Recombinant Human PH20: Baseline Analysis of the Reactive Antibody Prevalence in the General Population Using Healthy Subjects

Abstract

BackgroundRecombinant human PH20 (rHuPH20) is used to depolymerize hyaluronan in the subcutaneous space, increasing the dispersion and absorption of co-administered drugs. While ~ 5 to 10% of rHuPH20 treatment-naïve healthy volunteers have demonstrated rHuPH20-reactive antibodies, associations with age, sex, fertility, and immune disorders remain unknown.ObjectivesUsing demographically diverse healthy volunteers, we assessed the prevalence of rHuPH20-reactive antibodies in the general population and potential associations with fertility and autoimmunity diseases.MethodsIn total, 896 subjects aged ≥ 12 years (767 adults; 129 children) without prior exposure to rHuPH20 were enrolled. A demographic and limited medical history review was performed, and K3-EDTA-anticoagulated plasma was analyzed for rHuPH20-reactive antibodies using a bridging immunoassay.ResultsAdult and pediatric positivity rates for rHuPH20-reactive antibodies were 5.2% (40/767) and 1.6% (2/129), respectively. Titers ranged from 5 to 2560 (median 30). In five antibody-positive subjects from whom repeated samples were available, antibody titers remained unchanged or decreased fourfold over periods up to 590 days. The prevalence of rHuPH20-reactive antibodies significantly increased with age (p = 0.0006) and was significantly higher in males than in females (p = 0.0010). Men who had fathered children had a significantly increased prevalence of rHuPH20-reactive antibodies than men who had not (p = 0.0036), whereas the rate of childbearing was not significantly different between rHuPH20 antibody-positive and -negative women. The prevalence between racial/ethnic groups was not significantly different, nor was the presence/absence of an autoimmune disorder.ConclusionsApproximately 1/20 of the adult population had rHuPH20-reactive antibodies. The reason remains unknown; however, no evidence for a negative effect on fertility or association with autoimmune disease was demonstrated.Electronic supplementary materialThe online version of this article (10.1007/s40259-018-0260-y) contains supplementary material, which is available to authorized users.

A Phase I Study to Evaluate the Safety, Tolerability, Pharmacokinetics, and Pharmacodynamics of Recombinant Human Hyaluronidase PH20 Administered Intravenously in Healthy Volunteers

“…No serious AEs, deaths, or discontinuations due to AEs were reported, and no clinically significant abnormal laboratory findings were observed. The prevalence of rHuPH20-reactive antibodies at baseline (8%) in the studied volunteers was within the range of a larger study of normal volunteers (5%) 27 and of previously studied disease-state populations (3%–12%). 28 …”

“…rHuPH20-reactive antibodies are prevalent in approximately 5% of the healthy US adult population. 27 The presence of rHuPH20-reactive antibodies was determined using a format-validated bridging ECL immunoassay. 28 Briefly, plasma samples were incubated overnight with biotin-conjugated rHuPH20 and Sulfo-TAG-conjugated rHuPH20.…”

Safety of recombinant human hyaluronidase PH20 for subcutaneous drug delivery

“…The immunogenicity profile of rHuPH20 has been characterized in more than 1900 patients from 16 clinical trials. rHuPH20-reactive antibodies are present in around 5% of the adult population in the absence of exposure to rHuPH20 [83]. Prevalence of rHuPH20-reactive antibodies increased significantly with age (P= 0.0006) and was significantly higher in males than females (P= 0.0007) [83].…”

“…rHuPH20-reactive antibodies are present in around 5% of the adult population in the absence of exposure to rHuPH20 [83]. Prevalence of rHuPH20-reactive antibodies increased significantly with age (P= 0.0006) and was significantly higher in males than females (P= 0.0007) [83]. In a study of rHuPH20 administered intravenously, rHuPH20-reactive antibodies at baseline were detected in 2 of 24 volunteers (both male), and were not associated with any unusual safety observations during the study [14].…”

Immunogenicity Challenges Associated with Subcutaneous Delivery of Therapeutic Proteins

“…No neutralizing anti-rHuPH20 antibodies were observed, and adverse events were not associated with anti-rHuPH20 positivity regardless of boosting after rHuPH20 exposure. Antibody positivity to rHuPH20 has been found in 5.2% of a large cohort not previously exposed to rHuPH20, and rates were significantly higher in males compared to females and varied with age [ 119 ]. The reasons for baseline prevalence of anti-rHuPH20 antibodies are not clear, but then rHuPH20 immunogenicity seems modest with no observed effects on adverse events or efficacy.…”