Gain-of-function complement activators as a new class of immunotherapeutic molecules

功能获得性补体激活剂作为一类新型免疫治疗分子

• 批准号: 10629623
• 负责人: Ruben Martinez Barricarte
• 金额: $ 49.51万
• 依托单位: VANDERBILT UNIVERSITY MEDICAL CENTER
• 依托单位国家: 美国
• 财政年份: 2023
• 资助国家: 美国
• 起止时间: 2023-06-15 至 2028-05-31
• 项目状态: 未结题
• 来源: https://reporter.nih.gov/project-details/10629623
• 关键词: Address; Amino Acid Sequence; Animal Model; Antibody Therapy; Area; Autoimmunity; Automobile Driving; B-Lymphocytes; Behavior; Binding; Binding Proteins; Biological; Biological Products; Biomedical Engineering; Bypass; CD19 gene; Cell Line; Cells; Chimeric Proteins; Clinical; Clinical Trials; Communicable Diseases; Complement; Complement Activation; Complement Factor B; Complement Inactivators; Consumption; Cytolysis; Development; Disease; Engineering; FDA approved; Future; Genes; Hematologic Neoplasms; Hereditary Disease; Human; Immune; Immune System Diseases; Immune response; Immune system; Immunity; Immunoglobulin Fragments; Immunologics; Immunology; Immunomodulators; Immunosuppression; Immunotherapeutic agent; Immunotherapy; Impairment; In Vitro; Inflammation; Invaded; Knowledge; Learning; Leucocytic infiltrate; Link; Literature; Malignant Neoplasms; Mediating; Mendelian disorder; Methods; Mining; Mission; Monoclonal Antibodies; Mus; Mutate; Mutation; Nature; Organism; Pathogenicity; Patients; Peripheral Blood Mononuclear Cell; Physiological; Plasma; Procedures; Protein Fragment; Proteins; Publishing; Research; Resistance; Safety; Sampling; Solid; Solid Neoplasm; Specificity; Surface; System; Testing; Therapeutic; Tissues; Translating; Tropism; Tumor Cell Line; Tumor Markers; Work; autoinflammation; cancer cell; cancer immunotherapy; cancer therapy; cell type; chimeric antigen receptor T cells; complement system; disease-causing mutation; efficacy testing; experimental study; gain of function; gain of function mutation; immune system function; immunoregulation; improved; in vitro testing; in vivo; inhibitor; innovation; insight; interest; mouse model; mutant; neoplastic cell; novel; novel strategies; novel therapeutics; overexpression; pathogen; preclinical study; prevent; rare genetic disorder; safety assessment; side effect; therapy development; tumor

SUMMARY The complement system comprises over 30 proteins, mostly plasmatic, forming the oldest branch of the human immune system. When activated by a pathogen, the complement system amplifies a loop that leads to the destruction of the invading organism. Plasma and surface inhibitors tightly regulate complement activation to prevent or limit self-damage. Unfortunately, gain-of-function (GOF) mutations in the complement activator factor B (FB) found in some rare patients cause permanent complement activation that can lead to autoinflammation. GOF-FB is more efficient at activating complement and is resistant to natural complement inhibitors. Given the enhanced activity of these mutants, we hypothesize that we can redirect GOF-FB to target specific malignant cells or tissues for therapeutic purposes and with minimal side effects. In this application, we propose generating and testing in vitro molecules to direct GOF complement activating proteins specifically to cancer cells and solid tumors. In Aim 1, we will fuse GOF-FB to single-chain variable antibody fragments (scFV) to direct complement activation to specific cells or antigenic targets. This engineered biologic approach to target immunotherapy will lead to less expensive and off-the-shelf alternatives to chimeric antigen receptor T cells (CAR-T) and be immediately relevant for hematologic malignancies. These molecules could also overcome some of the current issues with antibody therapies, including complement consumption and inhibition by the tumor cells. In Aim 2, we will couple GOF-FB to proteins that bind components of the solid tumor or its microenvironment. This approach will promote inflammation in regions in and around solid tumors and enhance local immune responses that can ultimately eliminate tumors or resolve tissue damage. Due to the nature of GOF-FB, these molecules will be resistant to tumor microenvironmental immune suppression mechanisms. In aim 3, we will generate murine GOF-FB that will pave the way to translate our findings to animal models allowing for in vivo proof of concept experiments, preclinical studies, and assessments of safety and efficacy. Our proposed work is highly innovative and yet supported by solid literature evidence. We propose to prove in vitro that GOF-FB can have potential as an anti-cancer therapy. These newly engineered molecules based on human complement immune disorders could pinpoint a new class of immune modulators with greater specificity, reach, and activity than current treatments. It represents a different direction from previous research performed in our lab, but the expertise required to carry out the proposed work and the collaborators are already in place. Furthermore, the proven efficacy of some FDA-approved complement inhibitors used to treat diseases caused by GOF mutations in complement activation assures that our approach will have minimal side effects that can be readily addressed. The work proposed here to leverage GOF mutations to identify new therapies could improve the treatment of a myriad of severe diseases, including cancer, autoimmunity, and even infectious diseases.

总结 补体系统包括超过30种蛋白质，大部分是血浆蛋白，形成人类补体系统最古老的分支。 免疫系统当被病原体激活时，补体系统放大了一个环， 破坏入侵的生物体。血浆和表面抑制剂严格调节补体激活， 防止或限制自我伤害。不幸的是，补体激活因子中的功能获得性（GOF）突变 在一些罕见的患者中发现的B（FB）可导致永久性补体激活，从而导致自身炎症。 GOF-FB在激活补体方面更有效，并且对天然补体抑制剂具有抗性。鉴于 增强这些突变体的活性，我们假设我们可以重定向GOF-FB靶向特定的恶性肿瘤， 用于治疗目的的细胞或组织，并且具有最小的副作用。在本申请中，我们提出生成 并测试体外分子以将GOF补体激活蛋白特异性地导向癌细胞和固体 肿瘤的目的1：将GOF-FB与单链抗体片段（scFV）融合， 激活特定细胞或抗原靶点。这种针对免疫治疗的工程生物学方法将 导致嵌合抗原受体T细胞（CAR-T）的更便宜和现成的替代品， 与恶性血液病直接相关。这些分子也可以克服一些电流 抗体治疗的问题，包括补体消耗和肿瘤细胞的抑制。在目标2中， 我们将GOF-FB与结合实体瘤成分或其微环境的蛋白质偶联。这 这种方法将促进实体瘤内和周围区域的炎症，并增强局部免疫反应。 最终可以消除肿瘤或解决组织损伤。由于GOF-FB的性质，这些分子 将抵抗肿瘤微环境免疫抑制机制。在目标3中，我们将生成 鼠GOF-FB，这将为将我们的发现转化为动物模型铺平道路，从而允许在体内证明 概念实验、临床前研究以及安全性和有效性评估。我们提出的工作高度 创新，但有坚实的文献证据支持。我们建议在体外证明GOF-FB可以具有 作为抗癌疗法的潜力。这些新设计的分子基于人类补体免疫 疾病可以确定一类新的免疫调节剂，其特异性，范围和活性比 目前的治疗。它代表了与我们实验室以前进行的研究不同的方向， 开展拟议工作所需的专门知识和合作者已经到位。而且 一些FDA批准的用于治疗GOF突变引起的疾病的补体抑制剂的有效性已得到证实 补体激活确保我们的方法将具有最小的副作用，这可以容易地解决。 这里提出的利用GOF突变来确定新疗法的工作可以改善对 无数的严重疾病，包括癌症，自身免疫，甚至传染病。