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Antibody Engineering
Targeted Therapies

Transforming Therapeutic Targets for Antibody Drug Discovery

Posted by on 24 January 2022
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Silvia Hnatova recalls a key discussion among leading researchers at the 2020 Antibody Engineering & Therapeutics virtual conference, which explored transforming therapeutic targets for antibody-based treatments.

The discussion included:

  • Thomas Schurpf, Associate Director of Discovery Biology at Scholar Rock
  • James Ernst, Senior Director, Head of Development Sciences at Xencor
  • Michael Curran, Associate Professor, Department of Immunology at The UT MD Anderson Cancer Center
  • Greg Lazar, Senior Director and Senior Scientist, Antibody Engineering at Genentech
  • Denise Faustman, Associate Professor of Medicine at Harvard Medical School

This fascinating panel session tackled many challenging topics and questions from the audience on transforming therapeutic targets. This included questions addressed to Dr Schürpf about his rationale behind engineering and testing anti-TGFβ1 antibodies in hot tumors.

He explained, referring to his individual talk from the virtual event, that he does not think that TGFβ1 inhibition is only relevant for cold tumors but also tumors in which T cells failed to invade the tumor. He referred to clinical studies by Genentech finding an association between TGFβ1 signaling and immune-excluded phenotype (T cells unable to penetrate the tumor and exert their function).

This extract is taken from the ebook Novel and Difficult Targets in Antibody Drug Discovery. Click here to read the full article.

In Dr Schürpf’s Phase I trials, checkpoint inhibition demonstrated efficacy in a subset of patients, but some of these patients did not respond to the therapy. His hypothesis is that SRKA1a1 could help to overcome this.

Pre-clinical mouse models and synergistic blockades

Dr Ernst and Dr Schürpf debated about pre-clinical mouse models and their relevance for studying the drugs of interest.

He wanted to recapitulate the phenomenon seen in the clinic where a subset of patients does not respond to therapy and repeat the tumor model in which T cells fail to invade the tumor.

Responding to another question from the audience, Dr Schürpf confirmed that his anti-TGFβ1 antibodies block LTBP1/3 pathways through integrin aVb6.

There was a discussion between Prof Curran and Dr Ernst about adding synergistic blockades against PD-1 and PDL1. Prof Curran cited research from several companies including MedImmune and Novartis, that has been lagging.

The challenges in using synergistic blockades are in co-developing two separate antibodies, taking them through clinical trials separately, and then co-marketing and co-pricing.

He debated whether there could be a significant improvement in outcomes when taking into account the price of development of synergistic antibodies. for PD-1, patient recruitment was problematic because the patients had many indications for trying both antibodies at the same time (PD-1, PDL1). He hopes that bispecific antibodies against PD-1 and PDL1 should be in the clinic next year.

Dr Lazar asked Prof Curran about PDL-1/V71 interaction that he remembered from his talk. Prof Curran explained that they have two candidate antibodies, one with triple action (anti-PD1, PD2, PDL-1/V71) and one without, concluding that the triple action antibody performs better.

He addressed conflicting results by other laboratories and there was some debate about the results from co-stimulation of PD1 and V71.

Innovating mAbs against TNFRSF members

The panel addressed a question from the audience about whether ’mAbs against TNFRSF members reduce the signal coming from the trimers simply by dimerizing the receptor?’ Prof Faustman responded with examples from her work.

For years, Prof Faustman’s lab tried to interrupt TNFRSF trimers, but ‘Ligands are much smarter than any antibody we could make’, she added. She gave up on trimers and focused on creating a new structure, a pure dimeric antagonist against TNFRSF.

This extract is taken from the ebook Novel and Difficult Targets in Antibody Drug Discovery. Click here to read the full article.

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