An inhibitory antibody targeting carbonic anhydrase XII abrogates chemoresistance and significantly reduces lung metastases in an orthotopic breast cancer model in vivo

Int J Cancer. 2018 Oct 15;143(8):2065-2075. doi: 10.1002/ijc.31607. Epub 2018 Aug 10.


Carbonic anhydrase XII (CAXII) is a membrane-tethered ectoenzyme involved in intracellular pH regulation and overexpressed across various types of human cancer. Because CAXII inhibition shows antitumor activity in vitro, it is thought that the enzyme is mandatory for maximum tumor growth, above all under hypoxic conditions. Recently, it has been shown that CAXII is co-expressed along with the P-glycoprotein (P-GP) on many tumor cells and that both proteins physically interact. Of interest, blocking CAXII activity also decreases P-GP activity in cancer cells both in vitro and in vivo. Previously, we have reported on the development of a monoclonal antibody, termed 6A10, which specifically and efficiently blocks human CAXII activity. Here, we demonstrate that 6A10 also indirectly reduces P-GP activity in CAXII/P-GP double-positive chemoresistant cancer cells, resulting in enhanced chemosensitivity as revealed by enhanced accumulation of anthracyclines and increased cell death in vitro. Even more important, we show that mice carrying human triple-negative breast cancer xenografts co-treated with doxorubicin (DOX) and 6A10 show a significantly reduced number of metastases. Collectively, our data provide evidence that the inhibition of CAXII with 6A10 is an attractive way to reduce chemoresistance of cancer cells and to interfere with the metastatic process in a clinical setting.

Keywords: 6A10 antibody; CAXII; P-glycoprotein; chemoresistance.

Publication types

  • Research Support, Non-U.S. Gov't

MeSH terms

  • ATP Binding Cassette Transporter, Subfamily B, Member 1 / metabolism
  • Animals
  • Antibodies, Blocking / pharmacology*
  • Antibodies, Monoclonal / pharmacology*
  • Breast Neoplasms / drug therapy*
  • Breast Neoplasms / metabolism
  • Carbonic Anhydrases / metabolism*
  • Cell Line, Tumor
  • Cell Proliferation / drug effects
  • Doxorubicin / pharmacology
  • Drug Resistance, Neoplasm / drug effects*
  • Female
  • Humans
  • Lung Neoplasms / metabolism
  • Lung Neoplasms / prevention & control*
  • Mice


  • ATP Binding Cassette Transporter, Subfamily B, Member 1
  • Antibodies, Blocking
  • Antibodies, Monoclonal
  • Doxorubicin
  • Carbonic Anhydrases
  • carbonic anhydrase XII