At Pascal, we discover and develop targeted agents that enable the body's own immune system to recognize and attack cancers. Pascal is advancing three research programs:
- Developing a therapeutic monoclonal antibody for treatment of B-cell precursor acute lymphoblastic leukemia, the most common childhood leukemia, in collaboration with the University of New Mexico;
- Optimizing novel classes of molecules that restore immune recognition and killing of cancer cells;
- Regulating activity of immune system calcium channels to combat cancers, infections, and autoimmune diseases.
Anti-VpreB Antibody for Leukemia
B-cell precursor acute lymphoblastic leukemia (BCP-ALL) is the most common childhood cancer. This disease is caused by mutations that arise during the early development of B lymphocytes. Licensed from the University of New Mexico, Pascal's anti-VpreB drug candidate is a high-affinity, fully human monoclonal antibody specific for VpreB, a subunit of the pre-B cell receptor (pre-BCR). The antibody kills BCP-ALL tumor cells in cell culture and exhibits properties amenable to engineering for enhanced cancer cell destruction. The VpreB target is expressed only on the leukemia cells and on pre-B cells, which represent a very early stage of B cell development. Therefore, targeting VpreB will specifically eliminate the tumor cells, while sparing mature activated and memory B cells that are essential for combating infection.
Restoration of Immune Surveillance
Cytolytic T cells recognize and destroy cancerous and infected cells by binding to a cell surface protein complex called Major Histocompatibility Complex Class I (MHC-I) when it displays a cancer or microbial antigen. However, many cancer and infected cells evade this T cell recognition by downregulating MHC-1 expression. Pascal, in collaboration with Wilf Jefferies of UBC, have identified several novel molecules that restore MHC-I expression, thus rendering the cancer or infected cells once again susceptible to recognition and destruction by the immune system. The ability to reactivate this pathway has tremendous potential in the field of immuno-oncology. The well-known checkpoint inhibitor antibodies, which block immune-inhibitory signals produced by some cancers, depend upon a robust cytolytic T cell - MHC-1 interaction. The checkpoint inhibitors are very effective, but only in a subset of cancer patients, typically less than 40%. By restoring MHC-I expression, the Pascal molecules have the potential to dramatically increase the number of patients that benefit from state-of-the-art immuno-oncology therapeutics.
Calcium Channel Antibody
Calcium signaling is necessary for the initiation of T lymphocyte activation and proliferation following an encounter with an altered self (cancer) or foreign (microbial) antigen. Two splice variants of the L-type calcium channel, CaV1.4, have been shown to regulate calcium entry into T cells, thus providing control of T cell function. Pascal is developing new monoclonal antibodies that specifically bind to L-type calcium channels involved in activation of the immune system's T cells to combat cancers, infections, and autoimmune diseases.
Dynamic pre-BCR homodimers fine-tune autonomous survival signals in B cell precursor acute lymphoblastic leukemia. Erasmus MF, Matlawska-Wasowska K, Kinjyo I, Mahajan A, Winter SS, Xu L, Horowitz M, Lidke DS, Wilson BS. Sci. Signal. 2016 Nov 29;9:1-17.
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.