Data from Inhibition of Megakaryocyte Differentiation by Antibody–Drug Conjugates (ADCs) is Mediated by Macropinocytosis: Implications for ADC-induced Thrombocytopenia Article Swipe
Hui Zhao
,
Sara Gulesserian
,
Sathish Kumar Ganesan
,
Jimmy Ou
,
Karen Morrison
,
Zhilan Zeng
,
Verónica Robles
,
Josh Snyder
,
Lisa Do
,
Héctor Aviña
,
Sher Karki
,
David R. Stover
,
Fernando Doñate
·
YOU?
·
· 2023
· Open Access
·
· DOI: https://doi.org/10.1158/1535-7163.c.6539179.v1
YOU?
·
· 2023
· Open Access
·
· DOI: https://doi.org/10.1158/1535-7163.c.6539179.v1
Thrombocytopenia is a common adverse event in cancer patients treated with antibody–drug conjugates (ADC), including AGS-16C3F, an ADC targeting ENPP3 (ectonucleotide pyrophosphatase/phosphodiesterase-3) and trastuzumab emtansine (T-DM1). This study aims to elucidate the mechanism of action of ADC-induced thrombocytopenia. ENPP3 expression in platelets and megakaryocytes (MK) was investigated and shown to be negative. The direct effect of AGS-16C3F on platelets was evaluated using platelet rich plasma following the expression of platelet activation markers. Effects of AGS-16C3F, T-DM1, and control ADCs on maturing megakaryocytes were evaluated in an in vitro system in which human hematopoietic stem cells (HSC) were differentiated into MKs. AGS-16C3F, like T-DM1, did not affect platelets directly, but inhibited MK differentiation by the activity of Cys-mcMMAF, its active metabolite. FcγRIIA did not appear to play an important role in ADC cytotoxicity to differentiating MKs. AGS-16C3F, cytotoxic to MKs, did not bind to FcγRIIA on MKs. Blocking the interaction of T-DM1 with FcγRIIA did not prevent the inhibition of MK differentiation and IgG1-mcMMAF was not as cytotoxic to MKs despite binding to FcγRIIA. Several lines of evidence suggest that internalization of AGS-16C3F into MKs is mediated by macropinocytosis. Macropinocytosis activity of differentiating HSCs correlated with cell sensitivity to AGS-16C3F. AGS-16C3F was colocalized with a macropinocytosis marker, dextran-Texas Red in differentiating MKs. Ethyl isopropyl amiloride (EIPA), a macropinocytosis inhibitor, blocked internalization of dextran-Texas Red and AGS-16C3F. These data support the notion that inhibition of MK differentiation via macropinocytosis-mediated internalization plays a role in ADC-induced thrombocytopenia. Mol Cancer Ther; 16(9); 1877–86. ©2017 AACR.See related article by Zhao et al., p. 1866
Related Topics
Concepts
Megakaryocyte
Pinocytosis
Drug
Antibody-drug conjugate
Antibody
Chemistry
Conjugate
Pharmacology
Cancer research
Medicine
Cell biology
Immunology
Biology
Biochemistry
Monoclonal antibody
Endocytosis
Receptor
Mathematics
Haematopoiesis
Mathematical analysis
Stem cell
Metadata
- Type
- preprint
- Language
- en
- Landing Page
- https://doi.org/10.1158/1535-7163.c.6539179.v1
- OA Status
- gold
- Related Works
- 10
- OpenAlex ID
- https://openalex.org/W4392699028
All OpenAlex metadata
Raw OpenAlex JSON
- OpenAlex ID
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https://openalex.org/W4392699028Canonical identifier for this work in OpenAlex
- DOI
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https://doi.org/10.1158/1535-7163.c.6539179.v1Digital Object Identifier
- Title
-
Data from Inhibition of Megakaryocyte Differentiation by Antibody–Drug Conjugates (ADCs) is Mediated by Macropinocytosis: Implications for ADC-induced ThrombocytopeniaWork title
- Type
-
preprintOpenAlex work type
- Language
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enPrimary language
- Publication year
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2023Year of publication
- Publication date
-
2023-04-03Full publication date if available
- Authors
-
Hui Zhao, Sara Gulesserian, Sathish Kumar Ganesan, Jimmy Ou, Karen Morrison, Zhilan Zeng, Verónica Robles, Josh Snyder, Lisa Do, Héctor Aviña, Sher Karki, David R. Stover, Fernando DoñateList of authors in order
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https://doi.org/10.1158/1535-7163.c.6539179.v1Publisher landing page
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YesWhether a free full text is available
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goldOpen access status per OpenAlex
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https://doi.org/10.1158/1535-7163.c.6539179.v1Direct OA link when available
- Concepts
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Megakaryocyte, Pinocytosis, Drug, Antibody-drug conjugate, Antibody, Chemistry, Conjugate, Pharmacology, Cancer research, Medicine, Cell biology, Immunology, Biology, Biochemistry, Monoclonal antibody, Endocytosis, Receptor, Mathematics, Haematopoiesis, Mathematical analysis, Stem cellTop concepts (fields/topics) attached by OpenAlex
- Cited by
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0Total citation count in OpenAlex
- Related works (count)
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10Other works algorithmically related by OpenAlex
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