Antibodies to transcobalamin II block in vitro proliferation of leukemic cells.
The plasma protein transcobalamin II (TCII) binds and delivers cobalamin (Cbl; vitamin B12) to all cells, which internalize the TCII/Cbl complex by receptor-mediated endocytosis. Congenital deficiency of TCII results in intracellular Cbl deficiency, one effect of which is to disrupt DNA synthesis, leading to megaloblastic anemia. We report here an in vitro culture system in which cell growth is dependent on delivery of Cbl to cells by TCII. Recombinant human holo-TCII was shown to support in dose-dependent manner the growth of the human erythroleukemic cell line K562 and the murine lymphoma cell line BW5147. Free Cbl also supported cell growth; however, at 100- to 1,000-fold higher concentrations than those effective in the presence of apo-TCII. To determine if cellular depletion of Cbl could be achieved by interfering with interactions between TCII/Cbl and its cell-surface receptor, several monoclonal antibodies raised against human TCII were studied. Three antibodies, found to compete for the same binding site on TCII, proved to be effective inhibitors of TCII/Cbl-dependent cell growth. Our results suggest that monoclonal anti-TCII antibodies that block the function of this protein may prove useful in antitumor therapies.
McLean
G R
GR
Biomedical Research Centre, University of British Columbia, Vancouver, Canada.
Quadros
E V
EV
Rothenberg
S P
SP
Morgan
A C
AC
Schrader
J W
JW
Ziltener
H J
HJ
D000911:Antibodies, Monoclonal / Q000494:pharmacology*; D017209:Apoptosis / Q000187:drug effects; D002455:Cell Division / Q000187:drug effects; D005492:Folic Acid / Q000502:physiology; D006131:Growth Inhibitors / Q000494:pharmacology*; D006801:Humans; D004915:Leukemia, Erythroblastic, Acute / Q000473:pathology; D015464:Leukemia, Myelogenous, Chronic, BCR-ABL Positive / Q000473:pathology; D008223:Lymphoma / Q000473:pathology; D014411:Neoplastic Stem Cells / Q000187:drug effects*; D014155:Transcobalamins / Q000037:antagonists & inhibitors* / Q000276:immunology; D014407:Tumor Cells, Cultured; D014805:Vitamin B 12 / Q000494:pharmacology / Q000502:physiology
D000911:Antibodies, Monoclonal; D006131:Growth Inhibitors; D014155:Transcobalamins; D005492:Folic Acid; D014805:Vitamin B 12