A Multimerizing Igg Framework with Improved Stabilization and Secretion of Soluble TCR and Peptide-MHC Complex for Diagnosis and Therapy in Cancer and Autoimmune Disease

Applications

This technology is a novel method of generating soluble T-cell receptors or MHC complexes with applications in research, cancer immunotherapy, or autoimmune therapy.

Problem Addressed

Cancer immunotherapies activate patients’ own immune systems to kill cancer cells. A common technique used in cancer immunotherapy uses soluble antibodies that bind to cancer cell specific antigens and induce an immune response against the cancer cells. However, a major limitation of antibody technologies is that they can only recognize antigens on the outside of the cell, and for some cancers, it is challenging or impossible to identify cancer-specific surface antigens. T-cell receptors (TCRs), which are normally embedded in T-cell membranes, bind to specific target antigens that arise from inside the cell. Soluble TCRs that act analogously to antibodies have therefore been proposed as a promising new immunotherapy strategy that could immensely increase the number of targetable antigens. Unfortunately, solubilizing TCRs remains extremely challenging and soluble TCRs are frequently unstable and suffer from low yields. This technology solves the stability issues associated with soluble TCRs, increases yield, and multimerizes the soluble TCRs to increase target affinity.

Technology

This technology is a new method for generating soluble TCRs with high affinity and yield. To make multimerized soluble TCRs, the inventors made a fusion protein that includes a TCR domain, Fc chain, and leucine zipper domain. The TCR domain recognizes intracellular antigens presented by MHC-I and gives the soluble TCR specificity against a particular antigen. The Fc chain, which is a component of antibodies, induces an immune response once the fusion protein is bound to target cells. Leucine zippers are very strong dimerization domains that facilitate multimerization of the soluble TCRs and provide additional stability to the final product. These novel soluble TCRs are much more stable than similar existing technologies and achieve yields up to 100 fold greater than previous designs. The simple design of this system is easy to customize and dramatically reduces the time and cost necessary to develop and produce soluble TCRs. Finally, this system can be tailored for immunosuppressive applications by swapping out TCR regions with peptide-MHCI/II to deplete target T-cell populations.

Advantages

  • Increased soluble TCR stability and yield
  • Easy to use, customizable system for faster and cheaper production of soluble TCRs
  • Can be functionalized for immune activating (TCR) or immune suppressing (MHC) applications