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

描述（由申请人提供）：恩富维肽（Fuzeon, T-20）是一种HIV进入抑制剂，目前每日两次皮下注射。虽然恩氟韦肽被证明是有效和安全的，但由于其给药频繁、给药繁琐以及在大多数患者中诱发注射部位反应，因此未得到充分利用。通过将恩福韦肽表达为重组XTEN融合物，我们希望改善所有这些特性，并创造出一种长效且更容易给药的药物。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，它可以增加与之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，容易通过肾脏滤过迅速消除。XTEN延长了暴露时间，因此通常每天两次给药的多肽预计将作为XTEN融合物每月给药。此外，由于XTEN的非结构化性质，已知它可以增加溶解度并限制聚变有效载荷的聚集。修改这些药物性质简化了生产和使用，使液体，而不是冻干制剂。在这里，我们的目标是将XTEN与经过验证的抗hiv药物恩富韦肽结合起来，生产出一种更优越、更具有临床相关性的药物。

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.