Gene/Protein Disease Symptom Drug Enzyme Compound
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Query: UNIPROT:P30536 (PBS)
 9,886 document(s) hit in 31,850,051 MEDLINE articles (0.00 seconds)

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.
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PMID: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. 751 86

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.
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PMID: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. 1110 77

Severe combined immunodeficient (SCID) mice injected i.v. with the human T-ALL cell line CCRF CEM (SCID-CEM mice) develop within 50 days life-threatening multi-organ growth of leukaemia cells. The development of leukaemia in SCID-CEM mice treated with three 10 microg i.v. doses of the anti-CD7 immunotoxin (IT) HB2-SAPORIN or the anti-CD38 IT OKT10-SAPORIN was significantly delayed compared with PBS sham-treated animals but 90% of animals treated with either IT eventually developed disseminated leukaemia cell growth. In contrast treatment of SCID-CEM mice with a combination of both ITs led not only to a significantly greater delay in time to leukaemia development but also in the numbers of animals remaining leukaemia free (60%). The native HB2 and OKT10 antibodies (both murine IgG1antibodies) exerted significant, though relatively weak therapeutic effects, probably mediated through an antibody-dependent cellular cytotoxicity (ADCC) mechanism. Moreover, there was no in vivo additivity of therapeutic effect when both antibodies were used in combination. Apparent, however, was that the combination of HB2-SAPORIN IT with OKT10 antibody led to an intermediate therapeutic effect that was significantly greater than that obtained when either was used alone but significantly less than that obtained when the two IT combination was utilized. This was similarly the case for the combination of OKT10-SAPORIN IT with HB2 antibody though the effect was less pronounced in this instance. This result suggests that the therapeutic effect of IT + antibody treatment results from an additivity between antibody-mediated delivery of saporin combined with a SCID mouse NK cell-mediated ADCC attack on the target cell directed through target cell bound antibody Fc engagement with FcgammaRIII on the NK cell surface. The combination of both ITs however gave the best therapeutic outcome in SCID-CEM mice probably as the result of (i) delivery of greater amounts of saporin to target CEM cells positive for both CD7 and CD38, (ii) delivery of an effective dose of saporin to CEM cells downregulated or negative for one of the target antigens and (iii) through ADCC mechanisms that interact additively with IT action. We have previously proposed that combination IT therapy would be one means of overcoming the problem of heterogeneity of antigen expression within a global tumour cell population and these additional findings support this and provide a further strengthening of the rationale for employing cocktails of ITs for the treatment of human malignancies.
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PMID:Therapy of human T-cell acute lymphoblastic leukaemia with a combination of anti-CD7 and anti-CD38-SAPORIN immunotoxins is significantly better than therapy with each individual immunotoxin. 1120 56