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BIA-Brukerstyrt innovasjonsarena

NextCore-TCR - a generic platform for therapeutic T cell receptor discovery

Alternative title: NextCore-TCR - en generisk plattformteknologi for utvikling av terapeutiske T celle reseptorer

Awarded: NOK 15.6 mill.

Project Number:

321642

Project Period:

2021 - 2025

Funding received from:

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The immune system is our natural defence against infectious diseases and malignant conditions. It consists of a huge number of proteins and cells that upon recognition of e.g., a virus or a cancer cell usually is activated and thus initiates a response that eliminates these from the body. T cells are one class of leukocytes that are imperative in such responses, and the key molecule allowing them to exert their function is a specialized cell surface receptor, the T cell receptor (TCR), that allows T cells to specifically recognize virus infected cells or cancer cells whilst sparing healthy tissue. When the immune system fails to eradicate malignant cells, one develops cancer. Recently, tremendous effort has been made to investigate how T cells can be used in effective cancer treatment. In particularly, a great focus has been on obtaining the right TCR that can target T cells to the cancer tissue with high accuracy and sensitivity. Due to current limitations in new TCR drug discovery, there is as demand for technologies enabling identification of such TCRs. Nextera is a biotechnology company that aims to develop specific and effective immunotherapy for cancer treatment. We have constructed a technology platform which facilitates characterization of the interplay between T cells and their target cells. In this project, we will further develop our technology so that it can be used to "scan" repertoires of billions of various TCRs to identify the most effective candidate which both specifically recognizes and kills cancer cells. We believe that our platform will represent a valuable TCR supply for development of novel and safer TCR drug candidates for cancer therapy. Due to the complexity of the TCRs and the novelty of the approach, the first part of the project has focused on the development of an optimized TCR format which enables generic, stable and functional expression of different TCRs. Further, TCR repertoires have been collected from natural immune cells from several healthy blood donors. The repertoires have been validated for the diversity of TCR genes and are now being integrated into our platform. The result will represent a 1st generation TCR library (prototype I). The performance of this library will be validated and further point the direction of the development of the final NextCore TCR library.

Nextera is a drug and target discovery company with the aim of developing safer and more efficacious drugs towards cancer and autoimmune disorders. This leverages the company’s proprietary and versatile discovery platform NextCore and with the current project, a novel arm of the NextCore family is being implemented termed NextCore-TCR. The latest generation immuno-oncology (IO) therapies have shown a remarkable ability to treat and occasionally even cure cancer by evoking or grafting an anti-cancer immune response into patients. A type of white blood cells called T cells are at the core of this immune response and a T cell acquires this ability through its T cell receptor (TCRs) surface protein. However, a major limitation in further improvements of IO therapy is the lack of a predictable and sustainable source of such TCRs. The project addresses this recognized unmet need with a unique solution where the NextCore platform is extended to encompass and integrate the TCR molecule and thereby becomes the first generic off-the-shelf supply of therapeutic TCR leads for further development. NextCore is a powerful protein engineering technology based on the Nobel Prize 2018 winning phage display method, which integrates development of both disease specificity and efficacy concomitantly with assessing and removing potential detrimental off-target reactivity. The R&D challenges in this project are associated with 1) generically accommodating the TCR to the platform format 2) leverage the huge TCR diversity found in vivo necessary to become a generic off-the-shelf supply 3) developing a discovery pipeline of drug leads with generic properties to allow successful translational to human therapy. Thus, the project is partnered with an internationally recognized environment at the Institute for Cancer Research/Oslo University Hospital (OUH) ensuring the necessary resources and competence for optimal preclinical assessment of the TCRs developed from the platform.

Funding scheme:

BIA-Brukerstyrt innovasjonsarena