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的成功有限。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mAb之一是曲妥珠单抗，其靶向HER2受体，并用于治疗25%至30%的过表达HER2受体的转移性乳腺癌。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，以及对于本申请的目的而言最重要的是募集和激活先天免疫系统的癌症杀伤细胞。癌症杀伤细胞如自然杀伤（NK）细胞在细胞表面上表达活化性Fcg受体（FcgR）。用曲妥珠单抗包被的肿瘤细胞被FcgR+ NK细胞攻击。曲妥珠单抗募集和激活FcgR+癌症杀伤细胞是其疗效的重要贡献者。曲妥珠单抗治疗在大约75%的乳腺癌患者中失败。这种失败可能与通过FcgR的不充分接合而导致的癌症杀伤细胞的次优接合和活化有关。 我们已经开发了重组Fcg受体靶向配体（FcRTL），其有效地激活NK细胞。FcRTL以比单体或聚集的IgG更高的亲合力结合FcgR。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型治疗剂，所述重组融合蛋白含有来自与FcRTL、R2和R4融合的抗HER2 mAb的重链和轻链可变区序列。使用FcRTL开发抗HER2 mAb类似物代表了治疗癌症的新方法。该申请的目标是开发基于FcRTL结构构建的新型mAb类似物。 公共卫生相关性：制造更好的免疫治疗乳腺癌的新技术：抗HER2抗体，曲妥珠单抗，用于治疗HER2过度表达的乳腺癌。曲妥珠单抗的功效受到肿瘤攻击先天免疫系统细胞上Fcg受体（FcgR）的结合和交联不足的限制。我们正在寻求一种新的策略来开发抗HER2单克隆抗体（mAb）类似物。我们已经开发了重组Fcg受体靶向配体（FcRTL），其结合低亲和力FcgR并激活NK细胞。我们建议将FcRTL配体系统应用于开发由重组融合蛋白组成的新型治疗剂，所述重组融合蛋白含有来自融合至FcRTL R2和R4的抗HER2 mAb的重链和轻链可变区序列。在抗HER2 mAb类似物的开发中使用FcRTL代表了优化用于治疗癌症的mAb的新方法。

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.