Development challenges of high concentration monoclonal antibody formulations

Kollár, Éva; Balázs, Boglárka; Tari, Tímea; Siró, István

doi:10.1016/j.ddtec.2020.08.005

Cited by 21 publications

(17 citation statements)

References 53 publications

Supporting

Mentioning

Contrasting

Order By: Relevance

“…However, CTK may be considered a potential critical quality attribute (pCQA) for subcutaneous (SC) administration. SC administration, an increasingly attractive alternative to IV administration for therapeutic antibodies, , replaces lengthy and costly infusions and enables at-home or even self-administrations , (a key benefit especially in the midst of a global coronavirus pandemic). SC administration raises additional pharmacokinetic (PK) concerns for drug development though because of incomplete bioavailability, where only a fraction of the dosed material successfully transports into circulation. , For instance, prior studies alluded to a relationship between the introduction of multiple positive charges and a decrease in SC bioavailability, , with plausible mechanisms including ionic interactions with the net negatively charged SC space , and/or increased first-pass catabolism by hematopoietic cells. , Although the exact mechanisms governing incomplete bioavailability are not fully understood, positively charged modifications such as CTK may be broadly and conservatively classified as adversely impacting SC PK based on the above findings.…”

Section: Introductionmentioning

confidence: 88%

Section: ■ Introductionmentioning

confidence: 99%

See 1 more Smart Citation

C-Terminal Lysine Processing of IgG in Human Suction Blister Fluid: Implications for Subcutaneous Administration

Ayalew¹,

Chan

Hu³

et al. 2022

Mol. Pharmaceutics

View full text Add to dashboard Cite

C-terminal lysine (CTK) is often classified as a potential critical quality attribute for therapeutic antibodies being developed for subcutaneous (SC) administration because of its potential to impact antibody SC bioavailability/pharmacokinetics (PK). This classification both inflates development costs and increases comparability risks for SC administration of antibodies. However, prior risk assessments of CTK have not fully considered biotransformation of CTK in the SC space, which may play an important role given that circulating carboxypeptidases in humans rapidly process CTK on intravenously administered antibodies. Here, CTK biotransformation in biofluid derived from human SC space was investigated. The representative fluid from the human SC space was sampled from 10 healthy human subjects using the suction blister method. Glycosylated antibody containing high levels of CTK (expressed using a carboxypeptidase D CRISPR/Cas9 knockout CHO cell line) was incubated in the collected suction blister fluids (SBFs), recovered using cognate antigen pulldowns, and characterized for remaining CTK levels using intact and reduced liquid chromatography−mass spectrometry (LC−MS) analysis. CTK processing (i.e., carboxypeptidase activity) was evident in all SBF and exhibited first-order kinetics with rate constants of 2.18 ± 0.57 d −1 (at 37 °C). PK simulations that integrated CTK processing pathways and their associated rate constants were subsequently performed using a range of clinically observed PK parameters for therapeutic antibodies, including atezolizumab-and pertuzumab-specific parameters. The impact of CTK content (even up to 100%) on SC PK outcomes such as bioavailability and C trough were modest (<14%) for all combinations of PK parameters tested in the sensitivity analysis. This study forms the cornerstone data package for derisking CTK as a PK liability for antibody SC programs and highlights the usefulness of fully considering biotransformation during product quality criticality assessments.

show abstract

Section: Introductionmentioning

confidence: 88%

Section: ■ Introductionmentioning

confidence: 99%

C-Terminal Lysine Processing of IgG in Human Suction Blister Fluid: Implications for Subcutaneous Administration

Ayalew¹,

Chan

Hu³

et al. 2022

Mol. Pharmaceutics

View full text Add to dashboard Cite

show abstract

“…Challenges of SC preparation formulation are related to the final product manufacturing, stability assurance as well as injectability of the medicine. 17 SC formulations are manufactured as liquid preparations in self-administration devices, so lower stability is expected and hence a shorter shelf-life. Also, a small number of buffers and excipients are approved for these types of formulations.…”

Section: Comparison Of IV and Sc Administration Routesmentioning

confidence: 99%

Pharmacokinetic characterization, benefits and barriers of subcutaneous administration of monoclonal antibodies in oncology

Homšek

Spasić

Nikolić

et al. 2022

J Oncol Pharm Pract

View full text Add to dashboard Cite

Objective Therapeutic monoclonal antibodies in oncology are slowly becoming the dominant treatment option for many different cancer types. The main route of administration, infusion, requires extensive product preparations, patient hospitalization and close monitoring. Patient comfort improvement, staff workload reduction and cost savings dictated the development of subcutaneous formulations. The aim of this review is to present pharmacokinetic characteristics of subcutaneous products, discuss the differences between intravenous and subcutaneous routes and to point out the advantages as well as challenges of administration route shift from the formulation development and pharmacometric angle. Data sources Food and Drug administration's Purple book database and electronic medicines compendium were used to identify monoclonal antibodies in oncology approved as subcutaneous forms. Using keywords subcutaneous, monoclonal antibodies, pharmacokinetics, model, as well as specific drugs previously identified, both PubMed and ScienceDirect databases were researched. Data summary There are currently six approved subcutaneous onco-monoclonal antibodies on the market. For each of them, exposure to the drug was similar in relation to infusion, treatment effectiveness was the same, administration was well tolerated by the patients and costs of the medical service were reduced. Conclusion Development of subcutaneous forms for existing and emerging new monoclonal antibodies for cancer treatment as well as shifting from administration via infusion should be encouraged due to patient preference, lower costs and overall lack of substantial differences in efficacy and safety between the two routes.

show abstract

“…5 Protein solutions, such as recombinant globular proteins and therapeutic monoclonal antibodies, are routinely formulated and subcutaneously administered at high concentrations (>50 mg/mL) due to potency concerns. 6 Undesirable high viscosity is a common occurrence in high-concentration formulations/ injections, which may even alter or render the drug ineffective. 7 Numerous variables other than the concentration, related to either the protein biomolecule (surface charge, shape, and molecular and charge anisotropy) or solution conditions (salt concentration, pH, solvent viscosity, and temperature) can further affect the protein solution viscosity.…”

Section: Introductionmentioning

confidence: 99%

“…Protein solutions, such as recombinant globular proteins and therapeutic monoclonal antibodies, are routinely formulated and subcutaneously administered at high concentrations (>50 mg/mL) due to potency concerns . Undesirable high viscosity is a common occurrence in high-concentration formulations/injections, which may even alter or render the drug ineffective .…”

Section: Introductionmentioning

confidence: 99%

Application of a Simple Short-Range Attraction and Long-Range Repulsion Colloidal Model toward Predicting the Viscosity of Protein Solutions

Virk

Underhill

2022

Mol. Pharmaceutics

View full text Add to dashboard Cite

Some hard-sphere colloidal models have been criticized for inaccurately predicting the solution viscosity of complex biological molecules like proteins. Competing short-range attractions and long-range repulsions, also known as short-range attraction and long-range repulsion (SALR) interactions, have been thought to affect the microstructure of a protein solution at low to moderate ionic strength. However, such interactions have been implicated primarily in causing phase transition, protein gelation, or reversible cluster formation, and their effect on protein solution viscosity change is not fully understood. In this work, we show the application of a hard-sphere colloidal model with SALR interactions toward predicting the viscosity of dilute to semi-dilute protein solutions. The comparison is performed for a globular-shaped albumin and Y-shaped therapeutic monoclonal antibody that are not explained by previous colloidal models. The model predictions show that it is the coupling between attractions and repulsions that gives rise to the observed experimental trends in solution viscosity as a function of pH, concentration, and ionic strength. The parameters of the model are obtained from measurements of the second virial coefficient and net surface charge/zeta-potential, without additional fitting of the viscosity.

show abstract

Development challenges of high concentration monoclonal antibody formulations

Cited by 21 publications

References 53 publications

C-Terminal Lysine Processing of IgG in Human Suction Blister Fluid: Implications for Subcutaneous Administration

C-Terminal Lysine Processing of IgG in Human Suction Blister Fluid: Implications for Subcutaneous Administration

Pharmacokinetic characterization, benefits and barriers of subcutaneous administration of monoclonal antibodies in oncology

Application of a Simple Short-Range Attraction and Long-Range Repulsion Colloidal Model toward Predicting the Viscosity of Protein Solutions

Contact Info

Product

Resources

About