## Key Discriminating Feature Between TKIs and mAbs ### Structural and Functional Differences **Key Point:** TKIs are small-molecule inhibitors that can penetrate cell membranes and bind intracellular kinase domains, whereas mAbs are large proteins that act on extracellular epitopes and cannot cross the blood-brain barrier efficiently. ### Comparative Table | Feature | TKIs | mAbs | | --- | --- | --- | | **Molecular size** | Small molecules (300–500 Da) | Large proteins (150 kDa) | | **Site of action** | Intracellular kinase domains | Extracellular receptors/ligands | | **BBB penetration** | Yes (lipophilic) | No (hydrophilic) | | **Route** | Oral | IV | | **Mechanism** | Competitive kinase inhibition | Receptor blockade, ADCC, CDC | | **Examples** | Imatinib, erlotinib, sunitinib | Trastuzumab, cetuximab, bevacizumab | ### Clinical Implications **High-Yield:** TKIs can achieve CNS penetration, making them preferred for brain metastases (e.g., erlotinib in EGFR-mutant lung cancer with brain involvement). mAbs cannot reliably cross the BBB and are limited to systemic and accessible tumors. **Clinical Pearl:** TKIs are also effective against intracellular fusion proteins (e.g., BCR-ABL in chronic myeloid leukemia), which mAbs cannot target because the epitope is not exposed on the cell surface. ### Why This Matters The ability to inhibit intracellular kinase cascades (especially in tyrosine kinase-driven malignancies) is the fundamental advantage of TKIs over mAbs. This extends their therapeutic window to tumors with oncogenic mutations in kinase domains (EGFR, ALK, ROS1, BRAF). [cite:Harrison 21e Ch 107]
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