title: TP-3 immunotoxins improve antitumor activity in mice with osteosarcoma.
abstract: We measured the antitumor activity of two types of TP-3 immunotoxins that target an antigen expressed in tumors associated with osteosarcoma. Development of novel agents for treatment of patients with osteosarcoma is important. We previously described a monovalent-disulfide-stabilized recombinant immunotoxin made from the TP-3 antibody. This agent is called TP-3(dsFv)-PE38 and is cytotoxic to human osteosarcoma cells in vitro. To improve antigen binding, we designed and produced a bivalent immunotoxin, TP-3(dsFv)2-PE38. We evaluated the activity of both molecules in vitro and in vivo using tumor-bearing mice. Compared with the monovalent TP-3 immunotoxin, the bivalent TP-3 immunotoxin showed an approximately sevenfold increase in cytotoxic activity against three osteosarcoma cell lines which react with the TP-3 monoclonal antibody. The apparent affinity of the bivalent TP-3 immunotoxin was 12-fold greater than that of the monovalent TP-3 immunotoxin. The antitumor activities of both TP-3 immunotoxins were measured using severe combined immunodeficient mice bearing osteosarcoma cell line OHS-M1 tumors. The dose at which the bivalent TP-3 immunotoxin produces complete regressions of tumors is (1/2) that of the monovalent TP-3 immunotoxin. Increasing the avidity of TP-3(dsFv)-PE38 significantly improves its cytotoxic activity in vitro and results in a twofold increase in antitumor activity in vivo. Because TP-3-based immunotoxins have good antitumor activity in mice, these molecules merit additional development for possible treatment of osteosarcoma in humans.
authors.affiliation: Laboratory of Molecular Biology, Center for Cancer Research, National Cancer Institute, National Institutes of Health, Bethesda, MD 20892-4264, USA. ondam@pop.nci.nih.gov
authors.forename: Masanori
authors.initials: M
authors.lastname: Onda
authors.forename: Øyvind S
authors.initials: ØS
authors.lastname: Bruland
authors.forename: Ira
authors.initials: I
authors.lastname: Pastan
mesh_terms: D000818:Animals; D001859:Bone Neoplasms / Q000188:drug therapy* / Q000276:immunology*; D004195:Disease Models, Animal; D004305:Dose-Response Relationship, Drug; D006801:Humans; D000922:Immunotoxins / Q000627:therapeutic use*; D051379:Mice; D016513:Mice, SCID; D012516:Osteosarcoma / Q000188:drug therapy* / Q000276:immunology*; D010446:Peptide Fragments / Q000276:immunology / Q000627:therapeutic use*; D013946:Thymopoietins / Q000276:immunology / Q000627:therapeutic use*; D016896:Treatment Outcome; D023041:Xenograft Model Antitumor Assays / Q000379:methods
chemical_list: D000922:Immunotoxins; D010446:Peptide Fragments; D013946:Thymopoietins; C051920:splenotritin