Effectiveness of HB2 (anti-CD7) – saporin immunotoxin in an in vivo model of human T-cell leukaemia developed in severe combined immunodeficient mice

Morland, Bruce; Barley, J.; Boehm, Deborah A.; Flavell, Sopsamorn U.; Ghaleb, Nagib; Kohler, Janice A.; Okayama, Keiko; Wilkins, Bridget S.; Flavell, David J.

doi:10.1038/bjc.1994.52

Cited by 23 publications

(21 citation statements)

References 33 publications

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“…The pattern of growth of CCRF CEM in non-conditioned SCID mice was virtually identical to that described by us previously for the growth of HSB-2, another human T-ALL cell line (Morland et al, 1994). In summary, SCID mice injected with two million CCRF CEM cells developed multi-organ involvement with observable growth of solid CCRF CEM tumours in liver, kidney, bone marrow, meninges and elsewhere.…”

Section: Growth Of Ccrf Cem Leukaemia In Scid Micesupporting

confidence: 84%

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

et al. 2001

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Immunotoxins (IT) are hybrid molecules comprised of an antibody coupled chemically or genetically to a toxin or ribosome inactivating protein (RIP) such as saporin Kreitman, 1999;Frankel et al, 2000). The antibody component allows for the selective delivery of the toxin to the surface of cells bearing the target antigen. In order to kill the target cell it is an absolute requirement that the conjugate is internalized by receptormediated endocytosis and that subsequently the toxin component is routed to the appropriate intracellular compartment where translocation of the toxin component to the cytosol can take place. Once in the cytosol RIPs such as saporin catalytically inactivate 28S ribosomal RNA via a highly specific N-glycosidase enzymatic activity (Endo, 1988) that results in cessation of protein synthesis in the cell and leads to apoptotic cell death (Bergamaschi et al, 1996). Arguably, the most important factor that theoretically limits the therapeutic efficacy of immunotoxins that have no bystander effect and which therefore have to exert their cytotoxic influence directly on all cells in the tumour, is the heterogeneity of target antigen expression within the global tumour cell population. Thus, relatively small numbers of tumour cells down-regulated or negative for the target antigen would escape killing by any single immunotoxin and if these surviving cells possess growth potential this would lead to subsequent tumour re-growth. One way of overcoming this problem would be to simultaneously target against more than one target molecule on the tumour cell surface in the expectation that multiple antigen-negative tumour cells would occur with a much lower frequency than single antigen-negative cells. There would also be the added bonus that targeting against more than one antigen on the tumour cell surface would ensure delivery of greater and therefore more effective quantities of the cytotoxic agent carried by antibody to tumour cells that were multiple antigen positive. Other factors such as the cell signalling effects and recruitment of cytotoxic host effectors may also work in conjunction to achieve an improved therapeutic effect when combinations of antibody-based therapeutics are utilized. We have 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 IgG 1 antibodies) 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...

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Section: Growth Of Ccrf Cem Leukaemia In Scid Micesupporting

confidence: 84%

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

et al. 2001

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“…and that a proportionatly greater excess of native HB2 antibody was required to block the cytotoxic activity of the 2-mer than was required for the 1-mer IT. Similarly, other workers have described similar increases in in vitro potency of ITs containing two toxin molecules per unit antibody (Marsh and Neville, 1986; (Fishwild et al, 1992;Jansen et al, 1992;Flavell et al, 1995a;Morland et al, 1994) (Dorshkind et al, 1985) (1997) 75(7), [1035][1036][1037][1038][1039][1040][1041][1042][1043] In order to determine the differential contribution that such diverse cytotoxic mechanisms contribute to the eventual therapeutic outcome, we are currently undertaking studies in NOD-SCID mice, which are naturally deficient in NK cells.…”

Section: Pharmacokinetic Profiles Of 1-mer and 2-mer Immunotoxinssupporting

confidence: 56%

“…The behaviour and characteristics of the human T-cell acute lymphoblastic leukaemia cell line HSB-2 in SCID mice has been described previously (Morland et al, 1994). In the present study,…”

Section: Hsb-2 Human T-cell Leukaemia In Scid Micementioning

confidence: 55%

Comparison of the potency and therapeutic efficacy of the anti-CD7 immunotoxin HB2-saporin constructed with one or two saporin moieties per immunotoxin molecule

Flavell

Boehm²,

Noss³

et al. 1997

Br J Cancer

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Summary Immunotoxins that carry two toxin molecules to the target cell should in theory have a greater anti-tumour effect than those that carry just one. We have investigated the therapeutic efficacy of two anti-CD7-saporin immunotoxins constructed with one saporin (HB2-Sap 1 -mer) or two saporin molecules (HB2-Sap 2-mer) per immunotoxin molecule. In vitro, the 2-mer immunotoxin was 5.6 times more effective than the 1 -mer immunotoxin at inhibiting protein synthesis in the CD7+ human T-cell acute lymphoblastic leukaemia (T-ALL) cell line HSB-2 and was also more effective at inhibiting HSB-2 cell proliferation. Flow cytometry revealed that the 2-mer immunotoxin had a reduced binding capacity to HSB-2 cells compared with the 1-mer immunotoxin or native HB2 antibody. In therapy studies in SCID mice with disseminated HSB-2 human leukaemia, the 2-mer immunotoxin performed marginally better than the 1-mer immunotoxin, but log-rank analysis did not reveal any significant differences between the two therapy groups. We therefore conclude that, although the 2-mer immunotoxin performed better than the 1 -mer immunotoxin against target HSB-2 cells in vitro, this improved performance was not reflected as an improved in vivo therapeutic outcome in the SCID mouse model. Keywords: immunotoxin; CD7; saporin; T-cell acute lymphoblastic leukaemiaImmunotoxins (ITs) have promising potential as therapeutic agents for cancer, particularly in the treatment of leukaemias and lymphomas, in which they have been shown to have marked activities Falini et al, 1992;Amlot et al, 1993; Grossbard et al, 1993). Comprising a monoclonal antibody component linked to a toxin or ribosome-inactivating protein (rip), such as ricin A chain or saporin, immunotoxins selectively deliver the toxin moiety only to cell populations expressing the target antigen recognized by the antibody. There are, however, a multitude of factors that can effect the potency of a given immunotoxin for its target cell, which can severely limit its therapeutic value. At the mechanistic level, such factors include the isotype and affinity (van-Oosterhout et al, 1994) of the antibody component, the proximity of the target antigen epitope to the target cell membrane (Press et al, 1988, the expression by the target cell of antigens unrelated to the target antigen and that probably assist in the internalization of immunotoxin by receptor-mediated endocytosis (van-Oosterhout et al, 1994) and, of pivotal importance, the fundamental nature of the target antigen and the ease with which it internalizes to the appropriate intracellular compartment once antibody has bound to its target ligand , Preijers 1988, Wargalla and Reisfeld 1989. Ultimately, the key determinants governing the therapeutic potency of any given immunotoxin revolve around two key issues: firstly, the in vivo accessibility of immunotoxin to the tumour and, secondly, the Correspondence to: D J Flavell efficiency of the internalization and trafficking process which delivers immunotoxin to the appropriate intracellular compa...

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“…When tested in a mouse model of human T-cell leukemia, this IT showed a therapeutic effect with a single intravenous (i.v.) dose of 10 µg of IT (0.5 mg/kg), achieving 50% survival at day +150 [59]. Further studies on this IT provided additional interesting information about the in vivo therapeutic efficacy of HB2/saporin-S6.…”

Section: Immunotoxinsmentioning

confidence: 99%

Saporin-S6: A Useful Tool in Cancer Therapy

Polito

Bortolotti

Mercatelli

et al. 2013

Toxins

113

115

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Thirty years ago, the type 1 ribosome-inactivating protein (RIP) saporin-S6 (also known as saporin) was isolated from Saponaria officinalis L. seeds. Since then, the properties and mechanisms of action of saporin-S6 have been well characterized, and it has been widely employed in the construction of conjugates and immunotoxins for different purposes. These immunotoxins have shown many interesting results when used in cancer therapy, particularly in hematological tumors. The high enzymatic activity, stability and resistance to conjugation procedures and blood proteases make saporin-S6 a very useful tool in cancer therapy. High efficacy has been reported in clinical trials with saporin-S6-containing immunotoxins, at dosages that induced only mild and transient side effects, which were mainly fever, myalgias, hepatotoxicity, thrombocytopenia and vascular leak syndrome. Moreover, saporin-S6 triggers multiple cell death pathways, rendering impossible the selection of RIP-resistant mutants. In this review, some aspects of saporin-S6, such as the chemico-physical characteristics, the structural properties, its endocytosis, its intracellular routing and the pathogenetic mechanisms of the cell damage, are reported. In addition, the recent progress and developments of saporin-S6-containing immunotoxins in cancer immunotherapy are summarized, including in vitro and in vivo pre-clinical studies and clinical trials.

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Effectiveness of HB2 (anti-CD7) – saporin immunotoxin in an in vivo model of human T-cell leukaemia developed in severe combined immunodeficient mice

Cited by 23 publications

References 33 publications

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

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

Comparison of the potency and therapeutic efficacy of the anti-CD7 immunotoxin HB2-saporin constructed with one or two saporin moieties per immunotoxin molecule

Saporin-S6: A Useful Tool in Cancer Therapy

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