1. Academic Validation
  2. Antibody-drug conjugates with dual payloads for combating breast tumor heterogeneity and drug resistance

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

  • Nat Commun. 2021 Jun 10;12(1):3528. doi: 10.1038/s41467-021-23793-7.
Chisato M Yamazaki # 1 Aiko Yamaguchi # 1 Yasuaki Anami 1 Wei Xiong 1 Yoshihiro Otani 2 Jangsoon Lee 3 Naoto T Ueno 3 Ningyan Zhang 1 Zhiqiang An 1 Kyoji Tsuchikama 4
Affiliations

Affiliations

  • 1 Texas Therapeutics Institute, The Brown Foundation Institute of Molecular Medicine, The University of Texas Health Science Center at Houston, Houston, TX, USA.
  • 2 Department of Neurosurgery, The University of Texas Health Science Center at Houston, Houston, TX, USA.
  • 3 Section of Translational Breast Cancer Research, Department of Breast Medical Oncology, The University of Texas MD Anderson Cancer Center, Houston, TX, USA.
  • 4 Texas Therapeutics Institute, The Brown Foundation Institute of Molecular Medicine, The University of Texas Health Science Center at Houston, Houston, TX, USA. Kyoji.Tsuchikama@uth.tmc.edu.
  • # Contributed equally.
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.

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