Marked difference in the in vivo antitumor efficacy between two immunotoxins targeted to different epitopes of common acute lymphoblastic leukemia antigen (CD10). Mechanisms involved in the differential activities of immunotoxins.
In the present study, two isotype-matching mAb, SN5d and SN5, which are directed toward two distinctively different epitopes of common acute lymphoblastic leukemia Ag (CD10) but show a very similar binding affinity to leukemia cells, were compared for their in vivo antitumor activity after conjugated to ricin A chain (RA). Our recently established nude mouse model carrying an ascitic tumor of NALM-6 human pre-B leukemia cells was used as the tumor model. A marked difference was observed in the in vivo antitumor efficacy between SN5d-RA and SN5-RA; SN5d-RA was much more effective than SN5-RA. Several experiments were carried out to gain information concerning the mechanisms involved in the different antitumor efficacy of the two immunotoxins. Although naked (unconjugated) mAb SN5d was much less effective than SN5d-RA conjugates in the in vivo tumor suppression, mAb SN5d was more effective than mAb SN5 in the in vivo tumor suppression. Additionally, marked differences were found between SN5d and SN5 in the induction of antigenic modulation and in the regulation of Ag biosynthesis and expression. Binding of SN5 to NALM-6 leukemia cells caused strong antigenic modulation (down-regulation of Ag expression) and strongly down-regulated Ag biosynthesis and cell surface expression of new Ag. In contrast, binding of SN5d to NALM-6 leukemia cells caused little modulation of overall cell surface expression of common acute lymphoblastic leukemia Ag; the decrease of old Ag by endocytosis after binding to mAb SN5d was compensated by newly exocytosed cell-surface expressed Ag. The present results appear to reveal a novel mechanism which regulates cytotoxic activities of antibodies and immunoconjugates.
Department of Molecular Immunology, Roswell Park Cancer Institute, Buffalo, NY 14263.
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D000818:Animals; D000911:Antibodies, Monoclonal / Q000276:immunology; D000943:Antigens, Differentiation / Q000276:immunology*; D000951:Antigens, Neoplasm / Q000276:immunology*; D002470:Cell Survival; D004705:Endocytosis; D000939:Epitopes; D006801:Humans; D007074:Immunoglobulin G / Q000276:immunology; D007167:Immunotherapy; D000922:Immunotoxins / Q000633:toxicity*; D066298:In Vitro Techniques; D051379:Mice; D008819:Mice, Nude; D009368:Neoplasm Transplantation; D009374:Neoplasms, Experimental / Q000473:pathology / Q000628:therapy; D015260:Neprilysin; D010447:Peptide Hydrolases / Q000494:pharmacology; D011233:Precipitin Tests; D012276:Ricin / Q000008:administration & dosage
D000911:Antibodies, Monoclonal; D000943:Antigens, Differentiation; D000951:Antigens, Neoplasm; D000939:Epitopes; D007074:Immunoglobulin G; D000922:Immunotoxins; D012276:Ricin; D010447:Peptide Hydrolases; D015260:Neprilysin