title: Clinical Immunogenicity of rHuPH20, a Hyaluronidase Enabling Subcutaneous Drug Administration.
abstract: 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.
authors.affiliation: Halozyme Therapeutics, Inc., 11388 Sorrento Valley Road, San Diego, California, 92121, USA, srosengren@halozyme.com.
authors.forename: Sanna
authors.initials: S
authors.lastname: Rosengren
authors.forename: Samuel S
authors.initials: SS
authors.lastname: Dychter
authors.forename: Marie A
authors.initials: MA
authors.lastname: Printz
authors.forename: Lei
authors.initials: L
authors.lastname: Huang
authors.forename: Richard I
authors.initials: RI
authors.lastname: Schiff
authors.forename: Hans-Peter
authors.initials: HP
authors.lastname: Schwarz
authors.forename: John K
authors.initials: JK
authors.lastname: McVey
authors.forename: Fred H
authors.initials: FH
authors.lastname: Drake
authors.forename: Dan C
authors.initials: DC
authors.lastname: Maneval
authors.forename: Don A
authors.initials: DA
authors.lastname: Kennard
authors.forename: Gregory I
authors.initials: GI
authors.lastname: Frost
authors.forename: Barry J
authors.initials: BJ
authors.lastname: Sugarman
authors.forename: Douglas B
authors.initials: DB
authors.lastname: Muchmore
mesh_terms: D000906:Antibodies / Q000097:blood*; D057134:Antibodies, Neutralizing / Q000097:blood*; D002986:Clinical Trials as Topic; D006801:Humans; D006821:Hyaluronoglucosaminidase / Q000008:administration & dosage* / Q000276:immunology; D007279:Injections, Subcutaneous; D007328:Insulin / Q000008:administration & dosage; D011994:Recombinant Proteins / Q000008:administration & dosage* / Q000276:immunology; D000069283:Rituximab / Q000008:administration & dosage; D000068878:Trastuzumab / Q000008:administration & dosage
chemical_list: D000906:Antibodies; D057134:Antibodies, Neutralizing; D007328:Insulin; D011994:Recombinant Proteins; D000069283:Rituximab; D006821:Hyaluronoglucosaminidase; D000068878:Trastuzumab