Targeted killing of colorectal cancer cell lines by a humanised IgG1 monoclonal antibody that binds to membrane-bound carcinoembryonic antigen.
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.
Conaghan
Pj
P
Cancer Research UK, Cancer & Immunogenetics Laboratory, Weatherall Institute of Molecular Medicine, Headington, Oxford, UK.
Ashraf
Sq
S
Tytherleigh
Mg
M
Wilding
Jl
J
Tchilian
E
E
Bicknell
D
D
Mortensen
N Jmcc
NJ
Bodmer
Wf
W
D000911:Antibodies, Monoclonal / Q000627:therapeutic use*; D058846:Antibodies, Monoclonal, Murine-Derived; D000912:Antibodies, Neoplasm / Q000494:pharmacology; D000918:Antibody Specificity; D000936:Antigen-Antibody Complex / Q000378:metabolism; D000951:Antigens, Neoplasm / Q000378:metabolism; D000954:Antigens, Surface / Q000378:metabolism; D002272:Carcinoembryonic Antigen / Q000276:immunology / Q000378:metabolism*; D045744:Cell Line, Tumor; D015179:Colorectal Neoplasms / Q000628:therapy*; D003602:Cytotoxicity, Immunologic; D016503:Drug Delivery Systems; D006801:Humans; D007140:Immunoglobulin Fab Fragments / Q000276:immunology; D007074:Immunoglobulin G / Q000627:therapeutic use; D007694:Killer Cells, Natural / Q000276:immunology; D017452:Receptors, IgG / Q000276:immunology
D000911:Antibodies, Monoclonal; D058846:Antibodies, Monoclonal, Murine-Derived; D000912:Antibodies, Neoplasm; D000936:Antigen-Antibody Complex; D000951:Antigens, Neoplasm; D000954:Antigens, Surface; D002272:Carcinoembryonic Antigen; D007140:Immunoglobulin Fab Fragments; D007074:Immunoglobulin G; C511152:PR1A3 monoclonal antibody; D017452:Receptors, IgG