Inhibition of Xenograft Tumor Growth and Down-Regulation of ErbB Receptors by an Antibody Directed against Lewis Y Antigen
Open Access
- 8 September 2006
- journal article
- Published by American Society for Pharmacology & Experimental Therapeutics (ASPET) in The Journal of pharmacology and experimental therapeutics
- Vol. 319 (3), 1459-1466
- https://doi.org/10.1124/jpet.106.107318
Abstract
The blood group-related Lewis Y antigen is expressed on the majority of human cancers of epithelial origin with only limited expression on normal tissue. Therefore, the Lewis Y antigen represents an interesting candidate for antibody-based treatment strategies. Previous experiments showed that the humanized Lewis Y-specific monoclonal antibody, IGN311, reduced ErbB-receptor-mediated stimulation of mitogen-activated protein kinase by altering receptor recycling. Here, we tested whether binding of IGN311 to growth factor receptors is relevant also to inhibition of tumor growth in vivo. Prolonged incubation with IGN311 of human tumor cell lines, which express high levels of ErbB1 (A431) or ErbB2 (SK-BR-3), resulted in down-regulation of the receptors and inhibition of cell proliferation. IGN311 inhibited the growth of tumors derived from A431 cells xenografted in nude mice. Treatment with IGN311 was associated with a down-regulation of ErbB1 in the excised tumor tissue. Importantly, these effects of IGN311 were also mimicked by the Fab fragment of IGN311. These data indicate that tumor cell growth inhibition by IGN311 cannot solely be accounted for by invoking cellular and humoral immunological mechanisms. A direct effect on signaling via binding to Lewis Y glycosylated growth factor receptors on tumor cells is also likely to contribute to the therapeutic effect of IGN311 in vivo.This publication has 16 references indexed in Scilit:
- Endocytosis and Sorting of ErbB2 and the Site of Action of Cancer Therapeutics Trastuzumab and GeldanamycinMolecular Biology of the Cell, 2004
- Antibodies Directed against Lewis-Y Antigen Inhibit Signaling of Lewis-Y Modified ErbB ReceptorsCancer Research, 2004
- Conditional mutation of the ErbB2 (HER2) receptor in cardiomyocytes leads to dilated cardiomyopathyProceedings of the National Academy of Sciences of the United States of America, 2002
- Increased expression of the blood group‐related Lewis Y antigen on synovial fluid granulocytes of patients with arthritic joint diseasesRheumatology, 2001
- Gemcitabine and carboplatin for patients with advanced non-small cell lung cancerSeminars in Oncology, 2001
- Use of hu-IgG-SCID mice to evaluate the in vivo stability of human monoclonal IgG antibodiesJournal of Immunological Methods, 1994
- Intermolecular cooperativity: a clue to why mice have IgG3?Immunology Today, 1992
- Correlation of Expression of H/LeY/LeBAntigens with Survival in Patients with Carcinoma of the LungThe New England Journal of Medicine, 1992
- Expression of Blood Group-Related Antigens, ABH, Lewisa, Lewisb, Lewisx, Lewisy, CA19-9, and CSLEX1 in Early Cancer, Intestinal Metaplasia, and Uninvolved Mucosa of the StomachAmerican Journal of Clinical Pathology, 1992
- Expression of Lewisa, Lewisb, and sialated Lewisa antigens in early and advanced human gastric cancersJournal of Surgical Oncology, 1990