Abstract：
Hyaluronan (HA) is a glycosaminoglycan that forms a gel-like barrier in the subcutaneous (SC) space, limiting bulk fluid flow and the dispersion of SC-administered therapeutics. Recombinant human hyaluronidase PH20 (rHuPH20) facilitates the rapid delivery of co-administered therapeutics by depolymerizing HA in the SC space. Administration of rHuPH20 can induce the formation of anti-rHuPH20 antibodies, or anti-drug antibodies (ADAs), with the potential to bind endogenous PH20 hyaluronidase in the adult testes and epididymis. Using a variety of relevant animal models and multiple dose regimens of rHuPH20 across the full spectrum of animal development, we demonstrated that rHuPH20 administration resulted in the formation of ADAs. Although these ADAs can bind both the recombinant rHuPH20 enzyme and recombinant versions of animal model-specific hyaluronidases, they had no impact on fertility parameters (as measured by sperm concentration and motility, litter size, and litter viability) or fetal development. We present the result of our nonclinical studies in order of the developmental lifecycle, beginning with adults. Toxicology studies that extend beyond the standard package are also presented. These studies demonstrate the favorable safety profile of rHuPH20 and ADAs in nonclinical models. Additionally, we identified substantial safety margins for clinically relevant doses of rHuPH20.
摘要：
透明质酸（HA）是一种糖胺聚糖，在皮下（SC）空间中形成凝胶状屏障，限制大量流体流动和SC给药治疗剂的分散。重组人透明质酸酶PH20(rHuPH20)通过在SC空间中解聚HA促进共同施用的治疗剂的快速递送。施用rHuPH20可以诱导抗rHuPH20抗体的形成，或抗药物抗体（ADAs），在成年睾丸和附睾中具有结合内源性PH20透明质酸酶的潜力。使用各种相关的动物模型和rHuPH20的多剂量方案在动物发育的全谱，我们证明rHuPH20给药导致ADAs的形成。尽管这些ADAs可以结合重组rHuPH20酶和动物模型特异性透明质酸酶的重组版本，它们对生育力参数没有影响(通过精子浓度和活力来衡量，垫料大小,和产仔活力）或胎儿发育。我们按照发育生命周期的顺序介绍了非临床研究的结果，从成年人开始。还介绍了超出标准包的毒理学研究。这些研究证明了rHuPH20和ADAs在非临床模型中的良好安全性。此外,我们确定了治疗相关剂量rHuPH20的实质性安全边际.
