GPCR Drug Discovery | Antibody Discovery


GPCRs are implicated in a wide variety of diseases where antibody therapeutics are currently used, such as inflammatory disease, metabolic disease and cancer. However, to date only one GPCR-targeted antibody has been approved and the pipeline for GPCR-targeted antibodies is sparse. This innovation gap reflects significant challenges unique to GPCR-focused antibody drug discovery.

Heptares StaR® proteins offer a breakthrough solution to the central challenge of GPCR antibody discovery that has limited success: producing a purified protein for use as an antigen against which antibodies can be raised. StaR® proteins enable antibody discovery by stabilising the GPCR protein outside the cellular membrane and maintaining the correct receptor folding. StaR® proteins preserve all biologically relevant epitopes and allow a diverse panel of functional antibodies to be obtained when used as antigen for in vivo immunization. This has previously proved impossible for GPCRs, which lose their conformational and functional integrity when removed from their natural environment in cell membranes.

Heptares has successfully used this approach to discover novel antibodies targeting the beta-1-adrenergic receptor (β1AR) that demonstrate potent agonist activity. Pharmacological characterisation reveals that these antibodies bind to diverse epitopes on the extracellular surface of the receptor to modulate its effect. The StaR® platform’s suitability to generate antibodies has been extended to other antibody discovery platforms such peptide, domain and scFv phage display.

Heptares’ unique GPCR capabilities combined to antibody development expertise provides a real opportunity to create a world-leading GPCR-antibody capability and to extend the potential of antibodies into this large but relatively untapped area.

Molecular model of a generic monoclonal antibody targeting a prototypical GPCR (orange) in the cell membrane.

Reference. Hutchings, Koglin and Marshall. MABS 2010.

Acknowledgements. Dr Andrew Doré and Dr Ben Tehan, Heptares Therapeutics Ltd, UK.

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