47 antibody 9E4 was a positive control. 2A1m and 2A1-xi (chimeric): murine anti-CD47 antibodies. QN-IgG1 and QN-IgG4P: variants of CC-90002

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Acknowledgements

The authors thank other team members from Celgene Corporation, including John Boylan, WenQing Yang, Maria Wang and Dale Baker for their contributions to the strategy and execution of the experiments

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  1. Heather K. Raymon

    Present address: Artiva Biotherapeutics, San Diego, CA, USA

Authors and Affiliations

  1. Bristol Myers Squibb, 10300 Campus Point Drive, Suite 100, San Diego, CA, 92121, USA

    Rama Krishna Narla, Hardik Modi, Daniel Bauer, Mahan Abbasian, Jim Leisten, Joseph R. Piccotti, Stephan Kopytek, Dan Zhu, Lilly Wong, Laure Escoubet, Heather K. Raymon & Kandasamy Hariharan

  2. Inhibrx, San Diego, CA, USA

    Brendan P. Eckelman, Quinn Deveraux & John Timmer

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  1. Rama Krishna Narla
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Narla, R.K., Modi, H., Bauer, D. et al. Modulation of CD47-SIRPα innate immune checkpoint axis with Fc-function detuned anti-CD47 therapeutic antibody. Cancer Immunol Immunother 71, 473–489 (2022). https://doi.org/10.1007/s00262-021-03010-6

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