GPCR PROTEINS

G (guanine nucleotide-binding) protein-coupled receptors (GPCRs) composed of 800 members represent the largest family human membrane receptors and are linked to numerous critical cellular and physiological functions such as homeostasis, proliferation and migration of cells as well as for the sensing of vision, taste and olfaction.

G (guanine nucleotide-binding) protein-coupled receptors (GPCRs) composed of 800 members represent the largest family human membrane receptors and are linked to numerous critical cellular and physiological functions such as homeostasis, proliferation and migration of cells as well as for the sensing of vision, taste and olfaction.

GPCRs are involved in 70% of cells communication by interaction with various extracellular ligands, including peptides, nucleotides, lipids, small organic compounds, ions and photons.

Abnormal expression and activity of GPCRs are engaged in many types of diseases, including cancer, infection, inflammation and cardiovascular disease and explain the incredible potential as drug targets.

Thus, GPCRs are the largest drug target family accounting for more than one third of FDA approved drugs even though only 80 GPCRs with majority of the aminergic class of receptors, are drugged and nearly all targeted by small molecules and the rest by peptides, leaving a remaing 3/4 of the undrugged GPCRs.

While small molecules are historical GPCRs therapeutic class, antibodies would provide substantial therapeutic opportunities by addressing potential advantages over small molecules by:

  • Their specificity
  • Dosing frequency
  • Restricted penetration
  • Other functional effects specifically mediated by the Fc region such as ADCC and CDC
  • Different modalities such as payload conjugaison offered by antibody drug conjugates
  • A longer half-life in some instances such as by FcRn-mediated recycling can provide a therapeutic index that is more desirable than that of small molecules and peptides

Today the antibody field is a dynamic therapeutic area with more than 70 approved monoclonal antibodies on the market in the US and Europe in 2018, but only 2 anti GPCR antibodies (M ogamulizumab / Poteligeo (Kyowa Hakko Kirin Co.) have been approved for te market in Japan and Erenumab-aooe/Aimovig (Amgen & Novartis).

Despite the undeniable potential of antibodies as a therapeutic class for GPCRs, many challenges remain to be addressed  for the discovery of life changing antibody biologics to GPCR antigens.

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