Vallera Daniel A, Oh Felix, Kodal Behiye, Hinderlie Peter, Geller Melissa A, Miller Jeffrey S, Felices Martin
Masonic Cancer Center, University of Minnesota, Minneapolis, MN 55455, USA.
Department of Radiation Oncology, University of Minnesota, Minneapolis, MN 55455, USA.
Cancers (Basel). 2021 Aug 8;13(16):3994. doi: 10.3390/cancers13163994.
Clinical studies validated antibodies directed against HER2, trastuzumab, and pertuzumab, as useful methodology to target breast cancer cases where HER2 is expressed. The hope was that HER2 targeting using these antibodies in ovarian cancer patients would prove useful as well, but clinical studies have shown lackluster results in this setting, indicating a need for a more comprehensive approach. Immunotherapy approaches stimulating the innate immune system show great promise, although enhancing natural killer (NK) function is not an established mainstream immunotherapy. This study focused on a new nanobody platform technology in which the bispecific antibody was altered to incorporate a cytokine. Herein we describe bioengineered CAM1615HER2 consisting of a camelid VHH antibody fragment recognizing CD16 and a single chain variable fragment (scFv) recognizing HER2 cross-linked by the human interleukin-15 (IL-15) cytokine. This tri-specific killer engager (TriKE) showed in vitro prowess in its ability to kill ovarian cancer human cell lines. In addition, we demonstrated its efficacy in inducing potent anti-cancer effects in an in vivo xenograft model of human ovarian cancer engrafting both cancer cells and human NK cells. While previous approaches with trastuzumab and pertuzumab faltered in ovarian cancer, the hope is incorporating targeting and cytokine priming within the same molecule will enhance efficacy in this setting.
临床研究证实，针对HER2的抗体、曲妥珠单抗和帕妥珠单抗，作为靶向HER2表达的乳腺癌病例的有效方法。人们希望在卵巢癌患者中使用这些抗体靶向HER2也能证明是有用的，但临床研究表明在这种情况下结果并不理想，这表明需要一种更全面的方法。刺激先天免疫系统的免疫疗法显示出巨大的前景，尽管增强自然杀伤（NK）功能并非既定的主流免疫疗法。本研究聚焦于一种新的纳米抗体平台技术，其中双特异性抗体经过改造以掺入一种细胞因子。在此，我们描述了生物工程化的CAM1615HER2，它由识别CD16的骆驼科VHH抗体片段和识别HER2的单链可变片段（scFv）组成，通过人白细胞介素-15（IL-15）细胞因子交联。这种三特异性杀伤衔接子（TriKE）在体外显示出杀死卵巢癌人类细胞系的能力。此外，我们在植入癌细胞和人类NK细胞的人类卵巢癌体内异种移植模型中证明了其诱导强效抗癌作用的功效。虽然之前使用曲妥珠单抗和帕妥珠单抗的方法在卵巢癌中效果不佳，但人们希望在同一分子中结合靶向和细胞因子启动将能增强在这种情况下的疗效。
