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

描述（由申请人提供）：单克隆抗体技术是上个世纪最显著的科学进步之一。这项研究的快速转化延长了数千名癌症患者的生存时间。尽管单克隆抗体，包括利妥昔单抗，曲妥珠单抗（赫赛汀）和西妥昔单抗的活性很有希望，但难治性或晚期癌症患者的反应率低于25%。抗肿瘤作用的主要机制之一是通过抗体依赖性细胞介导的细胞毒性（ADCC），其中携带Fc受体的自然杀伤（NK）细胞结合抗体靶向的肿瘤细胞并介导杀伤功能。常规的细胞毒性化疗诱导骨髓抑制，减少NK细胞的群体，从而降低ADCC的功效。相反，增强NK细胞功能的疗法独特地提供了改善单克隆抗体活性而不增加对非癌细胞的毒性的能力。我们最近已经证明，ADCC功能可以增强，靶细胞杀伤可以通过针对CD 137的第二抗体增强，CD 137是NK细胞活化细胞表面分子。我们推测，通过触发NK细胞上的活化标志物CD 137，我们可以增强单克隆抗体治疗的抗肿瘤功效。为了支持这一假设，我们将证明NK细胞暴露于抗体靶向肿瘤后，CD 137的NK细胞表达增加，包括利妥昔单抗治疗的淋巴瘤、曲妥珠单抗治疗的乳腺癌和西妥昔单抗治疗的结肠癌和头颈癌。其次，我们将研究用激动性抗CD 137抗体刺激活化的NK细胞是否增强对抗体靶向肿瘤的体外细胞毒性。最后，我们将确定激动性抗CD 137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协同增强人淋巴瘤、乳腺癌和结肠癌以及头颈癌异种移植物的体内治疗。由于激动性抗CD 137抗体目前作为单一疗法处于I/II期临床试验中，如果我们的假设是有效的，则该策略可以立即临床转化为任何已经被证实的单克隆抗体疗法的肿瘤。)

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. )