PR1A3

A review.A polemic in response to Conaghan et al. (Br. J. Cancer 2008, 98, 1217-1225) is given.In their study, Conaghan et al. presented a statement that 'there are so far no unconjugated, or 'naked' antibodies to carcinoembryonic antigen (CEA) being used for treatment of colorectal cancer'.They also demonstrated some promising in vitro activity of a humanized anti-CEA antibody, PR1A3.The authors believed that Conaghan et al.'s statement is incorrect and hence, provided explanation for this.They also offered evidence for the superiority of the combined modality naked anti-CEA monoclonal antibody (MAb) immunotherapy and chemotherapy treatments.

The distribution of carcinoembryonic antigen (CEA) in colorectal cancer (CRC) differs from that in normal colorectal tissue, being found on all borders of the cell membrane and hence enabling access to intravenous antibody, making CEA a good target for antibody-based therapy. The distinctive anti-CEA antibody, PR1A3, binds only membrane-bound CEA. Humanised PR1A3 (hPR1A3) was assessed both in vitro cytotoxicity and binding assays with colorectal cancer cell lines expressing varying levels of CEA. Human peripheral blood mononuclear cells (PBMCs) and purified natural killer (NK) cells were used as effectors. The in vitro assays demonstrated hPR1A3 CEA-specific binding and antibody-dependent and CEA-specific killing of human colorectal cancer cell lines by human PBMCs. The effect increased with increasing concentration of antibody and surface CEA, and was lost by using the parent murine IgG1 PR1A3. Killing was also blocked by antibody to the Fc-gammaIIIA receptor. Purified human NK cells were effective at much lower effector:target ratios than unfractionated PBMCs, indicating that NK cells were the main mediators of hPR1A3-based CEA-specific killing. The results support the development of hPR1A3 for therapy of colorectal cancer.