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The in vitro and in vivo targeting of the plant toxin saporin to T-cell acute lymphoblastic leukaemia

The in vitro and in vivo targeting of the plant toxin saporin to T-cell acute lymphoblastic leukaemia
The in vitro and in vivo targeting of the plant toxin saporin to T-cell acute lymphoblastic leukaemia

Children with acute lymphoblastic leukaemia have a 70% chance of cure with conventional chemotherapeutic drugs. The outlook for those children with recurrent disease remains poor. The work presented in this thesis investigates the potential to selectively target leukaemic cells with the potent cytotoxic plant toxin saporin. It is believed that such novel approaches to therapy may prove more successful in treating relapsed children and may add to the armoury of conventional drug treatments.

The plant toxin saporin is a potent inactivator of normal cellular protein production. Two methods were used to deliver saporin to the CD7 cell surface epitope of T-cell leukaemia cells in culture. The first utilised a bispecific antibody with dual specificity for saporin and CD7, the second an immunotoxin comprising monoclonal anti-CD7 antibody chemically conjugated to saporin. Both methods proved successful at selectively delivering saporin to HSB-2 cells in culture with high potency. Various attempts at further enhancing the cytotoxicity of the bispecific antibody and immunotoxin delivery of saporin utilising a range of chemical potentiators proved unsuccessful.

In order to investigate the in vivo efficacy of the immunotoxin a model of human T-cell leukaemia was established in mice with severe combined immunodeficiency. This recent approach to xenograft experiments resulted in a disseminated leukaemia in these mice closely mimicking the spectrum of disease seen in humans. Therapy of mice with transplanted human leukaemia using the saporin immunotoxin resulted in significant prolongation in their survival compared to untreated controls.

The results from the work presented in this thesis add to the growing research interest in methods of targeted therapy. It has also aided the development of other immunotoxins within the Simon Flavell Research Laboratory which are about to enter into phase 1 clinical trials in human patients.

University of Southampton
Morland, Bruce Jonathan
7307ce59-1809-480b-8f85-fe6157608960
Morland, Bruce Jonathan
7307ce59-1809-480b-8f85-fe6157608960

Morland, Bruce Jonathan (1993) The in vitro and in vivo targeting of the plant toxin saporin to T-cell acute lymphoblastic leukaemia. University of Southampton, Doctoral Thesis.

Record type: Thesis (Doctoral)

Abstract

Children with acute lymphoblastic leukaemia have a 70% chance of cure with conventional chemotherapeutic drugs. The outlook for those children with recurrent disease remains poor. The work presented in this thesis investigates the potential to selectively target leukaemic cells with the potent cytotoxic plant toxin saporin. It is believed that such novel approaches to therapy may prove more successful in treating relapsed children and may add to the armoury of conventional drug treatments.

The plant toxin saporin is a potent inactivator of normal cellular protein production. Two methods were used to deliver saporin to the CD7 cell surface epitope of T-cell leukaemia cells in culture. The first utilised a bispecific antibody with dual specificity for saporin and CD7, the second an immunotoxin comprising monoclonal anti-CD7 antibody chemically conjugated to saporin. Both methods proved successful at selectively delivering saporin to HSB-2 cells in culture with high potency. Various attempts at further enhancing the cytotoxicity of the bispecific antibody and immunotoxin delivery of saporin utilising a range of chemical potentiators proved unsuccessful.

In order to investigate the in vivo efficacy of the immunotoxin a model of human T-cell leukaemia was established in mice with severe combined immunodeficiency. This recent approach to xenograft experiments resulted in a disseminated leukaemia in these mice closely mimicking the spectrum of disease seen in humans. Therapy of mice with transplanted human leukaemia using the saporin immunotoxin resulted in significant prolongation in their survival compared to untreated controls.

The results from the work presented in this thesis add to the growing research interest in methods of targeted therapy. It has also aided the development of other immunotoxins within the Simon Flavell Research Laboratory which are about to enter into phase 1 clinical trials in human patients.

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Published date: 1993

Identifiers

Local EPrints ID: 458369
URI: http://eprints.soton.ac.uk/id/eprint/458369
PURE UUID: 5ed3a625-e253-4326-94e7-38aca065718b

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Date deposited: 04 Jul 2022 16:47
Last modified: 23 Jul 2022 00:15

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Author: Bruce Jonathan Morland

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