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  • Review Article
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The clinical development of antibody–drug conjugates — lessons from leukaemia

Nature Reviews Clinical Oncology volume 18, pages 418–433 (2021)Cite this article

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Abstract

Advances in our understanding of cancer biology have enabled drug development to progress towards better targeted therapies that are both more effective and safer owing to their lack of off-target toxicities. In this regard, antibody–drug conjugates (ADCs), which have the potential to combine the selectivity of therapeutic antibodies with the cytotoxicity of highly toxic small molecules, are a rapidly developing drug class. The complex and unique structure of an ADC, composed of a monoclonal antibody conjugated to a potent cytotoxic payload via a chemical linker, is designed to selectively target a specific tumour antigen. The success of an ADC is highly dependent on the specific properties of its components, all of which have implications for the stability, cytotoxicity, pharmacokinetics and antitumour activity of the ADC. The development of therapeutic ADCs, including gemtuzumab ozogamicin and inotuzumab ozogamicin, provided great knowledge of the refinements needed for the optimization of such agents. In this Review, we describe the key components of ADC structure and function and focus on the clinical development and subsequent utilization of two leukaemia-directed ADCs — gemtuzumab ozogamicin and inotuzumab ozogamicin — as well as on the mechanisms of resistance and predictors of response to these two agents.

Key points

  • The development of antibody–drug conjugates (ADCs) has enabled the targeted delivery of potent cytotoxins to cancer cells while also limiting the extent of off-target effects.

  • The structural components of ADCs include a monoclonal antibody, a linker and a payload, all of which affect the antitumour activity, toxicity and pharmacokinetics to varying degrees.

  • Gemtuzumab ozogamicin, for patients with acute myeloid leukaemia, was the first ADC to be approved and has paved the way for the emergence of several novel ADCs in both haematological malignancies and solid tumours.

  • Inotuzumab ozogamicin has significantly improved the outcomes of patients with acute lymphoid leukaemia both as a single agent and when administered in combination with HCVD, in patients with acute lymphoid leukaemia compared with cytotoxic chemotherapy alone

  • Expression of drug efflux pumps and/or single nucleotide polymorphisms can reduce the efficacy of ADCs

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Fig. 1: Antibody–drug conjugate constructs.
Fig. 2: Mechanism of action of antibody–drug conjugates.

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  1. These authors contributed equally: Elias Jabbour, Shilpa Paul.

Authors and Affiliations

  1. Department of Leukemia, University of Texas MD Anderson Cancer Center, Houston, TX, USA

    Elias Jabbour

  2. Department of Clinical Pharmacy, University of Texas MD Anderson Cancer Center, Houston, TX, USA

    Shilpa Paul & Hagop Kantarjian

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  1. Elias Jabbour
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Competing interests

E.J. has acted as a consultant for and received research funding from Abbvie, Amgen, Bristol-Myers Squibb, Pfizer and Takeda. H.K. has acted as a consultant for and received research funding from Abbvie, Amgen, Bristol-Myers Squibb, Pfizer and Takeda. S.P. declares no competing interests.

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Jabbour, E., Paul, S. & Kantarjian, H. The clinical development of antibody–drug conjugates — lessons from leukaemia. Nat Rev Clin Oncol 18, 418–433 (2021). https://doi.org/10.1038/s41571-021-00484-2

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