Neutrophil and complement attracting anti-cancer monoclonal antibody conjugates:

描述(由申请人提供)：治疗性单抗在癌症中的引入已经成熟，目前已被批准用于包括乳腺癌在内的各种癌症类型。即使与化疗药物联合使用，未经修饰的单抗在消除转移性肿瘤方面也往往具有中等的疗效。药物/毒素单抗结合物可能会带来额外的临床益处，但制造成本高昂，并可能与长期毒性和耐药性相关。需要一种利用单抗的精致特异性与提高免疫活性相结合的方法。 免疫系统中没有被广泛用于癌症治疗的一个手臂是先天免疫系统。先天免疫是抵御真菌和细菌等感染性病原体的第一道防线。这种手臂使用与中性粒细胞相关的强大的细胞毒性武器，中性粒细胞是最丰富的白细胞。挑战一直是以一种肿瘤特异性的方式捕捉这种效应器功能。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。通过将这种糖结合到针对乳腺癌细胞的单抗上，已经证明了肿瘤的完全摧毁。 Herceptin(曲妥珠单抗)是一种单抗，用于治疗肿瘤显示HER2分子的乳腺癌患者。在人乳腺癌的小鼠异种移植模型中，与裸露的Herceptin相比，Herceptin-β-1，6-葡聚糖结合物治疗Herceptin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体内生长而不发生排斥反应。赫赛汀在欧盟的专利将于2014年到期，在世界其他地区的专利将于2016-2019年到期，因此，有可能在临床上取得更好的赫赛汀结合物。就像在任何免疫治疗方法中一样，需要使用具有免疫能力的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个模型中得到最好的解决。免疫Xcite的独特方法比抗体药物/毒素结合物(ADC)有很大的好处： 如果β-1，6-葡聚糖方法确实能够在临床环境下以最小的毒性利用中性粒细胞的强大杀伤机制，那么一种强大的单一疗法可能成为可能，并对临床上HER2阳性的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.