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Overexpression of HER2 has been reported in many types of cancer, making it a perfect candidate for targeted immunotherapy. The combination of two FDA approved monoclonal antibodies (mAbs), trastuzumab and pertuzumab, has more robust anti-tumor activity in patients with HER2-overexpressing breast cancer. We recently produced a new humanized anti-HER2 mAb, hersintuzumab, which recognizes a different epitope than trastuzumab and pertuzumab on HER2. This mAb, in combination with trastuzumab, exhibits more potent anti-tumor activity than each parental mAb alone. Here we have developed a novel bispecific anti-HER2 antibody (BsAb) designated as trasintuzumab, composed of trastuzumab and hersintuzumab, using dual variable domain immunoglobulin (DVD-Ig) technology. Both variable domains of trasintuzumab are fully functional and have similar affinities to the parental mAbs and are also able to bind to natural HER2 on the surface of several HER2-expressing cell lines. Trasintuzumab was found to inhibit the growth of different types of tumor cell lines through suppression of the AKT and ERK signaling pathways as efficiently as the combination of the parental mAbs. It also induced tumor regression as potently as the combination of the two mAbs in nude mice bearing ovarian and gastric cancer xenografts. Our data suggest that trasintuzumab may be a promising BsAb therapeutic candidate for the treatment of HER2-overexpressing cancers. [ABSTRACT FROM AUTHOR]

The human epidermal growth factor receptor (HER/ErbB) family-targeted therapies result in a significant improvement in cancer immunotherapy. Monoclonal antibodies (MAb) against HER2 demonstrated a survival benefit for patients; however, drug resistance unavoidably occurs due to the overexpression of HER3, which leads to treatment failure. Effective inhibition of HER3 besides HER2 is thought to be required to overcome resistance and enhance therapeutic efficacy. The present study describes the production and characterization of a novel MAb, designated 1G5D2, which acts as a natural bispecific antibody targeting extracellular domains (ECD) of both HER2 and HER3. In this study, 1G5D2 was produced by hybridoma technology against HER3-ECD, and its structural and functional characteristics were studied by various methodologies, including enzyme linked-immunosorbent assays, flow cytometry, immunoblotting, cell signaling, and cell proliferation assays. 1G5D2 specifically binds to both HER2 (subdomain III + IV) and HER3 (subdomain I + II) expressed on tumor cells, and these receptors compete with each other for binding to this MAb. Competition flow cytometry experiments demonstrated that 1G5D2 does not compete with heregulin and recognizes an epitope out of HER3 ligand-binding site. Evaluation of 1G5D2 inhibitory effects in tumor cell lines co-expressing HER2 and HER3 showed that 1G5D2 synergizes with trastuzumab to inhibit both PI3K/AKT and MAPK/ERK pathways and potently downregulates the proliferation of these tumor cells more efficiently than each MAb alone. 1G5D2 is the first reported hybridoma antibody, which acts as a natural HER2/HER3 bispecific antibody. It might potentially be a suitable therapeutic candidate for HER2/HER3 overexpressing cancer types. [ABSTRACT FROM AUTHOR]