Molecular specific and cell selective cytotoxicity induced by a novel synthetic HLA-DR antibody mimic for lymphoma and leukemia.
Like rituximab, monoclonal antibodies reactive with human leukocyte antigen have potent antilymphoma activity. However, size limits their vascular and tissue penetration. To mimic monoclonal antibody binding, nanomolecules have been synthesized, shown specific for the beta 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 antilymphoma 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.
DeNardo
G L
GL
University of California, Davis Medical Center, Sacramento, CA 95816, USA. gldenardo@ucdavis.edu
Mirick
G R
GR
Hok
S
S
DeNardo
S J
SJ
Beckett
L A
LA
Adamson
G N
GN
Balhorn
R L
RL
D000818:Animals; D045744:Cell Line, Tumor / Q000473:pathology / Q000637:transplantation; D002470:Cell Survival; D006684:HLA-DR Antigens / Q000276:immunology*; D006801:Humans; D007136:Immunoglobulins / Q000276:immunology*; D019169:Jurkat Cells; D007938:Leukemia / Q000188:drug therapy / Q000276:immunology* / Q000401:mortality / Q000473:pathology; D008223:Lymphoma / Q000188:drug therapy / Q000276:immunology* / Q000401:mortality / Q000473:pathology; D051379:Mice; D008807:Mice, Inbred BALB C; D008819:Mice, Nude; D009368:Neoplasm Transplantation; D016019:Survival Analysis; D014183:Transplantation, Heterologous
D006684:HLA-DR Antigens; D007136:Immunoglobulins