Opportunities for functional selectivity in GPCR antibodies

Abstract

Monoclonal antibodies (mAbs) have been used for decades as tools to probe the biology and pharmacology of receptors in cells and tissues. They are also increasingly being developed for clinical purposes against a broad range of targets, albeit to a lesser extent for G-protein-coupled receptors (GPCRs) relative to other therapeutic targets. Recent pharmacological, structural and biophysical data have provided a great deal of new insight into the molecular details, complexity and regulation of GPCR function. Whereas GPCRs used to be viewed as having either "on" or "off" conformational states, it is now recognized that their structures may be finely tuned by ligands and other interacting proteins, leading to the selective activation of specific signaling pathways. This information coupled with new technologies for the selection of mAbs targeting GPCRs will be increasingly deployed for the development of highly selective mAbs that recognize conformational determinants leading to novel therapeutics.

Figure 1. Model representation of an Fab (blue, PDB ID 3KJ6) bound to the extracellular domain of a GPCR

(red, PDB ID 4DJH).

Figure 2. State-specific recognition of GPCRs

Functionally selective ligands can stabilize GPCRs in conformations that confer unique signaling properties. In principle, it should be possible to generate mAbs that recognize specific ligand-bound conformational states (A), as well as conformations induced by homo- or hetero-dimerization (B).