Novel HER2 targeting immunotherapeutics for breast cancer

描述（由申请人提供）：用免疫疗法治疗实体瘤取得了有限的成功。肿瘤治疗的一种方法是用抗癌单克隆抗体（mab）靶向肿瘤。FDA批准用于治疗实体瘤的首批单克隆抗体之一是曲妥珠单抗，靶向HER2受体，用于治疗25%至30%的HER2受体过表达的转移性乳腺癌。被认为有助于曲妥珠单抗疗效的机制包括对肿瘤细胞生长的抑制作用，血管生成因子的下调，最重要的是对该应用的目的，先天免疫系统的癌症杀伤细胞的招募和激活。自然杀伤细胞（NK）等癌症杀伤细胞在细胞表面表达活化的Fcg受体（fcgr）。包被曲妥珠单抗的肿瘤细胞被FcgR+ NK细胞攻击。曲妥珠单抗对FcgR+癌症杀伤细胞的招募和激活是其疗效的重要因素。曲妥珠单抗治疗在大约75%的乳腺癌患者中失败。这种失败可能与未充分参与fcgr的次优参与和癌症杀伤细胞激活有关。我们已经开发了重组Fcg受体靶向配体（FcRTL），可以有效激活NK细胞。与单个或聚集的IgG相比，FcRTLs结合fcgr的亲和度更高。我们建议使用我们的FcRTL配体系统来开发由重组融合蛋白组成的新疗法，该融合蛋白含有来自抗her2单抗的重链和轻链可变区序列，这些序列与FcRTL、R2和R4融合。利用FcRTLs开发抗her2单抗类似物代表了一种治疗癌症的新方法。该申请的目标是开发基于FcRTL结构的新型单抗类似物。

DESCRIPTION (provided by applicant): Treatment of solid tumors with immunotherapy has met with limited success. One approach to tumor therapy has been to target tumors with anti-cancer monoclonal antibodies (mAbs). One of the first mAbs approved by the FDA for treatment of solid tumors is Trastuzumab which targets the HER2 receptor and is used to treat 25 to 30% of metastatic breast cancers that overexpress the HER2 receptor. Mechanisms thought to contribute to the efficacy of Trastuzumab include an inhibitory effect on tumor cell growth, downregulation of angiogenic factors, and most importantly to the Aims of this application, recruitment and activation of cancer-killing cells of the innate immune system. Cancer-killing cells such as Natural Killer (NK) cells express activatory Fcg receptors (FcgRs) on the cell surface. Tumor cells coated with Trastuzumab are attacked by FcgR+ NK cells. Recruitment and activation of FcgR+ cancer-killing cells by Trastuzumab is an important contributor to its efficacy. Trastuzumab treatment fails in approximately 75% of breast cancer patients. This failure may link to sub-optimal engagement and activation of cancer-killing cells through insufficient engagement of FcgRs. We have developed recombinant Fcg receptor-targeted ligands (FcRTL) that are potently activate NK cells. FcRTLs bind FcgRs with higher avidity than monomeric or aggregated IgG. We propose to use our FcRTL ligand system to develop novel therapeutics comprised of recombinant fusion proteins that contain heavy and light chain variable region sequences from anti-HER2 mAbs fused to the FcRTLs, R2 and R4. Use of FcRTLs to develop anti-HER2 mAb analogs represents a novel approach for the treatment of cancer. The goal of the application is to develop novel mAb analogs built upon an FcRTL structure. PUBLIC HEALTH RELEVANCE: New Technology for making a better immunotherapeutic for treating breast cancer: Anti-HER2 antibody, Trastuzumab, is used for the treatment of HER2-overexpressing breast cancer. The efficacy of Trastuzumab is limited by insufficient binding and crosslinking of Fcg receptors (FcgRs) on tumor-attacking innate immune system cells. We are pursuing a novel strategy to develop anti-HER2 monoclonal antibody (mAb) analogs. We have developed recombinant Fcg receptor-targeted ligands (FcRTL) that bind low affinity FcgRs and activate NK cells. We propose to apply the FcRTL ligand system to the development of novel therapeutics comprised of recombinant fusion proteins that contain heavy and light chain variable region sequences from anti-HER2 mAbs fused to the FcRTLs, R2 and R4. Use of FcRTLs in the development of anti-HER2 mAb analogs represents a novel approach to optimize mAbs for the treatment of cancer.