Table 1 Major differences between monoclonal antibodies and small molecule tyrosine kinase inhibitors.
From: Molecular mechanisms of acquired resistance to tyrosine kinase targeted therapy
| Â | mAb | Small molecule TKI |
|---|---|---|
Administration | Intravenous | Oral or parenteral |
Target availability | Must be extracellular | Extra/intra-cellular |
Cost | US$ 4,200/month (trastuzumab) | US $1,800/month (gefitinib) |
Size | ~150,000 daltons | ~400 daltons |
Diffusion | Near vessels, surrounding tumor area; inefficient delivery | Easy to diffuse, translocate though plasma membranes, may reach brain tissues |
Toxicity | Low toxicity | Mid-high toxicity |
Half-Life | Days-weeks | <72 h |
Mechanism of Action | Disrupt ligand-receptor or receptor-receptor (homo/hetrodimerization) interactions, receptor downregulation, induction of apoptosis | Bind to target kinase(s), inhibit phosphorylation and downstream signaling pathways. Induce apoptosis. |
Approval success rate | 18-24% | 5% |
Mechanisms of resistance | Protein Modifications: Switch of surface receptors. Shedding of the extracellular portion of the receptor. Expression of truncated receptors. Modification of receptor structure. Activation of downstream signaling pathways. | Genetic modifications: Point Mutations (Activating mutations). Amplifications (Target gene). Deletions. Protein Modifications: Overexpression of the target protein. Activation of alternative pathways. Overexpression of Multidrug resistance genes. |