Highly Aggregated Antibody Therapeutics Can Enhance the in Vitro Innate and Late-stage T-cell Immune Responses

Joubert, Marisa K.; Hokom, Martha; Eakin, Catherine M.; Zhou, Lei; Deshpande, Meghana; Baker, Matthew; Goletz, Theresa J.; Kerwin, Bruce A.; Chirmule, Naren; Narhi, Linda O.; Jawa, Vibha

doi:10.1074/jbc.m111.330902

Cited by 235 publications

(299 citation statements)

References 61 publications

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“…11 In vitro techniques seem to have more predictive potential in this field and are currently being explored for studying formulation-related immunogenicity, including the role of aggregates. 10,23 In contrast, methods for in vivo prediction include the entire immune machinery and environment necessary to better simulate the extremely complex scenario that results in complete immune responses, especially when protein aggregates are involved. Thus, currently the use of animal models to predict immunogenicity in vivo seems to be the most promising approach to predict aggregate-related ADA responses.…”

Section: Size Exclusion Chromatography (Sec) It Is Clear Frommentioning

confidence: 99%

Immunogenicity of different stressed IgG monoclonal antibody formulations in immune tolerant transgenic mice

Filipe

Jiskoot

Basmeleh

et al. 2012

mAbs

140

130

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Section: Size Exclusion Chromatography (Sec) It Is Clear Frommentioning

confidence: 99%

Immunogenicity of different stressed IgG monoclonal antibody formulations in immune tolerant transgenic mice

Filipe

Jiskoot

Basmeleh

et al. 2012

mAbs

140

130

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“…16 Such irreversible aggregates can decrease protein activity and stability, and may elicit adverse immunogenic reactions in patients. [17][18][19] In addition, parenteral administration of highly viscous liquids requires thicker gauge needles that may cause more painful injections. 2 Previous work has shown that reversible self-association (RSA) between different IgG1 mAbs can result from different binding interfaces, despite high sequence similarity between the mAbs.…”

Section: Introductionmentioning

confidence: 99%

Charge-mediated Fab-Fc interactions in an IgG1 antibody induce reversible self-association, cluster formation, and elevated viscosity

Arora

Esfandiary³

et al. 2016

mAbs

103

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Concentration-dependent reversible self-association (RSA) of monoclonal antibodies (mAbs) poses a challenge to their pharmaceutical development as viable candidates for subcutaneous delivery. While the role of the antigen-binding fragment (Fab) in initiating RSA is well-established, little evidence supports the involvement of the crystallizable fragment (Fc). In this report, a variety of biophysical tools, including hydrogen exchange mass spectrometry, are used to elucidate the protein interface of such non-covalent protein-protein interactions. Using dynamic and static light scattering combined with viscosity measurements, we find that an IgG1 mAb (mAb-J) undergoes RSA primarily through electrostatic interactions and forms a monomer-dimer-tetramer equilibrium. We provide the first direct experimental mapping of the interface formed between the Fab and Fc domains of an antibody at high protein concentrations. Charge distribution heterogeneity between the positively charged interface spanning complementarity-determining regions CDR3H and CDR2L in the Fab and a negatively charged region in C H 3/Fc domain mediates the RSA of mAb-J. When arginine and NaCl are added, they disrupt RSA of mAb-J and decrease the solution viscosity. Fab-Fc domain interactions between mAb monomers may promote the formation of large transient antibody complexes that ultimately cause increases in solution viscosity. Our findings illustrate how limited specific arrangements of amino-acid residues can cause mAbs to undergo RSA at high protein concentrations and how conserved regions in the Fc portion of the antibody can also play an important role in initiating weak and transient protein-protein interactions.

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“…Protein aggregates in the size range of 0.1-10 µm are believed to be the most immunogenic (33). Recently, new animal testing methods have been developed that together with in-silico predication models, can provide additional help to explain potential immunogenicity (34,35).…”

Section: Unwanted Immunogenicity Of Biologicals That Contain Monoclonmentioning

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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Highly Aggregated Antibody Therapeutics Can Enhance the in Vitro Innate and Late-stage T-cell Immune Responses

Cited by 235 publications

References 61 publications

Immunogenicity of different stressed IgG monoclonal antibody formulations in immune tolerant transgenic mice

Immunogenicity of different stressed IgG monoclonal antibody formulations in immune tolerant transgenic mice

Charge-mediated Fab-Fc interactions in an IgG1 antibody induce reversible self-association, cluster formation, and elevated viscosity

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

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