Developing Functional Monoclonal Antibodies for beta3 Adrenergic Receptor


G protein-coupled receptors (GPCRs), one of the most commonly used and successful targets for drugs, are a large family of multi-transmembrane proteins and an important class of receptors. Over 40% of all modern medicines interact with this protein group. These cell surface receptors are acted on by a wide variety of ligands, including small molecules and soluble proteins. Monoclonal antibody therapy has major advantages over small molecule therapy---mAbs are more selective and therefore tend to have fewer non-specific or off-target toxicity issues, while having a longer duration of action than small molecule drugs. Unfortunately, it is extremely difficult to create antibodies against GPCRs using traditional approaches, especially for clinical applications. We have combined a proprietary immunization technology using our patented GPCR high expression system and in-depth expertise in developing well-designed and validated GPCR functional assays to select mAb leads that perturb disease-relevant signaling pathways. In this presentation, we will detail the development of 3 adrenergic receptor mAbs. Our preliminary data has shown that several mAb clones specifically bind to the receptor while increasing the receptor function by acting as agonists or positive allosteric modulators. This strategy is applicable to GPCR’s that cannot be addressed by small molecule therapeutics and should open the door for innovative therapeutics.

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