"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

基本信息

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
项目类别：
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

项目摘要

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性关节炎 (RA) 的“主要细胞因子”。该疗法通过降低血浆水平，彻底改变了 RA 和相关炎症性疾病的治疗这种促炎细胞因子的循环 TNFα 的主要来源是滑膜单核细胞和巨噬细胞，反过来，它们又被“危险相关分子模式”（DAMP）激活。最初是响应这种激活而产生的，随后被 TNFα 转换酶 (TACE) 裂解为最近的一份报告表明，阿达木单抗等抗 TNFα 抗体可与 tmTNFα 结合并产生可溶性 TNFα。被内化并运输到溶酶体该提案的目标是利用内化。 tmTNFα，以开发抗体药物偶联物 (ADC)，将抗炎有效负载直接传递至 TNFα- 产生最多 TNFα 的单核细胞/巨噬细胞将内化最多的抗 TNFα。 ADC，而非炎症组织将很少或没有 ADC 内化，随着炎症消退，TNFα 表达。会减少，药物输送速度会减慢，从而限制 ADC 的副作用和免疫抑制。经典“打地鼠”游戏的玩家，ADC 然后通过身体无害地摧毁，警惕地等待着该项目的两个主要目标是：1) 确定靶向 tmTNFα 的 ADC 是内部有效地和溶酶体加工和 2) 证明 tmTNFα 表达细胞的激活可以通过提供免疫抑制剂的抗 TNFα ADC 来抑制。本文提出的方案将提供 tmTNFα 作为 ADC 靶标的体外验证，并将将该技术定位为真正的专门针对 TNFα 表达细胞的治疗开发计划可能会带来改善。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。

项目成果

期刊论文数量（3）

专著数量（0）

科研奖励数量（0）

会议论文数量（0）

专利数量（0）

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

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

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