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.


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.

Publication types

  • Research Support, N.I.H., Extramural
  • Research Support, Non-U.S. Gov't
  • Research Support, U.S. Gov't, Non-P.H.S.

MeSH terms

  • Animals
  • Antineoplastic Agents / pharmacology
  • Antineoplastic Combined Chemotherapy Protocols / pharmacology*
  • Breast Neoplasms / complications
  • Breast Neoplasms / drug therapy*
  • Cell Line, Tumor
  • Female
  • Humans
  • Immunoconjugates / pharmacokinetics
  • Immunoconjugates / pharmacology*
  • Immunoconjugates / therapeutic use
  • Immunoconjugates / toxicity
  • Immunohistochemistry
  • Inflammation / complications
  • Mice
  • Oligopeptides / pharmacology
  • Oligopeptides / therapeutic use
  • Receptor, ErbB-2 / immunology*
  • Receptor, ErbB-2 / metabolism
  • Trastuzumab / pharmacology
  • Trastuzumab / therapeutic use
  • Xenograft Model Antitumor Assays


  • Antineoplastic Agents
  • Immunoconjugates
  • Oligopeptides
  • monomethylauristatin F
  • ERBB2 protein, human
  • Receptor, ErbB-2
  • Trastuzumab
  • monomethyl auristatin E