Abstract
BackgroundS1P3 is a lipid-activated G protein-couple receptor (GPCR) that has been implicated in the pathological processes of a number of diseases, including sepsis and cancer. Currently, there are no available high-affinity, subtype-selective drug compounds that can block activation of S1P3. We have developed a monoclonal antibody (7H9) that specifically recognizes S1P3 and acts as a functional antagonist.Methodology/Principal FindingsSpecific binding of 7H9 was demonstrated by immunocytochemistry using cells that over-express individual members of the S1P receptor family. We show, in vitro, that 7H9 can inhibit the activation of S1P3-mediated cellular processes, including arrestin translocation, receptor internalization, adenylate cyclase inhibiton, and calcium mobilization. We also demonstrate that 7H9 blocks activation of S1P3 in vivo, 1) by preventing lethality due to systemic inflammation, and 2) by altering the progression of breast tumor xenografts.Conclusions/SignificanceWe have developed the first-reported monoclonal antibody that selectively recognizes a lipid-activated GPCR and blocks functional activity. In addition to serving as a lead drug compound for the treatment of sepsis and breast cancer, it also provides proof of concept for the generation of novel GPCR-specific therapeutic antibodies.
Highlights
The use of monoclonal antibodies to antagonize transembrane receptors has met with tremendous clinical and commercial success over the course of the past decade
7H9 Blocks Activation of S1P3 Since stimulation of S1P3 results in the activation of multiple downstream processes, we evaluated 7H9 for its ability to inhibit a number of distinct S1P3-mediated events
Following stimulation with 1 mM Sphingosine 1-phosphate (S1P) (B), arrestin translocates to the plasma membrane and is rapidly internalized into intracellular vesicles
Summary
The use of monoclonal antibodies (mAbs) to antagonize transembrane receptors has met with tremendous clinical and commercial success over the course of the past decade. The success of antibody drugs is based on their exquisite specificity and affinity, which are essential components of targeted molecular therapy. With 23 antibody drugs currently approved for clinical use and annual sales in the tens of billions of dollars [1], these biologics are being used for a wide range of indications such as inflammatory diseases, autoimmune diseases, stroke, and heart disease, but the greatest therapeutic antibody success stories involve the treatment of cancer. Examples of some the most effective and widely used, anti-cancer therapeutic antibody drugs include trastuzumab (HerceptinH, a HER2 inhibitor), bevacizumab (AvastinH, a VEGF inhibitor), and panitumumab (VectibixTM, an EGFR inhibitor). We have developed a monoclonal antibody (7H9) that recognizes S1P3 and acts as a functional antagonist
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