Leading researchers discuss the challenges and methods of transforming therapeutic targets for antibody-based treatments
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:
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).
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.
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.
He added that due to on-going approvals 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.
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.
They don’t know if they exist naturally, but by selective antibody binding, they can prevent the trimer occurring and that are inhibitory. Her current work encompasses this principle instead of focus on the trimers, confirmed by work from other authors.
The session was closed by Dr Lazar expressing concerns about not testing clinical hypotheses and making judgments about therapeutic targets much earlier, before the clinical process is completed (currently ~5 years).
Antibody Engineering & Therapeutics returns as a hybrid event from December 12 - 16, 2021, online and in-person at Marriott Marquis San Diego.
