Binding characteristics and antitumor properties of 1A10 bispecific antibody recognizing gp40 and human transferrin receptor.
The bispecific murine monoclonal antibody (MAb) 1A10 has specificity for the human transferrin receptor (TfR) and the human tumor-associated antigen gp40. This antibody, therefore, functions as an "antigen fork" by binding to two distinct antigens on the same malignant cell. Highly purified 1A10 inhibits the growth of cells coexpressing high levels of human TfR and the tumor-associated antigen gp40 by binding to both target antigens. In SW948 cells, the majority of 1A10 binding is via its gp40 specificity, and half-maximal inhibition of cell growth by 3-(4, 5-dimethylthiazol-2-yl)-2,5-diphenyltetrazolium bromide assay requires 20-30-micrograms/ml concentrations of 1A10. The binding of 1A10 correlates with growth inhibition in the cell lines HT-29, SK-OV-3, OVCAR-2, and OVCAR-3. The growth of OVCAR-10 cells, which express little gp40 and TfR, is not inhibited by 1A10. However, SK-BR-3 cells, which express abundant gp40 and extremely high levels of TfR, are insensitive to the effects of 1A10. In some cell lines, combined exposure to 1A10 and the iron chelator deferoxamine mesylate has synergistic antiproliferative effects. A single i.p. dose of 600 micrograms 1A10 is sufficient to achieve an estimated tumor concentration of at least 30 micrograms/ml for 7 days in C.B17/Icr-scid mice bearing SW948 human tumor xenografts. Treatment of scid mice bearing day 2 or day 4 SW948 xenografts with single or multiple 1A10 doses inhibits tumor growth in a dose-related fashion. Antitumor effects are not seen with therapy using either parental antibody of 1A10. The antiproliferative properties of 1A10 in tumor cells overexpressing gp40 and TfR suggest avenues for the development of new bispecific antibody-promoted treatment strategies.
Department of Medical Oncology, Fox Chase Cancer Center, Philadelphia, Pennsylvania 19111, USA.
A R
AR
Amoroso
J I
JI
Clark
S
S
Litwin
S
S
Hsieh-Ma
T
T
Shi
R K
RK
Alpaugh
G P
GP
Adams
E J
EJ
Wolf
D B
DB
Ring
L M
LM
Weiner
D000818:Animals; D018033:Antibodies, Bispecific / Q000276:immunology* / Q000494:pharmacology / Q000627:therapeutic use; D000951:Antigens, Neoplasm / Q000276:immunology*; D000970:Antineoplastic Agents / Q000276:immunology / Q000494:pharmacology / Q000627:therapeutic use; D001667:Binding, Competitive; D002455:Cell Division / Q000187:drug effects; D006801:Humans; D008562:Membrane Glycoproteins / Q000276:immunology*; D051379:Mice; D016513:Mice, SCID; D009368:Neoplasm Transplantation; D009374:Neoplasms, Experimental / Q000628:therapy; D011869:Radioligand Assay; D011990:Receptors, Transferrin / Q000276:immunology*; D014407:Tumor Cells, Cultured
D018033:Antibodies, Bispecific; D000951:Antigens, Neoplasm; D000970:Antineoplastic Agents; D008562:Membrane Glycoproteins; D011990:Receptors, Transferrin; C035267:glycoprotein 40 antigen, human