Investigating High-Concentration Monoclonal Antibody Powder Suspension in Nonaqueous Suspension Vehicles for Subcutaneous Injection

Bowen, Mayumi; Armstrong, Nick; Maa, Yuh‐Fun

doi:10.1002/jps.23324

Cited by 47 publications

(22 citation statements)

References 34 publications

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“…The viscosity increases for aggregated samples ranged from 0.1 to ~2 cP, which is a small viscosity increase compared those observed elsewhere: (i) due to non-native aggregation of monoclonal antibodies [22]; (ii) solution non-idealities due to monomer protein-protein interactions of native antibodies at high concentrations (~ 15 w/v %) [3]; (iii) at high concentrations (~ 30 w/v %) for other globular proteins [52].…”

Section: Accepted Manuscriptmentioning

confidence: 54%

“…For protein-based therapeutics, the presence of aggregates during drug administration has the potential to induce an immune response and possibly jeopardize drug effectiveness and patient safety [1]. Recently, high protein-concentration formulations have been a growing focus area due to the low-volume dosing requirement for subcutaneous administration [2,3]. At high protein concentrations, non-ideal proteinprotein interactions may give rise to reversible, self-associated protein states and increases in solution viscosity [4].…”

Section: Introductionmentioning

confidence: 99%

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Aggregate structure, morphology and the effect of aggregation mechanisms on viscosity at elevated protein concentrations

Barnett

Wei

Amin

et al. 2015

Biophysical Chemistry

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Non-native aggregation is a common issue in a number of degenerative diseases and during manufacturing of protein-based therapeutics. There is a growing interest to monitor protein stability at intermediate to high protein concentrations, which are required for therapeutic dosing of subcutaneous injections. An understanding of the impact of protein structural changes and interactions on the protein aggregation mechanisms and resulting aggregate size and morphology may lead to improved strategies to reduce aggregation and solution viscosity. This report investigates non-native aggregation of a model protein, α-chymotrypsinogen, under accelerated conditions at elevated protein concentrations. Far-UV circular dichroism and Raman scattering show structural changes during aggregation. Size exclusion chromatography and laser light scattering are used to monitor the progression of aggregate growth and monomer loss. Monomer loss is concomitant with increased β-sheet structures as monomers are added to aggregates, which illustrate a transition from a native monomeric state to an aggregate state. Aggregates grow predominantly through monomer-addition, resulting in a semi-flexible polymer morphology. Analysis of aggregation growth kinetics shows that pH strongly affects the characteristic timescales for nucleation (τn) and growth (τg), while the initial protein concentration has only minor effects on τn or τg. Low-shear viscosity measurements follow a common scaling relationship between average aggregate molecular weight (Mw(agg)) and concentration (σ), which is consistent with semi-dilute polymer-solution theory. The results establish a link between aggregate growth mechanisms, which couple Mw(agg) and σ, to increases in solution viscosity even at these intermediate protein concentrations (less than 3w/v %).

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Section: Accepted Manuscriptmentioning

confidence: 54%

Section: Introductionmentioning

confidence: 99%

Aggregate structure, morphology and the effect of aggregation mechanisms on viscosity at elevated protein concentrations

Barnett

Wei

Amin

et al. 2015

Biophysical Chemistry

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show abstract

“…We realize that real‐time stability studies are obviously the most reliable demonstration of a product's shelf life, and accelerated storage testing, based on the Arrhenius equation, is a practical means of quality assurance for biological standards . However, we chose to use a simpler test for preliminary analysis, which has been previously described in the literature . Briefly, ∼30 mg of dried Microglassified™ lysozyme prepared in n ‐pentanol was aliquoted in glass vials and secured with rubber‐lined plastic caps.…”

Section: Methodsmentioning

confidence: 99%

Enzyme Dehydration Using Microglassification™ Preserves the Protein's Structure and Function

Aniket

Gaul

Bitterfield

et al. 2015

Journal of Pharmaceutical Sciences

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Controlled enzyme dehydration using a new processing technique of Microglassification™ has been investigated. Aqueous solution microdroplets of lysozyme, α-chymotrypsin, catalase, and horseradish peroxidase were dehydrated in n-pentanol, n-octanol, n-decanol, triacetin, or butyl lactate, and changes in their structure and function were analyzed upon rehydration. Water solubility and microdroplet dissolution rate in each solvent decreased in the order: butyl lactate > n-pentanol > triacetin > n-octanol > n-decanol. Enzymes Microglassified™ in n-pentanol retained higher activity (93%-98%) than n-octanol (78%-85%) or n-decanol (75%-89%), whereas those Microglassified™ in triacetin (36%-75%) and butyl lactate (48%-79%) retained markedly lower activity. FTIR spectroscopy analyses showed α-helix to β-sheet transformation for all enzymes upon Microglassification™, reflecting a loss of bound water in the dried state; however, the enzymes reverted to native-like conformation upon rehydration. Accelerated stressed-storage tests using Microglassified™ lysozyme showed a significant (p < 0.01) decrease in enzymatic activity from 46,560 ± 2736 to 31,060 ± 4327 units/mg after 3 months of incubation; however, it was comparable to the activity of the lyophilized formulation throughout the test period. These results establish Microglassification™ as a viable technique for enzyme preservation without affecting its structure or function.

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“…However, lyophilization is also harmful to the protein structure by nature of the processes of freezing, drying, and redissolution. Thus, novel concentration methods have been demanded for high-concentration protein solutions, such as gelation [10,11], crystallization [12], liquid-liquid separation [13], and spray drying [14,15].…”

Section: Introductionmentioning

confidence: 99%

Aggregative protein–polyelectrolyte complex for high-concentration formulation of protein drugs

Kurinomaru

Shiraki

2017

International Journal of Biological Macromolecules

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Investigating High-Concentration Monoclonal Antibody Powder Suspension in Nonaqueous Suspension Vehicles for Subcutaneous Injection

Cited by 47 publications

References 34 publications

Aggregate structure, morphology and the effect of aggregation mechanisms on viscosity at elevated protein concentrations

Aggregate structure, morphology and the effect of aggregation mechanisms on viscosity at elevated protein concentrations

Enzyme Dehydration Using Microglassification™ Preserves the Protein's Structure and Function

Aggregative protein–polyelectrolyte complex for high-concentration formulation of protein drugs

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