Practice question

Ado-trastuzumab emtansine T-DM1 marketed Kadcyla HER2-targeted antibody-drug conjugate combining trastuzumab IgG1 maytansinoid DM1 potent antimicrotubule derived maytansine Maytenus ovatus plant modified thiol conjugation via noncleavable SMCC succinimidyl 4 N maleimidomethyl cyclohexane 1 carboxylate thioether linker reacting lysine epsilon amino groups forming stable amide bond drug-antibody ratio approximately 3.5 DM1 per antibody retaining HER2 binding affinity 5 nM ECD IV juxtamembrane 580-630. Upon binding HER2 185 kDa overexpressed up to 2 million copies per cell ERBB2 amplification 17q12 forming homodimers heterodimers driving PI3K Akt MAPK signaling HER2 T-DM1 complex internalizes clathrin-mediated endocytosis Rab5 early endosomes trafficking lysosomes pH 4.5 proteolytic degradation cathepsins degrades antibody backbone amino acids leaving lysine MCC DM1 catabolite retaining antimitotic potency. Catabolite inhibits tubulin polymerization binding vinca site near tip microtubule plus end suppressing dynamic instability increased catastrophe decreased rescue causing cell cycle arrest G2/M spindle assembly checkpoint mitochondrial apoptosis JNK activation phosphorylating Bim. Trastuzumab moiety provides HER2 signaling blockade preventing ligand-independent dimerization inhibiting PI3K Akt plus ADCC via Fc gamma RIIIa NK and phagocytosis. Indicated HER2-positive metastatic breast cancer after prior trastuzumab taxane EMILIA phase 3 991 patients improved PFS 9.6 vs 6.4 months HR 0.65