Strain-Independent Therapeutic Antibodies for Influenza

总结 在第二B阶段的建议中，我们寻求资金来完成CF-404的IND开发，CF-404是一种混合物， 三种天然人单克隆抗体（mAb）。已在小鼠模型中确定了活性， 代表了甲型和B型流感的所有主要流行毒株。通过提供泛流感治疗，我们 避免与菌株分型相关的延迟，并通过及时治疗改善预期结果。我们 这里特别提出解决与通过吸入递送mAb混合物有关的监管问题。我们 背景技术工作证明吸入递送提供了比全身递送更好的上级功效， 剂量降低约10倍。行业领导者Aerogen Pharma的吸入技术成立， 适用于住院患者，包括使用呼吸机的患者。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， amantastrin，现在由于耐药性而基本上无用。第二类是神经氨酸酶抑制剂， 目前正在经历类似的阻力。最新的一类，聚合酶抑制剂， 显示出令人担忧的耐药菌株早期出现的迹象（在3期试验中为10%）。相比之下， 对逃避我们单克隆抗体的病毒进行的体外强化筛选表明，抗性可能要小得多 比小分子抗病毒药物更常见。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.