Calcium Channel Blockers
Pascal’s Calcium Channel Program was initiated with the acquisition of intellectual property (IP) from The University of British Columbia and the Jefferies Group. The IP relates to methods and compounds (agents) that modulate voltage-gated calcium channels. The program’s objective is to identify new calcium channel regulators (blockers) that activate the immune system’s T cells to combat cancers, infections and autoimmune diseases.
Calcium channels are a multi-member family of over 10 different proteins. Calcium channel activity is highly regulated and the channel, in turn, regulates the concentration of calcium ions (Ca2+) that act as universal second messengers in virtually all cell types.
Calcium signalling is known to play an important role in adaptive immunity. Two splice variants of the CaV1.4 calcium channel that regulates Ca2+ entry into T cells of the immune system have been identified in humans. In a study related to the Pascal IP acquisition, it was demonstrated that CaV1.4 plays an important role in the function, development, and survival of naive T cells, T cells that have not been activated by encountering specific antigens. The immune system requires adequate numbers of naive T cells for continuous response to unfamiliar pathogens.
Other studies have indicated that the Ca2+ signal plays a role in proliferation and migration processes in cancer. The studies identified alterations in the expression of proteins involved in the movement of Ca2+ across the cell plasma membrane.
Pascal is developing new monoclonal antibodies that specifically bind to an ectodomain (protruding section) of a CaV1 protein on the cell’s surface. The binding of the antibodies to an ectodomain of the target CaV1 molecule can modulate the function of the CaV1 channel, thus providing control of T cell function in ways not possible with current technology.
The antibodies will be tested for their ability to inhibit or activate calcium channels, ultimately leading to the regulation of T cell activity with the objective of enhancing this activity for the treatment of cancers, infections and autoimmune diseases.
Weft, warp, and weave: the intricate tapestry of calcium channels regulating T lymphocyte function. Omilusik KD, Nohara LL, Stanwood S, Jefferies WA. Front Immunol. 2013 Jun 24;4:164.
The Ca(v)1.4 calcium channel is a critical regulator of T cell receptor signaling and naive T cell homeostasis. Omilusik K, Priatel JJ, Chen X, Wang YT, Xu H, Choi KB, Gopaul R, McIntyre-Smith A, Teh HS, Tan R, Bech-Hansen NT, Waterfield D, Fedida D, Hunt SV, Jefferies WA. Immunity. 2011 Sep 23;35(3):349-60.
Tweeters, Woofers and Horns: The Complex Orchestration of Calcium Currents in T Lymphocytes. Nohara LL, Stanwood SR, Omilusik KD, Jefferies WA. Front Immunol. 2015 May 21;6:234.