Original Article

Cancer Immunology, Immunotherapy

, Volume 57, Issue 7, pp 1017-1027

A33 antigen displays persistent surface expression

  • Margaret E. AckermanAffiliated withDepartment of Biology, Massachusetts Institute of Technology
  • , Cecile ChalouniAffiliated withDepartment of Cell Biology, Ludwig Institute for Cancer Research, Yale University School of Medicine
  • , Michael M. SchmidtAffiliated withDepartment of Biological Engineering, Massachusetts Institute of Technology
  • , Vivek V. RamanAffiliated withDepartment of Biological Engineering, Massachusetts Institute of Technology
  • , Gerd RitterAffiliated withLudwig Institute for Cancer Research, New York Branch, Memorial Sloan-Kettering Cancer Center
  • , Lloyd J. OldAffiliated withLudwig Institute for Cancer Research, New York Branch, Memorial Sloan-Kettering Cancer Center
  • , Ira MellmanAffiliated withDepartment of Cell Biology, Ludwig Institute for Cancer Research, Yale University School of Medicine
  • , K. Dane WittrupAffiliated withDepartment of Biological Engineering, Massachusetts Institute of TechnologyDepartment of Chemical Engineering, Massachusetts Institute of Technology Email author 

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Abstract

The A33 antigen is a cell surface glycoprotein of the small intestine and colonic epithelium with homology to tight junction-associated proteins of the immunoglobulin superfamily, including CAR and JAM. Its restricted tissue localization and high level of expression have led to its use as a target in colon cancer immunotherapy. Although the antigen is also present in normal intestine, radiolabeled antibodies against A33 are selectively retained by tumors in the gut as well as in metastatic lesions for as long as 6 weeks. Accordingly, we have studied the trafficking and kinetic properties of the antigen to determine its promise in two-step, pretargeted therapies. The localization, mobility, and persistence of the antigen were investigated, and this work has demonstrated that the antigen is both highly immobile and extremely persistent—retaining its surface localization for a turnover halflife of greater than 2 days. In order to explain these unusual properties, we explored the possibility that A33 is a component of the tight junction. The simple property of surface persistence, described here, may contribute to the prolonged retention of the clinically administered antibodies, and their uncommon ability to penetrate solid tumors.

Keywords

A33 antigen Radioimmunotherapy Colon cancer Tight junction Immunoglobulin superfamily