"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: 10430241
• 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 2024-05-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/10430241
• 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; 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; 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.

项目摘要： 肿瘤坏死因子α（TNFα）通常被认为是类风湿关节炎（RA）中的“主要细胞因子”。抗TNFα 治疗通过耗尽血浆水平来彻底改变RA和相关炎症性疾病的治疗 这种促炎性细胞因子。循环TNFα的主要来源是滑膜单核细胞和巨噬细胞，它们是 反过来，“与危险相关的分子模式”（潮湿）激活了。跨膜TNFα（TMTNFα）为 最初是针对这种激活产生的，随后通过TNFα转化酶（TACE）裂解 产生了固体TNFα。最近的一份报告表明，抗TNFα抗体（如Adalimumab）与TMTNFα结合， 内化并被贩运到溶酶体。该提议的目的是利用 TMTNFα是为了开发抗体药物缀合物（ADC），该抗体有效载荷直接提供给TNFα- 产生细胞。产生最多TNFα的单核细胞/巨噬细胞将内部化最大的抗TNFα ADC，虽然非燃料的组织几乎不会内化或没有ADC。随着炎症发作的消退，TNFα表达 将降低，药物递送的速度会减慢，从而限制ADC的副作用和免疫抑制。像 经典的“ whack -a -mole”游戏的玩家，ADC随后无害地通过身体循环，等待着 下一个炎症事件。该项目的两个主要目的是：1）确定针对TMTNFα的ADC是 有效地内化和溶酶体处理以及2）证明了表达TMTNFα的细胞的激活 可以通过提供免疫抑制剂的抗TNFαADC来抑制。实现目标 本文提出的将提供TMTNFα作为ADC目标的体外验证，并将该技术定位为真实 治疗开发计划。专门针对TNFα表达细胞的药物可能会改善 类风湿关节炎，银屑病关节炎，溃疡性结肠炎和斑块牛皮癣的治疗方法。

项目成果

Design and Characterization of Immune-Stimulating Imidazo[4,5-c]quinoline Antibody-Drug Conjugates.

• DOI: 10.1021/acs.molpharmaceut.2c00392
• 发表时间: 2022-09-05
• 期刊: MOLECULAR PHARMACEUTICS
• 影响因子: 4.9
• 作者: Fang, Siteng;Brems, Brittany M.;Olawode, Emmanuel O.;Miller, Jared T.;Brooks, Tracy A.;Tumey, L. Nathan
• 通讯作者: Tumey, L. Nathan

Evaluation of an ester-linked immunosuppressive payload: A case study in understanding the stability and cleavability of ester-containing ADC linkers.

• DOI: 10.1016/j.bmcl.2022.128953
• 发表时间: 2022-11-01
• 期刊: BIOORGANIC & MEDICINAL CHEMISTRY LETTERS
• 影响因子: 2.7
• 作者: Jackson, Courtney P.;Fang, Siteng;Benjamin, Samantha R.;Alayi, Tchilabalo;Hathout, Yetrib;Gillen, Sarah M.;Handel, Jillian P.;Brems, Brittany M.;Howe, Justin M.;Tumey, L. Nathan
• 通讯作者: Tumey, L. Nathan

ValCitGlyPro-dexamethasone antibody conjugates selectively suppress the activation of human monocytes.

ValCitGlyPro-地塞米松抗体缀合物选择性抑制人单核细胞的活化。

• DOI: 10.1039/d3md00336a
• 发表时间: 2023
• 期刊: RSC medicinal chemistry
• 影响因子: 4.1
• 作者: Howe,JustinM;Fang,Siteng;Watts,KelseyA;Xu,Fanny;Benjamin,SamanthaR;Tumey,LNathan
• 通讯作者: Tumey,LNathan