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

描述（由申请人提供）：单克隆抗体技术是过去25年来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）具有良好的活性，但在难治性或晚期癌症患者中的反应率低于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。传统的细胞毒性化疗诱导骨髓抑制，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克隆抗体活性的能力，而不会增加对非癌细胞的毒性。我们最近已经证明，ADCC功能可以增强，靶细胞杀伤可以通过针对CD137的第二抗体增强，CD137是一种NK细胞活化细胞表面分子。我们假设通过触发NK细胞上的激活标记CD137，我们可以增强单克隆抗体治疗的抗肿瘤效果。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，CD137的NK细胞表达增加，包括利妥昔单抗的淋巴瘤，曲妥珠单抗的乳腺癌，西妥昔单抗的结肠癌和头颈癌。其次，我们将研究用激动性抗cd137抗体刺激活化NK细胞是否能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cd137抗体分别与利妥昔单抗、曲妥珠单抗和西妥昔单抗联合使用是否能协同增强人淋巴瘤、乳腺癌、结肠癌和头颈癌异种移植物的体内治疗。由于激动性抗cd137抗体目前正处于I/II期临床试验中，作为单一疗法，如果我们的假设是有效的，该策略可以立即临床转化为已经有单克隆抗体治疗的任何肿瘤。

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. )