Neutrophil and complement attracting anti-cancer monoclonal antibody conjugates:

描述（由申请人提供）：在癌症中引入治疗性单克隆抗体（mAb）已经成熟，mAb现已获批用于各种癌症类型，包括乳腺癌。未修饰的mAb倾向于在消除转移性肿瘤方面具有中等功效，甚至当与化疗剂组合时。药物/毒素mAb偶联物可能带来额外的临床益处，但制造昂贵，并且可能与长期毒性和耐药性问题相关。需要一种利用mAb的精确特异性以及改善的免疫活性的方法。 在癌症治疗中尚未被广泛利用的免疫系统的一个分支是先天免疫系统。先天免疫是抵抗真菌和细菌等感染因子的第一道防线。这支手臂使用了与中性粒细胞（最丰富的白色血细胞）相关的强大细胞毒性武器。挑战是以肿瘤特异性方式捕获这种效应子功能。一种独特的真菌细胞壁多糖，β-1，6-葡聚糖，已被确定为吸引中性粒细胞到真菌感染部位的关键分子。通过将这种糖连接到靶向乳腺癌细胞的mAb上，已经证明了完全的肿瘤破坏。 赫赛汀（曲妥珠单抗）是一种用于治疗肿瘤显示HER 2分子的乳腺癌患者的mAb。在人乳腺癌的小鼠异种移植模型中，与裸赫赛汀相比，用赫赛汀-β-1，6-葡聚糖缀合物治疗赫赛汀耐药肿瘤导致肿瘤破坏和消除。这些实验是在缺乏完整免疫系统的标准癌症小鼠模型中进行的，以允许人类肿瘤在小鼠中生长而不排斥。赫赛汀将于2014年在欧盟和2016-2019年在世界其他地区失效，因此，有可能开发出上级赫赛汀结合物用于临床。与任何免疫学方法一样，需要使用免疫活性小鼠进行额外的研究，以探索β-1，6-葡聚糖技术如何在完整的免疫环境中相互作用。此外，与这种方法相关的任何毒性都可以在这种模型中得到最好的解决。ImmuneXcite的独特方法比抗体药物/毒素缀合物（ADC）具有实质性益处： 如果β-1，6-葡聚糖方法确实能够在临床环境中以最小的毒性吸收嗜中性粒细胞的强大杀伤机制，那么一种强大的新单药疗法可能成为可能，并对临床中HER 2阳性转移性乳腺癌患者的治疗产生重大影响。

DESCRIPTION (provided by applicant): The introduction of therapeutic monoclonal antibodies (mAbs) in cancer has come of age with mAbs now approved for various cancer types including breast cancer. Unmodified mAbs tend to have moderate efficacy in eliminating metastatic tumors even when combined with chemotherapeutic agents. Drug/Toxin mAb conjugates may bring additional clinical benefit but are expensive to manufacture and may be associated with long-terms toxicity and resistance concerns. An approach which leverages on the exquisite specificity of mAbs coupled with improved immune activity is needed. One arm of the immune system that has not been extensively exploited in cancer therapeutics is the innate immune system. Innate immunity is the first line of defense against infectious agents such as fungi and bacteria. This arm employs the powerful cytotoxic armament associated with neutrophils, the most abundant white blood cell. The challenge has been to capture this effector function in a tumor specific manner. A unique fungal cell wall polysaccharide, beta-1,6-glucan, has been identified as a key molecule in attracting neutrophils to the site of fungal infection. By attaching this saccharide to mAbs which target breast cancer cells, complete tumor destruction has been demonstrated. Herceptin (trastuzumab) is a mAb used to treat breast cancer patients whose tumors display the HER2 molecule. In mouse xenograft models of human breast cancer, treatment of Herceptin resistant tumors with the Herceptin-beta-1,6-glucan conjugate resulted in tumor destruction and elimination compared to naked Herceptin. These experiments were performed in standard cancer mouse models lacking a complete immune system to allow human tumor growth in mice without rejection. Herceptin will go out of patent in 2014 in the EU and 2016-2019 in the rest of the world, and therefore, it would be possible to progress a superior Herceptin conjugate toward the clinic. As in any immunotherapeutic approaches, additional studies employing immune competent mice are needed to explore how the beta-1,6-glucan technology might interact in an intact immune environment. In addition, any toxicity associated with this approach can best be addressed in this model. ImmuneXcite's unique approach has substantial benefits over antibody drug/toxin conjugates (ADCs): If indeed the beta-1,6-glucan approach is able to co-opt the powerful killing mechanism of neutrophils in clinical setting with minimal toxicity, a powerful new monotherapy may be possible and significantly impact treatment of HER2 positive metastatic breast cancer patients in the clinic.