Efficacy of an anti-CD5-ricin A chain immunoconjugate in an improved human peripheral blood lymphocyte--reconstituted severe combined immunodeficient mouse model.
Severe combined immunodeficient mice reconstituted with human peripheral blood lymphocytes (hu-PBL-SCID mice) were used to evaluate in vivo efficacy of a mouse IgG1 monoclonal antibody (mAb)-ricin toxin A chain immunoconjugate (H65-RTA) directed against the CD5 cell surface antigen present on human T-cells. Initial studies demonstrated that plasma levels of human soluble interleukin-2 receptor (sIL-2R) are predictive of human T-cell engraftment in spleens and blood of SCID mice transplanted with human PBL. Therefore, chimeric mice with detectable plasma levels of human sIL-2R were used in subsequent studies. Systemic injection of such mice with H65-RTA resulted in a significant depletion of human T-cells from spleens, blood and bone marrow, and a decrease in plasma levels of human sIL-2R as compared to vehicle-treated control animals. The effect of H65-RTA was dose-dependent, treatment schedule-dependent, and mAb-specific, as an isotype-, linker- and toxin-matched immunoconjugate of irrelevant binding specificity was not efficacious. Moreover, human T-cells remained depleted from SCID tissues for at least 10 days after cessation of H65-RTA treatment, indicating that the cells were killed by the immunoconjugate. Unconjugated H65 mAb and an H65-derived F(ab')2-RTA conjugate, but not unconjugated F(ab')2, were also efficacious, suggesting that the Fc portion of the mAb and the toxin moiety may both play a role in the mechanism of human T-cell depletion by H65-RTA in this model. Results indicate that the hu-PBL-SCID mouse model can be used to compare in vivo efficacy of immunosuppressive agents specifically directed against human T-cells.
Kohn
F R
FR
Department of Pharmacology and Toxicology, XOMA Corporation, Berkeley, CA 94710.
Fishwild
D M
DM
Kung
A H
AH
D000818:Animals; D015703:Antigens, CD / Q000276:immunology*; D018956:CD5 Antigens; D004305:Dose-Response Relationship, Drug; D006801:Humans; D007136:Immunoglobulins / Q000097:blood; D000922:Immunotoxins / Q000008:administration & dosage / Q000494:pharmacology*; D008212:Lymphocyte Depletion; D017710:Lymphocyte Transfusion; D051379:Mice; D016513:Mice, SCID; D015375:Receptors, Interleukin-2 / Q000032:analysis; D012276:Ricin / Q000494:pharmacology*; D013601:T-Lymphocytes / Q000637:transplantation*; D014183:Transplantation, Heterologous
D015703:Antigens, CD; D018956:CD5 Antigens; D007136:Immunoglobulins; D000922:Immunotoxins; D015375:Receptors, Interleukin-2; D012276:Ricin