NOT-NS-20-030: Use of anchored biologics to treat vesicant induced neovascularization

NOT-NS-20-030：使用锚定生物制剂治疗发泡剂诱导的新血管形成

• 批准号: 10228255
• 负责人: ROBERT M SHANKS
• 金额: $ 11.54万
• 依托单位: UNIVERSITY OF PITTSBURGH AT PITTSBURGH
• 依托单位国家: 美国
• 财政年份: 2017
• 资助国家: 美国
• 起止时间: 2017-04-01 至 2022-03-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/10228255
• 关键词: Adrenal Cortex Hormones; Age related macular degeneration; Anti-Inflammatory Agents; Antibodies; Award; Binding; Biochemical; Biological; Bioterrorism; Blinded; Blindness; Cataract; Cauterize; Cell surface; Cells; Chemical Injury; Chemicals; Chronic; Cornea; Corneal Neovascularization; Data; Diabetic Retinopathy; Drug Targeting; Effectiveness; Epithelial; Exposure to; Extracellular Matrix; Eye; FDA approved; Fright; Future; Glaucoma; Goals; Grant; Hour; Human; Immune; Inflammation; Keratitis; Laceration; Measurement; Measures; Mechlorethamine; Military Personnel; Modeling; Modern Medicine; Mus; Mustard Gas; Patients; Peptides; Pharmaceutical Preparations; Photophobia; Poisoning; Procedures; Reagent; Research; Residencies; Sialic Acids; Silver Nitrate; Technology; Tertiary Protein Structure; Testing; Time; Topical application; Treatment Protocols; Vascular Endothelial Growth Factors; Vascularization; Vesicants; Visual Acuity; Visual impairment; Wheat Germ Agglutinins; Work; antibody conjugate; base; bevacizumab; chemical threat; cytokine; effective therapy; experimental study; eye dryness; in vivo; in vivo Model; interest; macromolecule; microbial; neovascularization; ocular pain; ocular surface; pathogen; prevent; programs; response; side effect; therapeutic target; treatment strategy; weapons

We have a long-standing interest in host-pathogen interactions in ocular microbial keratitis with the ultimate goal of developing better treatment strategies. Severe keratitis is a very damaging sequela of chemical injuries and causes vision impairment or loss after exposure to sulfur mustard, which has been used in warfare and by terrorist organizations such as ISIS. This application is in response to the NOT-NS-20-030 FOA, which is directed to supplement existing awards to expand research into developing countermeasures to chemical threats including sulfur mustard exposure, and is in accord with our desire to expand our work to chemically- induced keratitis. Corneal vascularization reduces transparency and furthermore drives inflammation by facilitating entry of various immune cells. Vascularization is therefore an appealing therapeutic target for treating keratitis. Anti-VEGF biologics have in recent years been remarkably successful in treating wet age-related macular degeneration and diabetic retinopathy, which naturally has led to interest in using these reagents to manage corneal neovascularization. The difficulty is that these biologics, which are soluble macromolecules, are washed out within minutes when applied topically to the eye and therefore have little or no efficacy. Our solution is to attach an “anchor” to the biologic i.e. a domain that binds to the cornea and therefore prevents wash-out. Currently we are using wheat germ agglutinin an anchor, which binds to GlcNAc and sialic acid that are very abundant on cell surfaces and extracellular matrix. This prolongs the residency time from a few minutes to at least 24 hours, and we have previously shown efficacy in a dry eye model by applying an anchored biologic just once daily. The hypothesis of this study is that targeted inactivation of VEGF using anchored biologics can prevent neovascularization in chemically challenged mouse corneas. The research plan is to 1) produce and validate biochemically a wheat germ agglutinin-conjugated antibody to mouse VEGF, 2) measure effects of application of the anchored antibody on vascularization in vivo in an established model of neovascularization, and 3) use the procedure to determine the extent that anchored anti-VEGF antibodies reduces neovascularization in response to nitrogen mustard. The long-term goal of this supplement is to generate preliminary data to guide further work and to obtain grant support under the CounterACT program to develop a biologic to block VEGF for use in humans.

我们长期以来一直对眼部微生物性角膜炎中的宿主-病原体相互作用感兴趣， 发展更好的治疗策略的最终目标。严重的角膜炎是一种非常有害的 化学伤害的后遗症，并在接触硫后导致视力受损或丧失 芥子气已被用于战争和ISIS等恐怖组织。这 申请是对NOT-NS-20-030 FOA的响应，该FOA旨在补充现有的 扩大研究以制定化学威胁的对策，包括 硫芥子气暴露，并在雅阁与我们的愿望，扩大我们的工作，以化学- 诱发角膜炎。 角膜血管化降低了透明度，并进一步通过以下方式驱动炎症： 促进各种免疫细胞的进入。因此，血管化是一种有吸引力的治疗方法， 用于治疗角膜炎靶点。近年来，抗VEGF生物制剂已经显著地 成功治疗湿性年龄相关性黄斑变性和糖尿病视网膜病变， 自然引起了人们对使用这些试剂来控制角膜新生血管形成的兴趣。的 困难在于这些生物制剂是可溶性大分子， 当局部应用于眼睛时，有效时间为10分钟，因此几乎没有或没有功效。我们的解决方案是 将“锚”附着到生物制品上，即结合到角膜上的结构域， 防止冲刷。目前，我们正在使用麦胚凝集素作为锚， GlcNAc和唾液酸在细胞表面和细胞外基质上非常丰富。这 将驻留时间从几分钟缩短到至少24小时， 通过每天一次应用锚定生物制剂，在干眼症模型中显示出有效性。 本研究的假设是，使用锚定生物制剂靶向灭活VEGF可以 防止化学激发的小鼠角膜中的新血管形成。研究计划是：（1） 生产和生物化学验证麦胚凝集素结合的小鼠抗体 VEGF，2）测量锚定抗体的应用对血管形成的影响， 建立的新血管形成模型，以及3）使用该程序来确定 锚定的抗VEGF抗体减少了对氮的反应， 芥末。这一补充的长期目标是产生初步数据，以指导进一步的 工作，并在CounterACT计划下获得赠款支持，以开发一种生物制剂， 用于人类的VEGF。

项目成果

Release of Moxifloxacin From Corneal Collagen Shields.

莫西沙星从角膜胶原盾的释放。

• DOI: 10.1097/icl.0000000000000421
• 发表时间: 2018
• 期刊: Eye & contact lens
• 作者: Zhou,Siwei;Hunt,KristinM;Grewal,ArmanS;Brothers,KimberlyM;Dhaliwal,DeepinderK;Shanks,RobertMQ
• 通讯作者: Shanks,RobertMQ

Extending the use of biologics to mucous membranes by attachment of a binding domain.

• DOI: 10.1038/s42003-023-04801-6
• 发表时间: 2023-05-02
• 期刊: COMMUNICATIONS BIOLOGY
• 影响因子: 5.9
• 作者: Shanks, Robert M. Q.;Romanowski, Eric G.;Romanowski, John E.;Davoli, Katherine;McNamara, Nancy A.;Klarlund, Jes K.
• 通讯作者: Klarlund, Jes K.

Gene Acquisition by a Distinct Phyletic Group within Streptococcus pneumoniae Promotes Adhesion to the Ocular Epithelium.

• DOI: 10.1128/msphere.00213-17
• 发表时间: 2017-09
• 期刊: mSphere
• 影响因子: 4.8
• 作者: Antic I;Brothers KM;Stolzer M;Lai H;Powell E;Eutsey R;Cuevas RA;Miao X;Kowalski RP;Shanks RMQ;Durand D;Hiller NL
• 通讯作者: Hiller NL

The Short-chain Fatty Acid Propionic Acid Activates the Rcs Stress Response System Partially through Inhibition of d-Alanine Racemase.

• DOI: 10.1128/msphere.00439-22
• 发表时间: 2023-02-21
• 期刊: mSphere
• 影响因子: 4.8