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.

Monoclonal anti-β1-adrenergic receptor antibodies activate G protein signaling in the absence of β-arrestin recruitment

“…The generation of purified StaR proteins and the corresponding StaR cDNA for immunization is an emerging technology that may provide the means to develop therapeutic mAbs to clinically important GPCR targets. 55 The study presented here has attained initial proof-of-concept, and provided valuable initial insight into the mechanism of action of these mAbs that show different interactions with the receptor as reflected by the varied pharmacological profiles mapping to different epitopes.…”

New Horizons in Therapeutic Antibody Discovery: Opportunities and Challenges versus Small-Molecule Therapeutics

“…88 Most sequence diversity resides in the extracellular N-terminus and loop regions, domains likely to be targeted by antibodies, lending support to the idea that antibodies may be useful GPCR therapeutics, particularly with their potential for high selectivity, affinity, and extended serum half-life. However, despite the fact that a range of GPCRand GPCR ligand-targeting antibodies are now in various stages of clinical and preclinical development, 88,89 it has not been easy or straightforward to target these receptors with LMs, and substantial effort has been invested in this pursuit. In addition, certain GPCRs may be more intractable to antibody therapeutics, especially those with limited extracellular domains or small, buried, and lipophilic binding pockets, where SMs may have better penetration.…”

The Use of Antibodies in Small-Molecule Drug Discovery

“…These methods include the generation and use of soluble ectodomains or chimeric fusions as antigens, or alternatively, the addition of neutralizing antibodies to endogenous binding partners and in vivo selection of overexpressed receptor. 59 Using these antigen presentation techniques, antibody phage display has identified membrane receptor modulators with agonistic and antagonistic activities covering a range of targets and disease indications. 60 …”