By George Vratsanos, MD, and Luke Devey, MD, Ph.D., Janssen Immunology
There are many critical decisions to be made in early-stage drug development, which must be informed by in-depth knowledge of disease biology. With the rapid advances in medical science, it is important to recognize that all of the expertise to guide these decisions cannot be found within a single company, a humbling and energizing achievement. For this reason, deep and lasting collaborative relationships between academia and industry can be mutually valuable: both parties bring complementary resources and expertise to a shared mission of seeing new scientific advances translate into new therapies.
Last year, Janssen Biotech and the University of Oxford established the Cartography collaboration to understand similarities and differences in pathogenic pathways underlying different immune-mediated inflammatory diseases, by creating a cellular map of expressed genes and proteins. Our goal is to better understand the disease at the molecular, cellular and pathway levels that will allow the identification of new actionable therapeutic targets. Additionally, as part of the Cartography collaboration, Janssen and Oxford are using the latest technology to dissect which types of patients – biologically – will respond best to targeted therapy, an approach often referred to as precision medicine. In this article, we describe how we work closely with collaborators at the University of Oxford, leveraging the latest technologies to build a systematic knowledge base to support decision-making in drug discovery and development. .
What has the collaboration achieved so far?
The Janssen-Oxford Cartography collaboration is a unique model of co-creation in drug development where industrial and academic colleagues work side-by-side to design rigorous and creative experiments. Janssen teams are paired with doctors and scientists from Oxford to create a consortium that contributes to a unique set of data we call an ‘atlas’ of disease. Carrying out this work presents many challenges, from recruiting patients to developing new analytical approaches, both in the laboratory and by computer.
So far, the team has laid the groundwork to accelerate our understanding of the pathophysiology of human diseases at the cellular and molecular levels, offering the possibility of discovering new drug targets, establishing new biomarker signatures and creating opportunities to identify new uses or indications for Janssen Therapeutics in development or on the market.
Our scope is broad: in the first phase, launched in 2021, the mapping covered all immune-mediated inflammatory diseases. This groundbreaking model has proven to be so successful that our strategic mapping collaboration with Oxford has been extended in a second phase to encompass additional disorders in four therapeutic areas: infectious diseases, vaccines, oncology and neurosciences. These areas will use the infrastructure established under the original project to fill knowledge gaps in an effective multi-faceted approach. Collaborative mapping projects will allow us to understand tissue-based cellular networks across multiple diseases and organs and link them to those in the blood. These single-cell datasets will be supplemented with additional multiomics data such as serum proteomics and bulk RNA and DNA sequences, creating a cross-organ atlas that can be referenced for additional multi-layered analysis. The project establishes a unique research ecosystem in which to collaborate across disciplines between Janssen and Oxford scientists.
As the data is integrated into the cellular map, our vision is to build a silicone resource for early validation of therapeutic targets and uncovering biomarkers and mechanistic strata of the patient population. The data generated is complete and complex. Computational biologists at Janssen and Oxford can then seek to gain new insights from the dataset and answer questions about specific target pathways, diseases and patient populations, enabling rapid decision-making on drugs in our R&D pipeline. As the atlas continues to grow into diseases across multiple therapeutic areas, it potentially allows us to compare the relevance of key mechanisms in various diseases.
New single-cell technology revealing pathogenic pathways
Advances in next-generation sequencing, minimally invasive biopsy techniques, and computational biology have enabled scientists to create in-depth profiles of individual cells. The detailed cellular map of genes and proteins that the Janssen and Oxford scientists are creating through their collaboration uses a new technique called cellular indexing of transcriptomes and epitopes by sequencing (CITE-Seq).1
CITE-Seq is capable of measuring cell surface proteins as well as single cell RNA sequencing to uncover pathogenic pathways active in cells. Next, a novel computational approach integrates cellular proteomics and transcriptomics into an efficient single-cell readout. CITE-Seq provides a detailed view of disease states, providing insight into disease processes within individual cells and even abnormalities in how these cells interact with each other. Oxford has outstanding experience using this pioneering technique, and the Janssen collaboration represents scaling up to enable disease insights to support pharmaceutical decision-making.
CITE-Seq technology is also being deployed in a new early phase clinical trial to understand the precise mechanism of action of new treatments under the Accelerated Arthritis Therapy Program (A-TAP ).
A-TAP: Collaborating in the translation of a new biology into the clinic
Funded by the Kennedy Trust for Rheumatology Research, A-TAP brings together the universities of Birmingham and Oxford, seven partners from the UK’s National Health Service (NHS) and industry to jointly develop treatments for inflammatory-mediated diseases. immune system based on the causes of inflammatory diseases.
A-TAP represents the first time that Janssen Immunology has collaborated with an academic partner on an early phase clinical trial to determine how one pathway may work across multiple diseases. In a clinical trial, guided by Bayesian cell-based findings, we are examining the biology of a programmed cell death receptor-1 (PD-1) agonist monoclonal antibody in three indications: rheumatoid arthritis (RA), ulcerative colitis (UC) and Sjögren’s syndrome (SS). In this context, samples can be taken for CITE-Seq analysis before and after new therapies to understand in detail how the drug has altered disease biology in the target tissue. By doing these multi-disease studies together, it will be possible to unify and analyze this data much more efficiently than it would be if it were a disparate collection of small individual collaborations.
Towards Mutually Beneficial Outcomes and Shared Goals
To successfully unlock the molecular drivers of immune-mediated inflammatory diseases, academia and industry must work together to find solutions. Our academic collaborators have a broad clinical footprint: their access to patients allows us to examine a wide variety of different diseases and break not only the bench-to-bedside silo, but also the bedside-to-bedside silo, the interspecialty silos. They also have a strong background in developing new laboratory techniques and computational approaches, allowing us to better analyze the molecular drivers of disease for individuals. We also benefit from access to some of the foremost experts in their fields of immunology who bring invaluable scientific knowledge and insights to our collaborations.
As industry collaborators, we offer our partners insight into the drug development process and how new scientific knowledge can support pharmaceutical decision-making. Collaborations also open up the possibility of a flow of published research. And together, we will design and conduct studies and analyze and interpret the data that we hope will open new avenues in bringing new medicines to patients.
Our innovative models of Mapping and A-TAP collaboration have demonstrated the mutually beneficial value of partnerships and meaningful outcomes in our shared goal of accelerating the development of molecularly targeted immune therapies. Ultimately, our goal is to enable clinicians to treat the right patients with the right drugs at the right doses that will lead to remission or potentially cures.
- Stoeckius, M., Hafemeister, C., Stephenson, W. et al. Simultaneous measurement of epitopes and transcriptomes in single cells. National Methods 14, 865–868 (2017). https://doi.org/10.1038/nmeth.4380.
About the authors:
George Vratsanos, MD, is Vice President, Translational Science and Medicine (TSM) for the Immunology Therapeutic Area at Janssen Research & Development, LLC. Prior to joining Janssen, Vratsanos served as Executive Head of the Global Immunology and Dermatology Franchise Program at Novartis. Prior to that, he led Roche’s clinical development in autoimmune diseases as a leader in translational medicine. A rheumatologist by training, Vratsanos received his MD from New York University and completed a postdoctoral fellowship in rheumatology/immunology at Yale University. He holds a BS and MS in Biomedical Engineering from Columbia University. follow him on LinkedIn.
Luke Devey, MD, Ph.D., is Vice President and Head of Translational Sciences for the Immunology Therapeutic Area at Janssen Research & Development, LLC. In May 2020, he was awarded the title of Visiting Professor of Immunology by the University of Oxford. Previously, Devey served as Executive Director, Head of Early Discovery Biology at Celgene. Prior to Celgene, he spent five years at GSK as Senior Director, Translational Medicine. Devey received his BSc in Medicine and Bachelor of Surgery (BMBCh) in Medicine and his MSc in Physiological Sciences from the University of Oxford, his Ph.D. in Medicine from the University of Birmingham and his MRCSEd from the Royal College of Surgeons of Edinburgh. follow him on LinkedIn.