Table 3. Main features of monoclonal antibodies and small molecule tyrosine kinase inhibitors against the IGF/IGF-1R pathway.

Features of interest	mAb against IGF-1R	mAb against IGF-1 and -2	Small molecule TKI
Mechanism of action	• Block IGF-1R from ligand binding • Receptor degradation of IGF-1R homodimer and IGF-1R/IR hybrids • Possible ADCC (if IgG1)	• Neutralizing ligand from binding to IGF-1Rand IR-A	• Kinase inhibition intracellular  ▴ (also inhibit ligand-independent activation, if relevant)
Signaling affected	• Specific • Inhibit signaling of:  ▴IGF-1R  ▴IGF-1R/IR-A hybrid • No effect on IR-A or IR-B	• Specific • Inhibit IGF-1 or IGF-2 signaling through:  ▴ IGF-1R  ▴ IGF-1R/IR-A  ▴IR-A • No effect on insulin signaling	• Less specific • Inhibit signaling of RTKs (by any ligand):  ▴IGF-1R  ▴IGF-1R/IR  ▴IR (to a lesser degree than for IGF-1R) • May inhibit targets beyond IGF-1R and IR (XL228; INSM-18)
Pharmacokinetics	• Long t1/2 (days to weeks) • PK interaction less likely in combination regimens • Poor CNS uptake	• Long t1/2 (days to weeks) • PK interaction less likely in combination regimens • Poor CNS uptake	• Short t1/2 (hours)

IGF-1R, type I insulin-like growth factor receptor; IR, insulin receptor; mAbs, monoclonal antibodies; TKIs, tyrosine kinase inhibitors; ADCC, antibody-dependent cell-mediated cytotoxicity; RTKs, receptor tyrosine kinases; PK, pharmacokinetics; t_1/2, half life; CNS, central nervous system.