A Potential Mechanism for ADC-Induced Neutropenia: Role of Neutrophils in Their Own Demise

Molecular Cancer Therapeutics
Hui ZhaoFernando Donate

Abstract

Neutropenia is a common adverse event in cancer patients treated with antibody-drug conjugates (ADC) and we aimed to elucidate the potential mechanism of this toxicity. To investigate whether ADCs affect neutrophil production from bone marrow, an in vitro assay was developed in which hematopoietic stem cells (HSC) were differentiated to neutrophils. Several antibodies against targets absent in HSCs and neutrophils were conjugated to MMAE via a cleavable valine-citrulline linker (vcMMAE-ADC) or MMAF via a noncleavable maleimidocaproyl linker (mcMMAF-ADC), and their cytotoxicity was tested in the neutrophil differentiation assay. Results showed that HSCs had similar sensitivity to vcMMAE-ADCs and mcMMAF-ADCs; however, vcMMAE-ADCs were more cytotoxic to differentiating neutrophils than the same antibody conjugated to mcMMAF. This inhibitory effect was not mediated by internalization of ADC either by macropinocytosis or FcγRs. Our results suggested that extracellular proteolysis of the cleavable valine-citrulline linker is responsible for the cytotoxicity to differentiating neutrophils. Mass spectrometry analyses indicated that free MMAE was released from vcMMAE-ADCs in the extracellular compartment when they were incubated with di...Continue Reading

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Citations

Nov 10, 2017·BioDrugs : Clinical Immunotherapeutics, Biopharmaceuticals and Gene Therapy·Penelope M Drake, David Rabuka
Mar 6, 2019·Journal of Leukocyte Biology·Kathleen R BashantNicole Toepfner
Jan 7, 2020·Médecine sciences : M/S·Alain BeckNicolas Joubert
Sep 18, 2020·Pharmaceuticals·Nicolas JoubertCaroline Denevault-Sabourin
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Mar 19, 2021·Advanced Healthcare Materials·Daniil A VishnevskiyVictor A Naumenko
Apr 1, 2021·Bioconjugate Chemistry·Jared T MillerL Nathan Tumey
Jul 16, 2020·Bioconjugate Chemistry·Hans-Georg LerchenHannah Jörißen

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