Protein–excipient interactions: Mechanisms and biophysical characterization applied to protein formulation development

Kamerzell, Tim J.; Esfandiary, Reza; Joshi, Sangeeta B.; Middaugh, C. Russell; Volkin, David B.

doi:10.1016/j.addr.2011.07.006

Cited by 434 publications

(358 citation statements)

References 516 publications

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“…[35][36][37] These sugars have been exploited extensively as pharmaceutical excipients in liquid as well as lyophilized formulations of therapeutic proteins. 35,36,38,39 Although sucrose can slowly hydrolyze to fructose and glucose under acidic conditions, potentially leading to nonenzymatic glycation of proteins, this degradation pathway could be a lesser concern in a Sm-TSP-2 formulation if it is formulated at neutral pH and/or subsequently lyophilized to a dried cake at a low water content. 27 Sorbitol and trehalose appeared to be better alternatives as stabilizing excipients, since they are unlikely to display chemical reactivity of sucrose, yet have comparable ability to physically stabilize Sm-TSP-2.…”

Section: Discussionmentioning

confidence: 99%

Biophysical and formulation studies of theSchistosoma mansoniTSP-2 extracellular domain recombinant protein, a lead vaccine candidate antigen for intestinal schistosomiasis

Cheng¹,

Curti²,

Rezende³

et al. 2013

Human Vaccines & Immunotherapeutics

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Section: Discussionmentioning

confidence: 99%

Biophysical and formulation studies of theSchistosoma mansoniTSP-2 extracellular domain recombinant protein, a lead vaccine candidate antigen for intestinal schistosomiasis

Cheng¹,

Curti²,

Rezende³

et al. 2013

Human Vaccines & Immunotherapeutics

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“…Extensive efforts have been devoted to the development of excipients for use in the formulation of proteins to confer improved stability (4). Excipients commonly used in the formulation of protein drugs include salts, sugars, amino acids, nonionic surfactants, chelators, antimicrobial preservatives, carrier proteins, and polymers (5). An alternate approach to promote stability or modify pharmacological activity of protein drugs is through direct chemical modification with a prosthetic functional group, commonly a synthetic polymer such as poly(ethylene glycol) (PEG) or a saturated alkyl segment (6)(7)(8)(9).…”

mentioning

confidence: 99%

Supramolecular PEGylation of biopharmaceuticals

Webber

Appel

Vinciguerra

et al. 2016

Proc. Natl. Acad. Sci. U.S.A.

187

262

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The covalent modification of therapeutic biomolecules has been broadly explored, leading to a number of clinically approved modified protein drugs. These modifications are typically intended to address challenges arising in biopharmaceutical practice by promoting improved stability and shelf life of therapeutic proteins in formulation, or modifying pharmacokinetics in the body. Toward these objectives, covalent modification with poly(ethylene glycol) (PEG) has been a common direction. Here, a platform approach to biopharmaceutical modification is described that relies on noncovalent, supramolecular host-guest interactions to endow proteins with prosthetic functionality. Specifically, a series of cucurbit [7]uril (CB [7])-PEG conjugates are shown to substantially increase the stability of three distinct protein drugs in formulation. Leveraging the known and high-affinity interaction between CB [7] and an N-terminal aromatic residue on one specific protein drug, insulin, further results in altering of its pharmacological properties in vivo by extending activity in a manner dependent on molecular weight of the attached PEG chain. Supramolecular modification of therapeutic proteins affords a noncovalent route to modify its properties, improving protein stability and activity as a formulation excipient. Furthermore, this offers a modular approach to append functionality to biopharmaceuticals by noncovalent modification with other molecules or polymers, for applications in formulation or therapy. supramolecular chemistry | protein engineering | drug delivery | protein formulation

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“…The native conformation of proteins in a medicinal product is usually protected by the addition of stabilisers. Oxidation reactions are catalysed by free radicals, light, and trace amounts of metal ions (4)(5)(6)(7)(8). Many studies have confirmed that oxidation of cysteine or methionine in the Fc region can alter the effector functions of mAbs, and decrease their binding to Fc receptors on immune cells (9,10).…”

Section: Chemical Instabilitymentioning

confidence: 99%

“…Here, excipients are used to maintain the pH (e.g., Tris, acetate, histidine, citrate buffers), to enhance the protein stability and prevent oxidation (e.g., sugars, polyols), to achieve an appropriate viscosity, or to bind metal ions and free radicals (e.g., chelators, antioxidants). Their addition can therefore stabilise solutions or lyophilisates (see section 3.2) over long periods of time (6).…”

Section: Protein Stabilisation In Pharmaceutical Formsmentioning

confidence: 99%

The importance of handling high-value biologicals: Physico-chemical instability and immunogenicity of monoclonal antibodies (Review)

Laptos

Omersel

2018

Exp Ther Med

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Abstract. The present review specifies the various chemical and physical factors that can influence drug stability and immunogenicity, and the treatment outcomes of antibody biologicals. Although monoclonal antibodies (mAbs) are known to be more resistant to environmental changes compared with other proteins, the molecules themselves can be subjected to chemical and physical processes that promote their degradation and transformation into their specific amino-acid moieties. With increasing use of medicinal products that contain mAbs, and their self-administration by the patients, the issue of the correct manipulation of these drugs is of increasing importance. This review summarises the correct handling of mAb biologicals from the point of view of the pharmacist, clinical biochemist and patient, as is supported by relevant cases from the literature and our own data and experience. In particular, if there is a break in the cold chain, both healthcare professionals and patients need to be aware of the potential pharmacokinetics and pharmacodynamics alterations to these biologicals. Furthermore, any alterations in the protein structure can induce harmful immune reactions, including anaphylaxis and cytokine storms, or result in the production of neutralising or blocking Abs. Overall, considering also that treatment costs usually remain high, drug stability can have a tremendous effect on the clinical, humanistic and economic outcomes of such treatments. IntroductionMonoclonal antibodies (mAbs) have revolutionised the treatment of oncological and autoimmune diseases over the past 10 years. Moreover, they are also successfully used in the management of asthma, hypersensitivity reactions, osteoporosis, skeletal-related events in patients with bone metastases from solid tumours, neovascular (wet) age-related macular degeneration, hyperlipidaemia, and many others. According to data from the U.S. National Institutes of Health and other publications, various ongoing clinical studies look promising for indications like Alzheimer's disease, infections, and type-1 diabetes (1,2).According to our local drug registration database (EU-Slovenia), there are currently 64 medical products that contain 40 active mAbs (data retrieved in November 2017). Among these, 39 are intended for intravenous administration, 22 for subcutaneous, and one each for intramuscular and intravitreal administration. For their pharmaceutical forms, 50 are solutions or concentrates for solution, 13 are in the form of powder for solutions, and one is a kit for radiopharmaceutical preparations for infusion. The data from the Agency for Medicines and Medical Devices of the Republic of Slovenia show a wide spectrum of the designs, forms and routes of administration of pharmaceutical drugs. In the earlier years of clinical use, these preparations were compounded by healthcare professionals in controlled environments, and administered in healthcare facilities. However, with the introduction of TNF-α inhibitors in pre-filled syringes in the last 10 years, medicin...

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Protein–excipient interactions: Mechanisms and biophysical characterization applied to protein formulation development

Cited by 434 publications

References 516 publications

Biophysical and formulation studies of theSchistosoma mansoniTSP-2 extracellular domain recombinant protein, a lead vaccine candidate antigen for intestinal schistosomiasis

Biophysical and formulation studies of theSchistosoma mansoniTSP-2 extracellular domain recombinant protein, a lead vaccine candidate antigen for intestinal schistosomiasis

Supramolecular PEGylation of biopharmaceuticals

The importance of handling high-value biologicals: Physico-chemical instability and immunogenicity of monoclonal antibodies (Review)

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