633. Preliminary Results from a Phase 1 Single Ascending-Dose Study Assessing Safety, Serum Viral Neutralizing Antibody Titers (sVNA), and Pharmacokinetic (PK) Profile of ADG20: an Extended Half-Life Monoclonal Antibody Being Developed for the Treatment and Prevention of Coronavirus Disease (COVID-19)

Paguntalan, Helen; Magyarics, Zoltán; Connolly, Lynn; Hershberger, Ellie; Narayan, Kristin; Gupta, Deepali; Ambrose, Paul G.; Engler, Frank; Campanaro, Ed; Das, Anita; Schmidt, Pete

doi:10.1093/ofid/ofab466.831

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“…This study established an optimized allometric scaling approach for predicting the pharmacokinetics of engineered mAbs in humans. Recently, other than YTE and LS mutations, several mutations to increase FcRn binding have been reported and evaluated in preclinical and clinical studies [29][30][31]. Also, YTE mutations were reported to be applied in ADC [32] and Fc-fusion protein [33] to prolong half-life.…”

Section: Discussionmentioning

confidence: 99%

Translational Approach for Predicting Human Pharmacokinetics of Engineered Therapeutic Monoclonal Antibodies with Increased FcRn-Binding Mutations

Haraya¹,

Tachibana²

2022

BioDrugs

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Introduction Recently, increasing FcRn binding by Fc engineering has become a promising approach for prolonging the half-life of therapeutic monoclonal antibodies (mAbs). This study is the first to investigate the optimization of an allometric scaling approach for engineered mAbs based on cynomolgus monkey data to predict human pharmacokinetics. Methods Linear two-compartmental model parameters (clearance [CL]; volume of distribution in the central compartment [ V c ]; inter-compartmental clearance [ Q ]; volume of distribution in the peripheral compartment [ V p ]) after the intravenous (IV) injection of engineered mAbs (M252Y/S254T/T256E or M428L/N434S mutations) in cynomolgus monkeys and humans were collected from published data. We explored the optimal exponent for allometric scaling to predict parameters in humans based on cynomolgus monkey data. Moreover, the plasma concentration–time profile of engineered mAbs after IV injection in humans was predicted using parameters estimated based on an optimized exponent. Results For engineered mAbs, a significant positive correlation between cynomolgus monkeys and humans was observed for CL, but not for other parameters. Whereas conventional exponents (CL: 0.8, Q : 0.75, V c : 1.0, V p : 0.95) previously established for normal mAbs showed poor prediction accuracy for CL and Q of engineered mAbs, the newly optimized exponents (CL: 0.55, Q : 0.6, V c : 0.95, V p : 0.95) achieved superior predictability for engineered mAbs. Moreover, the optimized exponents accurately predicted plasma mAb concentration–time profiles after IV injection of engineered mAbs in humans. Conclusions We found that engineered mAbs require specially optimized exponents to accurately predict pharmacokinetic parameters and plasma concentration–time profiles after IV injections in humans based on cynomolgus monkey data. This optimized approach can contribute to a more accurate prediction of human pharmacokinetics in the development of engineered mAbs.

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Section: Discussionmentioning

confidence: 99%

Translational Approach for Predicting Human Pharmacokinetics of Engineered Therapeutic Monoclonal Antibodies with Increased FcRn-Binding Mutations

Haraya¹,

Tachibana²

2022

BioDrugs

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“…This was a randomized, double-blind, placebo-controlled, single ascending dose, phase 1 study conducted at a single center in the USA. The doses of adintrevimab selected for this study were based on a quantitative systems pharmacology (QSP) whole-body physiologically based pharmacokinetic (PBPK) model for extended half-life monoclonal antibodies following IV and IM administration [ 11 ]. The model was developed based on published literature describing monoclonal antibody distribution kinetics in humans, including binding affinity to Fc receptors and IM bioavailability [ 12 ].…”

Section: Methodsmentioning

confidence: 99%

Safety, Pharmacokinetics, Serum Neutralizing Titers, and Immunogenicity of Adintrevimab, a Monoclonal Antibody Targeting SARS-CoV-2: A Randomized, Double-Blind, Placebo-Controlled, Phase 1 Dose-escalation Study in Healthy Adults

et al. 2023

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Introduction Adintrevimab is a fully human immunoglobulin G1 extended half-life monoclonal antibody that was developed to have broad neutralization against SARS-CoV, SARS-CoV-2, and other SARS-like CoVs with pandemic potential. Here we report the safety, pharmacokinetics (PK), serum viral neutralizing antibody (sVNA) titers, and immunogenicity results of the first three cohorts evaluated in the first-in-human study of adintrevimab in healthy adults. Methods This is a phase 1, randomized, placebo-controlled, single ascending-dose study of adintrevimab administered intramuscularly (IM) or intravenously (IV) to healthy adults aged ≥ 18–55 years with no current or prior SARS-CoV-2 infection. Participants were randomized 8:2 to adintrevimab or placebo in each of three dose cohorts: adintrevimab 300 mg IM (cohort 1), 500 mg IV (cohort 2), and 600 mg IM (cohort 3). Follow-up was 12 months. Blood samples were taken predose and at multiple time points postdose up to month 12 to assess sVNA, PK, and antidrug antibodies (ADAs). Results Thirty participants received a single dose of adintrevimab ( n = 24; 8 per cohort) or placebo ( n = 6). All except one adintrevimab participant in cohort 1 completed the study. No participants in any treatment arm experienced a study drug-related adverse event. Across adintrevimab-treated participants, 11 (45.8%) experienced at least one TEAE. All but one TEAE were mild in severity, and all were either viral infection or respiratory symptoms. There were no serious adverse events, discontinuations due to adverse events, or deaths. Adintrevimab exhibited a linear and dose-proportional PK profile and extended serum half-life (mean 96, 89, and 100 days in cohorts 1, 2, and 3, respectively). Participants receiving adintrevimab demonstrated dose-dependent increased sVNA titers and breadth across multiple variants. Conclusion Adintrevimab at doses of 300 mg IM, 500 mg IV, and 600 mg IM was well tolerated in healthy adults. Adintrevimab demonstrated dose-proportional exposure, rapid development of neutralizing antibody titers, and an extended half-life. Supplementary Information The online version contains supplementary material available at 10.1007/s40121-023-00794-1.

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Translational Approach for Predicting Human Pharmacokinetics of Engineered Therapeutic Monoclonal Antibodies with Increased FcRn-Binding Mutations

Translational Approach for Predicting Human Pharmacokinetics of Engineered Therapeutic Monoclonal Antibodies with Increased FcRn-Binding Mutations

Safety, Pharmacokinetics, Serum Neutralizing Titers, and Immunogenicity of Adintrevimab, a Monoclonal Antibody Targeting SARS-CoV-2: A Randomized, Double-Blind, Placebo-Controlled, Phase 1 Dose-escalation Study in Healthy Adults

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