EBF recommendation on practical management of critical reagents for antidrug antibody ligand-binding assays

Immunogenicity assays are required to measure antidrug antibodies that are generated against biotherapeutic modalities. As for any ligand-binding assays, critical reagents (CR) play a crucial role in immunogenicity assays, as the robustness and reliability of an assay are defined by the quality and long-term availability of these reagents. The current regulatory guidelines do not provide clear directions on how to implement and verify lot-to-lot changes of CR during an assay life cycle, or the acceptance criteria that should be used when implementing new lots of CR. These aspects were extensively discussed within the European Bioanalysis Forum community. In this paper, CR for immunogenicity assays are identified and the minimum requirements for introducing new lots of CR in immunogenicity assays are described

EBF recommendation on practical management of critical reagents for PK ligand-binding assays

Critical reagents play a crucial role in ligand-binding assays; the robustness and reliability of an assay is defined by the quality and long-term availability of these reagents. However, neither regulatory guidelines nor relevant scientific papers provide clear directions for set-up, life cycle management and, more importantly, the acceptance criteria required for the testing of the critical reagents for pharmacokinetic, biomarker and immunogenicity assays. The ambiguity from current guidelines can be a challenge for the bioanalytical community. Members of the European Bioanalysis Forum community undertook a more pragmatic approach on how to assess the impact of critical reagents. In this paper, a review and corresponding gap analysis of the current guidelines and relevant papers will be provided as well as decision trees proposed for lot-to-lot changes of critical reagents for pharmacokinetic assays

CSF-1 antibody Lacnotuzumab in a Phase 1 Healthy Volunteer Study and Mechanistic Investigation of Safety Outcomes

The colony-stimulating factor-1 (CSF-1) receptor pathway has been implicated in a variety of diseases, and CSF-1–dependent mechanisms are involved in bloodborne protein clearance. Lacnotuzumab is a novel, high-affinity, humanized, anti–CSF-1 monoclonal antibody that prevents CSF-1 mediated receptor activation. The presentedThis phase 1, two-part, double-blind study in healthy volunteers assessed the safety and tolerability of lacnotuzumab and its pharmacokinetic (PK) and pharmacodynamic properties. Part A (n = 36) was a single, ascending-dose assessment of eight lacnotuzumab doses (0.01 to 20 mg/kg); in part B (n = 16), lacnotuzumab was administered at either 5 or 10 mg/kg. In each study cohort, individuals were randomized 3:1 to lacnotuzumab or placebo. Lacnotuzumab was generally well tolerated. At higher doses (10 and 20 mg/kg), creatine kinase (CK) elevations (>5x the upper limit of normal, but asymptomatic and reversible) and mild transient periorbital swelling were reported. At all doses, theThe majority of adverse events (AEs) were low grade, no unexpected or novel AEs were observed, and there were no discontinuations for AEs. Serum-fFree/unbound lacnotuzumab serum concentration-time profiles showed nonlinear PK s across doses from 0.01–20 mg/kg, with faster apparent elimination at lower doses or concentrations; this was consistent with apparent target-mediated drug disposition. Lacnotuzumab also showed dose-dependent, on-target effects on multiple downstream biomarkers. Preclinical investigations of the CK elevation and periorbital swelling observed after lacnotuzumab administration suggest that these are reversible, non-pathological events linked to inhibition of the CSF-1 pathway. These data support further evaluation of lacnotuzumab in clinical studies