Immunogenicity of branched polyethylene glycol modified interferon alpha.

AIM: To assess the immunogenicity of Peginterferon alpha-2 b(Pegberon) and its effect on the efficacy and safety in phase III clinical trial, by comparing it with the control drug Pegasys. METHODS: 770 patients were recruited in total. 509 were treated with Pegberon plus ribavirin and 261 were treated with Pegasys plus ribavirin. After treatment of 12 and 24 weeks, plasma samples were collected from individual patients for detecting the anti-therapeutic antibodies (ATA) and hepatitis C RNA(HCV RNA), to evaluate the production of antibodies and their adverse effect on the efficacy and safety of the treatments. With data obtained from the treatments with Pegberon or Pegasys, gross comparison analysis was performed. RESULTS: The incidence of treatment-induced neutralizing antibodies (NAb) of Pegberon group (0.7%, 3/454) was significantly lower than Pegasys group (5.0%,12/238)(p < .001). Among all patients, the rates of sustained virological response 24 (SVR24) were significantly different between baseline ATA positive (60.7%,34/56) and baseline ATA negative patients (76.2%,544/714)(p = .010), between baseline NAb positive (36.0%,9/25) and baseline NAb negative patients (76.4%,569/745)(p < .001) and between induced ATA positive (72.7%,40/55) and sustained ATA negative patients(84.0%,492/586)(p = .034). The incidence of potential immunogenicity-related adverse reactions (AR) showed no significant difference between Pegberon (55.6%,283/509) and Pegasys groups (53.6%,140/261)(p = .605) and the profiles of these AR were also similar between the two groups. CONCLUSION: The incidence of treatment-induced Nab in Pegasys group was significantly higher than the Pegberon group. Baseline ATA, induced ATA and baseline NAb all affected the efficacy. The profiles of potential immunogenicity-related AR were similar between two drug groups, indicating the immunogenicity had no significant adverse effect on safety.

Modeling approach to investigate the effect of neonatal Fc receptor binding affinity and anti-therapeutic antibody on the pharmacokinetic of humanized monoclonal anti-tumor necrosis factor-α IgG antibody in cynomolgus monkey.

PURPOSE: Several neonatal Fc receptor (FcRn) variants of an anti-tumor necrosis factor (TNF)-α humanized monoclonal IgG antibodies (mAbs) were developed but the effect of their differential FcRn binding affinities on pharmacokinetic (PK) behavior were difficult to be definitively measured in vivo due to formation of anti-therapeutic antibody (ATA). A semi-mechanistic model was developed to investigate the quantitative relationship between the FcRn binding affinity and PK of mAbs in cynomolgus monkey with the presence of ATA. METHODS: PK and ATA data from cynomolgus monkeys which received a single intravenous dose of adalimumab, wild-type or two FcRn variant (N434H and N434A) anti-TNF-α mAbs were included in the analysis. Likelihood-based censored data handling method was used to include many PK observations with BQL values for model development. A fully integrated PK-ATA model was developed and used to fit simultaneously to the PK/ATA data. RESULTS AND CONCLUSIONS: The PK and ATA time-profiles and effect of FcRn-binding affinity on PK of mAbs were well described by the model and the parameters were estimated with good precision. The model was used successfully to construct quantitative relationships between FcRn binding affinity and PK of anti-TNF-α mAbs in the presence of the ATA-mediated elimination and interferences.