Clinical Immunogenicity of rHuPH20, a Hyaluronidase Enabling Subcutaneous Drug Administration

被引:40
作者
Rosengren, Sanna [1 ]
Dychter, Samuel S. [1 ]
Printz, Marie A. [1 ]
Huang, Lei [1 ]
Schiff, Richard I. [2 ]
Schwarz, Hans-Peter [3 ]
Mcvey, John K. [4 ]
Drake, Fred H. [1 ]
Maneval, Dan C. [1 ]
Kennard, Don A. [1 ]
Frost, Gregory I. [1 ]
Sugarman, Barry J. [1 ]
Muchmore, Douglas B. [1 ]
机构
[1] Halozyme Therapeut Inc, San Diego, CA 92121 USA
[2] Baxter Biosci, Deerfield, IL USA
[3] Baxter Biosci, Vienna, Austria
[4] Baxter Healthcare Corp, Deerfield, IL 60015 USA
关键词
anti-drug antibodies; clinical trial; immunogenicity; rHuPH20; subcutaneous drug delivery; RECOMBINANT HUMAN HYALURONIDASE; PRIMARY IMMUNODEFICIENCY; THERAPEUTIC PROTEINS; HOST ANTIBODIES; PH-20; RECOMMENDATIONS; TOLERABILITY; AUTOIMMUNITY; IMMUNIZATION; TRASTUZUMAB;
D O I
10.1208/s12248-015-9782-0
中图分类号
R9 [药学];
学科分类号
1007 ;
摘要
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.
引用
收藏
页码:1144 / 1156
页数:13
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