NK Cell-Dependent Cancer Immunotherapy with Semi-Synthetic Peptide-Protein Bio-Conjugates

摘要： 癌症免疫疗法在与癌症的斗争中占据了中心舞台。单抗及其免疫原性 相关同行仍然处于癌症免疫治疗应用的前沿。然而，新的 以及改进的疗法和/或治疗方法，可以克服它们的产生， 给药和药理学限制，包括治疗耐药性的演变 仍然有广泛的需求。发展技术创新的关键，可能 克服这些限制的是具有靶向和效应器的中小分子 抗体的功能。为了达到这个目标，我们的研究目标是模拟抗体 半合成多肽-蛋白质生物偶联物的靶向和效应器功能。在这 应用方面，选择了多肽序列Pep42作为靶向葡萄糖调节的基因 78kodalton(GRP78)蛋白存在于肿瘤表面，而不存在于正常组织。选定的 肿瘤抗原B7-H6与NK细胞结合NKp30受体并具有免疫刺激作用 通过释放炎性细胞因子的活性，最终引发肿瘤溶解和死亡。 然而，肿瘤中B7-H6的下调或脱落会降低NK的NKp30活性 细胞，最终削弱它们的抗肿瘤免疫反应。因此，我们建议 新型Pep42-B7-H6结合物的开发 对缺乏细胞表面B7-H6的高表达GRP78肿瘤的杀伤作用拟议中的项目 将通过两个具体目标来解决：1)Pep42-B7-H6结合物的制备和 2)抗癌效果评价。值得注意的是，Pep42-B7-H6的结合物是 预计将加强对逃避NK细胞依赖的弹性肿瘤的癌症免疫治疗 免疫，同时提供对半合成抗体模拟物生产的洞察。

Abstract: Cancer immunotherapy has taken center stage in the fight against cancer. The mAb and their related counterparts remain at the forefront of cancer immunotherapy applications. However, new and improved therapeutics and/or treatment methods that may overcome their production, administration, and pharmacological limitations, including the evolution of treatment resistance are still in widespread demand. Key to the development of technological innovations that may overcome these limitations are small to intermediate size molecules with the targeting and effector functions of antibodies. Towards this goal, our research objective is to mimic antibody targeting and effector functions with semi-synthetic peptide-protein bioconjugates. In this application, the peptide sequence, Pep42, has been selected to target the Glucose Regulated Protein of 78 kilodalton (GRP78) on the surface of tumors but not on healthy tissues. The selected tumor antigen, B7-H6, exhibits NKp30 receptor binding on NK cells and immunostimulatory activity by the release of inflammatory cytokines that ultimately trigger tumor lysis and death. However, the downregulation or shedding of B7-H6 from tumors reduces NKp30 activation of NK cells, ultimately diminishing their anti-tumor immune responses. Therefore, we propose the development of new Pep42-B7-H6 conjugates that provide effective NK cell targeting and killing of GRP78 overexpressing tumors that lack cell surface B7-H6. The proposed project will be addressed by two specific aims: 1) the preparation of the Pep42-B7-H6 conjugates and 2) evaluation of their anti-cancer effects. Significantly, the Pep42-B7-H6 conjugates are anticipated to potentiate cancer immunotherapy of resilient tumors that evade NK cell-dependent immunity while providing insights into the production of semi-synthetic antibody mimics.