A clinical population pharmacokinetic/pharmacodynamic model for BIIB059, a monoclonal antibody for the treatment of systemic and cutaneous lupus erythematosus.

A population pharmacokinetic/pharmacodynamic (popPK/PD) model for BIIB059 (anti-blood dendritic cell antigen 2 [anti-BDCA2]), a humanized immunoglobulin G1 monoclonal antibody currently under development for the treatment of SLE and CLE, is presented. BIIB059 binds BDCA2, a plasmacytoid dendritic cell (pDC)-specific receptor that inhibits the production of IFN-I and other inflammatory mediators when ligated. Phase 1 PK and PD data of healthy adult volunteers (HV, n = 87) and SLE subjects (n = 22) were utilized for the development of the popPK/PD model. The data included single and multiple dosing of intravenous and subcutaneous BIIB059. BDCA2 internalization (PD marker) was measured for all subjects by monitoring reduction of BDCA2 on pDC cell surface and used for development of the popPD model. A two-compartment popPK model with linear plus non-linear elimination was found to best describe BIIB059 PK. BDCA2 levels were best captured using an indirect response model with stimulation of the elimination of BDCA2. Clearance in SLE subjects was 25% higher compared to HV (6.87 vs 5.52 mL/h). Bodyweight was identified as only other covariate on clearance and central volume. The estimates of EC50 and Emax were 0.35 µg/mL and 8.92, respectively. No difference in EC50 and Emax was observed between SLE and HV. The popPK/PD model described the data accurately, as evaluated by pcVPCs and bootstrap. The presented popPK/PD model for BIIB059 provides valuable insight into the dynamics and dose-response relationship of BIIB059 for the treatment of SLE and CLE and was used to guide dose selection for the Phase 2 clinical study (NCT02847598).

Evaluation of highly sensitive immunoassay technologies for quantitative measurements of sub-pg/mL levels of cytokines in human serum.

A comprehensive cross-platform and cross-assay evaluation using nine technology platforms and four cytokine immunoassays (IL-6, TNFα, IL-17a, IL-2) was performed by comparing assay precision, sensitivity, parallelism and data correlation between platforms. The precision was acceptable for most evaluated assays. In addition to comparing the analytical assay sensitivity using a spiked recombinant analyte in buffer, forty serum samples from both normal controls and multiple sclerosis patients were used to measure the frequency of endogenous analyte detection (FEAD) as a parameter of each assay's ability to detect the endogenous analyte. The highest FEAD measurements were observed on the Simoa™, Erenna®, Milliplex® and Imperacer® platforms. However, only Simoa and Erenna results showed a high correlation across all evaluated cytokine assays, followed by a more moderate correlation of results across platforms for the V-plex™, high sensitivity ELISA and the Ella™ IL-6 and TNFα assays. In contrast, results from the evaluated cytokine assays on the Milliplex, AMMP™ ViBE® and Imperacer platforms did not correlate to each other nor to other evaluated assays. Acceptable parallelism was observed for the Simoa, Erenna, V-plex and Ella assays but not for the Milliplex, AMMP ViBE and Imperacer assays. In conclusion, the Simoa, Erenna,V-plex and Ella platforms performed well in one or more evaluated cytokine assays. Among those, the Simoa and Erenna assays had the highest sensitivity for detection of cytokines present at sub-pg/mL levels in human serum. In addition, the cross-platform and cross-assay comparisons demonstrated that different immunoassays may yield different results, which underscores the importance of performing such comparative evaluations, especially in the absence of reliable reference standards for the quantitative assessments of biomarkers in immunoassays.

Persistent Antigen and Prolonged AKT-mTORC1 Activation Underlie Memory CD8 T Cell Impairment in the Absence of CD4 T Cells.

Recall responses by memory CD8 T cells are impaired in the absence of CD4 T cells. Although several mechanisms have been proposed, the molecular basis is still largely unknown. Using a local influenza virus infection in the respiratory tract and the lung of CD4(-/-) mice, we show that memory CD8 T cell impairment is limited to the lungs and the lung-draining lymph nodes, where viral Ags are unusually persistent and abundant in these mice. Persistent Ag exposure results in prolonged activation of the AKT-mTORC1 pathway in Ag-specific CD8 T cells, favoring their development into effector memory T cells at the expense of central memory T cells, and inhibition of mTORC1 by rapamycin largely corrects the impairment by promoting central memory T cell development. The findings suggest that the prolonged AKT-mTORC1 activation driven by persistent Ag is a critical mechanism underlying the impaired memory CD8 T cell development and responses in the absence of CD4 T cells.

Promiscuous binding of extracellular peptides to cell surface class I MHC protein.

Algorithms derived from measurements of short-peptide (8-10 mers) binding to class I MHC proteins suggest that the binding groove of a class I MHC protein, such as K(b), can bind well over 1 million different peptides with significant affinity (<500 nM), a level of ligand-binding promiscuity approaching the level of heat shock protein binding of unfolded proteins. MHC proteins can, nevertheless, discriminate between similar peptides and bind many of them with high (nanomolar) affinity. Some insights into this high-promiscuity/high-affinity behavior and its impact on immunodominant peptides in T-cell responses to some infections and vaccination are suggested by results obtained here from testing a model developed to predict the number of cell surface peptide-MHC complexes that form on cells exposed to extracellular (exogenous) peptides.