Purpose: Gastrointestinal cancers remain areas of high unmet need despite advances in targeted and immunotherapies. Here, we demonstrate potent, tumor-selective efficacy with PF-07062119, a T-cell engaging CD3 bispecific targeting tumors expressing Guanylyl Cyclase C (GUCY2C), which is expressed widely across colorectal cancer and other gastrointestinal malignancies. In addition, to address immune evasion mechanisms, we explore combinations with immune checkpoint blockade agents and with antiangiogenesis therapy.
View Article and Find Full Text PDFSince the identification of phosphodiesterase activity in brain tissue more than 40 years ago, 11 distinct gene families have been identified, differing with respect to localization, regulation, affinity for cAMP and cGMP, and distinct functions within cells. PDEs 1, 2, 4, and 10 are currently of special interest to CNS pharmacology because of their high expression in specific areas of the brain and the behavioral effects of inhibitors of these enzymes in rodents. Efficient high-throughput PDE enzyme assays are essential for PDE-targeted drug discovery, and this unit details two types of assays.
View Article and Find Full Text PDFWe have isolated cDNAs encoding PDE4A8 (phosphodiesterase 4 isoform A8), a new human cAMP-specific PDE4 isoform encoded by the PDE4A gene. PDE4A8 has a novel N-terminal region of 85 amino acids that differs from those of the related 'long' PDE4A4, PDE4A10 and PDE4A11 isoforms. The human PDE4A8 N-terminal region has diverged substantially from the corresponding isoforms in the rat and other mammals, consistent with rapid evolutionary change in this region of the protein.
View Article and Find Full Text PDFAn alpha7 nicotinic acetylcholine receptor sequence was cloned from Rhesus monkey (Macaca mulatta). This clone differs from the mature human alpha7 nicotinic acetylcholine receptor in only four amino acids, two of which are in the extracellular domain. The monkey alpha7 nicotinic receptor was characterized in regard to its functional responses to acetylcholine, choline, cytisine, and the experimental alpha7-selective agonists 4OH-GTS-21, TC-1698, and AR-R17779.
View Article and Find Full Text PDFWe report here the cloning and characterization of two novel PDE4D isoforms, PDE4D6 and PDE4D7. PDE4D6 is a supershort form and PDE4D7 a long form of PDE4D. In addition, we have identified another novel long-form variant, PDE4D8, in silico.
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