CalciMedica science and technology encompasses molecular targets, screening technology and lead compounds associated with the calcium release-activated calcium (CRAC) channel or Icrac pathway, a network essential for the activation of immune cells. The Icrac pathway is schematically shown below.
In lymphocytes and mast cells, activation of antigen or Fc receptors causes the release of calcium (Ca2+) from intracellular stores, which in turn leads to Ca2+ influx through specialized CRAC channels in the plasma membrane. The subsequent rise in intracellular Ca2+ activates calcineurin, a phosphatase that regulates the transcription factor NFAT. In resting cells, NFAT is phosphorylated and resides in the cytoplasm, but when dephosphorylated by calcineurin, NFAT translocates to the nucleus and activates different genetic programs depending on stimulation conditions and cell type. In response to infections and during transplant rejection, NFAT partners with the transcription factor AP-1 (Fos-Jun) in the nucleus of “effector” T cells, thereby transactivating cytokine genes, genes that regulate T cell proliferation and other genes that orchestrate an active immune response (Rao et al., Annu Rev Immunol., 1997).
In contrast, in T cells recognizing self antigens, NFAT is activated in the absence of AP-1, and activates a transcriptional program known as “anergy” that suppresses autoimmune responses (Macian et al., Cell, 2002).
Finally, in a subclass of T cells known as regulatory T cells which suppress autoimmunity mediated by self-reactive effector T cells, NFAT partners with the transcription factor FOXP3 to activate genes responsible for suppressor function (Wu et al., Cell, August 2006).
Orai1, the CRAC channel subunit, and STIM1, the calcium sensor located in the endoplasmic reticulum, function together as gatekeepers of the Icrac pathway. STIM1 and Orai1 were cited in the journal Science among signaling breakthroughs of 2005 and 2006, respectively. STIM1 and Orai1 were discovered by CalciMedica founders, and CalciMedica has acquired exclusive rights to both STIM1 and Orai1.
The therapeutic value of inhibiting the Icrac pathway has been established by the clinical use of calcineurin inhibitors (cyclosporine A and tacrolimus) for preventing organ transplant rejection. However, this class of compounds has been associated with nephrotoxicity and neurotoxicity resulting from inhibition of calcineurin in those organs. CalciMedica’s strategy is selective inhibition of CRAC channels, upstream from calcineurin, by targeting STIM1 and Orai1 that act as gatekeepers of the Icrac pathway. The SCID patient carrying a loss-of-function mutation in Orai1 does not display impairment in major organs, thus suggesting that CRAC channel inhibitors may have a better safety profile than calcineurin inhibitors.
CalciMedica is currently developing a CRAC channel inhibitor, CM4620, that inhibits the uncontrolled increase in intracellular calcium in pancreatic acinar cells, which leads to digestive enzyme activation, mitochondrial dysfunction, ER stress, and necrosis. This compound also inhibits the Icrac pathway in human T cells, blocking the release of IL-2 and TNFα, and has been shown to reduce neutrophil activation. CM4620 has demonstrated activity in vivo in several animal models of acute pancreatitis, both on pancreatic necrosis and markers of systemic inflammation, like lung myeloperoxidase.