Targeted Killing of Colorectal Cancer Cell Lines by a Humanised IgG1 Monoclonal Antibody That Binds to Membrane-bound Carcinoembryonic Antigen

Overview

Journal Br J Cancer

Specialty Oncology

Date 2008 Mar 20

PMID 18349843

Citations 13

Authors

Pj Conaghan

Sq Ashraf

Mg Tytherleigh

Jl Wilding

E Tchilian

D Bicknell

N Jmcc Mortensen

Wf Bodmer

Affiliations

Soon will be listed here.

Abstract

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.

Citing Articles

Tumor resistance to anti-mesothelin CAR-T cells caused by binding to shed mesothelin is overcome by targeting a juxtamembrane epitope.

Liu X, Onda M, Schlomer J, Bassel L, Kozlov S, Tai C Proc Natl Acad Sci U S A. 2024; 121(4):e2317283121.

PMID: 38227666 PMC: 10823246. DOI: 10.1073/pnas.2317283121.

CEACAMS 1, 5, and 6 in disease and cancer: interactions with pathogens.

Thomas J, Klebanov A, John S, Miller L, Vegesna A, Amdur R Genes Cancer. 2023; 14:12-29.

PMID: 36741860 PMC: 9891707. DOI: 10.18632/genesandcancer.230.

Immunotherapeutic progress and application of bispecific antibody in cancer.

Kang J, Sun T, Zhang Y Front Immunol. 2022; 13:1020003.

PMID: 36341333 PMC: 9630604. DOI: 10.3389/fimmu.2022.1020003.

Structural design of tetravalent T-cell engaging bispecific antibodies: improve developability by engineering disulfide bonds.

Yu L, Huang N, Ge L, Sun H, Fu Y, Liu C J Biol Eng. 2021; 15(1):18.

PMID: 34187511 PMC: 8243740. DOI: 10.1186/s13036-021-00272-7.

Adjuvant properties of IFN-γ and GM-CSF in the scFv6.C4 DNA vaccine against CEA-expressing tumors.

Zanetti B, Ferreira C, Vasconcelos J, Han S Gene Ther. 2021; 30(1-2):41-50.

PMID: 34108629 DOI: 10.1038/s41434-021-00270-w.

References

Allum W, Macdonald F, Anderson P, FIELDING J . Localisation of gastrointestinal cancer with a 131 I labelled monoclonal antibody to CEA. Br J Cancer. 1986; 53(2):203-10. PMC: 2001340. DOI: 10.1038/bjc.1986.36. View

Olszewski A, Grossbard M . Empowering targeted therapy: lessons from rituximab. Sci STKE. 2004; 2004(241):pe30. DOI: 10.1126/stke.2412004pe30. View

Boyum A . Separation of leukocytes from blood and bone marrow. Introduction. Scand J Clin Lab Invest Suppl. 1968; 97:7. View

Gold P, Freedman S . DEMONSTRATION OF TUMOR-SPECIFIC ANTIGENS IN HUMAN COLONIC CARCINOMATA BY IMMUNOLOGICAL TOLERANCE AND ABSORPTION TECHNIQUES. J Exp Med. 1965; 121:439-62. PMC: 2137957. DOI: 10.1084/jem.121.3.439. View

Moretta A, Tambussi G, Ciccone E, Pende D, Melioli G, Moretta L . CD16 surface molecules regulate the cytolytic function of CD3CD16+ human natural killer cells. Int J Cancer. 1989; 44(4):727-30. DOI: 10.1002/ijc.2910440429. View

Nimmerjahn F, Ravetch J . Divergent immunoglobulin g subclass activity through selective Fc receptor binding. Science. 2005; 310(5753):1510-2. DOI: 10.1126/science.1118948. View

Wiratkapun S, Kraemer M, Seow-Choen F, Ho Y, Eu K . High preoperative serum carcinoembryonic antigen predicts metastatic recurrence in potentially curative colonic cancer: results of a five-year study. Dis Colon Rectum. 2001; 44(2):231-5. DOI: 10.1007/BF02234298. View

Hammarstrom S . The carcinoembryonic antigen (CEA) family: structures, suggested functions and expression in normal and malignant tissues. Semin Cancer Biol. 1999; 9(2):67-81. DOI: 10.1006/scbi.1998.0119. View

Adams G, Schier R, McCALL A, Simmons H, Horak E, Alpaugh R . High affinity restricts the localization and tumor penetration of single-chain fv antibody molecules. Cancer Res. 2001; 61(12):4750-5. View

10.

Stewart L, Young S, Watson G, Mather S, Bates P, Band H . Humanisation and characterisation of PR1A3, a monoclonal antibody specific for cell-bound carcinoembryonic antigen. Cancer Immunol Immunother. 1999; 47(6):299-306. PMC: 11037341. DOI: 10.1007/s002620050534. View

11.

Durbin H, Bodmer W . A sensitive micro-immunoassay using beta-galactosidase/anti-beta-galactosidase complexes. J Immunol Methods. 1987; 97(1):19-27. DOI: 10.1016/0022-1759(87)90100-1. View

12.

Welt S, Divgi C, Real F, Yeh S, Garin-Chesa P, Finstad C . Quantitative analysis of antibody localization in human metastatic colon cancer: a phase I study of monoclonal antibody A33. J Clin Oncol. 1990; 8(11):1894-906. DOI: 10.1200/JCO.1990.8.11.1894. View

13.

Arnould L, Gelly M, Penault-Llorca F, Benoit L, Bonnetain F, Migeon C . Trastuzumab-based treatment of HER2-positive breast cancer: an antibody-dependent cellular cytotoxicity mechanism?. Br J Cancer. 2006; 94(2):259-67. PMC: 2361112. DOI: 10.1038/sj.bjc.6602930. View

14.

Liljefors M, Nilsson B, Hjelm Skog A, Ragnhammar P, Mellstedt H, Frodin J . Natural killer (NK) cell function is a strong prognostic factor in colorectal carcinoma patients treated with the monoclonal antibody 17-1A. Int J Cancer. 2003; 105(5):717-23. DOI: 10.1002/ijc.11139. View

15.

Granowska M, Jass J, Britton K, Northover J . A prospective study of the use of 111In-labelled monoclonal antibody against carcino-embryonic antigen in colorectal cancer and of some biological factors affecting its uptake. Int J Colorectal Dis. 1989; 4(2):97-108. DOI: 10.1007/BF01646868. View

16.

Brattain M, Fine W, Khaled F, Thompson J, Brattain D . Heterogeneity of malignant cells from a human colonic carcinoma. Cancer Res. 1981; 41(5):1751-6. View

17.

Durbin H, Young S, Stewart L, Wrba F, Rowan A, Snary D . An epitope on carcinoembryonic antigen defined by the clinically relevant antibody PR1A3. Proc Natl Acad Sci U S A. 1994; 91(10):4313-7. PMC: 43775. DOI: 10.1073/pnas.91.10.4313. View

18.

Carter P . Potent antibody therapeutics by design. Nat Rev Immunol. 2006; 6(5):343-57. DOI: 10.1038/nri1837. View

19.

DELALOYE B, Bischof-Delaloye A, Buchegger F, Von Fliedner V, Grob J, Volant J . Detection of colorectal carcinoma by emission-computerized tomography after injection of 123I-labeled Fab or F(ab')2 fragments from monoclonal anti-carcinoembryonic antigen antibodies. J Clin Invest. 1986; 77(1):301-11. PMC: 423340. DOI: 10.1172/JCI112291. View

20.

Richman P, Bodmer W . Monoclonal antibodies to human colorectal epithelium: markers for differentiation and tumour characterization. Int J Cancer. 1987; 39(3):317-28. DOI: 10.1002/ijc.2910390309. View