Therapy of human T-cell acute lymphoblastic leukaemia in severe combined immunodeficient mice with two different anti-CD7-saporin immunotoxins containing hindered or non-hindered disulphide cross-linkers.
A SCID mouse model of human T-ALL has been used to determine the in vivo therapeutic efficacy of two anti-CD7-saporin immunotoxins constructed with either a hindered (HB2-SMPT-Sap) or non-hindered (HB2-SPDP-Sap) disulphide bond between antibody and saporin. Groups of 10 SCID mice were injected intravenously (i.v.) with 2 x 10(6) human T-ALL HSB-2 cells followed seven days later by i.v. injection with either a single dose or with 3 doses of HB2-SPDP-Sap or HB2-SMPT-Sap given on alternate days. Control groups received equivalent sham injections of PBS or molar equivalent amounts of unconjugated HB2 antibody+saporin. Animals receiving a single dose of HB2-SMPT-Sap showed better survival than animals receiving a single dose of HB2-SPDP-Sap but the difference was not shown to be significant by log-rank analysis. When given as a triple dose both immunotoxins performed similarly. Comparison of single-dose with triple-dose IT therapy revealed that the therapeutic effect of a triple dose of HB2-SPDP-Sap was significantly better than that of single dose, but this was not the case with HB2-SMPT-Sap. Pharmacokinetic studies of HB2-SPDP-Sap and HB2-SMPT-Sap in normal and HSB-2 leukaemia bearing SCID mice failed to reveal any difference in clearance rates for these two IT's. We conclude from these studies that there is no therapeutic advantage to be gained from constructing the HB2-Sap IT with a hindered disulphide bond in this particular model of human T-ALL.
Flavell
D J
DJ
Simon Flavell Leukaemia Research Laboratory, University Department of Pathology, Southampton General Hospital, UK.
Boehm
D A
DA
Okayama
K
K
Kohler
J A
JA
Flavell
S U
SU
D000818:Animals; D000906:Antibodies / Q000378:metabolism / Q000494:pharmacology; D015703:Antigens, CD / Q000276:immunology; D019011:Antigens, CD7; D000945:Antigens, Differentiation, T-Lymphocyte / Q000276:immunology; D000972:Antineoplastic Agents, Phytogenic / Q000494:pharmacology*; D002675:Child, Preschool; D003432:Cross-Linking Reagents / Q000737:chemistry / Q000494:pharmacology; D004195:Disease Models, Animal; D004220:Disulfides / Q000737:chemistry / Q000494:pharmacology*; D004305:Dose-Response Relationship, Drug; D004591:Electrophoresis, Polyacrylamide Gel; D005260:Female; D006801:Humans; D000922:Immunotoxins / Q000276:immunology / Q000378:metabolism / Q000494:pharmacology*; D015459:Leukemia-Lymphoma, Adult T-Cell / Q000188:drug therapy* / Q000276:immunology* / Q000378:metabolism; D008297:Male; D051379:Mice; D008807:Mice, Inbred BALB C; D008810:Mice, Inbred C57BL; D008813:Mice, Inbred ICR; D016513:Mice, SCID; D009699:N-Glycosyl Hydrolases; D009363:Neoplasm Proteins / Q000096:biosynthesis; D009368:Neoplasm Transplantation; D010940:Plant Proteins / Q000494:pharmacology*; D054789:Ribosome Inactivating Proteins, Type 1; D000076985:Saporins; D013329:Structure-Activity Relationship; D013388:Succinimides / Q000737:chemistry / Q000494:pharmacology; D014407:Tumor Cells, Cultured
D000906:Antibodies; D015703:Antigens, CD; D019011:Antigens, CD7; D000945:Antigens, Differentiation, T-Lymphocyte; D000972:Antineoplastic Agents, Phytogenic; D003432:Cross-Linking Reagents; D004220:Disulfides; D000922:Immunotoxins; D009363:Neoplasm Proteins; D010940:Plant Proteins; D054789:Ribosome Inactivating Proteins, Type 1; D013388:Succinimides; C058151:4-succinimidyloxycarbonyl-alpha-methyl-alpha(2-pyridyldithio)toluene; C018151:N-succinimidyl 3-(2-pyridyldithio)propionate; D009699:N-Glycosyl Hydrolases; D000076985:Saporins