Overcoming challenges in co-formulation of proteins with contradicting stability profiles - EPO plus G-CSF

Krieg, Dennis; Svilenov, Hristo; Gitter, Julian Hendryk; Winter, Gerhard

doi:10.1016/j.ejps.2019.105073

Cited by 5 publications

(5 citation statements)

References 33 publications

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“…Thus, a formulation must provide the means to stabilize the combined molecules against these degradation pathways, during long-term storage 17,[20][21][22] . As combination products are only recently emerging, there have been few studies into their stability in the mixture, with the aim of understanding how the multiple protein components interact and degrade during storage or in the final stages of drug product manufacturing 4,23 .…”

Section: Stability Enhancement In a Mab And Fab Coformulationmentioning

confidence: 99%

Stability enhancement in a mAb and Fab coformulation

Zhang

Dalby

2020

Sci Rep

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Multiple therapeutic proteins can be combined into a single dose for synergistic targeting to multiple sites of action. Such proteins would be mixed in dose-specific ratios to provide the correct potency for each component, and yet the formulations must also preserve their activity and keep degradation to a minimum. Mixing different therapeutic proteins could adversely affect their stability, and reduce the shelf life of each individual component, making the control of such products very challenging. In this study, a therapeutic monoclonal antibody and a related Fab fragment, were combined to investigate the impact of coformulation on their degradation kinetics. Under mildly destabilizing conditions, these proteins were found to protect each other from degradation. The protective effect appeared to originate from the interaction of Fab and IgG1 in small soluble oligomers, or through the rapid coalescence of pre-existing monomeric IgG1 nuclei into a dead-end aggregate, rather than through macromolecular crowding or diffusion-limitations.

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Section: Stability Enhancement In a Mab And Fab Coformulationmentioning

confidence: 99%

Stability enhancement in a mAb and Fab coformulation

Zhang

Dalby

2020

Sci Rep

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“…Circular dichroism (CD) can be used to assess the protein secondary and tertiary structure, as well as the thermal stability of co-formulated proteins. 73,74 For example, a mixture of two compatible mAbs exhibited a far-UV and near-UV CD spectra identical to the calculated spectrum from measurements with the individual mAbs. 42 Such measurements could provide information that the structure of the individual mAbs does not change (e.g., due to cross-interactions) when the proteins are mixed in the same solution.…”

Section: Structure and Conformational Stabilitymentioning

confidence: 60%

It is Never Too Late for a Cocktail - Development and Analytical Characterization of Fixed-dose Antibody Combinations

Krieg

Winter

Svilenov

2022

Journal of Pharmaceutical Sciences

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“…It is commonly known that freezing of solutions can result in a pH shift (30)(31)(32). pH sensitivity is a welldocumented problem for proteins (33) and AAV vectors alike (13,23). Taking this into account, all formulations used were buffered in 10 mM potassium phosphate pH 7.4 because potassium phosphate buffer causes a smaller pH shift than sodium phosphate.…”

Section: Resultsmentioning

confidence: 99%