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Development of anti-drug antibodies (ADAs) and neutralizing antibodies (NAbs) to monoclonal antibodies may adversely impact pharmacokinetics, efficacy, and/or safety. To describe incidence, titer, and persistence of dupilumab ADAs and NAbs, and their effects on pharmacokinetics, efficacy, and safety in patients with atopic dermatitis (AD). This analysis included seven phase 3 randomized, placebo-controlled (N=2,992) and two long-term open-label extension (N=2,287) trials of subcutaneous dupilumab in adults and pediatric patients with moderate-to-severe AD. ADA, NAb, and dupilumab concentration in serum were assessed using validated immunoassays. ADA impacts on efficacy (EASI) and safety were assessed. Treatment-emergent ADAs were observed in up to 8.6% (aged ≥18 years), 16.0% (12-17 years), 5.3% (6-11 years), and 2.0% (6 months to 5 years) dupilumab-treated patients. Among dupilumab-treated patients, ≤3.7% had persistent responses, <1% had high titers (≥10,000), and ≤5.1% were NAb-positive. NAbs were more common in patients with moderate- and high-titer ADA responses. High-titer ADAs, while infrequent, were the variable most associated with lower dupilumab concentrations in serum and loss of efficacy, independent of NAb status. Efficacy was generally similar in ADA-positive and -negative patients. For most patients with high- or moderate-titer ADAs, titers decreased and efficacy improved over time with continued dupilumab treatment. ADA-positive and -negative patients had similar incidences of treatment-emergent and serious treatment-emergent adverse events. One patient with high-titer ADAs developed serum sickness. In patients with AD, ADAs and NAbs had minimal impact on dupilumab concentration, efficacy, and safety, except for high-titer ADAs in a small number of patients. ClinicalTrials.gov, identifiers (NCT02277743, NCT02277769, NCT02260986, NCT02395133, NCT01949311, NCT03054428, NCT03345914, NCT02612454, and NCT03346434).

REGN1908‐1909, a 1:1 cocktail of two fully human IgG4 monoclonal antibodies (mAbs), REGN1908 and REGN1909, is being evaluated for treatment of cat allergy. Both REGN1908 and REGN1909 bind to the dominant cat allergen, Fel d 1. Adults with cat allergy confirmed by skin prick test (SPT) were randomized to single subcutaneous administration of placebo (n = 6) or REGN1908‐1909 at doses of 150 (n = 6), 300 (n = 6), or 600 mg (n = 6). Blood samples were taken at prespecified time points for pharmacokinetic (PK) analysis and exploratory evaluation of biomarkers (IgE and SPT). Safety was assessed. Drug concentration‐time profiles in serum for ascending doses of REGN1908‐1909 were consistent with linear PKs. Noncompartmental analysis showed that maximum concentration (Cmax) and exposure increased proportionately with dose, with similar time to maximum concentration (Tmax) for REGN1908 and REGN1909 (6.2 to 8.2 days across doses), and a longer terminal half‐life for REGN1908 (~ 30 days) relative to REGN1909 (~ 21 days). Adverse events were not dose dependent; there were no dose‐limiting toxicities. REGN1908‐1909 is characterized by linear and dose‐proportional kinetics of the two individual mAb components. A single 600 mg dose maintains total mAb mean concentrations in serum above the target (mean of ~ 10 mg/L) for 8–12 weeks. Maintaining this mean target concentration resulted in translational pharmacodynamic effects: maximal mast cell degranulation in a passive cutaneous anaphylaxis mouse model, and maintenance of clinical efficacy measured by Total Nasal Symptom Score in a previous proof‐of‐mechanism study.

The 2019 13 Workshop on Recent Issues in Bioanalysis (WRIB) took place in New Orleans, LA, USA on April 1–5, 2019 with an attendance of over 1000 representatives from pharmaceutical/biopharmaceutical companies, biotechnology companies, contract research organizations and regulatory agencies worldwide. WRIB was once again a 5-day, week-long event – a full immersion week of bioanalysis, biomarkers, immunogenicity and gene therapy. As usual, it was specifically designed to facilitate sharing, reviewing, discussing and agreeing on approaches to address the most current issues of interest including both small- and large-molecule bioanalysis involving LCMS, hybrid LBA/LCMS, LBA cell-based/flow cytometry assays and qPCR approaches. This 2019 White Paper encompasses recommendations emerging from the extensive discussions held during the workshop and is aimed to provide the bioanalytical community with key information and practical solutions on topics and issues addressed, in an effort to enable advances in scientific excellence, improved quality and better regulatory compliance. Due to its length, the 2019 edition of this comprehensive White Paper has been divided into three parts for editorial reasons. This publication (Part 3) covers New Insights in Biomarker Assay Validation, Current & Effective Strategies for Critical Reagent Management, Flow Cytometry Validation in Drug Discovery & Development & CLSI H62, Interpretation of the 2019 FDA Immunogenicity Guidance and Gene Therapy Bioanalytical Challenges. Part 1 (Innovation in Small Molecules and Oligonucleotides & Mass Spectrometry Method Development Strategies for Large Molecule Bioanalysis) and Part 2 (Recommendations on the 2018 FDA BMV Guidance, 2019 ICH M10 BMV Draft Guideline and regulatory agencies' input on bioanalysis, biomarkers, immunogenicity and gene therapy) are published in volume 11 of , issues 22 and 23 (2019), respectively.

Hepatitis B virus (HBV) infection is a worldwide health problem and therefore it was necessary to develop a safe and effective vaccine. There is currently a great need for a \"universal vaccine\" for hepatitis which will not only elicit an effective anti-HBs response in normal individuals but also in non-responders. A monoclonal internal image anti-idiotype (2F10) has been made, that mimics the protective group specific a determinant of HBsAg. It has been demonstrated that this anti-id can elicit HBsAg-specific antibodies in mice of the H-2$\\rm\\sp {d,q\\ or\\ f}$ haplotype. B10.M mice of the H-2$\\rm\\sp {f}$ haplotype are nonresponders to HBsAg, yet immunization with the anti-id circumvents the non-responsiveness in these mice and elicits an anti-HBs response. The aims of this research project are (1) to investigate the molecular mechanisms that lead to a lack of antibody production following immunization of B10.M mice with HBsAg; (2) to elucidate the mechanism by which 2F10 circumvents non-responsiveness in B10.M mice; (3) to delineate the B and T cell epitopes contained within the 2F10 peptide (2F10 peptide has been shown to mimic 2F10 anti-id and HBsAg, both at the B and T cell level); (4) to potentiate the immunological properties of the 2F10 peptide; (5) to test if HBsAg specific cytotoxic T cells could be elicited by immunizing mice with the 2F10 anti-id, HBsAg or 2F10 peptide. Aims 1 and 2 demonstrated that 2F10 can generate and provide T cell help for anti-HBs production and thus circumvents the non-responsiveness in B10.M mice. The 2F10 peptide has been previously shown to mimic 2F10 anti-id and HBsAg, both at the B and T cell level. Sequence analysis revealed that the mimicry of this 15mer sequence is due to its partial sequence homology with the 'a' determinant epitope of HBsAg. Studies in Aim 3 showed that the 2F10 peptide (15 mer) contains two contiguous T cell epitopes. One of these epitopes (8 mer) is a part of the CDR (complimentary determining region) portion of the 2F10 anti-id and can elicit HBsAg specific response both at the B and T cell level. The other sequence a part of the FWR (Frame Work Region) of the 2F10 anti-id is unable to elicit HBsAg specific responses. Immune potentiation of the 2F10 peptide (Aim 4) was achieved by constructing its octameric conformation: MAP (Multiple Antigenic Peptides). The 2F10 MAP could elicit significantly higher levels of anti-HBs antibodies than the 2F10 peptide. The 2F10 peptide MAP qualitatively mimics the B and T cell properties of the 2F10 peptide. It also primes the B and T cells in vivo, such that they are successfully recalled by a subsequent challenge dose of HBsAg. It has become increasingly clear that cytotoxic T cell responses are needed for protection against HBV infection. We tested if cytotoxic T cells could be elicited against HBsAg by immunizing mice with 2F10 anti-id, HBsAg or the 2F10 peptide (Aim 5). Mice immunized with 2F10 or HBsAg emulsified in a transfection agent called DOTAP, produced strong cytotoxic T cell responses against both 2F10 and HBsAg. These responses were shown to be mediated by CD8$\\sp+$ T cells and were restricted to Class I molecules.