Strain-Independent Therapeutic Antibodies for Influenza

摘要 在这个IIB阶段的提案中，我们寻求资金来完成支持IND的CF-404的开发，这是一种 三种天然人类单抗(MAbs)。已经在小鼠模型中建立了针对 所有主要的甲型和乙型流感流行株的代表通过提供泛流感治疗，我们 避免与菌株分型相关的延误，预计及时治疗会改善结果。我们 在此特别提出，以解决与吸入输送单抗混合物有关的监管问题。我们的 背景研究表明，与全身给药相比，吸入给药提供了更好的疗效， 剂量降低了约10倍。来自行业领先者Aerogen Pharma的吸入技术被确立为 适用于住院患者，包括那些使用呼吸机的患者。由于对现有流感的抗药性 治疗药物，对我们的产品有很高的需求。第一类小分子疗法-- 金刚烷胺，由于耐药性，现在基本上是无用的。第二类，神经氨酸酶抑制剂，是 目前正在经历类似的耐药性出现。最新的一类聚合酶抑制剂已经 出现了令人担忧的耐药菌株早期出现的迹象(在第三阶段试验中有10%)。相反， 对逃脱单抗的病毒的体外密集选择表明，抗药性可能要小得多 比普通的小分子抗病毒药物。因此，预计CF-404的影响很大。

SUMMARY In this Phase IIB proposal, we seek funding to complete the IND-enabling development of CF-404, a mixture of three native human monoclonal antibodies (mAbs). Activity has been established in mouse models against representatives of all major circulating strains of influenza A and B. By providing a pan-influenza treatment, we avoid delays associated with strain typing, with improved outcomes expected from the prompt treatment. We specifically propose here to address regulatory issues relating to delivery of the mAb mixture by inhalation. Our background work demonstrated that inhaled delivery provides superior efficacy compared to systemic delivery, at ~10-fold lower dose. The inhalation technology from industry leader Aerogen Pharma is established as suitable for hospitalized patients, including those on a ventilator. Due to drug resistance to the existing influenza therapeutic drugs, there is a high need for our product. The first class of small molecule therapeutics, the amantadines, are now largely useless due to drug resistance. The second class, neuraminidase inhibitors, are currently experiencing similar emergence of resistance. The newest class, polymerase inhibitors, has already shown worrisome signs of early emergence of drug resistant strains (10% in the Phase 3 trials). By contrast, intensive selection in vitro for virus that escapes our mAbs has shown that resistance is likely to be far less common than for the small molecule antivirals. The impact of CF-404 is thus expected to be high.