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• W2912894184 abstract "2402 Monoclonal IgG1 antibodies cetuximab and trastuzumab have become standard of care for the treatment of patients with advanced colon and breast cancer, respectively. Mode of action of these antibodies includes inhibition of signalling and antibody-dependent cellular cytotoxicity (ADCC). Numerous efforts are ongoing to increase the anti-tumor activity of therapeutic antibodies, which typically require weekly doses of 2-8 mg/kg and show only limited efficacy as monotherapy in metastatic disease. Conventional antibodies such as cetuximab and trastuzumab cannot directly engage T cells, which are considered the most potent cytotoxic cells in the organism. This is because T cells lack antibody-binding Fcγ receptors. We have developed so called BiTE antibodies that can redirect T cells --irrespective of T cell receptor specificity and peptide antigen presentation-- to tumor cells expressing a particular surface antigen.
 Here, we have converted both cetuximab and trastuzumab into T cell-engaging BiTE antibodies. Respective single-chain antibodies were crafted from the variable domains of cetuximab and trastuzumab and genetically linked to anti-CD3 single-chain antibodies that confer the particular T cell-engaging properties of BiTE antibodies. The resulting EGFR- and HER-2-specific BiTE antibodies were stable 55 kDa proteins with binding specificity to EGFR and HER-2 on tumor cells, respectively, and to CD3 on T cells. Both showed potent redirected lysis of EGFR- and HER-2-expressing target cell lines by peripheral human T cells at half maximal concentrations of 0.1-0.2 ng/ml (ca. 2-4 picomolar). Redirected lysis was highly specific for target antigens. Concomitant T cell activation was only observed in the presence of target cells but not when cetuximab- and trastuzumab-based BiTE antibodies were incubated with T cells alone.
 The anti-tumor activity of cetuximab and trastuzumab was directly compared with that of the corresponding BiTE antibodies in cytotoxicity assays using identical assay conditions and the same donors as source for peripheral mononuclear effector cells (PBMC). BiTE antibodies consistently showed a higher activity than the conventional antibodies. In contrast to the IgG1 antibodies, the BiTE antibodies led to a complete lysis of target cells during the assay period. Data from animal models will be presented that compare the efficacy of cetuximab and trastuzumab side-by-side with that of respective BiTE antibodies.
 Our data show that established therapeutic monoclonal antibodies can be successfully converted into BiTE antibodies, with the potential to engage T cells for highly potent and strictly target-dependent tumor cell elimination." @default.
• W2912894184 created "2019-02-21" @default.
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• W2912894184 date "2008-05-01" @default.
• W2912894184 modified "2023-09-23" @default.
• W2912894184 title "Conversion of Cetuximab and Trastuzumab into T cell-engaging BiTE antibodies creates novel drug candidates with superior anti-tumor activity" @default.
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