A novel human monoclonal antibody specific to the A33 glycoprotein recognizes colorectal cancer and inhibits metastasis

Abstract

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 Vdomain 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.

Intestinal phenotype is maintained by Atoh1 in the cancer region of intraductal papillary mucinous neoplasm

“…36 Altogether, the development of cancer therapy using GPA33 antibody might be useful in the therapy of GPA33-positive IPMN. 37,38 Although GPA33 was expressed in all samples of intestinal-type IPMN in the present study, conducting further analysis using a large number Atoh1 exerts different roles in tumorigenesis in different types of tumors. It serves as a tumor suppressor in Merkel cell carcinoma and sporadic colon cancer, whereas it becomes an oncogene in smallcell lung carcinoma and mucinous colon cancer.…”

“…Using animal models, GPA33 antibody was developed in combination with CD3 antibody and resulted in tumor growth inhibition 36 . Altogether, the development of cancer therapy using GPA33 antibody might be useful in the therapy of GPA33‐positive IPMN 37,38 . Although GPA33 was expressed in all samples of intestinal‐type IPMN in the present study, conducting further analysis using a large number of samples is necessary to understand the frequency of GPA33‐positive cancer in IPMN.…”

The role of microvesicles as biomarkers in the screening of colorectal neoplasm

“…With little overlap, total plasma annexin‐V+ MVs were significantly high in patients with BCRP, and CRC compared to healthy controls. Furthermore, biomarkers that were described for their prognostic, but often poor diagnostic values in colorectal neoplasia, such as CEA, 14 EPHB2, 15 ICAM‐1, 16 LGR5, 17 A33, 18 CD31 19 and CD42a (a platelet membrane glycoprotein), 29 can be used to isolate MV populations that we discovered to have exceptionally high predictive value. Most importantly, MVs were highly predictive of BCRP, yielding an impressively positive predictive value of 93%.…”

“…Biomarkers with potential roles in tumorigenesis and progression, such as carcinoembryonic antigen (CEA), 14 ephrin‐type‐B receptor 2 (EPHB2), 15 intracellular adhesion molecule 1 (ICAM‐1 or CD54), 16 leucine‐rich repeat containing G protein‐coupled receptor 5 (LGR5), 17 glycoprotein A33 antigen (A33), 18 platelet endothelial cell adhesion molecule (PECAM‐1), also known as CD31, 19 and platelet membrane glycoprotein IX, also known as CD42a, 20 may demonstrate a useful role in early CRC detection. For example, the serum level of CEA is currently used to monitor therapy and recurrence, however, due to poor sensitivity and specificity it is unreliable for early detection of patients with colorectal neoplasm 21 .…”