Novel HER2 targeting immunotherapeutics for breast cancer

新型 HER2 靶向乳腺癌免疫疗法

• 批准号: 8063581
• 负责人: Mark Allen Jensen
• 金额: $ 26.91万
• 依托单位: ITERATIVE THERAPEUTICS, INC.
• 依托单位国家: 美国
• 财政年份: 2010
• 资助国家: 美国
• 起止时间: 2010-05-01 至 2014-04-30
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/8063581
• 关键词: Activated Natural Killer Cell; Affinity; Angiogenic Factor; Antibodies; Avidity; Binding; Biological Assay; Cancer Patient; Cell Cycle Progression; Cell Proliferation; Cell surface; Cells; Cloning; Development; Down-Regulation; ERBB2 gene; FDA approved; Failure; Glycocalyx; Goals; Growth; HER2 inhibition; Human; Immune system; Immunoglobulin G; Immunoglobulin Variable Region; Immunotherapeutic agent; Immunotherapy; Ligand Binding; Ligands; Light; Link; Malignant Neoplasms; Measures; Monoclonal Antibodies; Mus; Natural Killer Cells; Peripheral Blood Mononuclear Cell; Recombinant Fusion Proteins; Recombinants; Relative (related person); Solid Neoplasm; Structure; System; Trastuzumab; Tumor Cell Line; Xenograft procedure; analog; antibody-dependent cell cytotoxicity; cancer therapy; cell growth; cell killing; crosslink; malignant breast neoplasm; meetings; mouse model; neoplastic cell; new technology; novel; novel strategies; novel therapeutics; overexpression; progenitor; public health relevance; receptor; research study; success; tumor

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.

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使用抗癌单克隆抗体（mAb）来靶向肿瘤。曲妥珠单抗是 FDA 批准用于治疗实体瘤的首批单克隆抗体之一，它以 HER2 受体为靶点，用于治疗 25% 至 30% 过度表达 HER2 受体的转移性乳腺癌。人们认为有助于曲妥珠单抗功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，以及最重要的本应用的目的、招募和激活先天免疫系统的杀癌细胞。自然杀伤 (NK) 细胞等癌症杀伤细胞在细胞表面表达激活性 Fcg 受体 (FcgR)。曲妥珠单抗包被的肿瘤细胞受到 FcgR+ NK 细胞的攻击。曲妥珠单抗招募和激活 FcgR+ 癌细胞是其疗效的重要贡献者。大约 75% 的乳腺癌患者曲妥珠单抗治疗失败。这种失败可能与 FcgR 结合不足导致癌症杀伤细胞的结合和激活欠佳有关。 我们开发了重组 Fcg 受体靶向配体 (FcRTL)，可有效激活 NK 细胞。 FcRTL 与 FcgR 的结合力比单体或聚集的 IgG 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型疗法，该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 mAb 类似物。 公共卫生相关性：用于治疗乳腺癌的更好免疫疗法的新技术：抗 HER2 抗体曲妥珠单抗用于治疗 HER2 过度表达的乳腺癌。曲妥珠单抗的功效因 Fcg 受体 (FcgR) 对攻击肿瘤的先天免疫系统细胞的结合和交联不足而受到限制。我们正在寻求一种开发抗 HER2 单克隆抗体 (mAb) 类似物的新策略。我们开发了重组 Fcg 受体靶向配体 (FcRTL)，可结合低亲和力 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疗法，该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 类似物代表了一种优化 mAb 治疗癌症的新方法。