An injectable hydrogel platform for sustained release of eCD4-Ig
用于持续释放 eCD4-Ig 的可注射水凝胶平台
基本信息
- 批准号:10841186
- 负责人:
- 金额:$ 83.73万
- 依托单位:
- 依托单位国家:美国
- 项目类别:
- 财政年份:2023
- 资助国家:美国
- 起止时间:2023-06-01 至 2025-05-31
- 项目状态:未结题
- 来源:
- 关键词:Acquired Immunodeficiency SyndromeAdverse eventAnimalsAntibodiesBiochemicalBiologicalBiological ProductsCell Culture TechniquesCellsCollaborationsConsciousControl AnimalDependovirusDoseDrug KineticsDrug resistanceEventFormulationHIV-1HIV-2Half-LifeHealthcareHumanHydrogelsImplantIndividualInfectionInfrastructureInjectableInjectionsIntramuscularLaboratoriesMacacaMacaca mulattaMediatingModelingMusNeedlesPathway interactionsPatientsPeptidesPersonsPopulationPreparationPropertyProphylactic treatmentProteinsRectumSIVSerumSerum ProteinsStigmatizationSystemTestingTherapeuticTissuesToxic effectTransgenesTransgenic MiceVariantViralVirusadeno-associated viral vectorantibody mimeticsantiretroviral therapybiophysical propertiescostdemographicsfitnessimmunogenicimmunogenicityimprovedin vivoinhibitorintravenous administrationmanufactureneonatal Fc receptorneutralizing antibodynovelpre-exposure prophylaxispreventprotein aggregationreceptorrectalsexually activeside effectsimian human immunodeficiency virustransmission process
项目摘要
PROJECT SUMMARY
Combined anti-retroviral therapy (cART) and pre-exposure prophylaxis (PrEP) represent major
milestones in the effort to eliminate AIDS and prevent new HIV-1 infections. They nonetheless have
limitations. For example, a life-time use of two or three compounds delivered to most every cell and
tissue in the body will likely come with undesirable, difficult-to-anticipate side effects. Access and
compliance also remain concerns, especially among infected persons who have not yet been reached
by our healthcare infrastructures. Similarly, PrEP requires both access and a conscious effort before a
potential transmission event, something that is not always realistic for the hardest-to-reach
demographics here and abroad. Here we will develop an approach that provides robust prophylaxis and
perhaps effective viral suppression for six months or more after a single injection. Specifically we will
optimize eCD4-Ig, a very broad and potent antibody-like molecule, for its delivery in an injectable
hydrogel, and we will optimize this hydrogel for delivery of eCD4-Ig. eCD4-Ig provides highly effective
protection in rhesus macaques from high-dose challenges with both SHIV-AD8 and SIVmac239. It also
has the breadth and potency to suppress an established SHIV-AD8 infection. This breadth appears
sufficient to suppress the wide diversity of viruses in an individual and in a population. As importantly,
HIV-1 has not developed easily accessible pathways of escape from eCD4-Ig as it has from neutralizing
antibodies. It is therefore an ideal payload for a safe, effective, and sustained hydrogel delivery system.
As we show, these hydrogels are well-tolerated, non-immunogenic, easily manufactured, and
deliverable with a high-gauge need. Importantly, they and their payloads can be immediately withdrawn
in case of an adverse event. Modeling suggest that they can sustain eCD4-Ig concentrations that could
provide effective prophylaxis for well over six months. We will test this possibility in human FcRn-
transgenic mice and in rhesus macaques, and confirm that our best eCD4-Ig/hydrogel formulations could
replace PrEP and/or cART.
项目总结
联合抗逆转录病毒疗法(CART)和暴露前预防(PrEP)是主要的
在努力消除艾滋病和预防新的艾滋病毒-1感染方面具有里程碑意义。尽管如此,他们还是有
限制。例如,两到三种化合物的终身使用几乎传递到每个细胞,并且
体内的组织可能会带来令人不快的、难以预料的副作用。访问和
遵守情况也仍然令人关切,特别是在尚未接触到的感染者中。
通过我们的医疗保健基础设施。同样,PrEP既需要访问权限,也需要有意识的努力才能
潜在的传播事件,对于最难到达的人来说并不总是现实的事情
国内外的人口统计数据。在这里,我们将开发一种方法,提供强有力的预防和
可能在一次注射后有效地抑制病毒六个月或更长时间。具体来说,我们将
优化eCD4-Ig,一种非常广泛和有效的类似抗体的分子,使其以注射形式递送
水凝胶,我们将对这种水凝胶进行优化,使其能够输送eCD4-Ig。ECD4-Ig提供高效免疫球蛋白
用SIV-AD8和SIVmac239保护恒河猴免受高剂量攻击。它还
具有抑制已建立的SHV-AD8感染的广度和效力。此宽度显示为
足以抑制病毒在个体和群体中的广泛多样性。同样重要的是,
HIV-1没有像它从中和中和一样容易地从eCD4-Ig中逃脱
抗体。因此,它是安全、有效和持续的水凝胶输送系统的理想有效载荷。
正如我们所展示的,这些水凝胶具有良好的耐受性、非免疫原性、易于制造和
具有高规格需求的可交付产品。重要的是,它们和它们的有效载荷可以立即撤回
以防发生不良事件。模拟表明,它们可以维持eCD4-Ig的浓度,
提供超过六个月的有效预防措施。我们将在人类FcRN中测试这种可能性-
转基因小鼠和恒河猴,并证实我们最好的eCD4-Ig/水凝胶配方可以
更换PrEP和/或购物车。
项目成果
期刊论文数量(6)
专著数量(0)
科研奖励数量(0)
会议论文数量(0)
专利数量(0)
Stable High-Concentration Monoclonal Antibody Formulations Enabled by an Amphiphilic Copolymer Excipient.
由两亲性共聚物赋形剂实现的稳定的高浓度单克隆抗体制剂。
- DOI:10.1002/adtp.202200102
- 发表时间:2023
- 期刊:
- 影响因子:4.6
- 作者:Klich,JohnH;Kasse,CatherineM;Mann,JosephL;Huang,Yaoqi;d'Aquino,AndreaI;Grosskopf,AbigailK;Baillet,Julie;Fuller,GeraldG;Appel,EricA
- 通讯作者:Appel,EricA
Subcutaneous delivery of an antibody against SARS-CoV-2 from a supramolecular hydrogel depot.
- DOI:10.1039/d2bm00819j
- 发表时间:2023-03-14
- 期刊:
- 影响因子:6.6
- 作者:Kasse, Catherine M.;Yu, Anthony C.;Powell, Abigail E.;Roth, Gillie A.;Liong, Celine S.;Jons, Carolyn K.;Buahin, Awua;Maikawa, Caitlin L.;Zhou, Xueting;Youssef, Sawsan;Glanville, Jacob E.;Appel, Eric A.
- 通讯作者:Appel, Eric A.
Heavy-chain CDR3-engineered B cells facilitate in vivo evaluation of HIV-1 vaccine candidates.
重链 CDR3 工程 B 细胞有助于对 HIV-1 候选疫苗进行体内评估。
- DOI:10.1016/j.immuni.2023.07.003
- 发表时间:2023
- 期刊:
- 影响因子:32.4
- 作者:He,Wenhui;Ou,Tianling;Skamangas,Nickolas;Bailey,CharlesC;Bronkema,Naomi;Guo,Yan;Yin,Yiming;Kobzarenko,Valerie;Zhang,Xia;Pan,Andi;Liu,Xin;Xu,Jinge;Zhang,Lizhou;Allwardt,AvaE;Mitra,Debasis;Quinlan,Brian;Sanders,RogierW;C
- 通讯作者:C
Translational Applications of Hydrogels.
- DOI:10.1021/acs.chemrev.0c01177
- 发表时间:2021-09-22
- 期刊:
- 影响因子:62.1
- 作者:Correa S;Grosskopf AK;Lopez Hernandez H;Chan D;Yu AC;Stapleton LM;Appel EA
- 通讯作者:Appel EA
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Eric Andrew Appel其他文献
Eric Andrew Appel的其他文献
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{{ truncateString('Eric Andrew Appel', 18)}}的其他基金
Co-Formulations of Amylin Analogues with Insulin Analogues for Treatment of Diabetes
用于治疗糖尿病的胰淀素类似物与胰岛素类似物的复合制剂
- 批准号:
10631619 - 财政年份:2022
- 资助金额:
$ 83.73万 - 项目类别:
An injectable hydrogel platform for sustained release of eCD4-Ig
用于持续释放 eCD4-Ig 的可注射水凝胶平台
- 批准号:
10079645 - 财政年份:2020
- 资助金额:
$ 83.73万 - 项目类别:
An injectable hydrogel platform for sustained release of eCD4-Ig
用于持续释放 eCD4-Ig 的可注射水凝胶平台
- 批准号:
10591755 - 财政年份:2020
- 资助金额:
$ 83.73万 - 项目类别:
An injectable hydrogel platform for sustained release of eCD4-Ig
用于持续释放 eCD4-Ig 的可注射水凝胶平台
- 批准号:
10170267 - 财政年份:2020
- 资助金额:
$ 83.73万 - 项目类别:
An injectable hydrogel platform for sustained release of eCD4-Ig
用于持续释放 eCD4-Ig 的可注射水凝胶平台
- 批准号:
10401854 - 财政年份:2020
- 资助金额:
$ 83.73万 - 项目类别:
Co-Formulations of Amylin Analogues with Insulin Analogues for Treatment of Diabetes
用于治疗糖尿病的胰淀素类似物与胰岛素类似物的复合制剂
- 批准号:
10539311 - 财政年份:2019
- 资助金额:
$ 83.73万 - 项目类别:
Co-Formulations of Amylin Analogues with Insulin Analogues for Treatment of Diabetes
用于治疗糖尿病的胰淀素类似物与胰岛素类似物的复合制剂
- 批准号:
10713360 - 财政年份:2019
- 资助金额:
$ 83.73万 - 项目类别:
Co-Formulations of Amylin Analogues with Insulin Analogues for Treatment of Diabetes
用于治疗糖尿病的胰淀素类似物与胰岛素类似物的复合制剂
- 批准号:
10078605 - 财政年份:2019
- 资助金额:
$ 83.73万 - 项目类别:
Co-Formulations of Amylin Analogues with Insulin Analogues for Treatment of Diabetes
用于治疗糖尿病的胰淀素类似物与胰岛素类似物的复合制剂
- 批准号:
10355438 - 财政年份:2019
- 资助金额:
$ 83.73万 - 项目类别:
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