Biodistribution and in vivo antitumor efficacy of the systemically administered anti-human T-leukemia immunotoxins and potentiation of their efficacy by alpha-interferon.
In this study, the systemically administered anti-human T-leukemia immunotoxins (ITs) are shown to be effective for tumor suppression in Ichikawa T-leukemia-bearing nude mice. In addition, their antitumor efficacy was markedly potentiated by recombinant human IFN-alpha. The combination of ITs and IFN-alpha effectively killed the tumor in the majority of the treated mice; 9 of the 12 treated mice survived tumor-free for as long as they were followed, i.e. for 140 days. Two different ITs, SN1-ricin A chain (RA) and SN2-RA, were used together to minimize the problem of tumor heterogeneity; monoclonal antibodies SN1 and SN2 are directed toward two different human T-leukemia associated cell surface antigens. In the biodistribution experiments, the paired label technique was used to include a reliable internal control. In an experiment, equal amounts of 125I-SN1-RA and 131I-labelled isotype-matching control IgG (IgG1-kappa)-RA were mixed and administered i.v. into tumor-bearing nude mice. In a separate experiment, a mixture of equal amounts of 125I-SN2-RA and 131I-control IgG-RA was administered i.v. This technique allowed us to distinguish the immunospecific uptake from the non-immunospecific uptake of ITs into individual organs. The present results clearly show that both SN1-RA and SN2-RA are specifically localized in tumors after systemic administration. For instance, 24 h after the administration of a radiolabelled mixture, the ratio of 125I/131I in the tumor was 7.0 and 23.5, respectively, for the SN1-RA/control IgG-RA mixture and the SN2-RA/control IgG-RA mixture. Such high ratios of 125I/131I were detected in the tumors throughout the experiments between 30 min and 24 h after the administration of the paired label mixture.
Yokota
S
S
Department of Molecular Immunology, Roswell Park Cancer Institute, Buffalo, NY 14263.
Okazaki
M
M
Yoshida
M
M
Seon
B K
BK
D000818:Animals; D000911:Antibodies, Monoclonal / Q000627:therapeutic use; D000951:Antigens, Neoplasm / Q000032:analysis; D004357:Drug Synergism; D005260:Female; D006801:Humans; D000922:Immunotoxins / Q000378:metabolism / Q000627:therapeutic use*; D007370:Interferon Type I / Q000627:therapeutic use*; D007457:Iodine Radioisotopes; D015459:Leukemia-Lymphoma, Adult T-Cell / Q000276:immunology / Q000628:therapy*; D051379:Mice; D008819:Mice, Nude; D011994:Recombinant Proteins; D012276:Ricin / Q000627:therapeutic use*; D014018:Tissue Distribution; D014407:Tumor Cells, Cultured
D000911:Antibodies, Monoclonal; D000951:Antigens, Neoplasm; D000922:Immunotoxins; D007370:Interferon Type I; D007457:Iodine Radioisotopes; D011994:Recombinant Proteins; D012276:Ricin