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Enzyme-Based Strategies to Generate Site-Specifically Conjugated Antibody Drug Conjugates

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Next Generation Antibody Drug Conjugates (ADCs) and Immunotoxins

Part of the book series: Milestones in Drug Therapy ((MDT))

Abstract

Antibody Drug Conjugates (ADCs) exploit the specificity of monoclonal antibodies for the targeting of highly potent small molecular weight toxins to cancer cells in order to selectively effect their destruction. It is expected that due to the targeting of ADCs to the tumor, these drugs will be associated with less side effects and a higher therapeutic index than standard chemotherapy. However, so far this promise of ADCs has only poorly translated into the clinic. Despite the fact that ADCs for cancer therapy have been developed for many decades, the field has experienced a number of failures of ADCs in clinical development, due to an unfavorable clinical benefit to safety relationship. The first ADC, Mylotarg®, an anti-CD33 ADC, approved for treatment of acute myeloid leukemia (AML) eventually had to be taken off the market 10 years post approval. To date only two ADCs, the anti-CD30 ADC brentuximab vedotin (Adcetris®) and the anti-HER-2 ADC trastuzumab-emtansine (Kadcyla®), are approved for cancer therapy. In fact, Kadcyla® is only approved as a second-line therapy in breast cancer due to a limited clinical benefit in comparison to standard therapy as a first-line therapy. There is an increasing body of evidence that first-generation ADCs, including the two marketed ADC products, that are generated by standard chemical conjugation, are associated with liabilities connected to the conjugation technologies employed, which have a negative impact on the therapeutic index and efficacy of these ADCs. Here, we describe novel conjugation approaches, with a specific focus on enzymatic conjugation technologies that aim at overcoming the limitations of first-generation ADCs, namely the heterogeneity of chemically conjugated ADCs and insufficient linker stability. While site-specific conjugation can also be achieved using novel chemical linker approaches, and while it is also possible to employ improved linkers in chemical conjugation technologies, there are additional compelling arguments for site-specific enzymatic conjugation of toxin payloads to antibodies. New developments and data related to the preclinical evaluation of such next-generation ADCs are discussed.

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  1. NBE-Therapeutics Ltd, Technology Park Basel, Hochbergerstr. 60C, CH-4057, Basel, Switzerland

    Roger R. Beerli & Ulf Grawunder

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  1. Roger R. Beerli
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Correspondence to Ulf Grawunder .

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  1. NBE-Therapeutics Ltd., Basel, Switzerland

    Ulf Grawunder

  2. Faculty of Health Sciences, University of Cape Town, Cape Town, South Africa

    Stefan Barth

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Beerli, R.R., Grawunder, U. (2017). Enzyme-Based Strategies to Generate Site-Specifically Conjugated Antibody Drug Conjugates. In: Grawunder, U., Barth, S. (eds) Next Generation Antibody Drug Conjugates (ADCs) and Immunotoxins. Milestones in Drug Therapy. Springer, Cham. https://doi.org/10.1007/978-3-319-46877-8_5

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