Antibody-drug conjugates with dual payloads for combating breast tumor heterogeneity and drug resistance

Chisato M. Yamazaki, Aiko Yamaguchi, Yasuaki Anami, Wei Xiong, Yoshihiro Otani, Jangsoon Lee, Naoto T. Ueno, Ningyan Zhang, Zhiqiang An and Kyoji Tsuchikama ()
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Chisato M. Yamazaki: The University of Texas Health Science Center at Houston
Aiko Yamaguchi: The University of Texas Health Science Center at Houston
Yasuaki Anami: The University of Texas Health Science Center at Houston
Wei Xiong: The University of Texas Health Science Center at Houston
Yoshihiro Otani: The University of Texas Health Science Center at Houston
Jangsoon Lee: The University of Texas MD Anderson Cancer Center
Naoto T. Ueno: The University of Texas MD Anderson Cancer Center
Ningyan Zhang: The University of Texas Health Science Center at Houston
Zhiqiang An: The University of Texas Health Science Center at Houston
Kyoji Tsuchikama: The University of Texas Health Science Center at Houston

Nature Communications, 2021, vol. 12, issue 1, 1-13

Abstract: Abstract 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.

Date: 2021
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DOI: 10.1038/s41467-021-23793-7

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