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

Flavell, David J.; Boehm, Deborah A.; Okayama, Keiko; Kohler, Janice A.; Flavell, Sopsamor N. U.

doi:10.1002/ijc.2910580317

Cited by 18 publications

(12 citation statements)

References 12 publications

(13 reference statements)

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“…Both anti-CD7 (Fishwild et al, 1992;Flavell et al 1994) and anti-CD19 (Ghetie et al, 1994a) antibodies exert anti-tumour effects in SCID mouse models of human leukaemia and lymphoma. A notable exception is the IgGl anti-CD19 antibody B43 which has no therapeutic effect in SCID mice bearing the human CALL cell line NALM-6 (Uckun et aL, 1992).…”

Section: Discussionmentioning

confidence: 99%

Therapy of human B‐cell lymphoma bearing scid mice is more effective with anti‐CD19‐and anti‐CD38‐saporin immunotoxins used in combination than with either immunotoxin used alone

Flavell¹,

Boehm²,

Emery³

et al. 1995

Intl Journal of Cancer

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The CD19+ CD38+ human Burkitt's lymphoma cell line Ramos grows aggressively when injected intravenously (i.v.) into severe combined immunodeficient (SCID) mice, killing 100% of animals within a 33-42 day period with widely disseminated disease. Treatment commencing 7 days after i.v. injection of Ramos cells, with 3 doses of an anti-CD19 immunotoxin (IT; BU12-SAPORIN) or an anti-CD38IT (OKT10-SAPORIN) led to a significant prolongation of survival compared with sham-treated controls; the anti-CD38 IT gave the greatest prolongation of survival, but all treated animals eventually succumbed to disease. When both ITs were used in combination at equivalent dose levels, the therapeutic outcome was significantly improved over that obtained for single IT therapy, with 20% of animals surviving disease-free to 300 days. When anti-CD38 IT was given in combination with anti-CD19 antibody there was no therapeutic improvement over anti-CD38 IT used alone. However, when anti-CD19 IT was given in combination with CD38 antibody, a significant prolongation of survival ensued over that obtained with anti-CD19 IT alone, though this was not as significantly pronounced as that obtained when both ITs were used in combination and was only as good as the survival obtained with OKT10 antibody used alone. CD19 and CD38 are expressed on the surface of the vast majority of B-cell lymphoma and common acute lymphoblastic leukaemia cells, and our findings provide a sound rationale for a combination immunotoxin trial in these diseases directed against both these target molecules.

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Section: Discussionmentioning

confidence: 99%

Therapy of human B‐cell lymphoma bearing scid mice is more effective with anti‐CD19‐and anti‐CD38‐saporin immunotoxins used in combination than with either immunotoxin used alone

Flavell¹,

Boehm²,

Emery³

et al. 1995

Intl Journal of Cancer

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“…Pioneering work was done with chemically linked immunotoxins by the group of Stirpe in Bologna and Flavell in Southampton, directing Saporin to human leukemia and lymphoma cells expressing differentiation antigens such as CD2, CD7, CD19 and CD22 on their plasma membrane surface [ 27 , 28 , 29 , 30 , 31 , 32 , 33 , 34 , 35 , 36 ]. In all of these studies the immunotoxins were demonstrated to act at sub-nanomolar concentration in vitro while exerting significant in vivo therapeutic effects in animal xenograft models.…”

Section: Saporin As a Component Of Immuno- Or Chimeric Toxinsmentioning

confidence: 99%

Strategies to Improve the Clinical Utility of Saporin-Based Targeted Toxins

Giansanti

Flavell

Angelucci

et al. 2018

Toxins

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Plant Ribosome-inactivating proteins (RIPs) including the type I RIP Saporin have been used for the construction of Immunotoxins (ITxs) obtained via chemical conjugation of the toxic domain to whole antibodies or by generating genetic fusions to antibody fragments/targeting domains able to direct the chimeric toxin against a desired sub-population of cancer cells. The high enzymatic activity, stability and resistance to conjugation procedures and especially the possibility to express recombinant fusions in yeast, make Saporin a well-suited tool for anti-cancer therapy approaches. Previous clinical work on RIPs-based Immunotoxins (including Saporin) has shown that several critical issues must be taken into deeper consideration to fully exploit their therapeutic potential. This review focuses on possible combinatorial strategies (chemical and genetic) to augment Saporin-targeted toxin efficacy. Combinatorial approaches may facilitate RIP escape into the cytosolic compartment (where target ribosomes are), while genetic manipulations may minimize potential adverse effects such as vascular-leak syndrome or may identify T/B cell epitopes in order to decrease the immunogenicity following similar strategies as those used in the case of bacterial toxins such as Pseudomonas Exotoxin A or as for Type I RIP Bouganin. This review will further focus on strategies to improve recombinant production of Saporin-based chimeric toxins.

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“…Taken together, these findings suggest that host-mediated antibody-dependent cell cytotoxicity (ADCC) positively contributes to HB2/saporin-S6 efficacy. Further attempts to improve the in vivo efficacy of this IT, both with the insertion of hindered or non-hindered disulfide cross-linkers or the coupling of one or two saporin-S6 moieties per IT molecule, failed to achieve significant differences in terms of pharmacokinetic and therapeutic effects [62,63]. The BU12 anti-CD19 mAb covalently coupled to saporin-S6 showed an IC 50 in the nM range for the CD19 + B-cell acute lymphoblastic leukemia cell line NALM-6.…”

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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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

Cited by 18 publications

References 12 publications

Therapy of human B‐cell lymphoma bearing scid mice is more effective with anti‐CD19‐and anti‐CD38‐saporin immunotoxins used in combination than with either immunotoxin used alone

Therapy of human B‐cell lymphoma bearing scid mice is more effective with anti‐CD19‐and anti‐CD38‐saporin immunotoxins used in combination than with either immunotoxin used alone

Strategies to Improve the Clinical Utility of Saporin-Based Targeted Toxins

Saporin-S6: A Useful Tool in Cancer Therapy

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