As part of WuXi AppTec’s ongoing efforts to collaboratively foster new thinking and actionable approaches in advancing breakthroughs for patients, we have launched a new interview series in 2022 – “Delivering on the Promise of New Modalities” – so leading voices of R&D can share how their approaches are addressing the barriers standing in the way of breakthroughs.

In our latest interview, we’re joined by Andrea van Elsas, Venture Partner at Third Rock Ventures and CSO of Abata Therapeutics, a company focused on translating the biology of regulatory T cells (Tregs) into transformational medicines for patients living with severe autoimmune and inflammatory diseases. The company launched last year with $95 million in Series A Financing to engineer T cells to tackle autoimmune diseases like multiple sclerosis (MS). Most recently, Abata announced the formation of an advisory board comprised of leading industry experts in Treg Biology, Cell Therapy and Corporate Development.

Hi Andrea, thanks for taking the time to join us today. Abata is developing targeted, autologous Treg cell therapies for serious autoimmune diseases. Could you please introduce your new modality approach to our audience?

Andrea: Regulatory T cells (Tregs) have been well characterized during the past 25 years, demonstrating a wide palette of functions evolved to suppress or limit inflammation and support tissue repair. One of Abata’s founders, Diane Mathis, has led the field publishing a wealth of high impact studies unraveling a critical role for Tregs in limiting overactive immune responses and promoting repair in various organs and tissues. Tregs use several mechanisms to inhibit inflammation by cell-cell interaction as well as by secretion of soluble immunosuppressive factors into the inflamed milieu. These highly potent Treg functions dominate the activity of, for instance, effector T cells such as those found in the aforementioned meningeal lymphoid aggregates, and they can be triggered once the T cell receptor detects myelin-associated antigens produced locally upon tissue destruction. Importantly, by studying lymphocyte trafficking into the brain another Abata founder and CMO Richard Ransohoff showed that T cells require TCR activation by cognate antigen presented on meningeal macrophages to stay in the brain.

Treg cell therapy has been clinically tested by a handful of teams during the past few years albeit not in progressive MS patients. Although Tregs were demonstrated to be safe, efficacy has not been optimal. We believe this is due to the fact that Tregs with the proper T cell receptors to direct them to the inflamed tissue are quite rare. By engineering a disease specific T cell receptor into Tregs we dramatically change the number of Tregs capable of trafficking into affected organs and treat ongoing disease using their polypharmacy capacity. It is a numbers game. Moreover, Treg cells are thought to stay around for a long time and differentiate into tissue-resident Tregs, potentially delivering highly durable clinical benefit even following a single dose of Tregs since durability matters in autoimmune disease. Also, in preclinical models Tregs are known to secrete factors that stimulate myelin repair adding to their potential durable benefit.

In addition to progressive MS, the Abata team is currently working on specific TCR engineered Tregs for two other diseases, type 1 diabetes and inclusion body myositis.

How your Treg approaches might make a difference to MS patients?

Andrea: With our first product candidate ABA-101, Abata is aiming to treat patients with progressive MS. ABA-101 is an autologous Treg product that we engineer to express a specific T cell receptor to guide Tregs to the disease site, a discovery project run in close collaboration with Abata founder Roland Martin. Several approved drugs are currently available to treat patients with relapsing remitting MS with considerable success. However, after the flaring phase of the disease passes there are no effective options to treat progressive MS. At least in part this can be explained by the finding that 1) relapsing remitting disease is driven by immune cells that enter the meningeal compartment from the periphery (blood), 2) drugs effectively used to treat RRMS target leukocytes in the periphery, 3) in contrast, progressive MS is driven by lymphoid aggregates that have formed in the meninges secreting factors that activate myeloid and other cells destroying the myelin sheet locally, and 4) the currently approved drugs for MS do not appear to affect inflammatory activity originating from these meningeal lymphoid infiltrates. Learning from oncology, with TCR-engineered Tregs Abata is taking a first step to use the incredible potential of cell therapy in autoimmune diseases with highly unmet medical need.

What are critical challenges in realizing the full potential of your new modality? What are Abata’s solutions?

Andrea: First, TCRs represent a key element of this therapeutic approach, however self-antigen specific TCRs are very rare and the rules and tools for HLA class II-restricted TCRs are being developed. Second, as a therapeutic modality, autologous cell therapy requires robust investment in well-controlled manufacturing processes, facilities and teams. Third, endpoints demonstrating clinical activity of any product in progressive MS patients have been highly variable from patient to patient.

Building from the TCR expertise of Abata founder Michael Birnbaum, Abata has recruited an exceptional team of scientist to set up and run an effective TCR discovery platform that includes optimizing the data science and tools for Treg functional studies and engineering. To maximize learning from the first few ABA-101 patient cohorts, Abata will exploit imaging technology that was developed by a Danny Reich, a key Abata advisor at the NIH, to allow quantitative determination of MS lesions before and after treatment. In addition to a variety of clinical biomarkers to determine Treg cell numbers and their activity in the meningeal compartment, we aim to show proof-of-principle for Abata’s TCR-engineered Treg platform. Following ABA-101, Abata aims to have three Treg products in clinical development by 2026.

How would Abata harness the potential of novel data technologies, AI, or machine learning?

Andrea: Abata recognized the potential high impact of AI and machine learning by working with existing experts at Third Rock Ventures as the company was being incubated. After its launch in 2021, Abata recruited a very strong data science team that now brings world class machine learning expertise to a variety of aspects that are critical to discover, manufacture and develop our Treg therapy. I believe we are only scratching the surface of possibilities for AI/machine learning in drug development and Abata is exploring novel applications as we speak.

Thanks Andrea for your insights! Any closing thoughts?

Andrea: In relation to Abata’s autologous engineered cell therapy product candidates, we aim to explore cutting edge science and technical solutions that might enable the production and application of Treg therapy at scale, to a much larger patient population than what the industry has dealt with thus far. A simple problem statement could be, how do we make Treg therapy available, not for 100 or 1000 patients, but for 100,000 patients per year.

 

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Andrea van Elsas PhD

Abata CSO and Venture Partner at Third Rock Ventures

Andrea van Elsas is a venture partner with Third Rock Ventures (since 2020). He most recently served as Chief Scientific Officer at Aduro Biotech following the acquisition of BioNovion, a company he co-founded 2011. From 1999 to 2011, he held various positions at Organon (acquired by Schering-Plough and later by Merck) in Oss, The Netherlands, and Cambridge, Massachusetts. As Director of Tumor Immunology, he oversaw the immuno-oncology portfolio and led the anti-PD1 program that later became known as pembrolizumab. As a postdoctoral researcher, Andrea worked in the lab of Nobel Laureate Jim Allison at the University of California, Berkeley and is a co-inventor on the original anti-CTLA-4 patents that formed the basis for the development of ipilimumab, the first checkpoint inhibitor approved in 2011 by the FDA for the treatment of melanoma. He currently serves as CSO at Abata Therapeutics, on the Scientific Advisory Board of Lava Therapeutics (chair) and on the Supervisory Board of Immunicum and InteRNA Technologies.