Human IgG1 Monoclonal Antibody Research Articles

Dupilumab: beyond atopic dermatitis, off-label use in dermatology

Dupilumab is a humanized IgG4 monoclonal antibody that targets the IL-4 receptor inhibiting the signaling of interleukin-4 and interleukin-13, two major cytokines in type 2 inflammatory diseases such as atopic dermatitis, asthma and nasosinusal polyposis. Since its approval for atopic dermatitis in 2017, the molecule has occasionally been used off-label in several dermatological conditions where standard treatments are often disappointing.Furthermore, what emerges from the data currently in the literature is a favourable safety profile with few, reversible side effects.

Lecanemab for Alzheimer's disease: new hope or another false dawn?

Lecanemab for Alzheimer's disease: new hope or another false dawn?

Bimekizumab, a Humanized Monoclonal Immunoglobulin G1 Antibody for the Treatment of Psoriatic Arthritis: A Systematic Review

Psoriatic arthritis (PsA), often accompanied by nail psoriasis, spine, enthesitis and iritis, is a typical complication of psoriasis. PsA leads to the destruction and/or ankylosis of the peripheral joints or spine, resulting in poor quality of life. Interleukin (IL)-23, IL-17 and tumour necrosis factor play pivotal roles in the pathogenesis of PsA and are targets for its treatment. Biological disease-modifying antirheumatic drugs targeting these cytokines and targeted synthetic disease-modifying antirheumatic drugs targeting Janus kinases are available and widely used in clinical practice. Despite the availability of these drugs, there are still unmet needs; for example, patients often resist treatment and relapse or develop intolerance. Bimekizumab is a humanized monoclonal IgG1 antibody that selectively and directly inhibits IL-17A and IL-17F expression. Recently, the efficacy and tolerability of bimekizumab have been reported in several large clinical trials, including two phase III studies. Bimekizumab brings rapid symptom relief and is effective in patients who are biologic-naïve and those who have inadequate responses or become intolerable to tumour necrosis factor inhibitors and require discontinuation; therefore, it is expected to be a novel blockbuster to overcome the unmet needs of PsA.

PAWG pilot study on quantification of SARS-CoV-2 monoclonal antibody - Part 2

Main textUnder the auspices of the Protein Analysis Working Group (PAWG) of the Comité Consultatif pour la Quantité de Matière (CCQM) a pilot study, CCQM-P216, was coordinated by the Chinese National Institute of Metrology (NIM), National Research Council of Canada (NRC) and the Bureau International des Poids et Mesures (BIPM).The global coronavirus pandemic has also led to increased focus on antibody quantitation methods. IgG are among the immunoglobulins produced by the immune system to provide protection against SARS-CoV-2. Anti-SARS-CoV-2 IgG can therefore be detected in samples from affected patients. Antibody tests can show whether a person has been exposed to SARS-CoV-2, and whether or not they potentially show lasting immunity to the disease. With the constant spread of the virus and the high pressure of re-opening economies, antibody testing played a critical role in the fight against COVID-19 by helping healthcare professionals to identify individuals who have developed an immune response, either via vaccination or exposure to the virus. Many countries have launched large-scale antibody testing for COVID-19. The development of measurement standards for the antibody detection of SARS-CoV-2 is critically important to deal with the challenges of the COVID-19 pandemic. In this study, the SARS-CoV-2 monoclonal antibody is being used as a model system to build capacity in methods that can be used in antibody quantification.The purpose of this pilot study was to develop measurement capabilities for larger proteins using a recombinant humanized IgG monoclonal antibody against Spike glycoprotein of SARS-CoV-2 (Anti-S IgG mAb) in solution. A Final Report on the first round of CCQM-P216 PAWG Pilot Study on Quantification of SARS-CoV-2 Monoclonal Antibody - Part 1 focusing on the assessment of both mass fraction determinations of different AAs in the material and mass fraction determinations of proteotypic peptides belonging to the constant region of the mAb has already been published in Metrologia. The present Final Report on the second round of CCQM-P216 - Part 2 was designed to investigate optional methods for the characterization of Anti-S IgG mAb in solution for the assessment of size heterogeneity purity determinations, mass fraction measurements of SARS-CoV-2 monoclonal antibody in the material by UV-VIS spectrophotometry, mass fraction measurements of proteotypic peptides belonging to the variable region of the mAb and mass fraction measurements of monomeric mAb in the material. Six Metrology Institutes or Designated Institutes and the BIPM participated in the second phase of the pilot study (Part 2).Acceptable agreement between all laboratories was for the assessment of size heterogeneity of the anti-S IgG mAb material. For example, a reference value with its corresponding expanded uncertainties of (99.48 ± 0.49) % has been obtained for the monomer. Good between laboratories for UV-VIS spectrophotometric analysis at a pre-agreed wavelength of 280 nm was obtained with individual relative expanded uncertainties from 2.8 % to 15.5 % and a mass concentration reference value and corresponding expanded uncertainty of (500.8 ± 15.4) mg/L.Mass fraction assignments of the target proteotypic peptide YSPSFQGQVTISADK in the variable region of the anti-S IgG mAb material by NIM and BIPM resulted in a reference value and corresponding expanded uncertainty of (9.8 ± 2.0) mg/kg.Both NIM and BIPM have provided estimates for the mass fraction of monomeric mAb in the material with individual relative expanded uncertainties of 4.3 % and 4.1 %, respectively. A mass fraction reference value and corresponding expanded uncertainty of (411 ± 88) mg/kg was calculated by applying an 'excess-variance' approach for the monomeric mAb mass fraction.In addition, a post-hoc assessment of the monomeric mAb mass fraction from the subset of that produced both amino acid and proteotypic peptide-based mass fraction results and SEC measurements during the 1st and present study round provided more detailed information. A reference value and its expanded uncertainty for the mass fraction of monomeric mAb in the anti-S IgG mAb material was calculated to be (434.3 ± 11.9) mg/kg applying an 'excess-variance' approach.The level of agreement was not significantly poorer than that achieved in previous studies with smaller or less complex proteins. The two-stage pilot study was a big step forward to build and improve capacity within NMIs/DIs to undertake future key comparisons in the field of mass fraction determinations of antibodies and other large proteins.To reach the main text of this paper, click on Final Report. Note that this text is that which appears in Appendix B of the BIPM key comparison database https://www.bipm.org/kcdb/.The final report has been peer-reviewed and approved for publication by the CCQM, according to the provisions of the CIPM Mutual Recognition Arrangement (CIPM MRA).

Enhanced delivery of a low dose of aducanumab via FUS in 5×FAD mice, an AD model

BackgroundAducanumab (Adu), which is a human IgG1 monoclonal antibody that targets oligomer and fibril forms of beta-amyloid, has been reported to reduce amyloid pathology and improve impaired cognition after administration of a high dose (10 mg/kg) of the drug in Alzheimer’s disease (AD) clinical trials. The purpose of this study was to investigate the effects of a lower dose of Adu (3 mg/kg) with enhanced delivery via focused ultrasound (FUS) in an AD mouse model.MethodsThe FUS with microbubbles opened the blood–brain barrier (BBB) of the hippocampus for the delivery of Adu. The combined therapy of FUS and Adu was performed three times in total and each treatment was performed biweekly. Y-maze test, Brdu labeling, and immunohistochemical experimental methods were employed in this study. In addition, RNA sequencing and ingenuity pathway analysis were employed to investigate gene expression profiles in the hippocampi of experimental animals.ResultsThe FUS-mediated BBB opening markedly increased the delivery of Adu into the brain by approximately 8.1 times in the brains. The combined treatment induced significantly less cognitive decline and decreased the level of amyloid plaques in the hippocampi of the 5×FAD mice compared with Adu or FUS alone. Combined treatment with FUS and Adu activated phagocytic microglia and increased the number of astrocytes associated with amyloid plaques in the hippocampi of 5×FAD mice. Furthermore, RNA sequencing identified that 4 enriched canonical pathways including phagosome formation, neuroinflammation signaling, CREB signaling and reelin signaling were altered in the hippocami of 5×FAD mice receiving the combined treatment.ConclusionIn conclusion, the enhanced delivery of a low dose of Adu (3 mg/kg) via FUS decreases amyloid deposits and attenuates cognitive function deficits. FUS-mediated BBB opening increases adult hippocampal neurogenesis as well as drug delivery. We present an AD treatment strategy through the synergistic effect of the combined therapy of FUS and Adu.

Human monoclonal natural IgG antibodies can penetrate MDA-MB-231 cells and transport intracellularly paclitaxel-loaded gold nanorods

BackgroundPrevious studies of our laboratory have shown the cell penetrating ability of polyclonal human IgGs present in Intravenous Immunoglobulin (IVIg) therapeutic preparations; those IgGs possessed Natural Antibodies (NAbs) activities, namely reactivity against several structurally unrelated self and non-self antigens (polyreactivity), due to which they can enter living cells. In this work, we isolated human monoclonal IgG Abs (h-mIgGs), derived from Multiple Myeloma patients’ sera with high mIgG concentration, exhibiting polyreactivity, and studied their penetration ability in triple negative, highly aggressive, metastatic MDA-MB-231 breast cancer cell line and their potential role as intracellular carriers of paclitaxel (PTX)-loaded gold nanorods (GNRs). Materials and methodsThe isolated h-mIgGs were tested regarding purity by SDS-PAGE, monoclonality by IsoElectric Focusing electrophoresis (IEF) and polyreactivity by ELISA. The cell–penetrating ability of h-mIgGs, alone or conjugated with GNRs and GNRs loaded with PTX, were tested by immunofluorescence (IF), and their effect on apoptosis and cell viability by FACS and MTT assay, respectively. ResultsAmong six isolated h-mIgGs, five were cell-penetrating antibodies (CPAbs) showing cytoplasmic localization in living MDA-MB-231 cells, with no effect on cell viability. In comparison to unconjugated CPAbs, CPAbs conjugates exhibited significantly augmented intracytoplasmic IF signal. One out of the five CPAbs exhibited optimum characteristics as far as antibody conjugation and cell penetration performance are concerned. The selected CPAb35-GNRs-PTX conjugate displayed a significant decrease on MDA-MB-231 cell viability when compared to GNRs-PTX conjugates and PTX alone. ConclusionsMonoclonal IgG antibodies isolated from Multiple Myeloma patients’ sera can penetrate cancer cells and transport intracellularly the chemotherapeutic agent PTX conjugated to gold nanorods. Extended screening of such h-mIgGs as potential drug-carriers might be an effective approach for their exploitation in biomedicine.

Lecanemab in patients with early Alzheimer’s disease: detailed results on biomarker, cognitive, and clinical effects from the randomized and open-label extension of the phase 2 proof-of-concept study

BackgroundLecanemab, a humanized IgG1 monoclonal antibody that targets soluble aggregated Aβ species (protofibrils), has demonstrated robust brain fibrillar amyloid reduction and slowing of clinical decline in early AD. The objective of this analysis is to report results from study 201 blinded period (core), the open-label extension (OLE), and gap period (between core and OLE) supporting the effectiveness of lecanemab.MethodsThe lecanemab study 201 core was a double-blind, randomized, placebo-controlled study of 856 patients randomized to one of five dose regimens or placebo. An OLE of study 201 was initiated to allow patients to receive open-label lecanemab 10mg/kg biweekly for up to 24 months, with an intervening off-treatment period (gap period) ranging from 9 to 59 months (mean 24 months).ResultsAt 12 and 18 months of treatment in the core, lecanemab 10 mg/kg biweekly demonstrated dose-dependent reductions of brain amyloid measured PET and corresponding changes in plasma biomarkers and slowing of cognitive decline. The rates of clinical progression during the gap were similar in lecanemab and placebo subjects, with clinical treatment differences maintained after discontinued dosing over an average of 24 months in the gap period. During the gap, plasma Aβ42/40 ratio and p-tau181 levels began to return towards pre-randomization levels more quickly than amyloid PET. At OLE baseline, treatment differences vs placebo at 18 months in the randomized period were maintained across 3 clinical assessments. In the OLE, lecanemab 10 mg/kg biweekly treatment produced dose-dependent reductions in amyloid PET SUVr, improvements in plasma Aβ42/40 ratio, and reductions in plasma p-tau181.ConclusionsLecanemab treatment resulted in significant reduction in amyloid plaques and a slowing of clinical decline. Data indicate that rapid and pronounced amyloid reduction correlates with clinical benefit and potential disease-modifying effects, as well as the potential to use plasma biomarkers to monitor for lecanemab treatment effects.Trial registrationClinicalTrials.gov NCT01767311.

591. Adintrevimab (ADI) Population Pharmacokinetics (PPK) in Phase 1 and Phase 2/3 COVID-19 Prevention and Treatment Study Participants

Abstract Background ADI is a fully human IgG1 monoclonal antibody engineered to have an extended half-life with high potency and broad neutralization against SARS-CoV-2 and other SARS-like coronaviruses with pandemic potential. Our objective was to develop a PPK model that describes the serum ADI concentration-time profile following intravenous (IV) and intramuscular (IM) administration. Methods The ADI PPK model was developed on PK data from a Phase 1 single-ascending dose study (24 adults, IV and IM) and from Phase 2/3 COVID-19 prevention (EVADE; 659 adults, IM) and treatment (STAMP; 189 adults, IM) studies. 1,486 PK samples were included in the analysis. The impact of covariates (e.g. body weight, age, and baseline viral load) on ADI serum disposition were evaluated. Prediction-corrected visual predictive check (PC-VPC) plots were used to qualify the PPK model. Participant-specific ADI exposure estimates were generated using individual post hoc PK parameters. Results The PPK model is comprised of 2 systemic compartments, zero-order infusion for IV administration and first-order absorption for IM administration and provided a robust fit to the data based on the PC-VPC plots and goodness-of-fit plots (data not shown). Body weight influenced clearance, intercompartmental clearance, and central and peripheral volume compartments. The relationship between body weight and clearance was not suggestive of the need for dose adjustment over the population weight range studied (38.6 to 178.7 kg). There was no apparent impact of baseline viral load or age on ADI clearance. The median [range] half-lives in days by study; Phase 1 (α1.71 [1.18-2.46]; β 125 [117-149]), Phase 2/3 prevention (α 1.86 [0.640-3.13]; β 136 [105-209]), and Phase 2/3 treatment (α 1.89 [0.631-3.01]; β 136 [108-206]). The population mean IM bioavailability estimate was 90.5%. The figure shows the PPK model median (90% confidence interval) concentration-time profile following a single 300 mg IM ADI dose by study. Conclusion The PPK model provided a precise and unbiased fit to the observed ADI concentration-time data and will be useful for future PK-pharmacodynamic analyses. Moreover, ADI demonstrated high IM bioavailability and a median terminal elimination half-life of 125 to 136 days. Disclosures Christopher M. Rubino, PharmD, Adagio Therapeutics: Grant/Research Support|Amplyx Pharmaceuticals, Inc: Grant/Research Support|AN2 Therapeutics: Grant/Research Support|Antabio SAS: Grant/Research Support|Arcutis Biotherapeutics, Inc: Grant/Research Support|B. Braun Medical Inc.: Grant/Research Support|Basilea Pharmaceutica: Grant/Research Support|Boston Pharmaceuticals: Grant/Research Support|Bravos Biosciences: Ownership Interest|Celdara Medical LLC: Grant/Research Support|Cidara Therapeutics Inc: Grant/Research Support|Cipla USA: Grant/Research Support|Crestone Inc: Grant/Research Support|CXC: Grant/Research Support|Debiopharm International SA: Grant/Research Support|Entasis Therapeutics: Grant/Research Support|Evopoint Biosciences Co.: Grant/Research Support|Fedora Pharmaceuticals: Grant/Research Support|GlaxoSmithKline: Grant/Research Support|Hoffmann-La Roche: Grant/Research Support|ICPD: Ownership Interest|ICPD Biosciences, LLC.: Ownership Interest|Insmed Inc.: Grant/Research Support|Iterum Therapeutics Limited: Grant/Research Support|Kaizen Bioscience, Co.: Grant/Research Support|KBP Biosciences USA: Grant/Research Support|Lassen Therapeutics: Grant/Research Support|Matinas Biopharma: Grant/Research Support|Meiji Seika Pharma Co., Ltd.: Grant/Research Support|Melinta Therapeutics: Grant/Research Support|Menarini Ricerche S.p.A: Grant/Research Support|Mutabilis: Grant/Research Support|Nabriva Therapeutics AG: Grant/Research Support|Novartis Pharmaceuticals Corp.: Grant/Research Support|Paratek Pharmaceuticals, Inc.: Grant/Research Support|PureTech Health: Grant/Research Support|Sfunga Therapeutics: Grant/Research Support|Spero Therapeutics,: Grant/Research Support|Suzhou Sinovent Pharmaceuticals Co.: Grant/Research Support|TauRx Therapeutics: Grant/Research Support|Tetraphase Pharmaceuticals: Grant/Research Support|tranScrip Partners: Grant/Research Support|Utility Therapeutics: Grant/Research Support|Valanbio Therapeutics, Inc.: Grant/Research Support|VenatoRx: Grant/Research Support|Wockhardt Bio AG: Grant/Research Support Anthony P. Cammarata, M.S., Adagio Therapeutics, Inc.: Grant/Research Support|Amplyx Pharmaceuticals, Inc.: Grant/Research Support|AN2 Therapeutics: Grant/Research Support|Antabio SAS: Grant/Research Support|Arcutis Biotherapeutics, Inc.: Grant/Research Support|B. Braun Medical Inc.: Grant/Research Support|Basilea Pharmaceutica: Grant/Research Support|Boston Pharmaceuticals: Grant/Research Support|Celdara Medical LLC: Grant/Research Support|Cidara Therapeutics Inc.: Grant/Research Support|Cipla USA: Grant/Research Support|Crestone Inc.: Grant/Research Support|CXC: Grant/Research Support|Debiopharm International SA: Grant/Research Support|Entasis Therapeutics: Grant/Research Support|Evopoint Biosciences Co.: Grant/Research Support|Fedora Pharmaceuticals: Grant/Research Support|GlaxoSmithKline: Grant/Research Support|Hoffmann-La Roche: Grant/Research Support|Insmed Inc.: Grant/Research Support|Iterum Therapeutics Limited: Grant/Research Support|Kaizen Bioscience, Co.: Grant/Research Support|KBP Biosciences USA: Grant/Research Support|Lassen Therapeutics: Grant/Research Support|Matinas Biopharma: Grant/Research Support|Meiji Seika Pharma Co., Ltd.: Grant/Research Support|Melinta Therapeutics: Grant/Research Support|Menarini Ricerche S.p.A.: Grant/Research Support|Mutabilis: Grant/Research Support|Nabriva Therapeutics AG: Grant/Research Support|Novartis Pharmaceuticals Corp.: Grant/Research Support|Paratek Pharmaceuticals, Inc.: Grant/Research Support|PureTech Health: Grant/Research Support|Sfunga Therapeutics: Grant/Research Support|Spero Therapeutics: Grant/Research Support|Suzhou Sinovent Pharmaceuticals Co.: Grant/Research Support|TauRx Therapeutics: Grant/Research Support|Tetraphase Pharmaceuticals: Grant/Research Support|tranScrip Partners: Grant/Research Support|Utility Therapeutics: Grant/Research Support|Valanbio Therapeutics, Inc.: Grant/Research Support|VenatoRx: Grant/Research Support|Wockhardt Bio AG: Grant/Research Support Paul Ambrose, PharmD, Adagio Therapeutics: Employee|Adagio Therapeutics: Stocks/Bonds|Institute for Clinical Pharmacodynamics: President Pete Schmidt, MD, Adagio Therapeutics: Employee|Adagio Therapeutics: Stocks/Bonds Myra Popejoy, PharmD, Adagio Therapeutics: Employee|Adagio Therapeutics: Stocks/Bonds Jean Gong, PhD, Adagio Therapeutics: Employee|Adagio Therapeutics: Stocks/Bonds Xia Pu, PhD, Adagio Therapeutics: Employee|Adagio Therapeutics: Stocks/Bonds.

226. Higher Doses of Adintrevimab, an Extended Half-Life Monoclonal Antibody, for the Treatment and Prevention of COVID-19: Preliminary Results from a Phase 1 Single Ascending-Dose Study

Abstract Background Adintrevimab is a fully human IgG1 monoclonal antibody engineered to have potent and broad neutralization against severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) and other SARS-like CoVs with pandemic potential. Adintrevimab is being assessed in two separate phase 2/3 clinical trials: the EVADE trial for prevention of COVID-19 in both post-exposure and pre-exposure settings and the STAMP trial for treatment of COVID-19. Here we report higher doses being evaluated in a healthy volunteer study given that emerging variants may have varying susceptibilities to adintrevimab. Previous results 300 mg IM, 600 mg IM, and 500 mg IV cohorts have been reported. Methods This is an ongoing Phase 1, randomized, placebo (PBO)-controlled, single ascending-dose study of adintrevimab administered intramuscularly (IM) or intravenously (IV) to healthy adults aged 18–50 years with no current SARS-CoV-2 infection. Participants were randomized 8:2 in 3 high dose cohorts (N=10/cohort: n=8 adintrevimab, n=2 PBO): adintrevimab 1200 mg IM, 1200 mg IV, and 4500 mg IV. Safety, tolerability, and pharmacokinetics (PK) were assessed up to 21 days post dose. Results Overall, 30 participants received adintrevimab (n=24) or PBO (n=6). Blinded safety data for all cohorts and PK for 1200 mg IV are reported. Through 21 days post dose all doses were well-tolerated, with no study drug-related adverse events (AEs), serious AEs, injection site reactions, or hypersensitivity reactions reported. The observed PK profile of the 1200 mg IV dose included Cmax of 423±105 µg/ml. Comparison of 500 mg and 1200 mg IV doses indicate dose proportionality of Cmax and exposure (AUC Day 21). Conclusion A single dose of adintrevimab, up to 4500 mg, was well tolerated. These preliminary safety data and PK support potential use of higher doses of adintrevimab as needed to address emerging SARS-CoV-2 variants. Disclosures Xia Pu, PhD, Adagio Therapeutics: Employee|Adagio Therapeutics: Stocks/Bonds Jean Gong, PhD, Adagio Therapeutics: Employee|Adagio Therapeutics: Stocks/Bonds Ed Campanaro, BSN, MSHS, Adagio Therapeutics: Employee|Adagio Therapeutics: Stocks/Bonds Kristin Narayan, PhD, Adagio Therapeutics: Employee|Adagio Therapeutics: Stocks/Bonds Deepali Gupta, B.Sc, Adagio Therapeutics: Employee|Adagio Therapeutics: Stocks/Bonds Frank Engler, PhD, Adagio Therapeutics: Advisor/Consultant Amanda Copans, PharmD, Adagio Therapeutics: Employee|Adagio Therapeutics: Stocks/Bonds Pete Schmidt, MD, Adagio Therapeutics: Employee|Adagio Therapeutics: Stocks/Bonds.

1132. Integrated Quantitative Systems Pharmacology (QSP) Characterizing Viral Dynamics After Intramuscular (IM) Adintrevimab (ADI) Administration in Participants with Mild to Moderate Coronavirus Disease (COVID-19)

Abstract Background ADI is a fully human IgG1 monoclonal antibody engineered to have an extended half-life with high potency and broad neutralization against SARS-CoV-2 and other SARS-like coronaviruses. The goal of our analysis was to develop a QSP model in which ADI concentrations in upper airway (UA) epithelial lining fluid (ELF) were linked to a viral dynamic model to describe the impact of ADI on SARS-CoV-2 viral load relative to placebo. Methods The QSP model was fit in NONMEM Version 7.4 using PK data from a Phase 1 study (N=24, IV and IM) and from Phase 2/3 COVID-19 prevention (EVADE; N=659, IM) and treatment (STAMP; N=189, IM) studies. Saliva and NP samples were collected from STAMP study participants (pts) infected with the delta or omicron variants. The viral dynamic model was based on a published model and was modified to include both active (V) and deactivated (DV) virus (Fig). The viral dynamic model was fit to the NP swab viral load data (2 samples/pt) standardized to time since infection based upon recorded symptom onset. Saliva data (7-8 samples/pt) was fit sequentially using a biophase compartment given the peak viral load was modestly lower and peaked later than Day 1. Viral dynamic model (A) and simulated median (90% PI) NP viral load reduction in ADI-treated or placebo participants for delta (B) and omicron (C) variants Results The QSP model provided an excellent fit to serum ADI concentration-time data after estimation of a transit rate to account for IM absorption, plasma volume, and the ADI-neonatal Fc receptor dissociation rate constant. The linked viral dynamic model captured the NP swab viral load data after estimating differences in within-host replication factor (R0) and viral production rate (p) by variant. Maximal ADI-induced effect (Smax) on stimulating viral clearance (c) was fixed to 0.43 based upon prior modeling. ADI concentration in UA ELF resulting in 50% of Smax (SC50) was estimated to be 0.086 for delta and 1.05 mg/L for omicron. Figure B and C show model-based simulated median (90% PI) viral load reduction in ADI-treated or placebo pts for delta and omicron variants. Conclusion This QSP model, in conjunction with information on new variants available early in outbreaks (IC50, infectivity (R0), viral production rate [each a model parameter]), allows for rapid dose identification in response to emerging variants. Disclosures Evan Tarbell, PhD, Adagio Therapeutics: Advisor/Consultant|Adagio Therapeutics: Grant/Research Support Scott A. Van Wart, PhD, Adagio Therapeutics: Advisor/Consultant|Adagio Therapeutics: Grant/Research Support Myra Popejoy, PharmD, Adagio Therapeutics: Employee|Adagio Therapeutics: Stocks/Bonds Kristin Narayan, PhD, Adagio Therapeutics: Employee|Adagio Therapeutics: Stocks/Bonds Ellie Hershberger, PharmD, Adagio Therapeutics: Employee|Adagio Therapeutics: Stocks/Bonds Xia Pu, PhD, Adagio Therapeutics: Employee|Adagio Therapeutics: Stocks/Bonds Jean Gong, PhD, Adagio Therapeutics: Employee|Adagio Therapeutics: Stocks/Bonds Christopher M. Rubino, PharmD, Adagio Therapeutics: Grant/Research Support|Amplyx Pharmaceuticals, Inc: Grant/Research Support|AN2 Therapeutics: Grant/Research Support|Antabio SAS: Grant/Research Support|Arcutis Biotherapeutics, Inc: Grant/Research Support|B. Braun Medical Inc.: Grant/Research Support|Basilea Pharmaceutica: Grant/Research Support|Boston Pharmaceuticals: Grant/Research Support|Bravos Biosciences: Ownership Interest|Celdara Medical LLC: Grant/Research Support|Cidara Therapeutics Inc: Grant/Research Support|Cipla USA: Grant/Research Support|Crestone Inc: Grant/Research Support|CXC: Grant/Research Support|Debiopharm International SA: Grant/Research Support|Entasis Therapeutics: Grant/Research Support|Evopoint Biosciences Co.: Grant/Research Support|Fedora Pharmaceuticals: Grant/Research Support|GlaxoSmithKline: Grant/Research Support|Hoffmann-La Roche: Grant/Research Support|ICPD: Ownership Interest|ICPD Biosciences, LLC.: Ownership Interest|Insmed Inc.: Grant/Research Support|Iterum Therapeutics Limited: Grant/Research Support|Kaizen Bioscience, Co.: Grant/Research Support|KBP Biosciences USA: Grant/Research Support|Lassen Therapeutics: Grant/Research Support|Matinas Biopharma: Grant/Research Support|Meiji Seika Pharma Co., Ltd.: Grant/Research Support|Melinta Therapeutics: Grant/Research Support|Menarini Ricerche S.p.A: Grant/Research Support|Mutabilis: Grant/Research Support|Nabriva Therapeutics AG: Grant/Research Support|Novartis Pharmaceuticals Corp.: Grant/Research Support|Paratek Pharmaceuticals, Inc.: Grant/Research Support|PureTech Health: Grant/Research Support|Sfunga Therapeutics: Grant/Research Support|Spero Therapeutics,: Grant/Research Support|Suzhou Sinovent Pharmaceuticals Co.: Grant/Research Support|TauRx Therapeutics: Grant/Research Support|Tetraphase Pharmaceuticals: Grant/Research Support|tranScrip Partners: Grant/Research Support|Utility Therapeutics: Grant/Research Support|Valanbio Therapeutics, Inc.: Grant/Research Support|VenatoRx: Grant/Research Support|Wockhardt Bio AG: Grant/Research Support Andrew Santulli, BSE, Adagio Therapeutics: Advisor/Consultant|Adagio Therapeutics: Grant/Research Support Paul Ambrose, PharmD, Adagio Therapeutics: Employee|Adagio Therapeutics: Stocks/Bonds|Institute for Clinical Pharmacodynamics: President.

Consistency of efficacy results across various clinical measures and statistical methods in the lecanemab phase 2 trial of early Alzheimer’s disease

Lecanemab (BAN2401) is a humanized IgG1 monoclonal antibody that preferentially targets soluble aggregated Aβ species (protofibrils) with activity at insoluble fibrils and slowed clinical decline in an 18-month phase 2 proof-of-concept study (Study 201; ClinicalTrials.gov NCT01767311) in 856 subjects with early Alzheimer's disease (AD). In this trial, subjects were randomized to five lecanemab dose regimens or placebo. The primary efficacy endpoint was change from baseline in the Alzheimer's Disease Composite Score (ADCOMS) at 12 months with Bayesian analyses. The key secondary endpoints were ADCOMS at 18 months and Clinical Dementia Rating-Sum-of-Boxes (CDR-SB) and Alzheimer's Disease Assessment Scale-Cognitive Subscale (ADAS-Cog14) at 18 months. The results have been published previously. Herein, we describe the results of sensitivity analyses evaluating the consistency of the lecanemab efficacy results in Study 201 at the identified dose, the ED90, across multiple statistical methods and multiple endpoints over the duration of the study. The protocol-specified analysis model was a mixed model for repeated measures (MMRM). Sensitivity analyses address the consistency of the conclusions using multiple statistical methods. These include a disease progression model (DPM), a natural cubic spline (NCS) model, a quadratic mixed model (QMM), and 2 MMRMs with additional covariates. The sensitivity analyses showed positive lecanemab treatment effects for all endpoints and all statistical models considered. The protocol-specified ADCOMS analysis showed a 29.7% slower decline than placebo for ADCOMS at 18 months. The various other analyses of 3 key endpoints showed declines ranging from 26.5 to 55.9%. The results at 12 months are also consistent with those at 18 months. The conclusion of the primary analysis of the lecanemab Study 201 is strengthened by the consistently positive conclusions across multiple statistical models, across efficacy endpoints, and over time, despite missing data. The 18-month data from this trial was utilized in the design of the confirmatory phase 3 trial (Clarity AD) and allowed for proper powering for multiple, robust outcomes.

The Impact of Tezepelumab in Uncontrolled Severe Asthma: A Systematic Review of Randomized Controlled Trials.

Asthma, a chronic illness, is characterized by inflammation and airway constriction. Uncontrolled severe asthma is related to poor quality of life and increased utilization of health resources. Conventional treatments are associated with a significant amount of adverse effects. Recent years have seen the identification of various molecular effectors and signaling pathways as interesting targets for the biological therapy of severe asthma that is resistant to current therapies. Because they only target some downstream components of the inflammatory response in asthma, leaving other components unaffected, current biologic treatments only lower the exacerbation rate by 50%. If we focus on the upstream mediators of the inflammatory response in asthma, it might have a greater effect and be more efficient. Tezepelumab is a human monoclonal IgG2 antibody that specifically binds to thymic stromal lymphopoietin (TSLP) at the level of its TSLPR (thymic stromal lymphopoietin receptor) binding site, inhibiting the interaction between human TSLP and TSLPR. It is being used to treat the cytokines on the respiratory epithelial layer known as "alarmins." It is the only biologic drug available for treating severe uncontrolled asthma, despite limitations in biomarker and phenotype. In light of recent developments, the lack of knowledge on tezepelumab prompts us to publish a comprehensive systematic review. We discovered that regardless of blood eosinophil level and fractional exhaled nitric oxide levels, tezepelumab dramatically lowers asthma exacerbation in patients with severe uncontrolled asthma when compared to placebo. Tezepelumab also lessens patients' demand for healthcare resources while improving clinical indicators of lung function, health-related quality of life, and asthma management in patients. Tezepelumab plays a role in enhancing pre-bronchodilator FEV1 and lowering blood eosinophil count and fractional exhaled nitric oxide in patients with or without chronic allergies (FeNO). There have been no reports of fatalities or severe adverse events connected to tezepelumab.

Modeled Impact of APOE4 Genotype on ARIA‐E Incidence in Patients Treated With Lecanemab

AbstractBackgroundLecanemab is a humanized IgG1 monoclonal antibody that preferentially targets soluble aggregated Aβ species with activity at insoluble fibrils. A multicenter, double‐blind, placebo‐controlled phase 2 study (Study 201 Core) was conducted in 856 patients with early Alzheimer’s disease (EAD). Patients could optionally participate in an open label extension (OLE) study at a dose of 10 mg/kg bi‐weekly (Q2W). Amyloid related imaging abnormalities — edema/effusion (ARIA‐E) was a main adverse event of special interest. Incidence of ARIA‐E was lecanemab dose‐dependent and greater in APOE4 carriers. A previously presented logistic model found steady‐state Cmax was a predictor of ARIA‐E incidence and more likely in APOE4 carriers (Hussein, 2019).MethodsThis work expands upon the previously developed logistic model by exploring the effect of APOE4 genotype (noncarrier, heterozygous carrier, homozygous carrier) on ARIA‐E incidence. Modeling was conducted using NONMEM 7.4.3 with data from Study 201 Core. Model predictions were compared to the observed incidence in the OLE study among patients newly treated with lecanemab (ie, placebo‐treated in the Core study).ResultsInclusion of APOE4 genotype as a covariate in the model with three categories (noncarrier, heterozygous carrier, homozygous carrier) led to a statistically significant decrease in model objective function (p <0.001). A model utilizing only 2 categories (homozygous carrier, others) was not significantly different from the model with 3 categories (p = 0.5297). Model‐predicted ARIA‐E rates for APOE4 homozygous carriers treated with lecanemab 10 mg/kg Q2W were 22.5% (versus 6.8% in heterozygous or 5.4% in noncarriers) and comparable to the observed 25% incidence in newly‐treated homozygous carriers (1/4) in the OLE study, and less than the 50% incidence in homozygous carriers (5/10) in the Core.ConclusionsThe incidence of ARIA‐E in subjects treated with lecanemab appears highest in APOE4 homozygous subjects. No statistically significant difference in ARIA‐E incidence was found between non‐carriers and heterozygous carriers. Data from the larger CLARITY‐AD study will be needed to confirm these findings.Reference: Hussein, et al., Population Pharmacokinetic (PK) and Exposure‐Response (ER) Analyses for Efficacy and Safety of BAN2401 in Patients with Early Alzheimer’s Disease (AD), International Conference on Alzheimer’s & Parkinson’s Diseases (AD/PD), 2019.

Neuropathological autopsy findings in an individual with Alzheimer’s disease who received long‐term treatment with lecanemab (BAN2401)

AbstractBackgroundAnti‐amyloid antibodies administered to patients with Alzheimer’s disease can result in marked reduction of brain amyloid as measured by neuroimaging with amyloid PET ligands. However, there is a lack of pathological data. Here we present neuropathological findings in a patient who received ∼173 weeks of (interrupted) treatment with lecanemab (BAN2401), a humanized IgG1 monoclonal antibody that preferentially targets soluble aggregated β‐amyloid species (protofibrils) and insoluble fibrils, in a Phase 2 study (NCT01767311, Alz Res Therapy 2021;13:80).MethodBrain autopsy was performed on an ∼85 year old whose lecanemab treatment history over 6 years was: 79 weeks 10mg/kg monthly in the double‐blind (DB) phase, then 98 weeks without treatment, then 94 weeks at 10mg/kg biweekly in the open‐label extension (OLE) phase, followed by ∼12 weeks of treatment discontinuation prior to death.ResultClinically, memory symptoms started age ∼77. Study entry was at age ∼80, with mild dementia, CDR 0.5, CDR‐SB 3, and MMSE 24. Florbetapir PET scan was positive at baseline, and negative after 53 weeks DB treatment and at start of OLE. These findings and clinical measures are shown in Table 1. ARIA was not observed during the study. Autopsy showed low brain weight (1052g) with diffuse atrophy, including hippocampi, consistent with atrophy seen on clinical MRI scans. Microscopic findings showed tau pathology including tangles and threads (by AT8 antibody and Bielschowsky staining) throughout neocortex (Braak NF stage VI; B3). Beta‐amyloid immunohistochemical stain (6E10) showed only modest amyloid load (Thal phase 2; A1), with near‐absence of diffuse amyloid deposits and only scattered clusters of neuritic plaques (CERAD stage B; C2).ConclusionIn this autopsy of an individual with Alzheimer’s disease treated with lecanemab, neuropathological changes showed tau and β‐amyloid deposits. However, the pattern of significant tau pathology, accompanied by only a mild degree of β‐amyloid deposits, (A1B3C2), is uncommon in typical (untreated) Alzheimer’s disease. For example, in the NACC neuropathology dataset, only 2% of brains with Braak B2 or B3 show Thal stage A0 or A1. This pattern suggests that lecanemab treatment resulted in a reduction in brain amyloid, consistent with the amyloid PET scanning results in this patient.

Subcutaneous Dose Selection of Lecanemab for Treatment of Subjects with Early Alzheimer’s Disease (EAD)

AbstractBackgroundLecanemab is a humanized IgG1 monoclonal antibody that preferentially targets soluble aggregated Aβ species (protofibrils) with activity at insoluble fibrils. Lecanemab 10 mg/kg IV biweekly dose (10BW) is being evaluated in the Clarity AD Phase 3 study in Early AD. A Phase 1 study was conducted to assess the absolute bioavailability (BA) of subcutaneous (SC) administration relative to IV infusion. Modeling and simulation analysis was conducted to demonstrate equivalence of a fixed weekly SC dose to body weight‐based IV 10BW dose with regard to lecanemab exposure, safety and efficacy.MethodBased on estimates of BA and absorption rate constant from Phase 1 and the population PK model describing lecanemab PK after IV infusion, estimates of the area under the concentration‐time curve (AUC) and maximum concentration (Cmax) at steady‐state were generated for the proposed fixed SC dose and IV 10BW. Exposure‐response simulations were conducted to compare positron emission tomography (PET) standard uptake ratio (SUVr)as a measure of pharmacodynamic effect, and incidence of amyloid related imaging abnormality‐E (ARIA‐E) as a measure of safety between SC and IV doses. The impact of body weight on the lecanemab exposure, reduction in amyloid PET SUVr and ARIA‐E risk when administered as a fixed SC dose and body weight‐based IV dose were explored.ResultPhase 1 data support a proposed fixed lecanemab SC dose of 720 mg administered weekly (720W). PK simulations demonstrate that the AUC of SC 720W were similar to IV 10BW. Exposure‐response simulations demonstrate comparable reduction in amyloid PET SUVr following SC 720W and IV 10BW, and lower incidence of ARIA‐E in SC 720W due to lower Cmax following SC administration. Lecanemab exposure differences between a fixed SC dose and body weight‐based IV dose were observed at the extremes of body weight; however, this did not have a meaningful effect on the reduction in PET SUVr and ARIA‐E risk.ConclusionThis analysis demonstrates that the proposed SC 720W results in equivalent AUC predicted to attain a comparable reduction in amyloid PET SUVr and a lower Cmax predicted to produce a lower incidence of ARIA‐E compared to IV 10BW.

Lecanemab (BAN2401) Infusion Reactions and Immunogenicity: Results from Randomized Phase 2 Study and an Open‐Label Extension (OLE).

AbstractBackgroundTreatment with 10 mg/kg lecanemab (BAN2401), a humanized IgG1 monoclonal antibody that preferentially targets soluble aggregated Aβ species, has been shown to reduce amyloid PET standard uptake value ratio (SUVr) and slow clinical decline in an 18‐month, phase 2 proof‐of‐concept study (Study 201 Core) in early Alzheimer’s disease with an OLE. The present analysis aimed to review infusion related reactions from Study 201 and the results of immunogenicity assessments from the completed lecanemab clinical trial.MethodsInfusion related reactions were summarized by treatment group using descriptive statistics. All adverse events were coded using MedDRA version 24.0 and graded based on CTCAE guidelines.Analysis of anti‐drug antibodies (ADA) and its impact on pharmacokinetics, pharmacodynamics, efficacy, and safety during Study 201 were undertaken. All ADA and NAb assays were developed and validated in accordance with FDA guidance and industry best practice and were performed using a tiered approach.ResultsIn Study 201 Core, 854 treated subjects (lecanemab:609; placebo:245) were randomized across 6 treatment groups. In the OLE phase a total of 180 subjects were treated with lecanemab 10 mg/kg biweekly (LEC10BW). Infusion‐related reactions were the most common adverse event associated with LEC10BW treatment, with 19.9% (32/161) of subjects compared to 3.3% (8/245) of placebo subjects. All events were mild/moderate in severity, most occurred with the first infusion, resulted in a low rate of discontinuations (LEC10BW:2.5%; placebo:0.8%). Over 70% of patients who initially experienced infusion‐related reactions had no further reactions with preventative medications. Infusion reaction data from the OLE were consistent with the Core study. The incidences of ADA for LEC10BW in the Core and OLE were 40.9% and 11.1% (Core placebo‐treated subjects), respectively; titers were very low (most ≤125). Detailed analysis of lecanemab ADA demonstrated no meaningful impact of ADA on pharmacokinetics, pharmacodynamics, efficacy, and safety.ConclusionsIn the lecanemab Study 201 Core and OLE, infusion‐related reactions were the most common adverse event, however were readily manageable with preventative medication, were of low severity, and resulted in minimal discontinuations. Lecanemab is a low‐risk molecule for immunogenicity based on ADA profile and minimal impact of ADA on pharmacokinetics, pharmacodynamics, efficacy, and safety.

Recent advances in atezolizumab-based programmed death-ligand 1 (PD-L1) blockade therapy for breast cancer.

Breast cancer, the most common cancer in women worldwide, is curable in∼70-80% of patients with early-stage, non-metastatic disorder. However, advanced breast cancer with distant organ metastases is incurable with available therapeutics. Thus, scientists have sought emerging strategies for treating metastatic breast cancers., Immune checkpoint inhibitors (ICIs) have represented a significant development in breast cancer immunotherapy. Now, targeting immune checkpoint molecules (e.g., programmed cell death protein 1 (PD-1) and programmed cell death ligand 1 (PD-L1)) have attracted increasing attention in the context of breast cancer therapy, chiefly triple-negative breast cancer (TNBC). Atezolizumab, a humanized IgG1 monoclonal antibody (mAb), has been designed to interfere with the binding of the PD-L1 ligand to its receptor. Targeting PD-L1 using atezolizumab potentiates T-cell responses to the tumor and consequently boosts tumor responses. The results of the IMpassion130 trial have recently led to the approval of the combination of atezolizumab and nab-paclitaxel to treat unresectable locally advanced or metastatic patients with PD-L1-positive TNBC. Herein, we summarize the clinical efficacy of atezolizumab in treating breast cancer and briefly discuss the possible immune-related adverse events (irAEs).

Absolute Bioavailability of a Single, Fixed Subcutaneous Dose of Lecanemab in Healthy Subjects

AbstractBackgroundLecanemab is a humanized IgG1 monoclonal antibody that preferentially targets soluble aggregated Aβ species (protofibrils) with activity at insoluble fibrils. A subcutaneous (SC) formulation is in development as an alternative to intravenous (IV) infusion. The present study evaluated the absolute bioavailability (BA), pharmacokinetics (PK), safety and immunogenicity of lecanemab following a single fixed 700 mg SC dose.MethodsThis was an open‐label, parallel‐group study conducted in healthy subjects that were randomized into IV or SC dose group; 5 Japanese subjects were randomized to the SC dose group. Serum samples for determination of lecanemab PK parameters were collected after single dose of 10 mg/kg IV infused over approximately 1 hour or fixed 700 mg SC injection in the abdomen. The absolute BA was determined by the ratio of dose normalized area under the curve from zero to infinity (AUC(0‐inf)) for SC versus IV dosing.ResultsThirty subjects received IV infusion and 29 subjects received SC injection. After SC dosing, maximum concentration was observed 72 hours post dose and was 4‐fold lower compared to IV infusion, which reflected the long absorption phase following SC administration compared with IV infusion. The AUC was 2‐fold lower for SC administration compared with IV infusion. Lecanemab half‐life (∼ 7 days) was similar following SC and IV administration. The absolute BA following a single SC 700 mg dose of lecanemab was 49.7% (90% CI: 43.5 – 56.8). PK of lecanemab after SC administration in Japanese subjects was similar to those in non‐Japanese subjects. Mild to moderate injection site reactions were experienced by 6 (20.7%) subjects in the SC dose group. Grade 1 and 2 infusion related reactions were experienced by 10 (33.3%) subjects in the IV dose group. One subject in IV and 2 in SC dose group, had confirmed treatment‐emergent positive anti‐drug antibodies (ADA), with low titers ranging from 16 to 32 with no subject being positive for neutralizing antibodies.ConclusionLecanemab was well tolerated following both SC and IV administrations. The estimate of absolute BA of SC compared to IV dosing will be used to define SC dose and dosing regimen equivalent to IV dosing.

Lifetime clinical benefits of lecanemab in early Alzheimer’s disease using simulation modeling

AbstractBackgroundAlzheimer’s disease (AD) is a progressive, neurodegenerative disease and imposes a substantial societal burden. Treatment strategies that slow disease progression may improve health outcomes and reduce burden. Lecanemab is a humanized IgG1 monoclonal antibody that preferentially targets soluble aggregated Aβ species. In the phase 2b BAN2401‐G000‐201 trial, lecanemab reduced clinical decline as measured by key global and cognitive scales at 18 months.MethodsA validated disease simulation model was used to assess lifetime health outcomes of lecanemab for patient with early AD (MCI due to AD and mild AD dementia) based on BAN2401‐G000‐201 trial data and published literature. The model captures the pathophysiology and management of AD, with the aim of evaluating the effects of disease modification on disease progression and translating them into meaningful health outcomes.ResultsLecanemab treatment was projected to delay disease progression, resulting in an increase in patient’s expected time in the early AD stages while reducing the time in more severe states. A 26% slowing of clinical decline on CDR‐SB in patients treated with lecanemab corresponded to a 7%, 13%, and 10% reduction in the proportion of patients progressing to mild, moderate, and severe AD dementia, respectively, over a lifetime horizon compared to the standard of care (SoC). Similarly, the estimated mean time to advance to mild, moderate, and severe AD dementia extended for lecanemab treatment by 2.51, 3.13, and 2.34 years, respectively. Scenario analyses indicated the potential lifetime impact of lecanemab was greater at earlier, younger onset AD. The incremental mean times for transition to mild and moderate AD dementia were 3.29 and 3.38 years, respectively, in younger adults (baseline mean age 65 vs. 71.5 years) with MCI due to AD only. Compared with SoC, lecanemab treatment improved patient’s quality of life over lifetime with additional 0.75 quality‐adjusted life‐years per patient (4.97 vs. 4.22).ConclusionsThe findings suggest that lecanemab treatment in early AD may have large health impacts by slowing disease progression to more severe stages of AD and reducing patient, caregiver, and public health burden. Predicted long‐term health outcomes provide a foundation for healthcare decision‐makers to understand the potential clinical and socioeconomic value of lecanemab.

199TiP A first-in-human phase I study of IPH5301, an anti-CD73 monoclonal antibody, alone or in combination with chemotherapy and trastuzumab, in patients with advanced solid tumors (CHANCES)

CD73 is an extracellular ectonucleotidase overexpressed in the tumor microenvironment (TME) of multiple cancers. Extracellular adenosine triphosphate (ATP) released by necrotic cells is hydrolyzed into adenosine monophosphate (AMP), which is subsequently degraded by CD73 into immunosuppressive adenosine. CD73 overexpression has been associated with poor prognosis, conferring resistance to chemotherapy and anti-HER2 therapy. IPH5301 is a humanized IgG1 monoclonal antibody (mAb) with a functionally silent Fc domain, specifically inhibiting both soluble and membrane CD73 enzymatic activity, and restoring proliferation of immune T cells more effectively than other anti-CD73 mAbs in clinical development.