西妥昔单抗
癌症研究
抗体
癌症干细胞
人源化抗体
人口
抗原
癌症
生物
免疫学
化学
医学
单克隆抗体
内科学
环境卫生
作者
Alexander Rau,Wolfgang Lieb,Oliver Seifert,Jonas Honer,Dennis Birnstock,Fabian Richter,Nadine Beha,Monilola A. Olayioye,Roland E. Kontermann
出处
期刊:Molecular Cancer Therapeutics
[American Association for Cancer Research]
日期:2020-07-01
卷期号:19 (7): 1474-1485
被引量:27
标识
DOI:10.1158/1535-7163.mct-19-1095
摘要
Abstract The frequent activation of HER3 signaling as a resistance mechanism to EGFR-targeted therapy has motivated the development of combination therapies that block more than one receptor tyrosine kinase. Here, we have developed a novel tetravalent, bispecific single-chain diabody-Fc fusion protein targeting EGFR and HER3 (also known as ErbB3) that integrates the antigen-binding sites of a humanized version of cetuximab as well as a recently developed anti-HER3 antibody, IgG 3-43. This bispecific antibody combines the binding and neutralizing properties of the parental antibodies, as observed in biochemical and in vitro two-dimensional and three-dimensional cell culture assays, and gave rise to long-lasting growth suppression in a subcutaneous xenograft head and neck tumor model. In triple-negative breast cancer (TNBC) cell lines, treatment with the bispecific antibody inhibited the proliferation and oncosphere formation efficiency driven by HER3 signaling. In an orthotopic MDA-MB-468 tumor model, this translated into antitumor effects superior to those obtained by the parental antibodies alone or in combination and was associated with a reduced number of cells with stem-like properties. These findings demonstrate that the bispecific antibody efficiently blocks not only TNBC proliferation, but also the survival and expansion of the cancer stem cell population, holding promise for further preclinical development.
科研通智能强力驱动
Strongly Powered by AbleSci AI