T cells play an essential role in cell-mediated immunity by defending the host via the highly selective recognition of specific antigens derived from foreign pathogens (for example, viruses) when “presented” on the cell surface of cells as a complex with a Major Histocompatibility Complex (MHC) protein. The TCR, a multimeric protein complex expressed on the surface of T cells, provides the antigen recognition function for the T cell. Importantly, peptide antigens are commonly derived from intracellular proteins, This central aspect to TCR-mediated recognition provides a unique opportunity to selectively target intracellular proteins that are unique or restricted in expression to tumor cells. By integrating a panel of advanced technologies, Axis Therapeutics is able to re-engineer T cell receptors to enhance affinity for the tumor antigen leading to a highly selective anti-tumor immune response. As the T cell therapies under development are autologous in nature (derived from the patient’s own cells) and highly selective for a tumor-derived antigen, the potential for “off target” activity is very low.
Axis Therapeutics is committed to developing genetically modified T cells with enhanced binding affinity to achieve better efficacy while reducing their off-target toxicity. The technology platform encompasses identification of appropriate tumor associated target proteins, cloning of the tumor specific TCR, TCR optimization, T cell modification and T cell amplification.
The majority of cancer cell associated antigens are derived from intracellular proteins, while the remaining are surface associated proteins expressed on the membrane or secreted.
While conventional CAR-T therapies are restricted to surface associated targets, TCR-T are capable of recognizing peptide antigens derived from intracellular proteins, a rich source of potential
tumor-specific antigenic targets.
Our Engineered TCR-Ts
1. High binding affinity and specificity
In a normal environment, the threshold for T cells to become activated and trigger a target-specific killing response is determined by the number of activating ligands, or clusters of TCR engaged with peptide/MHC ligands expressed by the target cell.
The greater the number of TCR clusters, the greater the chance of triggering T cell activation and attack against the tumor and the lower the chance of tolerance.
Tumors utilize several mechanisms to escape recognition by the hosts immune response, including downregulation of MHC protein expression leading to a reduction in the number of potential T cell activating ligands on the tumor cell surface. As a result, the number of engaged TCRs is reduced leading to a reduced potential for T cell activation.
Enhancing the binding affinity of tumor antigen reactive TCRs is expected to overcome the sub-optimal presentation of tumor antigens at the cell surface and effectively lower the activation threshold while reducing off-target, or non-specific cell killing.
2. High expression level and persistence
In addition to enhancing the affinity of tumor-reactive TCRs, the Axis Therapeutics platform also promotes preferential pairing of the transgenic TCR alpha- and beta-chains resulting in a high percentage of engineered cells expressing the properly paired affinity enhanced TCR. In pilot clinical studies, T cells expressing the affinity enhanced TCR have been detected in the circulation of treated patients for extended periods of time, indicating persistence post-transfusion which in turn is expected to enable anti-tumor immune activity in patients for extended periods of time.
3. Broad patient coverage
Peptide antigens derived from foreign pathogens and intracellular proteins are presented at the cell surface for recognition by T cells in the context of an MHC protein. The genetic locus encoding human MHC (also known as Human Leukocyte Antigen, or HLA) is comprised of multiple MHC alleles, resulting in considerable variation in expression among the human population, although some MHC alleles are expressed more frequently in different ethnic groups (for example, HLA-A*02:01 in the Caucasian population).
Our world-class TCR-T technology enables us to develop unique High Affinity TCR-T candidates that can recognize peptide antigens presented by multiple diverse MHC allele products to provide our TCR-T adoptive cell therapies for the vast majority of eligible patients.