Public Funding for T-Cypher Bio Limited

The immune system plays a key role in a broad range of disease -- including cancer, infection and autoimmunity. In recent years, treatment approaches which modulate the immune system have proved effective in a range of major diseases. T-cells are a key component of the immune system, with the capability of exquisitely recognising diseased or healthy tissue and acting powerfully to eliminate cells and tissues where required. However, altered T-cell responses have also been shown to cause inflammation in certain circumstances. Ulcerative colitis is an important form of bowel inflammation which carries a major burden on patients and their families. Current treatments are largely inadequate and non-specific and can often be limited by side-effects and risks. Members of the proposed team have shown that T-cells can contribute to the bowel inflammation. However, it is still unclear what triggers the T-cells. This is an important question if we are to find new approaches to treatment. T-Cypher Bio has developed a powerful approach to discover "antigens" that trigger T-cells and has focussed on developing therapeutics based on the receptors that recognise these antigens for the treatment of cancer. Here, T-Cypher Bio will work with pioneers in the role of T-cells in inflammation and the use of novel single cell technologies, Professor Alison Simmons and Professor Graham Ogg at the University of Oxford. Specifically, samples will be taken from patients with Ulcerative Colitis and controls to define antigens and T-cells using the T-Cypher technology (T-Cypher-seq) and other approaches to examine individual T-cells in the tissue samples. These large patient-derived data-sets will provide the basis to develop therapeutic approaches to control the inflammation. T-Cypher will innovate to increase the types of T-cells which can be examined, allowing access to new inflammatory disease markets. The insights will be directly applicable to inflammatory bowel disease, but the principles will be rapidly extended to other important causes of inflammation at other parts of the body. The team is highly complementary, unique, and well-placed to make major advances in the field; ultimately striving to bring benefits to patients, as well as to the wider UK health economy.

We are Orbit Discovery Ltd, a rapidly growing biotechnology company that works collaboratively with its partners to rapidly identify and characterise advanced peptide therapeutic drugs for a range of chronic diseases using a highly efficient in vitro screening technique. We want to develop synthetic biology technology for screening of potential drug targets with synthetic peptides possessing characteristics not possible in natural peptides. This means that we will make peptides that have a far greater application for a variety of diseases. This will enable more efficient production of stable peptide therapeutics, less likely to degrade when administered orally. Which essentially means, we will make better medicines, that can be taken orally, improving treatment effectiveness and making treatment more manageable. This project will enable Orbit to overcome limitations of structural constraints that limit target specificity, affinity and addressability and enable safer and faster drug development.

Orbit Discovery Ltd was established in November 2015 as a spin-out from Oxford University. The founding IP relates to a peptide display platform and its use for the identification of novel peptides and for the identification of T-cell epitopes in high throughput screens. We provide services identifying and characterising advanced therapeutics for a range of chronic diseases. **Target Markets** Companies making modified TCRs as drug products for Cancer Immunotherapy have a current pressing need to identify off-target binding of their products to ensure safety; there have been several reported patient deaths in clinical trials due to cardiac or gastric inflammation as a direct result of treatment with modified TCRs. **Project Description** This project aims to investigate and validate a broad screening solution that would enable these companies to more comprehensively and reliably screen their products earlier in development. This would reduce the risk of medical side-effects or fatalities during clinical trials and would speed up the development and deployment of more effective cancer treatments.

Display technologies are of great utility in the identification of proteins and other molecules that bind with high specificity and high affinity to targets of interest. These technologies, such as phage display and mRNA or ribosomal display, have revolutionized the development of small peptide therapeutics and also diagnostic tools in applications in cancer, infectious disease, autoimmune, neurodegenerative and inflammatory pathologies. While representing current state-of-the-art, difficulties in constraining peptides prior to screening the target and a lack of the ability to screen cell surface targets limit the utility of these technologies. Moreover, as targets of interest are typically immobilized on plastic sur-faces for screening, they can often exhibit incorrect conformations or reduced activity due to denatura-tion resulting from harsh conditions or from conformational changes. Orbit Discovery has developed a novel in vitro peptide display approach that solves many of the existing peptide display challenges. In the proposed project, Orbit plans to move their screening platform based on the Orbit technology from one based on solid base biopanning to one based on the screening of targets in-solution, thus eliminat-ing the associated problems with protein immobilization to a surface and allowing for the screening of conformationally correct, fully active targets.