Some People Stay Well, Others Get Sick: Could Resilience Guide Drug Discovery?
The Resiliome™ platform has already guided meaningful discoveries, with one asset in Phase 1 trials.
Drug discovery typically focuses on processes gone wrong, but perhaps there is equal opportunity in looking at what goes well.
Biologics—therapies made from living cells or components—have transformed modern medicine. Many are designed to mimic naturally occurring biological mechanisms in ways that can be difficult to achieve with chemically synthesized drugs. As a result, they provide highly targeted, highly effective treatment options.
Yet, as with much of drug development, many of the biologics that show potential early on do not make it to patients. A lack of adequate science sits among the drivers of high late-stage attrition rates. There is a lot we are yet to understand about the science behind disease, but when the success of novel therapeutics depends on it, this knowledge gap leaves a lot of room for error and researchers are left returning to the same targets time and again.
Dr. Jane K. Osbourn, OBE, chief executive officer at Alchemab Therapeutics, believes that changing the starting point of therapeutic discovery could open opportunities. Technology Networks sat down with Osbourn to discuss the Resiliome™, a database of antibody sequences from disease-resilient individuals designed to guide the development of antibody therapeutics. The platform has already led to meaningful discoveries, with one asset currently in clinical trials.
What is the Resiliome, and how was it built?
Jane K. Osbourn, OBE, PhD (JKO):
The Resiliome is Alchemab’s proprietary database of over half a billion high-quality antibody sequences contained within B-cell receptors (BCRs) from people resilient to a range of different diseases.
B-cell receptors
B-cell receptors are transmembrane receptor complexes found on B cells. They recognize and bind specific antigens. Binding triggers an intracellular signaling cascade and antigen internalization. The antigen is then presented to T cells, resulting in a broader immune response.
The Resiliome has been created over five years by building collaborative relationships with leading clinical researchers and cohort coordinators to access patient samples for BCR sequencing and serum profiling.
The Resiliome also contains data on immunological profiles of age-matched controls and disease progressors to enable identification of specific antibodies that are associated only with resilience to disease. It includes samples from healthy, aged individuals, and individuals resilient to neurodegenerative, immunological/autoimmune, oncology and infectious disease conditions.
IH:
JKO:
Classical drug discovery starts with a hypothesis about a disease process and focuses on how you intervene to stop that pathogenic decline. This has been successful and delivered many great drugs to the market over the past decades, but increasingly we are seeing pharma and biotech working on the same small pool of targets, which are defined by their role in disease pathology. Alchemab’s approach turns these ideas on their head.
“Rather than studying disease, we study wellness.” — Dr. Jane K. Osbourn, OBE.
We aim to identify antibodies and their cognate targets that are involved in disease prevention. By finding people resilient to disease, we have effectively found nature’s successful clinical trial.
“These resilient people have, in some cases, and by some serendipity, produced protective autoantibodies that block disease onset and/or progression; they have made their own successful drug.” — Dr. Jane K. Osbourn, OBE.
Our job is to find the autoprotective antibodies associated with their resilience, work out what they bind to, and why they might be relevant to disease prevention. Perhaps it is better described as a process of drug “uncovery” rather than drug “discovery.” By taking this approach and mining our Resiliome, we have found antibodies to novel targets not previously associated with disease, as well as antibodies with novel mechanisms of action on known targets.
IH:
JKO:
ATLX-1282 was discovered in individuals resilient to onset of frontotemporal dementia from a collaborative partnership with the Genetic Frontotemporal Dementia Initiative cohort team. The antibody binds a neuronal receptor which has relevance in a number of neurodegenerative conditions including amyotrophic lateral sclerosis.
Eli Lilly licensed this asset and is now taking it into the next phase of clinical development.
IH:
What has the ATLX-1282 program revealed about the strengths and limitations of the Resiliome-based approach and AI-enabled antibody discovery so far?
JKO:
The ATLX-1282 program demonstrated that we can find first-in-class antibodies to novel targets with disease relevance.
“It is wonderful to see these opportunities emerging in chronic neurodegenerative conditions and this demonstrates the applicability of the Resiliome-based approach to chronic disease in general.” — Dr. Jane K. Osbourn, OBE.
In any condition where you can define and access a resilient cohort of patients, there is the possibility for BCR responses to be involved in that resilience, and the indication could potentially benefit from the Resiliome approach.
The approach requires high-quality sequence data from as large a cohort of resilient individuals as possible to drive success. There are technical challenges related to antigen identification, which we have worked on for over five years to resolve. Once you have a resiliency-associated lead antibody, the next piece of the jigsaw is then proving protective causality and not just correlation. This has to be done in a bespoke way for each antibody and target, which takes creative thinking and great assay development skills.
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