CA-327 (Oral, Small Molecule, PDL1/TIM3 Antagonist)
In recent years, there has been considerable focus on harnessing the body’s own immune system to fight human cancers.
Evolved to identify and attack foreign antigens, including tumor antigens, the immune system is tightly regulated by inhibitory “immune-checkpoint” pathways that minimize damage to healthy tissue. Normal tissues engage these checkpoints to block the activation of an immune cell that would otherwise target them. Similarly, cancer cells have evolved to utilize some of the same inhibitory immune-checkpoint pathways to block immune cell activation that would target them.
A promising new approach to generating effective anti-tumor immune response involves disabling a tumor’s ability to block immune cell activation. This is done by creating drugs that target the inhibitory immune-checkpoints on the surface of T cells and other immune cells in patients with cancer. This approach has resulted in the approval of four new anti-cancer drugs in the last few years that target the Cytotoxic T-Lymphocyte-Associated Protein 4 (CTLA4) or the Programmed Cell Death Protein-1 (PD1) checkpoint pathways.
In the case of PD1, the cognate ligands Programmed Cell Death Ligand-1 (PDL1) and Programmed Cell Death Ligand-2 (PDL2) are expressed on tumor cells (or are present within the tumor microenvironment) and bind to PD1 on T cells. This PD1/PDL1 interaction results in T cell inactivation. The new drugs seek to prevent this interaction, and thereby prevent T cell inactivation, by binding to the PD1 checkpoint on T cells before a tumor does. This new approach of checkpoint inhibition has shown very promising results in clinical trials for treatment of multiple cancers.
It has been previously shown that modulation of PD1/PDL1 interaction by either anti-PD1 antibodies or anti-PDL1 antibodies can lead to increased levels of T cell activation and increased anti-tumor activity.
In addition to PD1, there are several other checkpoints involved in the modulation of immune responses to tumor cells. One such checkpoint is T-cell immunoglobulin and mucin domain containing protein-3 (TIM3), which shares some structural similarity with PDL1. TIM3 is also a potent suppressor of T cell functions and is co-expressed with programmed cell death-1 (PD1) receptors on certain T cells. TIM3 modulates immune response by binding to one or more of its ligands: galectin 9 (GAL9), phosphatidyl serine, high mobility group protein B1 (HMGB1) and Ceacam-1. Animal studies have demonstrated that combined inhibition of PDL1 and TIM3 results in improved anti-tumor responses in certain tumor models, highlighting their independent roles in regulating immune response to tumors.
In 2015, Curis and Aurigene established a collaboration to focus on the discovery, development and commercialization of small molecule drug candidates in the fields of immuno-oncology and precision oncology. In October 2016, Curis exercised its option within the collaboration to license the PDL1/TIM3 antagonist program from Aurigene. CA-327 is the development candidate from this program and is currently undergoing IND-enabling studies.
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