Colorectal cancer represents the second most common cause of
cancer-related death. The human A33 transmembrane
glycoprotein is a validated
tumor-associated
antigen, expressed in 95% of primary and metastatic
colorectal cancers. Using phage display technology, we generated a human
monoclonal antibody (termed A2) specific to human A33 and we compared its
epitope and performance to those of previously described clinical-stage anti-human A33
antibodies. All
antibodies recognized a similar
immunodominant epitope, located in the V-domain of A33, as revealed by SPOT analysis. The A2 antibody homogenously stained samples of poorly, moderately, and well differentiated
colon adenocarcinomas. All
antibodies also exhibited an intense staining of healthy human colon sections. The A2 antibody, reformatted in murine
IgG2a format, preferentially localized to A33-transfected CT26 murine
colon adenocarcinomas in immunocompetent mice with a homogenous distribution within the
tumor mass, while other
antibodies exhibited a patchy uptake in neoplastic lesions. A2 efficiently induced killing of A33-expressing cells through antibody-dependent cell-mediated cytotoxicity in vitro and was able to inhibit the growth of A33-positive murine CT26 and C51 lung
metastases in vivo. Anti-A33
antibodies may thus represent useful vehicles for the selective delivery of bioactive payloads to
colorectal cancer, or may be used in
IgG format in a setting of
minimal residual disease.