Development of humanized bispecific antibodies reactive with cytotoxic lymphocytes and tumor cells overexpressing the HER2 protooncogene
| Autor: | M R Shalaby, Paul Carter, M Feldmann, H M Shepard, M L Rodrigues, P C Beverley, L. G. Presta |
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| Jazyk: | angličtina |
| Rok vydání: | 1992 |
| Předmět: |
Antigens
Differentiation T-Lymphocyte Cytotoxicity Immunologic Models Molecular CD3 Complex medicine.drug_class Protein Conformation Receptor ErbB-2 CD3 Immunology Molecular Sequence Data Receptors Antigen T-Cell Breast Neoplasms Complementarity determining region Immunoglobulin light chain Monoclonal antibody Polymerase Chain Reaction Antigen Antigens CD Proto-Oncogene Proteins Sequence Homology Nucleic Acid Proto-Oncogenes medicine Immunology and Allergy Cytotoxic T cell Humans Amino Acid Sequence Cloning Molecular biology Base Sequence Antibodies Monoclonal Genetic Variation Articles Oligonucleotides Antisense Flow Cytometry Molecular biology Oligodeoxyribonucleotides Monoclonal biology.protein Female Antibody T-Lymphocytes Cytotoxic |
| Zdroj: | The Journal of Experimental Medicine |
| ISSN: | 1540-9538 0022-1007 |
| Popis: | The HER2 protooncogene encodes a 185-kD transmembrane phosphoglycoproteins, human epidermal growth factor receptor 2 (p185HER2), whose amplified expression on the cell surface can lead to malignant transformation. Overexpression of HER2/p185HER2 is strongly correlated with progression of human ovarian and breast carcinomas. Recent studies have shown that human T cells can be targeted with bispecific antibody to react against human tumor cells in vitro. We have developed a bispecific F(ab')2 antibody molecule consisting of a humanized arm with a specificity to p185HER2 linked to another arm derived from a murine anti-CD3 monoclonal antibody that we have cloned from UCHT1 hybridoma. The antigen-binding loops for the anti-CD3 were installed in the context of human variable region framework residues, thus forming a fully humanized BsF(ab')2 fragment. Additional variants were produced by replacement of amino acid residues located in light chain complementarity determining region 2 and heavy chain framework region 3 of the humanized anti-CD3 arm. Flow cytometry analysis showed that the bispecific F(ab')2 molecules can bind specifically to cells overexpressing p185HER2 and to normal human peripheral blood mononuclear cells bearing the CD3 surface marker. In additional experiments, the presence of bispecific F(ab')2 caused up to fourfold enhancement in the cytotoxic activities of human T cells against tumor cells overexpressing p185HER2 as determined by a 51Cr release assay. These bispecific molecules have a potential use as therapeutic agents for the treatment of cancer. |
| Databáze: | OpenAIRE |
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