RT Journal Article
SR Electronic
T1 A novel human monoclonal antibody specific to the A33 glycoprotein recognizes colorectal cancer and inhibits metastasis
JF bioRxiv
FD Cold Spring Harbor Laboratory
SP 748962
DO 10.1101/748962
A1 Patrizia Murer
A1 Louis Plüss
A1 Dario Neri
YR 2019
UL http://biorxiv.org/content/early/2019/08/28/748962.abstract
AB 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 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 settings of minimal residual disease.ADCCAntibody-dependent cell-mediated cytotoxicityCDRComplementarity-determining regionCEACarcinoembyogenic antigenCFSE5(6)-Carboxyfluorescein diacetate N-succinimidyl esterCRCColorectal cancerEGFREndothelial growth factor receptorHAHAHuman anti-human antibodyMwMolecular weightPBMCPeripheral blood mononuclear cellscFvSingle chain variable fragmentVEGFVascular endothelial growth factorVLVariable domain of the light chainVHVariable domain of the heavy chain