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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, suppress

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 PI3

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 17q

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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