Cell cycle inhibition by an anti-cyclin D1 antibodychemically modified for intracellular delivery.
Antibodies, especially monoclonal antibodies, are highly specific for their target antigens and have found extensive clinical application in the treatment of infectious diseases and neoplasia. However, they have a major shortcoming which, if overcome, would greatly expand their utility: an inability to penetrate the outer membrane of cells and act on intracellular targets. We demonstrated previously that this deficiency could be overcome by covalent linkage of an oligoarginine sequence to the conserved carbohydrate moiety present in the CH2 region of immunoglobulins. Immune specificity was maintained but no attempt was made to test for biological activity related to specificity. Here, we report that a polyarginated monoclonal anti-cyclin D1 enters cells and inhibits cell cycle progression. We demonstrate this with NIH 3T3 cells and with two tumor cell lines, HT29 and SW480. As many tumors overexpress cyclin D1, an intracellular anti-cyclin D1, properly targeted, has the potential to be a novel broad range inhibitor of tumor cell multiplication. Moreover, success with intracellular anti-cyclin D1 suggests that polyarginated antibodies, in general, could be a new, widely applicable experimental tool to investigate and influence intracellular processes, whether native to cells or introduced into cells by outside entities such as viruses.
Chen
Bi-Xing
BX
Department of Microbiology, Columbia University, 701 West 168 Street, New York, NY 10032, USA.
Erlanger
Bernard F
BF
D000818:Animals; D000911:Antibodies, Monoclonal / Q000737:chemistry / Q000494:pharmacology*; D002453:Cell Cycle / Q000187:drug effects*; D049109:Cell Proliferation; D019938:Cyclin D1 / Q000276:immunology*; D016503:Drug Delivery Systems; D019073:HT29 Cells / Q000187:drug effects; D006801:Humans; D007124:Immunoenzyme Techniques; D051379:Mice; D041681:NIH 3T3 Cells / Q000187:drug effects; D009369:Neoplasms / Q000473:pathology; D010455:Peptides / Q000737:chemistry*; D014407:Tumor Cells, Cultured
D000911:Antibodies, Monoclonal; D010455:Peptides; D019938:Cyclin D1; C015462:polyarginine