The Evolution of Commercial Antibody Formulations

Mieczkowski, Carl

doi:10.1016/j.xphs.2023.03.026

Cited by 10 publications

(3 citation statements)

References 40 publications

Supporting

Mentioning

Contrasting

Order By: Relevance

“…Credited to favorable tolerability, safety, effectiveness, and durability [50], there has been a rapid increase of mAb use for disease treatment and prevention. As of January 2023, the Food and Drug Administration approved more than 165 mAb products for use across a variety of diseases, including rheumatoid arthritis, cancer, Crohn's disease, psoriasis, and hyperlipidemia [51], and to prevent infections such as respiratory syncytial virus (RSV) [52] and severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) [53]. As more mAbs are being developed, and increasingly used for prevention and treatment of infections, cancer, and other diseases, our investigation provides important knowledge based on a systematic analysis of five pairs of anti-HIV mAbs for the research and development of LS-formulated mAbs, especially those against HIV.…”

Section: Discussionmentioning

confidence: 99%

Impact of LS Mutation on Pharmacokinetics of Preventive HIV Broadly Neutralizing Monoclonal Antibodies: A Cross-Protocol Analysis of 16 Clinical Trials in People without HIV

Mayer,

Zhang,

deCamp

et al. 2024

Pharmaceutics

View full text Add to dashboard Cite

Monoclonal antibodies are commonly engineered with an introduction of Met428Leu and Asn434Ser, known as the LS mutation, in the fragment crystallizable region to improve pharmacokinetic profiles. The LS mutation delays antibody clearance by enhancing binding affinity to the neonatal fragment crystallizable receptor found on endothelial cells. To characterize the LS mutation for monoclonal antibodies targeting HIV, we compared pharmacokinetic parameters between parental versus LS variants for five pairs of anti-HIV immunoglobin G1 monoclonal antibodies (VRC01/LS/VRC07-523LS, 3BNC117/LS, PGDM1400/LS PGT121/LS, 10-1074/LS), analyzing data from 16 clinical trials of 583 participants without HIV. We described serum concentrations of these monoclonal antibodies following intravenous or subcutaneous administration by an open two-compartment disposition, with first-order elimination from the central compartment using non-linear mixed effects pharmacokinetic models. We compared estimated pharmacokinetic parameters using the targeted maximum likelihood estimation method, accounting for participant differences. We observed lower clearance rate, central volume, and peripheral volume of distribution for all LS variants compared to parental monoclonal antibodies. LS monoclonal antibodies showed several improvements in pharmacokinetic parameters, including increases in the elimination half-life by 2.7- to 4.1-fold, the dose-normalized area-under-the-curve by 4.1- to 9.5-fold, and the predicted concentration at 4 weeks post-administration by 3.4- to 7.6-fold. Results suggest a favorable pharmacokinetic profile of LS variants regardless of HIV epitope specificity. Insights support lower dosages and/or less frequent dosing of LS variants to achieve similar levels of antibody exposure in future clinical applications.

show abstract

Section: Discussionmentioning

confidence: 99%

Impact of LS Mutation on Pharmacokinetics of Preventive HIV Broadly Neutralizing Monoclonal Antibodies: A Cross-Protocol Analysis of 16 Clinical Trials in People without HIV

Mayer,

Zhang,

deCamp

et al. 2024

Pharmaceutics

View full text Add to dashboard Cite

show abstract

“…The pharmaceutical formulations of therapeutic proteins display a range of compositions for liquid, frozen and lyophilized forms. Relevant to the potential formation mechanisms of radicals is the fact that these formulations can generally contain several classes of compounds in addition to the protein, such as buffers, surfactants, amino acids, cryoprotectants, chelators and additional tonicifiers [1,29]. Besides the intended functions in the formulations, each of these respective components may play a role in free radical generation through its chemical properties and/or impurities, which may be introduced via chemical synthesis, purification and/or storage.…”

Section: Composition Of Pharmaceutical Formulations Of Therapeutic Pr...mentioning

confidence: 99%

Primary Processes of Free Radical Formation in Pharmaceutical Formulations of Therapeutic Proteins

Schöneich

2023

Biomolecules

View full text Add to dashboard Cite

Oxidation represents a major pathway for the chemical degradation of pharmaceutical formulations. Few specific details are available on the mechanisms that trigger oxidation reactions in these formulations, specifically with respect to the formation of free radicals. Hence, these mechanisms must be formulated based on information on impurities and stress factors resulting from manufacturing, transportation and storage. In more detail, this article focusses on autoxidation, metal-catalyzed oxidation, photo-degradation and radicals generated from cavitation as a result of mechanical stress. Emphasis is placed on probable rather than theoretically possible pathways.

show abstract

“…Although antibody therapeutics are now preferably formulated as liquid formulations, offering greater flexibility for patients, such as self-administration through pen devices [ 1 , 2 ], lyophilization remains the standard method when a particular molecule is facing stability issues [ 3 ]. Numerous reviews have been provided on the rational design of robust and optimized freeze-drying processes [ 4 , 5 , 6 , 7 ], as well as ideas for speeding up the typically lengthy process [ 8 , 9 , 10 , 11 ].…”

Section: Introductionmentioning

confidence: 99%

Microwave-Assisted Freeze–Drying: Impact of Microwave Radiation on the Quality of High-Concentration Antibody Formulations

Härdter,

Geidobler,

Presser

et al. 2023

Pharmaceutics

View full text Add to dashboard Cite

Microwave-assisted freeze-drying (MFD) offers significant time savings compared to conventional freeze-drying (CFD). While a few studies have investigated the stability of biopharmaceuticals with low protein concentrations after MFD and storage, the impact of MFD on high-concentration monoclonal antibody (mAb) formulations remains unclear. In this study, we systematically examined the effect of protein concentration in MFD and assessed protein stability following MFD, CFD, and subsequent storage using seven protein formulations with various stabilizers and concentrations. We demonstrated that microwaves directly interact with the active pharmaceutical ingredient (API), leading to decreased physical stability, specifically aggregation, in high-concentration antibody formulations. Furthermore, typically used sugar:protein ratios from CFD were insufficient for stabilizing mAbs when applying microwaves. We identified the intermediate drying phase as the most critical for particle formation, and cooling the samples provided some protection for the mAb. Our findings suggest that MFD technology may not be universally applicable to formulations well tested in CFD and could be particularly beneficial for formulations with low API concentrations requiring substantial amounts of glass-forming excipients, such as vaccines and RNA-based products.

show abstract

The Evolution of Commercial Antibody Formulations

Cited by 10 publications

References 40 publications

Impact of LS Mutation on Pharmacokinetics of Preventive HIV Broadly Neutralizing Monoclonal Antibodies: A Cross-Protocol Analysis of 16 Clinical Trials in People without HIV

Impact of LS Mutation on Pharmacokinetics of Preventive HIV Broadly Neutralizing Monoclonal Antibodies: A Cross-Protocol Analysis of 16 Clinical Trials in People without HIV

Primary Processes of Free Radical Formation in Pharmaceutical Formulations of Therapeutic Proteins

Microwave-Assisted Freeze–Drying: Impact of Microwave Radiation on the Quality of High-Concentration Antibody Formulations

Contact Info

Product

Resources

About