Therapy of human non-small-cell lung carcinoma using antibody targeting of a modified superantigen.

2.50
Hdl Handle:
http://hdl.handle.net/10541/85601
Title:
Therapy of human non-small-cell lung carcinoma using antibody targeting of a modified superantigen.
Authors:
Forsberg, G; Ohlsson, L; Brodin, T; Björk, P; Lando, P A; Shaw, David M; Stern, Peter L; Dohlsten, M
Abstract:
Superantigens activate T-cells by linking the T-cell receptor to MHC class II on antigen-presenting cells, and novel reactivity can be introduced by fusing the superantigen to a targeting molecule. Thus, an antibody-targeted superantigen, which activates T cells to destroy tumour cells, might be used as cancer therapy. A suitable target is the 5T4 oncofetal antigen, which is expressed on many carcinomas. We constructed a fusion protein from a Fab of a monoclonal antibody recognizing the 5T4 antigen, and an engineered superantigen. The recombinant product 5T4FabV13-SEA(D227A)bound the 5T4 antigen expressed on the human non-small-cell lung cancer cell line Calu-1 with a Kd of 1.2 nM while the substitution of Asp227 to Ala in the superantigen moiety reduced binding activity to MHC class II. 5T4FabV13-SEA(D227A)tumour reactivity was demonstrated in 7/7 NSCLC samples by immunohistochemistry, while normal tissue reactivity was low to moderate. 5T4FabV13-SEA(D227A)induced significant T-cell-dependent in vitro killing of sensitive 5T4 bearing Calu-1 cells, with maximum lysis at 10(-10)M, while the capacity to lyse MHC class II expressing cells was approximately 1000 times less effective. Immunotherapy of 5T4FabV13-SEA(D227A)against human NSCLC was investigated in SCID mice reconstituted with human peripheral blood mononuclear cells. Mice carrying intreperitoneally growing Calu-1 cells showed significant reduction in tumour mass and number after intravenous therapy with 5T4FabV13-SEA(D227A). Thus, 5T4FabV13-SEA(D227A)has highly attractive properties for therapy of human NSCLC.
Affiliation:
Active Biotech Research AB, Box 724, 220 07 Lund, Sweden.
Citation:
Therapy of human non-small-cell lung carcinoma using antibody targeting of a modified superantigen. 2001, 85 (1):129-36 Br. J. Cancer
Journal:
British Journal of Cancer
Issue Date:
6-Jul-2001
URI:
http://hdl.handle.net/10541/85601
DOI:
10.1054/bjoc.2001.1891
PubMed ID:
11437414
Type:
Article
Language:
en
ISSN:
0007-0920
Appears in Collections:
All Paterson Institute for Cancer Research

Full metadata record

DC FieldValue Language
dc.contributor.authorForsberg, Gen
dc.contributor.authorOhlsson, Len
dc.contributor.authorBrodin, Ten
dc.contributor.authorBjörk, Pen
dc.contributor.authorLando, P Aen
dc.contributor.authorShaw, David Men
dc.contributor.authorStern, Peter Len
dc.contributor.authorDohlsten, Men
dc.date.accessioned2009-11-06T16:09:24Z-
dc.date.available2009-11-06T16:09:24Z-
dc.date.issued2001-07-06-
dc.identifier.citationTherapy of human non-small-cell lung carcinoma using antibody targeting of a modified superantigen. 2001, 85 (1):129-36 Br. J. Canceren
dc.identifier.issn0007-0920-
dc.identifier.pmid11437414-
dc.identifier.doi10.1054/bjoc.2001.1891-
dc.identifier.urihttp://hdl.handle.net/10541/85601-
dc.description.abstractSuperantigens activate T-cells by linking the T-cell receptor to MHC class II on antigen-presenting cells, and novel reactivity can be introduced by fusing the superantigen to a targeting molecule. Thus, an antibody-targeted superantigen, which activates T cells to destroy tumour cells, might be used as cancer therapy. A suitable target is the 5T4 oncofetal antigen, which is expressed on many carcinomas. We constructed a fusion protein from a Fab of a monoclonal antibody recognizing the 5T4 antigen, and an engineered superantigen. The recombinant product 5T4FabV13-SEA(D227A)bound the 5T4 antigen expressed on the human non-small-cell lung cancer cell line Calu-1 with a Kd of 1.2 nM while the substitution of Asp227 to Ala in the superantigen moiety reduced binding activity to MHC class II. 5T4FabV13-SEA(D227A)tumour reactivity was demonstrated in 7/7 NSCLC samples by immunohistochemistry, while normal tissue reactivity was low to moderate. 5T4FabV13-SEA(D227A)induced significant T-cell-dependent in vitro killing of sensitive 5T4 bearing Calu-1 cells, with maximum lysis at 10(-10)M, while the capacity to lyse MHC class II expressing cells was approximately 1000 times less effective. Immunotherapy of 5T4FabV13-SEA(D227A)against human NSCLC was investigated in SCID mice reconstituted with human peripheral blood mononuclear cells. Mice carrying intreperitoneally growing Calu-1 cells showed significant reduction in tumour mass and number after intravenous therapy with 5T4FabV13-SEA(D227A). Thus, 5T4FabV13-SEA(D227A)has highly attractive properties for therapy of human NSCLC.en
dc.language.isoenen
dc.subjectCancer Antigensen
dc.subjectLung Canceren
dc.subject.meshAnimals-
dc.subject.meshAntigen-Antibody Reactions-
dc.subject.meshAntigens, Neoplasm-
dc.subject.meshCarcinoma, Non-Small-Cell Lung-
dc.subject.meshCloning, Molecular-
dc.subject.meshCytokines-
dc.subject.meshEscherichia coli-
dc.subject.meshFemale-
dc.subject.meshHistocompatibility Antigens Class II-
dc.subject.meshHumans-
dc.subject.meshImmunoglobulin Fragments-
dc.subject.meshImmunohistochemistry-
dc.subject.meshImmunotherapy-
dc.subject.meshLung Neoplasms-
dc.subject.meshMembrane Glycoproteins-
dc.subject.meshMice-
dc.subject.meshMice, Inbred C57BL-
dc.subject.meshMice, SCID-
dc.subject.meshRecombinant Fusion Proteins-
dc.subject.meshSuperantigens-
dc.subject.meshXenograft Model Antitumor Assays-
dc.titleTherapy of human non-small-cell lung carcinoma using antibody targeting of a modified superantigen.en
dc.typeArticleen
dc.contributor.departmentActive Biotech Research AB, Box 724, 220 07 Lund, Sweden.en
dc.identifier.journalBritish Journal of Canceren

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