"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.

项目总结： 肿瘤坏死因子α(肿瘤坏死因子α)是类风湿关节炎(RA)的主要细胞因子。抗肿瘤坏死因子α 治疗已经彻底改变了类风湿关节炎和相关炎症性疾病的治疗，因为它耗尽了血浆中 这种促炎细胞因子。循环中肿瘤坏死因子α的主要来源是滑膜单核细胞和巨噬细胞， 进而被“危险相关分子模式”(DAMPS)激活。跨膜肿瘤坏死因子α(tmTNFα)是 最初是响应这种激活而产生的，随后被肿瘤坏死因子α转换酶(TACE)切割成 产生可溶性肿瘤坏死因子α。最近的一份报告显示，抗肿瘤坏死因子α抗体，如阿达莫单抗，可与肿瘤坏死因子α和 变得内化并被贩卖到溶酶体内。这项提议的目标是利用 为了开发抗体药物结合物(ADC)，将抗炎有效载荷直接传递到肿瘤坏死因子α-α- 生产细胞。产生最多肿瘤坏死因子α的单核/巨噬细胞将内化最多的抗肿瘤坏死因子α。 ADC，而非炎症组织内化的ADC很少或没有。随着炎症的消退，肿瘤坏死因子α的表达 会降低，药物释放速度会减慢，从而限制了ADC的副作用和免疫抑制。就像一个 玩家的经典“打鼹鼠”游戏，然后ADC无害地在体内循环，警惕地等待 下一个煽动性事件。这个项目的两个主要目标是：1)建立靶向tmTNFα的ADC是 有效内化和溶酶体处理；2)证明表达tmTNFα的细胞的激活 可被提供免疫抑制剂的抗肿瘤坏死因子αadc抑制。目标的实现 这里提出的将提供tmtntfα作为adc靶点的体外验证，并将使这项技术真正 治疗发展计划。针对表达肿瘤坏死因子α的细胞的药物可能会导致改善 治疗类风湿性关节炎、牛皮癣关节炎、溃疡性结肠炎和斑块型牛皮癣。

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