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Data from Tumor-Associated Macrophages Can Contribute to Antitumor Activity through FcγR-Mediated Processing of Antibody–Drug Conjugates
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Data from Tumor-Associated Macrophages Can Contribute to Antitumor Activity through FcγR-Mediated Processing of Antibody–Drug Conjugates
Data from Tumor-Associated Macrophages Can Contribute to Antitumor Activity through FcγR-Mediated Processing of Antibody–Drug Conjugates
FL
Fu Li
Fu Li
MU
Michelle Ulrich
Michelle Ulrich
MJ
Mechthild Jonas
Mechthild Jonas
IS
Ivan J. Stone
Ivan J. Stone
GL
Germein Linares
Germein Linares
XZ
Xinqun Zhang
Xinqun Zhang
LW
Lori Westendorf
Lori Westendorf
DB
Dennis R. Benjamin
Dennis R. Benjamin
CL
Che-Leung Law
Che-Leung Law
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3 April 2023
other
Published by
American Association for Cancer Research (AACR)
https://doi.org/10.1158/1535-7163.c.6539563
Abstract
The primary mechanism of antibody–drug conjugates (ADC) is targeted delivery of a cytotoxic payload to tumor cells via cancer-associated membrane receptors. However, the tumor microenvironment likely plays a role in ADC penetration, distribution, and processing and thus impacts the overall antitumor activity. Here, we report on the potential contribution of Fc–FcγR interactions between ADCs and tumor-associated macrophages (TAM) to the preclinical antitumor activities of ADCs. In the CD30+ L-428 Hodgkin lymphoma model, anti-CD30-vcMMAE and a non-binding control (hIgG-vcMMAE) demonstrated similar antitumor activity as well as similar payload release in the tumors. IHC analysis revealed L-428 tumors contained highly abundant TAMs, which were confirmed to bind ADCs by IHC and flow cytometry. The infiltration of TAMs was further found to correlate with the antitumor activity of the non-binding hIgG-vcMMAE in five additional xenograft models. hIgG1V1-vcMMAE, bearing a mutation in the Fc region which ablates Fc gamma receptor (FcγR) binding, lost antitumor activity in three TAM-high xenograft models, suggesting Fc–FcγR interactions modulate the TAM-ADC interaction. Our results suggest that TAMs can contribute to ADC processing through FcγR interaction in preclinical tumor models and may represent an important additional mechanism for drug release from ADCs. Correlative studies in clinical trials will further shed light on whether TAMs play a role in patients' response to ADC therapies. Mol Cancer Ther; 16(7); 1347–54. ©2017 AACR.
Keywords
ANTITUMOR ACTIVITY
ANTIBODY
FCΓR
ADC
DRUG
ASSOCIATED MACROPHAGES
TUMOR ASSOCIATED
PAYLOAD
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Open Access