TY - JOUR
T1 - Antibody-drug conjugates with dual payloads for combating breast tumor heterogeneity and drug resistance
AU - Yamazaki, Chisato M.
AU - Yamaguchi, Aiko
AU - Anami, Yasuaki
AU - Xiong, Wei
AU - Otani, Yoshihiro
AU - Lee, Jangsoon
AU - Ueno, Naoto T.
AU - Zhang, Ningyan
AU - An, Zhiqiang
AU - Tsuchikama, Kyoji
N1 - Funding Information:
We gratefully acknowledge Professor Junichi Kurebayashi (Kawasaki Medical School) for kindly providing the cell line KPL-4. We thank Dr. Huey Liu for her technical assistance in animal studies, Dr. Leomar Ballester for his valuable input on tumor tissue analysis, Dr. Georgina T. Salazar for editing the manuscript, and Dr. Yin Yuen Ha (Summer) for proofreading. This work was supported by the Department of Defense Breast Cancer Research Program (W81XWH-18-1-0004 and W81XWH-19-1-0598 to K.T.), the Cancer Prevention and Research Institute of Texas (RP150551 and RP190561 to Z.A.), the Welch Foundation (AU-0042-20030616 to Z.A.), MD Anderson’s Cancer Center Support Grant (P30CA016672, for the use of the Cytogenetics and Cell Authentication Core, Flow Cytometry and Cellular Imaging Facility, and Research Animal Support Facility), the University of Texas System (Regents Health Research Scholars Award to K.T.), and the Japan Society for the Promotion of Science (postdoctoral fellowship to A.Y. and Y.A.).
Publisher Copyright:
© 2021, The Author(s).
PY - 2021/12/1
Y1 - 2021/12/1
N2 - Breast tumors generally consist of a diverse population of cells with varying gene expression profiles. Breast tumor heterogeneity is a major factor contributing to drug resistance, recurrence, and metastasis after chemotherapy. Antibody-drug conjugates (ADCs) are emerging chemotherapeutic agents with striking clinical success, including T-DM1 for HER2-positive breast cancer. However, these ADCs often suffer from issues associated with intratumor heterogeneity. Here, we show that homogeneous ADCs containing two distinct payloads are a promising drug class for addressing this clinical challenge. Our conjugates show HER2-specific cell killing potency, desirable pharmacokinetic profiles, minimal inflammatory response, and marginal toxicity at therapeutic doses. Notably, a dual-drug ADC exerts greater treatment effect and survival benefit than does co-administration of two single-drug variants in xenograft mouse models representing intratumor HER2 heterogeneity and elevated drug resistance. Our findings highlight the therapeutic potential of the dual-drug ADC format for treating refractory breast cancer and perhaps other cancers.
AB - Breast tumors generally consist of a diverse population of cells with varying gene expression profiles. Breast tumor heterogeneity is a major factor contributing to drug resistance, recurrence, and metastasis after chemotherapy. Antibody-drug conjugates (ADCs) are emerging chemotherapeutic agents with striking clinical success, including T-DM1 for HER2-positive breast cancer. However, these ADCs often suffer from issues associated with intratumor heterogeneity. Here, we show that homogeneous ADCs containing two distinct payloads are a promising drug class for addressing this clinical challenge. Our conjugates show HER2-specific cell killing potency, desirable pharmacokinetic profiles, minimal inflammatory response, and marginal toxicity at therapeutic doses. Notably, a dual-drug ADC exerts greater treatment effect and survival benefit than does co-administration of two single-drug variants in xenograft mouse models representing intratumor HER2 heterogeneity and elevated drug resistance. Our findings highlight the therapeutic potential of the dual-drug ADC format for treating refractory breast cancer and perhaps other cancers.
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U2 - 10.1038/s41467-021-23793-7
DO - 10.1038/s41467-021-23793-7
M3 - Article
C2 - 34112795
AN - SCOPUS:85107557650
SN - 2041-1723
VL - 12
JO - Nature communications
JF - Nature communications
IS - 1
M1 - 3528
ER -