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: 10841186
• 负责人: Eric Andrew Appel
• 金额: $ 83.73万
• 依托单位: BOSTON CHILDREN'S HOSPITAL
• 依托单位国家: 美国
• 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: https://reporter.nih.gov/project-details/10841186
• 关键词: Acquired Immunodeficiency Syndrome; Adverse event; Animals; Antibodies; Biochemical; Biological; Biological Products; Cell Culture Techniques; Cells; Collaborations; Conscious; Control Animal; Dependovirus; Dose; Drug Kinetics; Drug resistance; Event; Formulation; HIV-1; HIV-2; Half-Life; Healthcare; Human; Hydrogels; Implant; Individual; Infection; Infrastructure; Injectable; Injections; Intramuscular; Laboratories; Macaca; Macaca mulatta; Mediating; Modeling; Mus; Needles; Pathway interactions; Patients; Peptides; Persons; Population; Preparation; Property; Prophylactic treatment; Proteins; Rectum; SIV; Serum; Serum Proteins; Stigmatization; System; Testing; Therapeutic; Tissues; Toxic effect; Transgenes; Transgenic Mice; Variant; Viral; Virus; adeno-associated viral vector; antibody mimetics; antiretroviral therapy; biophysical properties; cost; demographics; fitness; immunogenic; immunogenicity; improved; in vivo; inhibitor; intravenous administration; manufacture; neonatal Fc receptor; neutralizing antibody; novel; pre-exposure prophylaxis; prevent; protein aggregation; receptor; rectal; sexually active; side effect; simian human immunodeficiency virus; transmission process

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

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: Advanced therapeutics
• 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: BIOMATERIALS SCIENCE
• 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: Immunity
• 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: Chemical reviews
• 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