Enhanced complement-mediated cytotoxicity by EGFR-directed monoclonal antibodies in the therapy of solid tumors.

EGFR 定向单克隆抗体在实体瘤治疗中增强补体介导的细胞毒性。

• 批准号: 196263374
• 负责人: Professorin Dr. Stefanie Derer
• 金额: --
• 依托单位: Sektion für Stammzell- und Immuntherapie
• 依托单位国家: 德国
• 项目类别: Research Grants
• 财政年份: 2011
• 资助国家: 德国
• 起止时间: 2010-12-31 至 2017-12-31
• 项目状态: 已结题
• 来源: https://gepris.dfg.de/gepris/projekt/196263374?language=en
• 关键词: Enhanced; complement; mediated; cytotoxicity; EGFR

The complement system constitutes the first-line defense against invading pathogens in in-nate immunity but can also be recruited by tumor targeting antibodies to eliminate tumor cells. Epidermal growth factor receptor (EGFR) targeting antibodies constitute a major treatment option for colorectal or head and neck tumor patients. In the background of high expression of complement-regulatory proteins (CRP) on solid tumor cells as well as of the fact that single EGFR targeting IgG1 antibodies lack the capacity to trigger efficient complement-dependent cytotoxicity (CDC), strategies have been implemented in the course of the expiring funding period to improve either the intrinsic capacity of antibodies to initiate the complement cascade or to interfere with tumor cells` resistance mechanisms. In short, as EGFR is also expressed on normal healthy tissues, we generated a CDC-optimized antibody targeting the tumor-specific EGFR variant III. Furthermore, we established an IgG3 isotype switch variant of the EGFR targeting antibody cetuximab encompassing superior C1q but low C4b or C3b binding capacities and therefore only potent CDC activity against tumor cells expressing low levels of the complement-regulatory protein CD55. Hence, we aim to further investigate tumor-specific CDC enhancing approaches to take advantage of the powerful anti-tumoral effector functions of the complement system. For this purpose, we would like to improve C4b and/or C3b binding to the CH1 domain of IgG3 EGFR antibodies to exploit initial strong C1q binding to the antibody. To reduce CD55 dependency of anti-EGFR-IgG3, we aim to target CRP-specific siRNAs to tumor cells via coupling to the generated EGFRvIII targeting antibody. Finally, both strategies shall be combined to solely sensitize tumor cells for anti-EGFR-IgG3 triggered complement activation. Furthermore, the expression levels of CRP shall be determined in different tumor entities and related to the CDC activity of anti-EGFR-IgG3. Based on these findings, CRP expression levels might be established as potential predictors for efficient complement activation by anti-EGFR IgG3. In summary, in the proposed follow-up project we aim to extend development of tumor-specific strategies with an increased cytotoxic potential for the EGFR-targeted antibody-based tumor therapy.

补体系统构成了天然免疫中抵抗入侵病原体的第一线防御，但也可以被肿瘤靶向抗体招募以消除肿瘤细胞。表皮生长因子受体（EGFR）靶向抗体构成了结肠直肠或头颈部肿瘤患者的主要治疗选择。在实体瘤细胞上补体调节蛋白（CRP）高表达以及单一EGFR靶向IgG 1抗体缺乏触发有效补体依赖性细胞毒性（CDC）的能力的背景下，在即将到期的资助期内，已经实施了一些策略，以提高抗体启动补体级联反应或干扰肿瘤细胞的内在能力。抵抗机制简而言之，由于EGFR也在正常健康组织上表达，我们产生了靶向肿瘤特异性EGFR变体III的CDC优化的抗体。此外，我们建立了EGFR靶向抗体西妥昔单抗的IgG 3同种型转换变体，其包含上级C1 q但低C4 b或C3 b结合能力，因此仅对表达低水平补体调节蛋白CD 55的肿瘤细胞具有有效的CDC活性。因此，我们的目标是进一步研究肿瘤特异性CDC增强方法，以利用补体系统强大的抗肿瘤效应子功能。为此，我们希望改善C4 b和/或C3 b与IgG 3 EGFR抗体的CH 1结构域的结合，以利用与抗体的初始强C1 q结合。为了降低抗EGFR-IgG 3的CD 55依赖性，我们的目标是通过偶联产生的EGFRvIII靶向抗体将CRP特异性siRNA靶向肿瘤细胞。最后，两种策略应组合以单独使肿瘤细胞对抗EGFR-IgG 3触发的补体活化敏感。此外，CRP的表达水平应在不同的肿瘤实体中确定，并与抗EGFR-IgG 3的CDC活性相关。基于这些发现，CRP表达水平可能被确立为抗EGFR IgG 3有效激活补体的潜在预测因子。总之，在拟议的后续项目中，我们的目标是扩展肿瘤特异性策略的开发，增加EGFR靶向抗体为基础的肿瘤治疗的细胞毒性潜力。