"Molecular whack-a-mole”: Targeting Transmembrane-TNFα for the Delivery of Anti-Inflammatory Drugs

“分子打地鼠”：靶向跨膜 TNFα 来输送抗炎药物

• 批准号: 10303479
• 负责人: Lawrence Tumey
• 金额: $ 7.85万
• 依托单位: STATE UNIVERSITY OF NY,BINGHAMTON
• 依托单位国家: 美国
• 财政年份: 2021
• 资助国家: 美国
• 起止时间: 2021-06-15 至 2023-05-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/10303479
• 关键词: Affinity; Anti-Inflammatory Agents; Anti-Tumor Necrosis Factor Therapy; Antibodies; Antibody-drug conjugates; Autoimmune; Autoimmune Diseases; B-Lymphocytes; Binding; Cell Adhesion Molecules; Cell Line; Cell surface; Cells; Chronic; Chronic small plaque psoriasis; Clathrin; Cleaved cell; Confocal Microscopy; DHODH gene; Development; Disease; Disease Progression; Drug Delivery Systems; Drug Industry; Dyes; Enzyme Inhibition; Enzyme Inhibitor Drugs; Enzymes; Event; Exhibits; Glucocorticoids; Goals; Human; IL8 gene; IRAK4 gene; Immunosuppression; Immunosuppressive Agents; In Vitro; Inflammation; Inflammatory; Interleukin-1; Interleukin-10; Interleukin-6; Investigation; Lead; Leukocytes; Ligands; Lymphocyte; Lysosomes; Malignant - descriptor; Measures; Mediating; Mole the mammal; Molecular; Myeloid Cells; Patients; Pattern; Peptide Hydrolases; Pharmaceutical Preparations; Pharmacologic Substance; Pharmacy Schools; Plasma; Positioning Attribute; Process; Program Development; Psoriatic Arthritis; Reporter; Reporting; Research; Resistance; Rheumatoid Arthritis; Source; Synovial Fluid; T-Lymphocyte; TNF gene; Technology; Therapeutic; Therapeutic Agents; Tissues; Toll-Like Receptor Pathway; Toll-like receptors; Toxic effect; Ulcerative Colitis; Validation; adalimumab; base; cell type; chemotherapy; cytokine; cytotoxic; cytotoxicity; design; effective therapy; experience; factor A; head-to-head comparison; improved; inflammatory marker; inhibitor/antagonist; interest; mTOR Inhibitor; macrophage; monocyte; next generation; novel therapeutics; prevent; receptor binding; recruit; response; side effect; small molecule; therapeutic development; uptake

Project Summary: Tumor necrosis factor α (TNFα) is often considered the “master cytokine” in rheumatoid arthritis (RA). Anti‐TNFα therapy has revolutionized the treatment of RA and related inflammatory disorders by depleting the plasma levels of this pro‐inflammatory cytokine. The primary source of circulating TNFα are synovial monocytes and macrophages that, in turn, have been activated by “danger‐associated‐molecular‐patterns” (DAMPs). Transmembrane TNFα (tmTNFα) is initially produced in response to this activation and is subsequently cleaved by TNFα converting enzyme (TACE) to produce soluble TNFα. A recent report has shown that anti‐TNFα antibodies such as adalimumab bind to tmTNFα and become internalized and trafficked to lysosomes. The goal of this proposal is to take advantage of the internalization of tmTNFα in order to develop antibody drug conjugates (ADCs) that deliver anti‐inflammatory payloads directly to TNFα‐ producing cells. The monocytes/macrophages that are producing the most TNFα will internalize the most anti‐TNFα ADC, while non‐inflamed tissue will internalize little or no ADC. As the inflammatory episode subsides, TNFα expression will decrease and the rate of drug‐delivery will slow, thus limiting side‐effects and immunosuppression of the ADC. Like a player of the classic “whack‐a‐mole” game, the ADC then harmlessly circulates through the body vigilantly awaiting the next inflammatory event. The two primary aims of this project are: 1) To establish that ADCs targeting tmTNFα are effectively internalized and lysosomally processed and 2) To demonstrate that the activation of tmTNFα‐expressing cells can be suppressed by an anti‐TNFα ADC that delivers an immunosuppressive agent. Accomplishment of the aims proposed herein will provide in vitro validation of tmTNFα as an ADC target and will position this technology for a true therapeutic development program. Agents that specifically target TNFα expressing cells may lead to improved treatments for rheumatoid arthritis, psoriatic arthritis, ulcerative colitis, and plaque psoriasis.

项目概要： 肿瘤坏死因子α（TNFα）通常被认为是类风湿关节炎（RA）的“主要细胞因子”。抗TNFα 治疗已经彻底改变了RA和相关炎性疾病的治疗， 这种促炎细胞因子循环TNFα的主要来源是滑膜单核细胞和巨噬细胞， 反过来，被“危险相关分子模式”（DAMP）激活。跨膜TNFα（tmTNFα）是 最初响应于这种活化而产生，随后被TNFα转化酶（TACE）裂解， 产生可溶性TNFα。最近的一份报告显示，抗TNFα抗体如阿达木单抗与tmTNFα结合， 被内化并被运送到溶酶体。本提案的目标是利用 tmTNFα，以开发将抗炎有效载荷直接递送至TNFα的抗体药物偶联物（ADC）。 产生细胞。产生最多TNFα的单核细胞/巨噬细胞将内化最多的抗TNFα ADC，而非炎症组织将内化很少或没有ADC。随着炎症发作消退，TNFα表达 将降低，药物递送速率将减慢，从而限制ADC的副作用和免疫抑制。像一个 经典的“打地鼠”游戏的玩家，ADC然后无害地通过身体循环警惕地等待着， 下一个炎症事件本项目的两个主要目的是：1）确定靶向tmTNFα的ADC是 有效内化和溶酶体加工，2）证明表达tmTNFα的细胞的活化 可通过递送免疫抑制剂的抗TNFα ADC抑制。实现目标 本文提出的方法将提供tmTNFα作为ADC靶点的体外验证，并将该技术定位于真正的 治疗发展计划。特异性靶向TNFα表达细胞的药物可能会改善 治疗类风湿性关节炎、银屑病关节炎、溃疡性结肠炎和斑块状银屑病。