ado-trastuzumab emtansine

Overview

Trastuzumab emtansine (T-DM1; ado-trastuzumab emtansine; brand name Kadcyla) is an antibody-drug conjugate combining trastuzumab (anti-ERBB2 IgG1) with the maytansinoid cytotoxin mertansine (DM1) via a non-cleavable thioether linker (SMCC). It is FDA-approved for HER2-positive metastatic breast cancer and early-stage breast cancer after neoadjuvant therapy. The HER2-targeted delivery restricts cytotoxic payload release to antigen-expressing cells via receptor-mediated endocytosis.

Evidence in the corpus

  • T-DM1 IC50 was <1 nM in HER2+ OE19 (esophageal) and NCI-N87 (gastric) cell lines but >100 nM in HER2− lines (HCT116 colorectal; CAL-27 HNSCC), demonstrating strict receptor-dependent potency over a >100-fold dynamic range PMID:27698471.
  • T-DM1 was more potent than free mertansine (~10 nM IC50 across all lines regardless of HER2 status), paclitaxel, cisplatin, trastuzumab, lapatinib, and erlotinib in HER2+ OE19 cells — the ADC format enhances selectivity without sacrificing potency in target-expressing cells PMID:27698471.
  • A single 0.25 nmol dose (~1.9 mg/kg) of T-DM1 combined with 2.5 Gy × 3 daily IR fractions increased tumour doubling time from 7 → 66 days in OE19 xenografts and from 9 → 113 days in NCI-N87 xenografts; HCT116 (HER2−) xenografts showed no benefit from adding T-DM1 to IR (Table 1, Fig. 5d). Long-term tumour control was observed only in HER2+ xenografts receiving T-DM1 + IR PMID:27698471.
  • T-DM1 at doses as low as 2 nM radiosensitized HER2+ OE19 cells and produced G2/M accumulation (pS10-Histone H3 IHC), consistent with intracellular maytansinoid release causing anti-tubulin-mediated mitotic arrest followed by enhanced radiation sensitivity PMID:27698471.
  • Authors propose combining T-DM1 with radiotherapy as warranting “speedy clinical evaluation” in HER2+ locally advanced cancers (esophageal, gastric, breast), given its existing FDA approval PMID:27698471.
  • RPPA HER2-high MIBC clusters 1 and 2 are candidates for trastuzumab or ado-trastuzumab-emtansine (T-DM1); ERBB2 is mutated in 12% and recurrently amplified in MIBC, with extracellular-domain S310 mutations (42% of ERBB2 mutations) attributed to APOBEC mutagenesis PMID:28988769

Resistance mechanisms

  • HER2-negative tumours show >100 nM IC50 for T-DM1 and no radiosensitization in vivo — HER2 expression is the essential gating biomarker PMID:27698471.

Cancer types (linked)

Sources

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