Antibody drug conjugates (ADCs) are touted for their ability to site selectively deliver a small molecule chemotherapeutic directly to a tumor cell, bypassing off target side effects from systemic circulation. To date, twelve ADCs have been FDA approved in the United States and >200 more in the clinical pipeline (clinicaltrials.gov).

While ADCs have proven successful in both solid and hematological cancers, resistance and tumor heterogeneity are major causes of failure clinically.[1] Tumor heterogeneity is known to lead to recurrence, metastasis, and acquired resistance to ADCs and other therapeutic strategies. Heterogenous tumors with differential drug sensitivities result in aggressive tumor growth, high relapse rates, and poor survival.[1]

To combat these challenges, the majority of chemotherapeutic regimens consist of a combination of drugs. Co-delivery of small molecules can overcome resistance, generate additive or synergistic effects, and enhance therapeutic efficacy.[2][3]

Emergence of tumors refractory to current therapies has given impetus to the evaluation of new ADC formats. This challenge has led to the exploration of dual-drug ADCs capable of delivering two mechanistically distinct payloads simultaneously. Strategies for the construction of dual-drug ADCs involve attachment of both drugs to one linker or through the use of two different conjugation sites on the antibody. Herein, we will review the synthesis and evaluation of the dual-drug ADCs reported to date. We focus on ADCs constructed by conjugation of linkers directly to antibody scaffolds and not to other formats or targeting molecules.

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Corresponding Authors: Christine S. Nervig, Ph.D. E-mail: Christine S. Nervig, Ph.D and Shawn C. Owen, Ph.D. E-mail: Shawn C. Owen, Ph.D; Phone (801) 581-8069

Key terms: ADC, bioconjugation, differential antigen expression, simultaneous delivery of drugs
Published In: ADC Review| Journal of Antibody-drug Conjugates

DOI: https://doi.org/10.14229/jadc.2023.01.05.001.

How to cite:
Nervig C.S.1 and Owen S.C. 1, 2, 3. Advances in the Development of Dual-Drug Antibody Drug Conjugates – J. ADC. January 5, 2023. DOI: 10.14229/jadc.2023.01.05.001.

1Department of Medicinal Chemistry, University of Utah, Salt Lake City, Utah 84112;
2Department of Molecular Pharmaceutics, University of Utah, Salt Lake City, Utah 84112
3Department of Biomedical Engineering, University of Utah, Salt Lake City, Utah 84112

Last Editorial Review: December 26, 2022

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Article History:

  • Original Manuscript Received October 24, 2022
  • Review results received December 13, 2022
  • Manuscript accepted for publication December 27, 2023

Featured image: Antibody. Photo courtesy: © 2016 – 2023 – Fotolia/Adobe. Used with permission.

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