期刊
BREAST CANCER RESEARCH AND TREATMENT
卷 153, 期 1, 页码 123-133出版社
SPRINGER
DOI: 10.1007/s10549-015-3503-3
关键词
HER2; Antibody-drug conjugates; Antibody therapy; Tumor models; MMAE
类别
资金
- National Science and Technology Major Project of China [2014ZX09508004001]
Human epidermal growth factor receptor-2 (HER2) is a validated therapeutic target for breast cancer and trastuzumab (Herceptin), a humanized anti-HER2 antibody, has significant anti-cancer effects in the clinic. However, breast cancer patients often experience disease progression after prolonged Herceptin treatment. To develop a more effective therapy, we generated humanized monoclonal antibody hertuzumab and hertuzumab-drug conjugates as novel breast cancer therapies. The hertuzumab was conjugated with small molecule cytotoxic agents monomethylauristatin E (MMAE) or monomethylauristatin F (MMAF) with various linkers to generate antibody-drug conjugates (ADCs), which were evaluated for their in vitro and in vivo anti-cancer activities. Among these ADCs, hertuzumab-vc-MMAE can be effectively internalized and potently kill HER2 over-expressing tumor cells. In xenograft tumor models, hertuzumab-vc-MMAE showed a more potent anti-tumor activity than T-DM1, a FDA-approved ADC drug. More importantly, this novel ADC drug also showed superior anti-tumor activity than T-DM1 in trastuzumab- and lapatinib-resistant xenograft tumor models, suggesting its potential as an improved therapy for HER2-positive breast cancers. The novel ADC, hertuzumab-vc-MMAE, is an effective and selective agent for the treatment of HER2-positive breast tumors.
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