Table 1.
Comparison of small molecule, siRNA and mAb therapeutic properties
| Property | Small molecule | siRNA | mAb |
|---|---|---|---|
| Molecular weight | ∼0.5 kDa | ∼10–15 kDa | ∼150 kDa |
| Manufacturing | chemical synthesis | chemical synthesis | cell line production |
| API heterogeneity | low | medium to high | high |
| Physicochemical properties | typically hydrophobic; neutral, basic, acidic subgroups | hydrophilic; negatively charged at physiological pH | hydrophilic; positive, negative, and neutral sites at physiological pH |
| Molecular target | protein | mRNA | protein |
| Selectivity | lower than the others | high | high |
| Site of action | intracellular and extracellular | intracellular | extracellular (ADCs can be intracellular) |
| Cellular uptake | passive and/or active | formulation-facilitated or receptor-mediated active | via endosomal pathway and recycled or degraded |
| Route of administration | oral or parenteral | parenteral | parenteral |
| Dosing frequency | daily | every three weeks to > monthly | weekly to monthly |
| Absorption | orally bioavailable, fast absorption | not orally bioavailable, s.c. absorption rate fast | not orally bioavailable, s.c. absorption rate slow |
| Distribution | extensive tissue distribution | select tissue distribution | limited to extracellular fluid |
| Metabolism | phase I and II drug metabolizing enzymes mediated | nuclease mediated | protease mediated |
| Renal or bile excretion | frequently | low | no |
| Immunogenicity risk | no | low; minimal impact on PK/PD or safety | yes; and likely to impact PK/PD or safety |
| PK/PD | usually direct correlation between blood PK and PD profile | indirect correlation between blood PK and PD profile; direct correlation between tissue PK and PD profile | direct correlation between blood PK and PD profile |
| Onset of action | fast | delayed | fast |
| PD duration | relatively short | long; could support up to yearly dosing interval | relatively long; weekly to monthly |
| DDI risk | high | low | low |
| PPB | variable; high impact on PK/PD | variable; low impact on PK/PD | low |
| Off-target toxicity | moderate probability | low probability by design | low probability |
| Volume of distribution | variable | extensive distribution to liver | small |
| Clearance | high | rapid plasma clearance, slow tissue clearance | low |
| Serum half-life | short | short | long |
Abbreviations: DDI, drug–drug interactions; PD, pharmacodynamics; PK, pharmacokinetics; PPB, plasma protein binding; s.c., subcutaneous; ADC, antibody-drug conjugate.