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Host-mediated antibody-dependent cellular cytotoxicity contributes to the in vivo therapeutic efficacy of an anti-CD7-saporin immunotoxin in a severe combined immunodeficient mouse model of human T-cell acute lymphoblastic leukemia

Host-mediated antibody-dependent cellular cytotoxicity contributes to the in vivo therapeutic efficacy of an anti-CD7-saporin immunotoxin in a severe combined immunodeficient mouse model of human T-cell acute lymphoblastic leukemia
Host-mediated antibody-dependent cellular cytotoxicity contributes to the in vivo therapeutic efficacy of an anti-CD7-saporin immunotoxin in a severe combined immunodeficient mouse model of human T-cell acute lymphoblastic leukemia
We have investigated the anti-leukemia effect that is exerted by the murine anti-CD7 antibody HB2 in a severe combined immunodeficient (SCID) mouse model of human T-cell acute lymphoblastic leukemia (T-ALL) and determined the contribution that this antibody effect makes to the therapeutic potency of a saporin immunotoxin (IT) constructed with the same antibody. The anti-leukemia effect is not exerted through complement-mediated lysis or through direct growth-inhibitory signaling after binding of antibody to the CD7 molecule on the T-ALL cell surface but rather through antibody-dependent cellular cytotoxicity (ADCC). Thus, the in vivo depletion of SCID mice of their natural killer cells almost completely abolishes the therapeutic effect of native HB2 anti-CD7 antibody and moreover significantly reduces the in vivo therapeutic performance of the anti-CD7 HB2-SAPORIN IT. Furthermore, an IT constructed with the F(ab')2 fragment of the same anti-CD7 antibody (HB2-F(ab')2-SAPORIN), which is incapable of recruiting natural killer cells, performed significantly less well therapeutically than HB2-SAPORIN IT. There was also a significant improvement in the therapeutic performance of the HB2-F(ab')2-SAPORIN IT in SCID-HSB-2 mice when used in combination with intact HB2 antibody, presumably through restoration of an ADCC attack on the target HSB-2 cell. These combined data indicate that ADCC in the SCID mouse does contribute additively together with toxin to the in vivo therapeutic potency of the HB2-SAPORIN IT directed against this human T-ALL cell line and that this has potentially important implications for the utility of this and other related classes of immunotherapeutic in human therapy.
0008-5472
5787-5794
Flavell, David J.
3a0f7124-7d44-42bc-b6f6-6fb12552fbd6
Warnes, Sarah
f724f4bf-86cf-4b7b-bf0a-69ba86e0185c
Noss, Armorel
6e9849eb-93cd-42bd-8e3c-b6bce650cae5
Flavell, Sopsamorn U.
fa2b4670-1836-42e2-b68a-5d646899d711
Flavell, David J.
3a0f7124-7d44-42bc-b6f6-6fb12552fbd6
Warnes, Sarah
f724f4bf-86cf-4b7b-bf0a-69ba86e0185c
Noss, Armorel
6e9849eb-93cd-42bd-8e3c-b6bce650cae5
Flavell, Sopsamorn U.
fa2b4670-1836-42e2-b68a-5d646899d711

Flavell, David J., Warnes, Sarah, Noss, Armorel and Flavell, Sopsamorn U. (1998) Host-mediated antibody-dependent cellular cytotoxicity contributes to the in vivo therapeutic efficacy of an anti-CD7-saporin immunotoxin in a severe combined immunodeficient mouse model of human T-cell acute lymphoblastic leukemia. Cancer Research, 58 (24), 5787-5794. (PMID:9865737)

Record type: Article

Abstract

We have investigated the anti-leukemia effect that is exerted by the murine anti-CD7 antibody HB2 in a severe combined immunodeficient (SCID) mouse model of human T-cell acute lymphoblastic leukemia (T-ALL) and determined the contribution that this antibody effect makes to the therapeutic potency of a saporin immunotoxin (IT) constructed with the same antibody. The anti-leukemia effect is not exerted through complement-mediated lysis or through direct growth-inhibitory signaling after binding of antibody to the CD7 molecule on the T-ALL cell surface but rather through antibody-dependent cellular cytotoxicity (ADCC). Thus, the in vivo depletion of SCID mice of their natural killer cells almost completely abolishes the therapeutic effect of native HB2 anti-CD7 antibody and moreover significantly reduces the in vivo therapeutic performance of the anti-CD7 HB2-SAPORIN IT. Furthermore, an IT constructed with the F(ab')2 fragment of the same anti-CD7 antibody (HB2-F(ab')2-SAPORIN), which is incapable of recruiting natural killer cells, performed significantly less well therapeutically than HB2-SAPORIN IT. There was also a significant improvement in the therapeutic performance of the HB2-F(ab')2-SAPORIN IT in SCID-HSB-2 mice when used in combination with intact HB2 antibody, presumably through restoration of an ADCC attack on the target HSB-2 cell. These combined data indicate that ADCC in the SCID mouse does contribute additively together with toxin to the in vivo therapeutic potency of the HB2-SAPORIN IT directed against this human T-ALL cell line and that this has potentially important implications for the utility of this and other related classes of immunotherapeutic in human therapy.

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Published date: 15 December 1998
Organisations: Faculty of Medicine, Centre for Biological Sciences

Identifiers

Local EPrints ID: 344800
URI: http://eprints.soton.ac.uk/id/eprint/344800
ISSN: 0008-5472
PURE UUID: 7ec0a9c9-5cb8-495b-b1ed-3d26313fcddf

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Date deposited: 19 Feb 2013 16:59
Last modified: 16 Jul 2019 21:50

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Contributors

Author: David J. Flavell
Author: Sarah Warnes
Author: Armorel Noss
Author: Sopsamorn U. Flavell

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