TL;DR: Despite tremendous unmet need, there are still no cures for inflammatory disease. Existing therapies fail for known reasons – yet nobody has thus far created therapeutics that fulfil all the necessary requirements. We need to find ways to turn off the causal upstream sources of inflammation rather than simply mopping up downstream inflammatory signals. With the emerging single-cell, systems and synthetic biology toolkits, we believe now is the perfect time to seize this opportunity. In partnership with AbbVie – an industry leader in inflammatory disease therapeutics – we are looking for optimal ways to selectively and durably induce immune tolerance to cure disease. To achieve this, we are assembling a world-class founding team to lead the mission. Will you join us?
The challenge
Immune-mediated inflammatory diseases (IMIDs) are chronic and debilitating disorders* that affect 3-7% of the global population, with a tremendous clinical and economic impact on society. The global market for anti-inflammatory drugs is predicted to hit $165 billion per year by 2030, yet no therapies are truly curative, and long-term drug-free remission is rare.
We still don’t understand exactly what causes most IMIDs, but know that it usually involves a complex interaction between genetic susceptibility and environmental triggers. While the treatment landscape for IMIDs has been transformed over the past two decades thanks to the advent of various biologic drugs – therapeutic responses are still often incomplete, occur in only a subset of patients, lead to drug resistance, or incur significant side effects.
To create curative therapeutics, we must find ways to durably restore immune homeostasis – turning off the causal upstream sources of inflammation rather than simply mopping up downstream inflammatory signals. Selectively (re)inducing immune tolerance has the potential to achieve this, and is an opportunity area where we will be building a new venture through our partnership with AbbVie – an industry leader in inflammatory disease therapeutics.
Why are current therapies not good enough?
So why are there still no cures for IMIDs, despite such demand and unmet need? The reasons are multifaceted but ultimately come down to gaps in our understanding of human immunity, compounded by suboptimal strategies used to treat disease that do not adequately address the underlying problems. Learning from clinical failures, it seems that curative therapeutics are principally constrained by our inability to: (1) determine precise causal disease mechanisms in humans, (2) address immune complexity and system-level redundancies, (3) address clinical heterogeneity, and (4) create therapeutics with on-disease specificity. Each must be solved – simultaneously – to deliver durable, tolerable and curative therapies.
To give a sense of the challenge: mammalian immunity is an extraordinarily complex system which is designed for phenotypic diversity, reflecting the vast and ever-changing spectra of threats that it must effectively respond to in order to protect the host. Every cell in the body contains many layers of molecular information (‘omics’) that govern its fate and function, and the interplay of these layers is already very challenging to model – even in one single cell. Multiply this by the dozens of diverse immune cell types, each composed of several subsets with unique functions, distributed across virtually all tissue environments which shape their phenotype, and all simultaneously interacting over a lifetime – not just with each other, but with the trillions of commensal microbes that constitute our microbiome – with an ability to form long-term or short-term ‘memories’ of such encounters through variable antigen receptors and epigenetic imprinting. System complexity of this magnitude is almost unfathomable. And that’s before you consider that adaptive immunity is informed by MHC molecules – the molecular ‘passports’ which all cells present to security personnel (T cells) to verify the presence of self or foreign antigens – which are so hypervariable in the human genome that there are roughly as many potential combinations of MHC alleles in a single human than there are atoms in the observable universe. Adding to this complexity, the redundancy of biological systems means that any singular point of therapeutic intervention often leads to compensatory mechanisms of resistance – even if that node represents a central hub in the inflammatory signalling network – as is the case for anti-TNFɑ therapies. It’s perhaps unsurprising, then, that we have not yet fully decoded this system, nor figured out the ideal ways to alter it.
The DSV methodology involves working backwards from desired outcomes to map these types of systemic constraints (in a process we call ‘scoping’) – before iteratively devising solutions that fulfil, circumvent or solve those constraints. In other words, we do not start with a specific modality, target or indication in mind – but take an unbiased systems-view of the factors holding back progress, and remain agnostic to the (combinations of) technologies required to achieve the desired outcome. This scoping process, led by a Founder-in-Residence with support from the DSV team, culminates in novel therapeutic approaches which are then triaged by their tractability, novelty, and potential impact – leading to the formation of high-quality companies that spin-out of DSV with the pre-seed investment and co-founding team required to prove experimental concepts and attract further investment.
Immune tolerance – a path toward cures
Immune tolerance is typically defined as a state of unresponsiveness towards factors that would otherwise elicit an immune reaction. This definition is relatively narrow, and we believe that the ultimate outcome we ought to aim for in IMID therapeutics is not just inducing immune unresponsiveness, but durably restoring immune homeostasis. The selective (re)introduction of immune tolerance mechanisms is one broad way of achieving this curative rebalancing – sometimes described as ‘immune reset’ – and is applicable to any IMID, irrespective of its pathomechanism.
We are at the beginning of an exciting era where a convergence of technologies – like single-cell & spatial multi-omics, a suite of novel therapeutic modalities, and great advances in predictive and generative machine learning models – are enabling us to understand and treat inflammatory disease with unprecedented precision. Ten years ago, much of this would have been impossible. The opportunity space is now expansive.
Why Deep Science Ventures?
Our approach of outcomes-led venture creation is unusual, but we believe it is the antidote for many of the systemic challenges in deeptech innovation – from knowledge silos and bureaucracy, to ‘technology-push’ approaches and fractured value chains. Over the past 5 years, we have built 35 companies and have a track record of success in the life sciences sector, with portfolio companies that have generated impact and gone on to raise significant funding. In 2021 alone, we created three oncology companies with CRUK: Enedra, Neobe and Stratosvir.
Unanswered questions
A recurring constraint across many complex and heterogeneous diseases, including IMIDs, is that therapeutics which are too precise can eventually be evaded (due to the redundancy of biological systems), while those which are too broad cause prohibitive toxicity (due to unintended effects elsewhere in the body). Imagine if we could temporally, spatially or functionally restrict the effect of therapeutics so that they are active only where they are needed, providing true on-disease specificity? Drawing on proven and validated mechanisms of human immune tolerance, can we identify optimal (combinations of) tolerogenic interventions – in a way that considers the whole system from the outset? Are there ways to overcome the redundancy of biological systems, and prevent the compensatory mechanisms of resistance that form around any singular point of therapeutic intervention? How can we leverage recent advances in single-cell-, systems- and synthetic-biology to dissect the complexity of IMIDs, and develop curative approaches that address root causes, tailored to the needs of individual patients?
These are among the many questions we urgently want to answer – and we are seeking a passionate, impact-driven and entrepreneurial immunologist to help us do this. If you’re frustrated by the way we currently treat inflammatory disease, and deeply motivated to change that by building a company that will develop novel, curative, tolerance-inducing therapies, we would love to hear from you. To find out more or to apply for the Founder-in-Residence role, please see the Job Description.
* IMIDs are a collection of ~80 diseases including rheumatoid arthritis, psoriasis, multiple sclerosis, Crohn’s disease, ulcerative colitis, type 1 diabetes, systemic lupus erythematosus, Sjögren’s syndrome, autoimmune hepatitis, and many more. While they often affect distinct tissues and exhibit variable symptoms, the pathological mechanisms can be as similar between diseases as they are within them, due to extensive heterogeneity. We therefore consider them here as one therapeutic area.