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#HER2-positive cancer

3 public questions tagged with this topic.

Immunological Applications

Ado-trastuzumab emtansine is used against:

HER2 positive metastatic breast cancers progressing after trastuzumab plus chemotherapy develop resistance mechanisms including truncated p95HER2 lacking extracellular binding epitope, upregulation of MUC4 masking epitope, activation of downstream PIK3CA H1047R mutation, and alternative receptor tyrosine kinase signaling AXL. Ado-trastuzumab emtansine also called T-DM1 extends HER2 targeting beyond signaling inhibition delivering cytotoxic maytansine chemically. Trastuzumab backbone retains anti-signaling activity via inhibition of HER2 heterodimerization and metalloprotease cleavage, suppression of PI3K-AKT, plus Fc mediated antibody dependent cellular cytotoxicity through FcγRIIIa. Chemical linker SMCC succinimidyl trans-4-(maleimidylmethyl) cyclohexane-1-carboxylate forms stable non-reducible thioether bond between cysteine sulfhydryl of antibody and primary amine of DM1 derivative maytansine that binds tubulin near vinca site with binding affinity 100 times vincristine inhibiting microtubule polymerization, causing aberrant mitosis with multipolar spindles and subsequent mitochondrial apoptosis. After HER2 mediated internalization to lysosome acidic proteases cathepsin B and L degrade antibody polypeptide releasing active metabolite lysine-MCC-DM1 retaining microtubule inhibitory activity while sparing systemic exposure because stable thioether prevents premature release in plasma, mitigating myelosuppression and neuropathy.

Ref: Verma et al NEJM 2012 367:1783 EMILIA T-DM1 HER2 DM1 non-cleavable; FDA ado-trastuzumab emtansine label.

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Immunological Applications

Trastuzumab (Herceptin) is used in treatment of:

HER2 proto-oncogene ERBB2 located chromosome 17q12 encoding 185 kDa receptor tyrosine kinase member EGFR family characterized by extracellular cysteine-rich domains, single transmembrane helix, and intracellular kinase domain. Amplification in 15 to 20 percent invasive breast carcinomas leads to overexpression up to two million receptors per cell versus normal 20,000, facilitating ligand independent homodimerization and heterodimerization with HER3 bound to neuregulin, triggering transphosphorylation of tyrosine residues creating docking sites for Shc, Grb2, p85 subunit of PI3K. Downstream PI3K-AKT-mTOR pathway inhibits BAD promoting survival plus cyclin D1 driving proliferation, MAPK cascade induces transcription of EGR1. Trastuzumab humanized IgG1 generated by grafting murine CDRs onto human framework binds domain IV juxtamembrane region near transmembrane spanning, sterically hindering metalloprotease ADAM10 cleavage that would release active extracellular domain and preventing dimerization interface exposure. Additional actions include antibody-dependent endocytosis reducing surface density, suppression of shed ECD, blockade of downstream signaling, and recruitment of NK cells for ADCC. Combined with paclitaxel or docetaxel improves disease-free survival by approximately 50 percent. Companion diagnostic immunohistochemistry scores 3+ or fluorescence in situ hybridization ratio above 2.0 identifies HER2-positive breast cancer candidates before therapy.

Ref: Slamon et al NEJM 2001 344:783 HER2 trastuzumab domain IV; Harari & Yarden Oncogene 2000 HER2 dimer PI3K signaling.

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Immunological Applications

Ado-trastuzumab emtansine is used against:

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

Ref: FDA Kadcyla Ado-Trastuzumab Emtansine HER2 ADC Label Mechanism; NEJM T-DM1 EMILIA Trial 2012 Verma et al; Nature Reviews Drug Discovery ADC HER2 Mechanism Review.

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