Anti-CD7 antibody and immunotoxin treatment of human CD7(+)T-cell leukaemia is significantly less effective in NOD/LtSz-scid mice than in CB.17 scid mice.
Groups of 8 to ten SCID (CB.17 scid/scid) or NOD/SCID (NOD/LtSz- scid/scid) mice were injected i.v. with two million human HSB-2 T-ALL cells on day 1 (SCID-HSB-2 and NOD/SCID-HSB-2 mice) and treated later with 3 i.v. 10 microg doses of the anti-CD7 antibody HB2 on days 7, 9 and 11 or with a single 10 microg dose of HB2-SAPORIN or a 7.4 microg dose of HB2-F(ab)(2)-SAPORIN immunotoxin (IT) on day 7. Treatment of SCID-HSB-2 mice with HB2-SAPORIN led to a significant prolongation in the time to development of signs and symptoms of disease compared with PBS sham-treated controls with 80% of animals surviving disease-free. In contrast treatment with HB2-F(ab)(2)-SAPORIN was significantly less effective in SCID-HSB-2 mice with 80% of animals in this treatment group developing leukaemia over the course of the study. HB2 antibody treatment of SCID-HSB-2 mice also led to a significant prolongation in time to leukaemia development compared with sham-treated controls with 37% of animals in this treatment group disease-free at termination of the study. In contrast HB2 antibody treatment of NOD/SCID-HSB-2 mice had no therapeutic effect in these animals and the therapeutic effectiveness of both HB2-SAPORIN and HB2-F(ab)(2)-SAPORIN ITs was similar and significantly reduced compared to the effect observed in SCID-HSB-2 mice. It was initially thought that the lack of therapeutic effect of antibody and IT in NOD-SCID-HSB-2 mice might relate to their putative lack of NK cells but flow cytometric and functional studies with NOD-SCID mouse splenocytes revealed that these animals do have some functional NK cells though fewer in number and possibly lower in functionality than those of SCID mice. We reason that the complete lack of therapeutic effect of HB2 antibody and the reduced effect of HB2-SAPORIN in NOD/SCID mice is due to the reduced cytolytic activity of NOD/SCID NK cells which is probably below a certain critical threshold value in these animals. We conclude from this that immunotherapeutics like HB2-SAPORIN would be more accurately assessed for intrinsic potency in NOD/SCID mice where the effects of NK cell and possibly other non-adaptive immune mechanisms would not have a significant influence.
Flavell
D J
DJ
The Simon Flavell Leukaemia Research Unit, Division of Cancer Sciences, University of Southampton School of Medicine, Southampton General Hospital, Southampton, Hampshire, SO16 6YD, UK.
Warnes
S L
SL
Noss
A L
AL
Flavell
S U
SU
D000818:Animals; D000911:Antibodies, Monoclonal / Q000008:administration & dosage*; D000920:Antibody-Dependent Cell Cytotoxicity; D019011:Antigens, CD7 / Q000276:immunology*; D004305:Dose-Response Relationship, Drug; D005260:Female; D006801:Humans; D018796:Immunoconjugates / Q000008:administration & dosage; D007140:Immunoglobulin Fab Fragments / Q000008:administration & dosage; D016130:Immunophenotyping; D000922:Immunotoxins / Q000008:administration & dosage*; D015459:Leukemia-Lymphoma, Adult T-Cell / Q000276:immunology / Q000401:mortality / Q000628:therapy*; D008297:Male; D051379:Mice; D016688:Mice, Inbred NOD; D016513:Mice, SCID; D009699:N-Glycosyl Hydrolases; D010940:Plant Proteins / Q000008:administration & dosage; D054789:Ribosome Inactivating Proteins, Type 1; D000076985:Saporins; D013045:Species Specificity; D013047:Specific Pathogen-Free Organisms; D013154:Spleen / Q000166:cytology / Q000187:drug effects / Q000276:immunology; D016019:Survival Analysis; D015996:Survival Rate; D016896:Treatment Outcome; D014407:Tumor Cells, Cultured; D023041:Xenograft Model Antitumor Assays
D000911:Antibodies, Monoclonal; D019011:Antigens, CD7; D018796:Immunoconjugates; D007140:Immunoglobulin Fab Fragments; D000922:Immunotoxins; D010940:Plant Proteins; D054789:Ribosome Inactivating Proteins, Type 1; D009699:N-Glycosyl Hydrolases; D000076985:Saporins