Novel HER2 targeting immunotherapeutics for breast cancer

描述(申请人提供)：用免疫疗法治疗实体肿瘤的成功有限。肿瘤治疗的一种方法是用抗癌单抗(MAbbs)靶向肿瘤。FDA批准的首批用于治疗实体瘤的单抗之一是曲妥珠单抗，它针对HER2受体，用于治疗25%至30%过度表达HER2受体的转移性乳腺癌。据认为，曲妥珠单抗的疗效机制包括抑制肿瘤细胞生长，下调血管生成因子，以及最重要的是该应用的目的，即招募和激活先天免疫系统的癌症杀伤细胞。自然杀伤(Natural Killer，NK)细胞等肿瘤杀伤细胞在细胞表面表达活化FCG受体(FcgRs)。包被曲妥珠单抗的肿瘤细胞受到FcgR+NK细胞的攻击。曲妥珠单抗对FcgR+肿瘤杀伤细胞的募集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FcgRs的参与不足而导致的肿瘤杀伤细胞的次优结合和激活有关。我们已经开发出能够有效激活NK细胞的重组FCG受体靶向配体(FcRTL)。FcRTL结合FcgRs的亲和力高于单体或聚集型Ig G。我们建议使用我们的FcRTL配基系统来开发由重组融合蛋白组成的新的治疗药物，该融合蛋白包含抗HER2单抗与FcRTL、R2和R4融合的重链和轻链可变区序列。利用FcRTL开发抗HER2单抗类似物代表了一种治疗癌症的新方法。该应用的目标是开发建立在FcRTL结构上的新型单抗类似物。 公共卫生意义：为治疗乳腺癌提供更好的免疫治疗的新技术：抗HER2抗体曲妥珠单抗用于治疗HER2过表达的乳腺癌。曲妥珠单抗的疗效受到FCG受体(FcgRs)对攻击肿瘤的天然免疫细胞的结合和交联性不足的限制。我们正在寻求一种新的策略来开发抗HER2单抗(MAb)类似物。我们已经开发了重组FCG受体靶向配体(FcRTL)，可以结合低亲和力的FcgRs并激活NK细胞。我们建议将FcRTL配基系统应用于由含有抗HER2单抗与FcRTL、R2和R4融合的重链和轻链可变区序列的重组融合蛋白组成的新疗法的开发。利用FcRTLS开发抗HER2单抗类似物是一种优化单抗治疗癌症的新方法。

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.