Development and evaluation of β-galactosidase-sensitive antibody-drug conjugates

Eur J Med Chem. 2017 Dec 15;142:376-382. doi: 10.1016/j.ejmech.2017.08.008. Epub 2017 Aug 4.


The selective destruction of tumour cells while sparing healthy tissues is one of the main challenges in cancer therapy. Antibody-drug conjugates (ADCs) are arguably the most rapidly expanding class of targeted cancer therapies. Efficient drug conjugation and release technologies are essential for the development of these new therapeutic agents. In response to the ever-increasing demand for efficient drug release systems, we have developed a new class of β-galactosidase-cleavable linkers for ADCs. Within this framework, novel payloads comprising a galactoside linker, the monomethyl auristatin E (MMAE) and cysteine-reactive groups were synthesized, conjugated with trastuzumab and evaluated both in vitro and in vivo. The ADCs with galactoside linkers demonstrated superior therapeutic efficacy in mice compared to the marketed trastuzumab emtansine used for the treatment of breast cancer.

Keywords: Antibody-drug conjugate; Cancer; Chemotherapy; Drug delivery; Enzyme-responsive systems; Self-immolative linker.

MeSH terms

  • Ado-Trastuzumab Emtansine
  • Animals
  • Antineoplastic Agents, Immunological / chemistry*
  • Antineoplastic Agents, Immunological / metabolism
  • Antineoplastic Agents, Immunological / pharmacology*
  • Antineoplastic Agents, Immunological / therapeutic use
  • Breast Neoplasms / drug therapy
  • Carcinoma, Ductal / drug therapy
  • Cell Line, Tumor
  • Cell Proliferation / drug effects
  • Female
  • Humans
  • Immunoconjugates / chemistry*
  • Immunoconjugates / metabolism
  • Immunoconjugates / pharmacology*
  • Immunoconjugates / therapeutic use
  • Maytansine / analogs & derivatives*
  • Maytansine / chemistry
  • Maytansine / metabolism
  • Maytansine / pharmacology
  • Maytansine / therapeutic use
  • Mice, Nude
  • Trastuzumab / chemistry*
  • Trastuzumab / metabolism
  • Trastuzumab / pharmacology*
  • Trastuzumab / therapeutic use
  • beta-Galactosidase / metabolism*


  • Antineoplastic Agents, Immunological
  • Immunoconjugates
  • Maytansine
  • beta-Galactosidase
  • Trastuzumab
  • Ado-Trastuzumab Emtansine