Zymeworks, Regeneron, Boehringer Ingelheim Pharma and Many Others are Betting on Antibody-Drug-Conjugates

Featured Image: London Tower Bridge. Photo Courtesy: 2018 Fotolia
Featured Image: London Tower Bridge. Photo Courtesy: 2018 Fotolia

Antibody-Drug -Conjugates (ADCs) have the potential to reduce off-target toxicities in patients by limiting the exposure of normal tissues to the payload and broaden the potential therapeutic window compared with traditional therapy. The field of ADC has been accelerating rapidly with approximately 80 ADCs in clinical development and 2 to 3 novel ADCs are likely to be approved within the next few years.

At the 5th Annual Immuno-Oncology Summit Europe in London, UK being held from March 9 – 12, 2020, experts from Zymeworks, Regeneron, Boehringer Ingelheim Pharma and many others will discuss their strategies in using ADCs as a transformative approach to cancer treatment by combining ADCs with other novel platforms such as bispecific antibody or oncolytic virus and many others to enhance their efficacy and safety profiles.

ADC Bio
 

ZW49 – A Novel Bispecific Antibody-Drug Conjugate (ADC) Targeting HER2-Expressing Cancers
John Babcook, PhD, Senior Vice President, Discovery Research, Zymeworks

ZW49 is a bispecific anti-HER2 ADC currently being evaluated in a Phase I clinical trial. In preclinical studies, ZW49 demonstrated complete tumor regressions in a panel of high and low HER2-expressing patient-derived xenografts, and promising efficacy in a model of breast cancer brain metastases at exposures tolerated in non-human primates. These results compared favorably when benchmarked against approved and leading HER2 ADCs in clinical development.

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Bispecific ADCs Targeting HER2: Intracellular Trafficking of the Antibody Dictates the Choice of Linker-Payload
Julian Andreev, PhD, Research Fellow, Oncology & Angiogensis, Regeneron Pharmaceuticals, Inc.

Bispecific ADCs bridging HER2 and high turnover proteins travel to lysosomes and improve efficacy of HER2 ADCs with stable linker-DM1. Biparatopic HER2 ADCs induce target recycling and require cleavable linker for greater efficacy. Combining various bispecific antibody approaches with correct linker-payload technology may allow to generate ADCs with better efficacy and safety profiles.

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Site-Selective Antibody Conjugates by Disulfide Bridging and Cysteine-to-Lysine Transfer
Jamie Baker, PhD, Chemistry, University College London

The selective chemical modification of specific amino-acid residues in antibodies and antibody fragments is likely to form the basis of the next generation of ADCs, and also offer the prospect of chemical bispecifics and related conjugates. In this talk, two different strategies will be presented for the construction of highly homogenous conjugates from native antibodies, precluding the need for engineering. The first strategy involves targeting the interchain disulfide bonds with bridging reagents. This has been exploited to generate potent ADCs, bispecific conjugates and even trispecifics. The second strategy we have recently pioneered involves the use of cysteine residues as temporary hooks, delivering conjugation reagents to specific lysine residues. The resultant lysine conjugates are site-selective and offer the advantage of generating clinically validated, robustly stable, amide linkages.

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Antibody-Cytokine Fusions: From Discovery to Phase III Clinical Trials
Dario Neri, PhD, Professor, Biomacromolecules, Chemistry and Applied Biosciences, ETH Zürich

Antibodies can be used as delivery vehicles for cytokine payloads, with the aim to generate a pro-inflammatory environment at the tumor site. In this lecture, I will present preclinical and clinical results on antibody-cytokine fusions, with a main emphasis on interleukin-2, interleukin-12 and tumor necrosis factor as therapeutic payloads.

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Antibody-Drug Conjugate and Oncolytic Virus-Based IO Combinations: Different Modalities – Common Themes
Philipp Müller, PhD, Senior Principal Scientist, Cancer Immunology & Immune Modulation, Boehringer Ingelheim Pharma GmbH & Co. KG

Despite the clinical breakthroughs achieved with checkpoint blockade, the overall proportion of patients experiencing durable responses remains relatively small. Therefore, the real promise for most cancer patients lies in complementary combination therapies, combining checkpoint blockade with the immune-promoting/supporting properties of other therapeutic modalities, which help breach physical barriers, overcome immunosuppression and improve immune cell infiltration in tumors. This talk will compare and highlight two of the latter categories: Antibody-drug conjugates and oncolytic viruses.

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