Immunoconjugate of monoclonal antibody A7 and mitomycin C-dextran conjugate linked through thioether bond.

概要

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Monoclonal antibody A7 against human colon cancer was conjugated with mitomycin C-dextran conjugate having anionic charge (MMCDan) through thioether bond in exchange for disulfide bond, because the disulfide bond in the immunoconjugate is more subject to cleavage <I>in vivo</I> than the thioether bond. The coupling was done using the bifunctional reagents succinimidyl 6-maleimidohexanoate (EMCS) for amino groups introduced MMCDan and S-acetylmercaptosuccinic anhydride (SAMSA)for antibody instead of using succinimidyl 3-(2-pyridyldithio)propionate (SPDP). This A7-MMCD conjugated with thioether bond, having MMC prodrug properties, released active MMC with a half life of 26.3 h and almost fully retained its antibody activity. The cytotoxicity of A7-MMCD against the human colon cancer cell line, SW1116 was comparable to free MMC and was also reduced by the addition of excess A7, which indicated that the cytotoxicity was mediated through its antigen-antibody binding. The A7-MMCD conjugated with thioether bond is expected to be more stable <I>in vivo</I> and to exhibit greater therapeutic effects than one conjugated with disulfide bond prepared previously.
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