Development of antibody drug conjugates as pan-filo antivirals

开发作为泛型抗病毒药物的抗体药物偶联物

• 批准号: 10759731
• 负责人: Gai Liu
• 金额: $ 30万
• 依托单位: MICROBIOTIX, INC
• 依托单位国家: 美国
• 财政年份: 2023
• 资助国家: 美国
• 起止时间: 2023-08-21 至 2025-07-31
• 项目状态: 未结题
• 来源: https://reporter.nih.gov/project-details/10759731
• 关键词: Address; Africa; Animal Model; Antibodies; Antibody-drug conjugates; Antiviral Agents; Binding; Binding Sites; Biological; Biological Assay; Bispecific Antibodies; Carrier Proteins; Case Fatality Rates; Categories; Cathepsins B; Centers for Disease Control and Prevention (U.S.); Cholesterol; Classification; Clinical Trials; Cytosol; Democratic Republic of the Congo; Development; Disease Outbreaks; Dose; Drug Design; Drug Kinetics; Ebola virus; Endosomes; Epidemic; Epitopes; Evaluation; Exhibits; Exposure to; FDA approved; Family; Filoviridae Infections; Filovirus; Future; Glycoproteins; Goals; Hepatitis C; Hepatitis C virus; Hospitalization; Human; In Vitro; Infection; Influenza; Lead; Life Cycle Stages; Link; Literature; Lysosomes; Marburgvirus; Medical; Membrane Fusion; Modeling; Monoclonal Antibodies; Mus; Nature; New Agents; Patients; Periodicals; Pharmaceutical Preparations; Phase; Prevention; Probability; Property; Proteins; RNA Interference; Reporting; Research; Route; Safety; Series; Serum; Small Business Innovation Research Grant; Sudan Ebola virus; Surface; Therapeutic; Therapeutic antibodies; Toxic effect; Vaccines; Vesicular stomatitis Indiana virus; Viral; Viral Hemorrhagic Fevers; Viral Physiology; Viral Proteins; Virion; Virulent; Virus; Virus Diseases; Work; Zaire Ebola virus; acute toxicity; bioweapon; clinical candidate; combat; cytotoxicity; design; drug development; improved; in vivo; inhibitor; late endosome; member; mortality; mouse model; neutralizing antibody; neutralizing monoclonal antibodies; nonhuman primate; novel; pathogenic virus; phenylpiperazine; preclinical development; prophylactic; receptor; receptor binding; small molecule; small molecule inhibitor; synergism; targeted delivery; viral entry inhibitor; virus classification

Project Summary Filoviruses cause severe hemorrhagic fevers and are among the deadliest human viruses with no approved treatment or prophylactic options. Periodic outbreaks, such as the recent epidemic of Ebola virus (EBOV) in West Africa, exhibit mortality rates ranging from 50-90%. They are classified as “Category A priority bioweapon agents” by the Centers for Disease Control and Prevention. The most advanced candidates for anti-filovirus therapy with proven efficacy in non-human primates (NHPs) utilize RNA interference (RNAi), high dose mixtures of monoclonal antibodies (mAbs), or repurposed influenza, herpes or hepatitis C inhibitors. Although they represent important advances, these approaches have serious limitations including the high therapeutic doses required (20-30 g of mAb/patient), limited spectrum (primarily Zaire ebolavirus) and/or narrow therapeutic windows (small molecules/RNAi). Building on recent work demonstrating the critical nature of endosomal interactions between the filoviral glycoprotein (GP) and the host cholesterol transport protein Niemann-Pick C1 (NPC1) for filoviral entry, we have developed antibodies and small molecules that disrupt this mechanism to inhibit viral entry. These include several bispecific GP-targeting pan-ebolavirus broadly neutralizing antibodies (bNAbs) efficacious in multiple animal models, with down-selection to a final cocktail based on NHP efficacy underway. In parallel, we identified a phenylpiperazine compound MBX-5321, which inhibits the GP-NPC1 interaction to block infections of virulent EBOV, SUDV and MARV at nM concentrations in vitro, demonstrates excellent PK/PD properties, exhibits excellent murine tolerability, has established efficacy in mice, and is currently being optimized for a targeted IND. In this proposal we will tether MBX-5321 to bispecific pan-filo bNABs to make broad-spectrum antibody-drug conjugates (ADCs) that synergistically inhibit viral entry. The objective of this proposal is to demonstrate that these ADCs will provide improved efficacy and selectivity for filovirus treatment over either agent alone, providing highly efficacious pan-filo agents, broadening the therapeutic window and easing drug stockpiling efforts. We will accomplish this objective through three specific aims: In Aim 1 we will synthesize and complete physical characterization of >40 ADCs demonstrating serum stability with efficient endosomal release. In Aim 2 we will prioritize ADCs through in vitro analysis of pan-filovirus inhibitory activity. In Aim 3 we prioritize ADCs for PK and toxicity and evaluate two pan-filovirus ADCs for in vivo efficacy in a mouse model of EBOV infection.

项目摘要 丝状病毒引起严重的出血热，是最致命的人类病毒之一， 治疗或预防选择。周期性的爆发，例如最近的埃博拉病毒（EBOV）流行， 西非的死亡率为50- 90%。它们被列为“A类优先生化武器 美国疾病控制和预防中心（Centers for Disease Control and Prevention）最先进的候选人抗丝状病毒 在非人灵长类动物（NHP）中已证实有效的治疗利用RNA干扰（RNAi）、高剂量混合物 单克隆抗体（mAb），或再利用的流感，疱疹或丙型肝炎抑制剂。虽然他们 虽然这些方法代表了重要的进步，但它们具有严重的局限性，包括高治疗剂量， 需要（20-30 g mAb/患者），有限的谱（主要是扎伊尔埃博拉病毒）和/或窄治疗 窗口（小分子/RNAi）。 基于最近的工作，证明了丝状病毒与病毒之间的内体相互作用的关键性质， 糖蛋白（GP）和宿主胆固醇转运蛋白尼曼-匹克C1（NPC 1）的丝状病毒进入，我们有 开发了抗体和小分子来破坏这种机制，以抑制病毒进入。这些包括 几种双特异性靶向GP的泛埃博拉病毒广泛中和抗体（bNAb）在多种免疫应答中有效， 动物模型，根据NHP的功效进行向下选择最终的鸡尾酒。同时，我们发现 一种苯基哌嗪化合物MBX-5321，其抑制GP-NPC 1相互作用以阻断强毒的 在体外nM浓度下的EBOV、SUDV和MARV显示出优异的PK/PD特性， 具有极好的鼠耐受性，已在小鼠中确立了疗效，目前正在针对靶向IND进行优化。 在该提案中，我们将MBX-5321与双特异性泛丝状bNAB连接以制备广谱抗体-药物组合物。 在一些实施方案中，所述药物组合物是协同抑制病毒进入的药物缀合物（ADC）。 本提案的目的是证明这些ADC将提高疗效和选择性 对于丝状病毒治疗，相对于单独的任一种试剂，提供了高效的泛丝状病毒试剂，拓宽了 治疗窗口和减轻药物储存的努力。我们将通过以下三个具体措施实现这一目标： 目的：在目的1中，我们将合成并完成>40个ADC的物理表征，证明血清 具有有效内体释放的稳定性。在目标2中，我们将通过泛丝状病毒的体外分析优先考虑ADC 抑制活性在目标3中，我们优先考虑ADC的PK和毒性，并评估两种泛丝状病毒ADC的体内PK和毒性。 在EBOV感染的小鼠模型中的有效性。