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Molecular specific and cell selective cytotoxicity induced by a novel synthetic HLA-DR antibody mimic for lymphoma and leukemia

Authors :
Rodney L. Balhorn
Gerald L. DeNardo
Sally J. DeNardo
Laurel A. Beckett
Saphon Hok
Grete N. Adamson
Gary R. Mirick
Source :
International Journal of Oncology.
Publication Year :
1992
Publisher :
Spandidos Publications, 1992.

Abstract

Like rituximab, monoclonal antibodies reactive with human leukocyte antigen have potent antilymphoma activity. However, size limits their vascular and tissue pene- tration. To mimic monoclonal antibody binding, nanomolecules have been synthesized, shown specific for the s subunit of HLA-DR10, and selective for cells expressing this protein. Selective high affinity ligands (SHALs) containing the 3-(2- ((3-chloro-5-trifluoromethyl)-2-pyridinyl)oxy)-anilino)-3- oxopropanionic acid (Ct) ligand residualized and had anti- lymphoma activity against expressing cells. Herein, we show the extraordinary potency in mice with human lymphoma xenografts of a tridentate SHAL containing this ligand. After titrating antilymphoma activity in cell culture, a randomized preclinical study of a tridentate SHAL containing the Ct ligand was conducted in mice with established and aggressive human lymphoma xenografts. Mice having HLA-DR10 expressing Raji B- or Jurkat's T-lymphoma xenografts were randomly assigned to receive either treatment with SHAL at a dose of 100 ng i.p. weekly for 3 consecutive weeks, or to be untreated. Primary end-points were cure, overall response rates and survival. Toxicity was also evaluated in these mice, and a USFDA general safety study was conducted in healthy Balb/c mice. In Raji cell culture, the threshold and IC50 concentrations for cytotoxic activity were 0.7 and 2.5 nmol (pm/ml media), respectively. When compared to treated Jurkat's xenografts or untreated xenografts, Raji xenografts treated with the SHAL showed an 85% reduction in hazard of death (P=0.014; 95% confidence interval 32-95% reduction). There was no evidence for toxicity even after i.p. doses 2000 times greater than the treatment dose associated with cure of a majority of the mice with Raji xenografts. When compared with control groups, treatment selectively improved response rates and survival in mice with HLA-DR10 expressing human lymphoma xenografts at doses not associated with adverse events and readily achievable in patients.

Details

ISSN :
10196439
Database :
OpenAIRE
Journal :
International Journal of Oncology
Accession number :
edsair.doi...........aa918052bf62cb83a63be8e72ebbdf63
Full Text :
https://doi.org/10.3892/ijo_00000176