Comparison of therapeutic antibodies and small-molecule compounds targeting GPCRs

AntibodySmall Molecule
General properties
  Mostly antagonistsAntagonists, agonists, and allosteric modulators
  Preference for extracellular epitopesBinding multiple pockets, including intracellular
  Administration mostly intravenous or subcutaneousOral administration possible
  Immunogenicity minimized by humanizationLow risk for immunogenicity
  Effector functionsNo effector functions
 Longer serum half-life, reduced dosing frequencyShorter serum half-life, variable dosing frequency
 Restricted blood-brain barrier penetrationGood blood-brain barrier penetration
 High target expression during immunization and selection neededDevelopment not dependent on target expression
 Higher costs of development and manufacturingLower costs of development and manufacturing
GPCR targeting
 Possibility of targeting low-druggability GPCRsPoor tractability, failed to target a variety of GPCRs (e.g., class B2, F)
 Enhanced selectivity and specificityLower selectivity, often target family-conserved binding sites
 Less off-target effectsOff-target effects
  Easy to label and functionalize, e.g., bispecifics, fragments, and conjugatesChallenging to label
Clinical development
 Lower overall rate of attrition and higher transition rates at all stages of developmentLower approval success rates