XTENylation of enfuvirtide to generate a bio-better product with improved dosing

描述（由申请方提供）：恩夫韦肽（Fuzeon，T-20）是一种肽类HIV进入抑制剂，目前每日两次皮下注射给药。虽然证明是有效和安全的，恩夫韦肽是利用不足，由于其频繁给药，繁琐的管理，并在大多数患者注射部位反应的诱导。在表达恩夫韦肽作为重组XTEN融合体时，我们期望改善所有这些特性，并创造出更长效和更容易给药的药物。Amunix开发了XTEN技术平台，以延长蛋白质药物的血清半衰期。XTEN是一种合成的非结构化多肽链，可增加与其融合的蛋白质的表观分子量，从而以类似于与聚乙二醇（PEG）结合的方式减缓肾脏清除。XTEN的明显靶点是肽类药物，由于其体积小，往往会通过肾脏过滤快速消除。XTEN减少暴露量，使得通常每天两次给药的肽预计每月作为XTEN融合物给药。此外，由于其非结构化性质，已知XTEN增加了稠合有效载荷的溶解度并限制了稠合有效载荷的聚集。改变这些药物性质通过使液体而不是冻干制剂成为可能而简化了制造和使用。在这里，我们的目标是将联合收割机XTEN与经验证的抗HIV药物恩夫韦肽相结合，以生产出一种上级和更临床相关的药物。 公共卫生相关性：感染艾滋病毒的患者在服用含有不同作用方式药物的联合治疗方案时最健康。尽管恩夫韦肽以一种独特的方式起作用，可以被纳入这些联合方案中，但它的缺点限制了它的纳入。在这里，我们建议使用我们的XTEN技术来制造更好的恩夫韦肽，更容易使用，副作用更少，价格更便宜，以便更多的患者可以服用。

DESCRIPTION (provided by applicant): Enfuvirtide (Fuzeon, T-20) is a peptide HIV entry inhibitor currently dosed twice daily by subcutaneous injection. While proven to be efficacious and safe, enfuvirtide is under-utilized due to its frequent dosing, cumbersome administration, and inducement of injection site reactions in most patients. In expressing enfuvirtide as a recombinant XTEN fusion, we expect to improve all of these properties and create a longer-acting and more easily administered drug. Amunix has developed the XTEN technology platform to extend the serum half-lives of protein pharmaceuticals. XTEN is a synthetic, unstructured polypeptide chain that increases the apparent molecular weight of proteins to which it is fused, thereby slowing kidney clearance in a manner analogous to conjugation with polyethylene glycol (PEG). Obvious targets for XTEN are peptide drugs which, due to their small size, tend to be eliminated quickly via kidney filtration. XTEN prolongs exposure such that peptides normally dosed twice daily are projected to be administered monthly as XTEN fusions. Additionally, XTEN, due to its unstructured nature, is known to increase the solubility of and limi the aggregation of fused payloads. Modifying these drug properties simplifies manufacturing and use by enabling liquid, rather than lyophilized, formulation. Here, our goal is to combine XTEN with the validated anti-HIV drug enfuvirtide to produce a superior and more clinically relevant pharmaceutical. PUBLIC HEALTH RELEVANCE: Patients infected with HIV are healthiest when taking combination regimens containing drugs that work in different ways. Even though enfuvirtide, which works in a unique way, can be incorporated in these combination regimens, it has disadvantages that limit its inclusion. Here, we propose to use our XTEN technology to make a better version of enfuvirtide that is easier to use, causes fewer side effects, and is less expensive so that it can be taken by more patients.