Enhancing tumor-targeted antibody therapy with a second NK activating antibody.

描述(申请人提供)：单抗技术是过去25年来最显著的科学进步之一。这项研究的快速翻译延长了数千名癌症患者的生存时间。尽管包括利妥昔单抗、曲妥珠单抗(赫赛汀)和西妥昔单抗在内的单抗有很好的活性，但难治性或晚期癌症患者的应答率不到25%。抗肿瘤作用的主要机制之一是通过抗体依赖的细胞介导的细胞毒性(ADCC)，即携带Fc受体的自然杀伤(NK)细胞与抗体靶向的肿瘤细胞结合并介导杀伤功能。传统的细胞毒化疗会导致骨髓抑制，减少NK细胞的数量，从而降低ADCC的疗效。相比之下，增强NK细胞功能的疗法独特地提供了提高单抗活性的能力，而不会增加对非癌细胞的毒性。我们最近已经证明，抗CD137的第二抗体可以增强ADCC的功能，并增强靶细胞杀伤作用。CD137是一种NK细胞激活的细胞表面分子。我们推测，通过触发NK细胞上的激活标记CD137，我们可以增强单抗治疗的抗肿瘤效果。为了支持这一假设，我们将证明在NK细胞暴露于抗体靶向肿瘤后，CD137的NK细胞表达增加，这些肿瘤包括利妥昔单抗治疗的淋巴瘤，曲妥珠单抗治疗的乳腺癌，以及西妥昔单抗治疗的结肠癌和头颈癌。其次，我们将研究激动型抗CD137抗体刺激活化的NK细胞是否增强了体外对抗体靶向肿瘤的细胞毒作用。最后，我们将确定激动型抗CD137抗体分别与利妥昔单抗、曲妥珠单抗和西妥昔单抗一起是否能协同增强体内对人类淋巴瘤、乳腺癌、结肠癌和头颈癌移植瘤的治疗。由于激动型抗CD137抗体目前处于单抗疗法的I/II期临床试验中，如果我们的假设有效，这一策略可以立即在临床上转化为任何已经证实有单抗疗法的肿瘤。) 公共卫生相关性：本项目中获得的知识可能支持一种新的广泛适用的方法，即通过激活抗CD137抗体来增强ADCC的主要杀伤机制，从而加强任何癌症的单抗治疗。

DESCRIPTION (provided by applicant): Monoclonal antibody technology is among the most notable scientific advances in the last quarter century. Rapid translation of this research has prolonged the survival of thousands of patients with cancer. Despite the promising activity of monoclonal antibodies, including rituximab, trastuzumab (herceptin), and cetuximab, the response rates among patients with either refractory or advanced cancer are suboptimal at less than 25%. One of the primary mechanisms of antitumor action is through antibody dependent cell-mediated cytotoxicity (ADCC) whereby a natural killer (NK) cell bearing an Fc receptor binds to the antibody-targeted tumor cell and mediates the killing function. Conventional cytotoxic chemotherapies induce myelosuppression, decreasing the population of NK cells, thereby reducing the efficacy of ADCC. In contrast, therapies which augment NK cell function uniquely offer the ability to improve activity of monoclonal antibodies without increasing toxicity to non-cancer cells. We have recently demonstrated that ADCC function can be augmented and target cell killing can be enhanced by a second antibody against CD137, an NK cell activation cell surface molecule. We hypothesize that by triggering the activation marker, CD137, on NK cells we can enhance the antitumor efficacy of monoclonal antibody therapy. To support this hypothesis we will demonstrate increased NK cell expression of CD137 occurs following NK cell exposure to antibody targeted tumors, including lymphoma by rituximab, breast cancer by trastuzumab, and colon and head and neck cancers by cetuximab. Second, we will investigate if stimulation of activated NK cells with agonistic anti-CD137 antibody enhances in-vitro cytotoxicity against antibody targeted tumors. Finally, we will determine if in-vivo treatment of xenografts of human lymphoma, breast cancer, and colon and head and neck cancers is synergistically enhanced by agonistic anti-CD137 antibody together with rituximab, trastuzumab, and cetuximab respectively. As agonistic anti-CD137 antibodies are currently in phase I/II clinical trials as monotherapy, if our hypothesis is valid, this strategy could be clinically translated immediately to any tumor for which there is already a proven monoclonal antibody therapy. ) PUBLIC HEALTH RELEVANCE: The knowledge gained in this project may support a new broadly-applicable approach to enhancing any monoclonal antibody therapy of cancer by augmenting the primary killing mechanism of ADCC with the activating anti-CD137 antibody.