Comparison of therapeutic antibodies and small-molecule compounds targeting GPCRs
| Antibody | Small Molecule |
|---|---|
| General properties | |
| Mostly antagonists | Antagonists, agonists, and allosteric modulators |
| Preference for extracellular epitopes | Binding multiple pockets, including intracellular |
| Administration mostly intravenous or subcutaneous | Oral administration possible |
| Immunogenicity minimized by humanization | Low risk for immunogenicity |
| Effector functions | No effector functions |
| Longer serum half-life, reduced dosing frequency | Shorter serum half-life, variable dosing frequency |
| Restricted blood-brain barrier penetration | Good blood-brain barrier penetration |
| Development | |
| High target expression during immunization and selection needed | Development not dependent on target expression |
| Higher costs of development and manufacturing | Lower costs of development and manufacturing |
| GPCR targeting | |
| Possibility of targeting low-druggability GPCRs | Poor tractability, failed to target a variety of GPCRs (e.g., class B2, F) |
| Enhanced selectivity and specificity | Lower selectivity, often target family-conserved binding sites |
| Less off-target effects | Off-target effects |
| Applications | |
| Easy to label and functionalize, e.g., bispecifics, fragments, and conjugates | Challenging to label |
| Clinical development | |
| Lower overall rate of attrition and higher transition rates at all stages of development | Lower approval success rates |