Reduction of EGP-2-positive pulmonary metastases by bispecific-antibody-redirected T cells in an immunocompetent rat model.
Effectiveness of bispecific-monoclonal-antibody (BsMAb)-mediated cellular anti-tumour activity was evaluated in vitro and in vivo in relation to the additional need for T-cell activation in a new immunocompetent rat tumour model. L37 tumour cells, derived from a squamous-cell carcinoma of the lung of Wag/Rij rats, were transfected with the cDNA coding for the human 38-kDa transmembrane pan-carcinoma-associated antigen EGP-2. Intravenous inoculation of EGP-2-positive L37 cells resulted in a rapid outgrowth of EGP-2-positive tumour nodules in the lungs. A BsMAb BIS-19, recognizing EGP-2 on the transfected tumour cells and the T-cell receptor of the rat, was made and allowed specific lysis of EGP-2-transfected L37 tumour cells by activated rat T lymphocytes in vitro. In vivo T-cell activation, assessed by up-regulation of IL-2-receptor expression, could be induced by daily injection of rat rIL-2. Intravenous treatment of tumour-bearing EGP-2-positive L37 tumour with BIS-19 together with rat rIL-2 resulted in almost complete disappearance of established tumour. In contrast, animals treated with BIS-19 alone, IL-2 alone or a combination of anti-EGP-2, anti-TcR and IL-2 showed much less or no tumour reduction. These results show effectiveness of systemic treatment with BsMAbs to induce anti-tumour activity in established tumours. Immune activation prior to or during treatment with BsMAbs, as achieved with IL-2, appears to be a prerequisite for successful treatment.
Kroesen
B J
BJ
Department of Clinical Immunology, University Hospital Groningen, The Netherlands.
Helfrich
W
W
Bakker
A
A
Wubbena
A S
AS
Bakker
H
H
Kal
H B
HB
The
T H
TH
de Leij
L
L
D000818:Animals; D018033:Antibodies, Bispecific / Q000494:pharmacology*; D000911:Antibodies, Monoclonal / Q000494:pharmacology; D000951:Antigens, Neoplasm / Q000235:genetics / Q000276:immunology*; D002294:Carcinoma, Squamous Cell / Q000276:immunology* / Q000556:secondary / Q000628:therapy*; D015815:Cell Adhesion Molecules / Q000235:genetics / Q000276:immunology*; D003601:Cytotoxicity Tests, Immunologic; D000071858:Epithelial Cell Adhesion Molecule; D005260:Female; D005434:Flow Cytometry; D007121:Immunocompetence; D007124:Immunoenzyme Techniques; D007167:Immunotherapy; D007376:Interleukin-2 / Q000494:pharmacology; D008175:Lung Neoplasms / Q000276:immunology* / Q000473:pathology / Q000628:therapy*; D008213:Lymphocyte Activation; D051381:Rats; D011919:Rats, Inbred Strains; D011948:Receptors, Antigen, T-Cell / Q000276:immunology*; D011994:Recombinant Proteins / Q000494:pharmacology; D013601:T-Lymphocytes / Q000187:drug effects / Q000276:immunology* / Q000502:physiology; D014162:Transfection; D014407:Tumor Cells, Cultured
D018033:Antibodies, Bispecific; D000911:Antibodies, Monoclonal; D000951:Antigens, Neoplasm; D015815:Cell Adhesion Molecules; D000071858:Epithelial Cell Adhesion Molecule; D007376:Interleukin-2; D011948:Receptors, Antigen, T-Cell; D011994:Recombinant Proteins