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Novel Non-cancer Targets for Therapeutic Antibodies

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Industry leaders developing non-cancer targets for therapeutic antibodies shared their work and expertise at the Antibody Engineering & Therapeutics conference in December 2020. The stream of presentations culminated in a panel discussion which highlighted common themes and challenges within the practice.

The panel included:

  • James Larrick, Managing Director and Chief Medical Officer, Panorama Research Institute and Velocity Pharmaceutical Development
  • David Shen, SVP, Biologics Research and CMC, NGM Biopharmaceuticals
  • Allan Lawrie, Professor of Translational Cardiopulmonary Science, Department of Infection
  • Inge van de Walle, Senior Scientist, Argenx
  • Yan Wu, Director and Staff Scientist, Antibody Engineering, Genentech, Inc.
  • Christoph Esslinger, CSO, Memo Therapeutics, Switzerland
  • Bo Yu, Co-Founder and Chief Scientific Officer Larix Bioscience LLC

The panel discussion was opened by Dr Lawrie introducing his research on a novel human therapeutic antibody targeting the osteoprotegerin/TRAIL pathway for pulmonary arterial hypertension (PAH).

Research with animal models

Dr Shen voiced his concerns about potential side-effects of such antibodies, such as bone degradation. Dr Lawrie addressed these, clarifying that although he didn’t register any, animal models need to be scrutinized and more pre-clinical data may be needed for the drug to enter the clinic.

Dr Esslinger pointed out that from his expertise, going early to the regulatory authority may be advantageous. Dr Lawrie agreed that, although long-term toxicology studies may be necessary in his case, he agrees having the conversations with regulatory authority may be good to avoid having to carry out unnecessary experiments.

Dr Wu said that the focus in antibodies raised in animal models should be on function, rather than cross-reactivity. She emphasized that we need to be ‘confident about the biology’ in antibodies coming out of animal models because the trials will be longer and the safety bar higher for such antibodies. Dr Larrick added that in PAH, the bar will be high, because there already are a lot of therapeutic compounds and it is ‘harder to come up with a new compound that would be interesting’.

Dr van de Walle pointed out that talking to physicians who treat the patients is very important: asking them what they need to try the compound in the patients and whether they need to see a proof-of-concept in animal models. This was agreed across the panel, citing examples from the history.

Human-derived antibodies

Dr Esslinger presented his company’s work developing human-derived antibodies. He uses a single-cell approach to copy information from B cells to HEK cells, which is a cheaper and easier model to work with. This is applicable in the current COVID-19 pandemic, serving for identification of COVID-19 antibodies in patients and aiding clinical trials. In addition, Dr Esslinger’s work includes viral diseases and cancer, with a focus on antibodies obtained directly from humans.

The panel continued with a question from the audience asking about ‘relevance of ex-vivo/organoid work to replace animal models, if the latter is no longer suitable’? Dr Esslinger added that organoids would be both time and labour-extensive and not required by the regulatory authority, as adapting the model would be ‘6 months and a financial burden to the company’. Dr Larrick emphasized that organoid models have been front and center of new companies, but it is not clear whether they will a good intermediary step between cell culture and animal models and remains to be determined.

The use of organoid models

The debate about organoids continued, asking whether they are used in non-oncology space. It was concluded that a good hospital connection is needed to obtain tissues and conduct experiments. Dr Wu added it was a hot topic and more relevant than ex-vivo. Dr Lawrie added that it is interesting, but in his line of work, animal models remain more relevant than in vitro models, as he lacks the human tissue necessary to create such models. Although it was agreed that organoids have potential in personalized medicine, there is still a long way to get to actual applications.

Dr van de Walle spoke about her work on multifocal motor neuropathy and their latest antibody targeting C2 (complement component 2). Dr Larrick pointed to her earlier research on C2 and that, although the potential of antibodies targeting C2 is interesting, it may not be enough for regulatory approval.

Applying antibody engineering to macular degeneration

There was some discussion about the role of the complement in cancer. Dr Tang contributed to the discussion explaining his antibody engineering work against C3 in macular degeneration. He pointed out that they are testing in animal models very rapidly. Dr Wu and Dr Tang discussed potential patient tolerance to repeated eye injections every few months. He said that based on their preliminary data, monthly injections are well-tolerated compared to the available alternatives.

Dr van de Walle asked whether Dr Tang’s antibody injection leaks to the system? Dr Tang replied ‘yes', highlighting that C3 levels are usually very high in the whole organism and eye injections are unlikely to affect the body’s immune response overall. Dr Shen confirmed that systemic effects with anti-C3 antibodies were previously investigated by others.

The panel closed the discussion with a final question from the audience about challenges to obtain ‘an agonistic antibody in an immunized library’. Dr Wu explained that agonist antibody is much more challenging to be developed into a drug than antagonist antibody. She concluded that as this depends on the assay, ‘it is much harder but not impossible’.

RELATED ARTICLE: Novel Antibody Therapeutic Modalities - Antibody Therapeutics eBook Series

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