Rosengren Sanna, Dychter Samuel S, Printz Marie A, Huang Lei, Schiff Richard I, Schwarz Hans-Peter, McVey John K, Drake Fred H, Maneval Dan C, Kennard Don A, Frost Gregory I, Sugarman Barry J, Muchmore Douglas B
Halozyme Therapeutics, Inc., 11388 Sorrento Valley Road, San Diego, California, 92121, USA,
AAPS J. 2015 Sep;17(5):1144-56. doi: 10.1208/s12248-015-9782-0. Epub 2015 May 13.
Recombinant human PH20 hyaluronidase (rHuPH20) is used to facilitate dispersion of subcutaneously delivered fluids and drugs. This report summarizes rHuPH20 immunogenicity findings from clinical trials where rHuPH20 was co-administered with SC human immunoglobulin, trastuzumab, rituximab, or insulin. Plasma samples were obtained from evaluable subjects participating in ten different clinical trials as well as from healthy plasma donors. A bridging immunoassay and a modified hyaluronidase activity assay were used to determine rHuPH20-reactive antibody titers and neutralizing antibodies, respectively. rHuPH20-binding antibody populations from selected subjects with positive titers were affinity-purified and subjected to further characterization such as cross-reactivity with endogenous PH20. Among individual trials, the prevalence of pre-existing rHuPH20-reactive antibodies varied between 3 and 12%, excepting the primary immunodeficiency (PID) studies. Incidence of treatment-induced rHuPH20 antibodies was 2 to 18%, with the highest titers (81,920) observed in PID. No neutralizing antibodies were observed. Within most trials, the kinetics of antibody responses were comparable between pre-existing and treatment-induced antibody responses, although responses classified as persistent were more common in subjects with pre-existing titers. There was no association between antibody positivity and either local or systemic adverse events. Pre-existing and treatment-induced antibody populations were of similar immunoglobulin isotypes and cross-reacted to endogenous PH20 to similar extents. No cross-reactivity to PH20 paralogs was detected. rHuPH20 induces only modest immunogenicity which has no association with adverse events. In addition, antibodies purified from baseline-positive individuals are qualitatively similar to those purified from individuals developing rHuPH20-reactive antibodies following exposure to the enzyme.
重组人PH20透明质酸酶（rHuPH20）用于促进皮下注射的液体和药物的扩散。本报告总结了rHuPH20与皮下注射用人免疫球蛋白、曲妥珠单抗、利妥昔单抗或胰岛素联合给药的临床试验中的免疫原性研究结果。血浆样本取自参与十项不同临床试验的可评估受试者以及健康血浆捐赠者。分别使用桥接免疫测定法和改良的透明质酸酶活性测定法来测定rHuPH20反应性抗体滴度和中和抗体。对选定的滴度呈阳性的受试者的rHuPH20结合抗体群体进行亲和纯化，并进行进一步表征，例如与内源性PH20的交叉反应性。在各个试验中，除原发性免疫缺陷（PID）研究外，预先存在的rHuPH20反应性抗体的患病率在3%至12%之间。治疗诱导的rHuPH20抗体的发生率为2%至18%，在PID研究中观察到最高滴度（81,920）。未观察到中和抗体。在大多数试验中，预先存在的抗体反应和治疗诱导的抗体反应的动力学具有可比性，尽管在预先存在滴度的受试者中，归类为持续性的反应更为常见。抗体阳性与局部或全身不良事件之间没有关联。预先存在的和治疗诱导的抗体群体具有相似的免疫球蛋白同种型，并且与内源性PH20的交叉反应程度相似。未检测到与PH20旁系同源物的交叉反应性。rHuPH20仅诱导适度的免疫原性，且与不良事件无关。此外，从基线呈阳性的个体中纯化的抗体在质量上与从接触该酶后产生rHuPH20反应性抗体的个体中纯化的抗体相似。
