Efficacy of an anti-CD7-ricin A chain immunoconjugate in a novel murine model of human T-cell leukemia.
In vivo efficacy testing of monoclonal antibody-based drugs specific for human leukemias is hampered by the paucity of suitable animal models, due in part to the inability of many anti-human monoclonal antibodies to cross-react with antigens expressed in animal tissues or cells. Moreover, human leukemic cells have proven difficult to establish in immunosuppressed mice except as solid tumors. We report here the establishment of a murine model for human leukemia displaying features of human disease, such as growth of malignant cells and localization of such cells to lymphoid compartments, and the effective depletion of leukemic cells from these mice by an immunoconjugate. Human T-leukemia cells (CEM) injected into cyclophosphamide-pretreated NIH-III mice engrafted in all mice (n = 41), with CEM cells detected in the bone marrow, spleen, and blood 4 weeks after injection. There was no evidence of solid tumors. Treatment of CEM-engrafted mice with 4A2-RTA30, an immunoconjugate of an anti-CD7 monoclonal antibody and ricin A chain (RTA30), resulted in a 100- to 200-fold overall depletion of CEM cells from the spleen and the bone marrow (P less than 0.02). This depletion was specific and toxin-dependent, as a control immunoconjugate had no demonstrable effect (P greater than 0.5). Depletion of CEM cells was also observed after treatment with unconjugated anti-CD7 mAb, but this effect was not significantly different from controls (P greater than 0.1). Therefore, significant depletion of CEM cells required the presence of the ricin A chain moiety. Further investigations revealed that CEM cells recovered from NIH-III mice expressed less CD7 antigen, but remained sensitive to subsequent in vitro exposure to 4A2-RTA30. In conclusion, we have established a model for studying the efficacy of immunoconjugates and have successfully depleted human T-leukemic cells from lymphoid tissues in immunodeficient mice by treatment with an anti-CD7-RTA30 immunoconjugate.
Fishwild
D M
DM
Department of Immunology, XOMA Corporation, Berkeley, California 94710.
Aberle
S
S
Bernhard
S L
SL
Kung
A H
AH
D000818:Animals; D000911:Antibodies, Monoclonal / Q000627:therapeutic use; D015703:Antigens, CD / Q000032:analysis / Q000276:immunology*; D019011:Antigens, CD7; D000945:Antigens, Differentiation, T-Lymphocyte / Q000276:immunology*; D002460:Cell Line; D003520:Cyclophosphamide / Q000494:pharmacology; D004334:Drug Administration Schedule; D004353:Drug Evaluation, Preclinical; D004354:Drug Screening Assays, Antitumor; D006649:Histocompatibility Antigens / Q000032:analysis; D006801:Humans; D007165:Immunosuppression Therapy; D000922:Immunotoxins / Q000627:therapeutic use* / Q000633:toxicity; D015459:Leukemia-Lymphoma, Adult T-Cell / Q000628:therapy*; D017493:Leukocyte Common Antigens; D008297:Male; D008562:Membrane Glycoproteins / Q000032:analysis; D051379:Mice; D008815:Mice, Inbred Strains; D009368:Neoplasm Transplantation / Q000379:methods; D012276:Ricin / Q000627:therapeutic use* / Q000633:toxicity; D014183:Transplantation, Heterologous
D000911:Antibodies, Monoclonal; D015703:Antigens, CD; D019011:Antigens, CD7; D000945:Antigens, Differentiation, T-Lymphocyte; D006649:Histocompatibility Antigens; D000922:Immunotoxins; D008562:Membrane Glycoproteins; D003520:Cyclophosphamide; D012276:Ricin; D017493:Leukocyte Common Antigens