Antibody-drug conjugates with dual payloads for combating breast tumor heterogeneity and drug resistance
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.
Document Details
- Document Type
- Pub Defense Publication
- Publication Date
- Jun 10, 2021
- Source ID
- 10.1038/s41467-021-23793-7
Entities
People
- Aiko Yamaguchi
- Chisato M Yamazaki
- Jangsoon Lee
- Kyoji Tsuchikama
- Naoto T Ueno
- Ningyan Zhang
- Wei Xiong
- Yasuaki Anami
- Yoshihiro Otani
- Zhiqiang An
Organizations
- Cancer Prevention and Research Institute of Texas
- Congressionally Directed Medical Research Programs
- Japan Society for the Promotion of Science
- Robert A. Welch Foundation
- University of Texas System