Impact of Product-Related Factors on Immunogenicity of Biotherapeutics

Singh, Satish Kumar

doi:10.1002/jps.22276

Cited by 350Biosimilars and Bioanalytical MethodsProtein purification and stabilityMonoclonal and Polyclonal Antibodies Research

Impact of Product-Related Factors on Immunogenicity of Biotherapeutics

Singh, Satish Kumar·2011·Journal of Pharmaceutical Sciences

DOI 10.1002/jps.22276

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Abstract

All protein therapeutics have the potential to be immunogenic. Several factors, including patient characteristics, disease state, and the therapy itself, influence the generation of an immune response. Product-related factors such as the molecule design, the expression system, post-translational modifications, impurities, contaminants, formulation and excipients, container, closure, as well as degradation products are all implicated. However, a critical examination of the available data shows that clear unequivocal evidence for the impact of these latter factors on clinical immunogenicity is lacking. No report could be found that clearly deconvolutes the clinical impact of the product attributes on patient susceptibility. Aggregation carries the greatest concern as a risk factor for immunogenicity, but the impact of aggregates is likely to depend on their structure as well as on the functionality (e.g., immunostimulatory or immunomodulatory) of the therapeutic. Preclinical studies are not yet capable of assessing the clinically relevant immunogenicity potential of these product-related factors. Simply addressing these risk factors as part of product development will not eliminate immunogenicity. Minimization of immunogenicity has to begin at the molecule design stage by reducing or eliminating antigenic epitopes and building in favorable physical and chemical properties.

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Sequence alone is not a reliable predictor of immunogenicity; determinants of immunogenicity include product characteristics such as oxidation and deamidation sites, as well as target biology, patient population, dosing routes, and regimen.
“However, sequence alone is not a reliable predictor of immunogenicity. Determinants of immunogenicity include product characteristics such as oxidation and deamidation sites, as well as target biology, patient population, dosing routes, and regimen.47”
From Tutorial on monoclonal antibody pharmacokinetics and its considerations in early development (2018) · cites this paper as [47]
Generation of ADAs is a multi-factorial issue and depends upon patients' genetic background and disease history as well as quality attributes of the protein therapeutics, particularly presence of aggregates and other degradants even in very minute quantities.
“Generation of ADAs is a multi-factorial issue and depends upon patients genetic background and disease history as well as quality attributes of the protein therapeutics, particularly, presence of aggregates and other degradants even in very minute quantities [190, 191].”
From Computational approaches to therapeutic antibody design: established methods and emerging trends (2020) · cites this paper as [191]

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Correlation between Factor VIII Genotype and Inhibitor Development in Hemophilia A
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Immunogenicity and tolerability of an investigational formulation of interferon-β1a: 24- and 48-week interim analyses of a 2-year, single-arm, historically controlled, phase IIIb study in adults with multiple sclerosis
Giovannoni, G., Барбараш, О. Л., Casset‐Semanaz, F., Jaber, A., King, J. O., Metz, L. M., Pardo, G., Simsarian, J., Sørensen, P. S., & Stubinski, B. (2007) · Clinical Therapeutics · doi:10.1016/j.clinthera.2007.06.002 · Cited by 55 · see citing works
Antibodies to Covalent Aggregates of Insulin in Blood of Insulin-Using Diabetic Patients
Robbins, D. C., Cooper, S. M., Fineberg, S. E., & Mead, P. M. (1987) · Diabetes · doi:10.2337/diab.36.7.838 · Cited by 53 · see citing works
Interleukin-2: evaluation of routes of administration and current delivery systems in cancer therapy.
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Development of antibodies to interferon beta in patients: technical and biological aspects.
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Immunogenicity of rDNA-derived pharmaceuticals
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Role of Glycosylation in Conformational Stability, Activity, Macromolecular Interaction and Immunogenicity of Recombinant Human Factor VIII
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Neutralizing and Binding Antibodies to IFN- β : Relative Frequency in Relapsing-Remitting Multiple Sclerosis Patients Treated with Different IFN- β Preparations
Scagnolari, C., Bellomi, F., Turriziani, O., Bagnato, F. R., Tomassini, V., Lavolpe, V., Ruggieri, M., Bruschi, F., Meucci, G., Dicuonzo, G., et al. (2002) · Journal of Interferon & Cytokine Research · doi:10.1089/107999002753536176 · Cited by 51 · see citing works

Flagged first, then by citations

7 of the 290 references couldn’t be matched to a known paper.

Sorted by citations

Protein Interactions with Polymer Coatings and Biomaterials
Wei, Q., Becherer, T., Angioletti‐Uberti, S., Dzubiella, J., Wischke, C., Neffe, A. T., Lendlein, A., Ballauff, M., & Haag, R. (2014) · Angewandte Chemie International Edition · doi:10.1002/anie.201400546 · Cited by 745 · see citing works
Microneedle technologies for (trans)dermal drug and vaccine delivery
van der Maaden, K., Jiskoot, W., & Bouwstra, J. A. (2012) · Journal of Controlled Release · doi:10.1016/j.jconrel.2012.01.042 · Cited by 657 · see citing works
“Furthermore, unwanted immunogenicity can lead to total loss of the therapeutic effect of a protein by neutralizing antibodies, and may even lead to depletion of endogenous proteins or breaking the immune-tolerance to self-antigens [145-150].”
Background
Immunogenicity of therapeutic proteins: Influence of aggregation
Ratanji, K. D., Derrick, J. P., Dearman, R. J., & Kimber, I. (2013) · Journal of Immunotoxicology · doi:10.3109/1547691x.2013.821564 · Cited by 596 · see citing works
“such as the dosing regimen, patient related factors such as MHC variants, or product related factors such as product design (Singh, 2011).”
Background
Analytical tools for characterizing biopharmaceuticals and the implications for biosimilars
Berkowitz, S. A., Engen, J. R., Mazzeo, J. R., & Jones, G. B. (2012) · Nature Reviews Drug Discovery · doi:10.1038/nrd3746 · Cited by 537 · see citing works
Aggregates in monoclonal antibody manufacturing processes
Vázquez‐Rey, M., & Lang, D. (2011) · Biotechnology and Bioengineering · doi:10.1002/bit.23155 · Cited by 480 · see citing works
Physicochemical Stability of Monoclonal Antibodies: A Review
Basle, Y. L., Chennell, P., Tokhadzé, N., Astier, A., & Sautou, V. (2019) · Journal of Pharmaceutical Sciences · doi:10.1016/j.xphs.2019.08.009 · Cited by 437 · see citing works
The pharmacology and therapeutic applications of monoclonal antibodies
Castelli, S., McGonigle, P., & Hornby, P. J. (2019) · Pharmacology Research & Perspectives · doi:10.1002/prp2.535 · Cited by 371 · see citing works
Tutorial on monoclonal antibody pharmacokinetics and its considerations in early development
Ovacik, M., & Lin, K. (2018) · Clinical and Translational Science · doi:10.1111/cts.12567 · Cited by 299 · see citing works
T-cell dependent immunogenicity of protein therapeutics: Preclinical assessment and mitigation
Jawa, V., Cousens, L. P., Awwad, M., Wakshull, E., Kropshofer, H., & Groot, A. S. D. (2013) · Clinical Immunology · doi:10.1016/j.clim.2013.09.006 · Cited by 271 · see citing works
“factors intrinsic to the final drug product itself that contribute to immunogenicity, may include modifications in the glycosylation profile [18–20], biophysical and biochemical attributes [21–24], or factors introduced during formulation [14,20,25,26].”
Background
Highly Aggregated Antibody Therapeutics Can Enhance the in Vitro Innate and Late-stage T-cell Immune Responses
Joubert, M. K., Hokom, M. M., Eakin, C. M., Zhou, L., Deshpande, M., Baker, M., Goletz, T. J., Kerwin, B. A., Chirmule, N., Narhi, L. O., et al. (2012) · Journal of Biological Chemistry · doi:10.1074/jbc.m111.330902 · Cited by 268 · see citing works
Immunogenicity of protein aggregates—Concerns and realities
Wang, W., Singh, S. K., Li, N., Toler, M. R., King, K. R., & Nema, S. (2012) · International Journal of Pharmaceutics · doi:10.1016/j.ijpharm.2012.04.040 · Cited by 268 · see citing works
Self-citation
A phase III randomised, double-blind, parallel-group study comparing SB4 with etanercept reference product in patients with active rheumatoid arthritis despite methotrexate therapy
Emery, P., Vencovský, J., Sylwestrzak, A., Leszczyński, P., Porawska, W., Baranauskaitė, A., Tseluyko, V., Ждан, В. М., Stasiuk, B., Milasiene, R., et al. (2015) · Annals of the Rheumatic Diseases · doi:10.1136/annrheumdis-2015-207588 · Cited by 231 · see citing works
Antigenic liposomes displaying CD22 ligands induce antigen-specific B cell apoptosis.
Macauley, M. S., Pfrengle, F., Rademacher, C., Nycholat, C. M., Gale, A., von Drygalski, A., & Paulson, J. (2013) · Journal of Clinical Investigation · doi:10.1172/jci69187 · Cited by 206 · see citing works
“Introduction Unwanted humoral immune responses to protein antigens are responsible for numerous medical conditions in the areas of autoimmunity (1), transplantation (2), allergies (3), and biotherapeutics (4).”
Immunogenicity of Biotherapeutics: Causes and Association with Posttranslational Modifications
Kuriakose, A., Chirmule, N. B., & Nair, P. (2016) · Journal of Immunology Research · doi:10.1155/2016/1298473 · Cited by 231 · see citing works
“Due to the lack of affinity maturation, this pathway typically results in an IgM-type response, which is transient, of low titer, and of poor specificity [72].”
Influential
Computational approaches to therapeutic antibody design: established methods and emerging trends
Norman, R. A., Ambrosetti, F., Bonvin, A. M. J. J., Colwell, L. J., Kelm, S., Kumar, S., & Krawczyk, K. (2020) · Briefings in Bioinformatics · doi:10.1093/bib/bbz095 · Cited by 219 · see citing works
“therapeutics, particularly, presence of aggregates and other degradants even in very minute quantities [190, 191].”
Background
Quality Attributes of Recombinant Therapeutic Proteins: An Assessment of Impact on Safety and Efficacy as Part of a Quality by Design Development Approach
Eon‐Duval, A., Broly, H., & Gleixner, R. (2012) · Biotechnology Progress · doi:10.1002/btpr.1548 · Cited by 218 · see citing works
“Oligomannose or high mannose forms are not normally found on IgGs in human serum(107) but are usually present at low levels (up to 15%)(109) on recombinant proteins produced in commonly used mammalian cell expression systems and may, therefore, be immunogenic in humans, although no such cases have been reported.(101)…”
BackgroundInfluential
Emerging Strategies for Developing Next-Generation Protein Therapeutics for Cancer Treatment
Kintzing, J. R., Interrante, M. V. F., & Cochran, J. R. (2016) · Trends in Pharmacological Sciences · doi:10.1016/j.tips.2016.10.005 · Cited by 192 · see citing works
The future of host cell protein (HCP) identification during process development and manufacturing linked to a risk‐based management for their control
Bracewell, D. G., Francis, R., & Smales, C. M. (2015) · Biotechnology and Bioengineering · doi:10.1002/bit.25628 · Cited by 187 · see citing works
Challenges and approaches for the development of safer immunomodulatory biologics
Sathish, J. G., Sethu, S., Bielsky, M.-C., de Haan, L., French, N. S., Govindappa, K., Green, J., Griffiths, C. E. M., Holgate, S. T., Jones, D., et al. (2013) · Nature Reviews Drug Discovery · doi:10.1038/nrd3974 · Cited by 186 · see citing works
Influence of N-glycosylation on effector functions and thermal stability of glycoengineered IgG1 monoclonal antibody with homogeneous glycoforms
Wada, R., Matsui, M., & Kawasaki, N. (2019) · mAbs · doi:10.1080/19420862.2018.1551044 · Cited by 186 · see citing works
“Closely related to the protein stability, the propensity towards protein aggregation is another important attribute that can be caused by protein instability, and it also needs to be considered because of the risk of immunogenicity.(26,27) Despite the recent efforts to elucidate the effect of the N-glycan on various a…”
Background
Identification and characterization of host cell protein product‐associated impurities in monoclonal antibody bioprocessing
Levy, N. E., Valente, K. N., Choe, L. H., Lee, K. H., & Lenhoff, A. M. (2013) · Biotechnology and Bioengineering · doi:10.1002/bit.25158 · Cited by 185 · see citing works
Challenges and Opportunities for the Subcutaneous Delivery of Therapeutic Proteins
Turner, M. R., & Balu‐Iyer, S. V. (2018) · Journal of Pharmaceutical Sciences · doi:10.1016/j.xphs.2018.01.007 · Cited by 177 · see citing works
Minimizing immunogenicity of biopharmaceuticals by controlling critical quality attributes of proteins
van Beers, M. M. C., & Bardor, M. (2012) · Biotechnology Journal · doi:10.1002/biot.201200065 · Cited by 172 · see citing works
“Yet, it is believed that PEGylation is more likely to reduce the immunogenicity of non-human proteins [13].”
Background
Effects of Surfaces and Leachables on the Stability of Biopharmaceuticals
Bee, J. S., Randolph, T. W., Carpenter, J. F., Bishop, S. M., & Dimitrova, M. N. (2011) · Journal of Pharmaceutical Sciences · doi:10.1002/jps.22597 · Cited by 160 · see citing works
Antibody Aggregation: Insights from Sequence and Structure
Li, W., Prabakaran, P., Chen, W., Zhu, Z., Feng, Y., & Dimitrov, D. S. (2016) · Antibodies · doi:10.3390/antib5030019 · Cited by 152 · see citing works
“Furthermore, antibody aggregation is highly undesirable, because it could compromise biological functions [12], induce immune responses by breaking B-cell tolerance [23,24] and evoke antibody clearance machinery in vivo [25].”
Background
Modulating the immune system through nanotechnology
Dacoba, T. G., Ana, O., Torres, D., Crecente‐Campo, J., & Alonso, M. J. (2017) · Seminars in Immunology · doi:10.1016/j.smim.2017.09.007 · Cited by 146 · see citing works
“Finally, the administration route [300,301] and patient-related issues, such as genetic predisposition to ADAs formation or cytokine pattern, could impact immunogenicity [302,303].”
Immunogenicity to Biologics: Mechanisms, Prediction and Reduction
Sethu, S., Govindappa, K., Alhaidari, M., Pirmohamed, M., Park, K., & Sathish, J. G. (2012) · Archivum Immunologiae et Therapiae Experimentalis · doi:10.1007/s00005-012-0189-7 · Cited by 148 · see citing works
“ADAs consist of low titre, transient IgM; high titre, persistent IgG (IgG1–IgG4) or IgE immunoglobulin isotypes (Baker et al. 2010; Baker and Jones 2007; Jefferis 2007; Singh 2011).”
BackgroundInfluential
Use of In Vitro Assays to Assess Immunogenicity Risk of Antibody-Based Biotherapeutics
Joubert, M. K., Deshpande, M., Yang, J., Reynolds, H., Bryson, C. J., Fogg, M. H., Baker, M., Herskovitz, J., Goletz, T. J., Zhou, L., et al. (2016) · PLoS ONE · doi:10.1371/journal.pone.0159328 · Cited by 119 · see citing works
Mechanism of Reversible Self-Association of a Monoclonal Antibody: Role of Electrostatic and Hydrophobic Interactions
Esfandiary, R., Parupudi, A., Casas‐Finet, J. R., Gadre, D., & Sathish, H. A. (2014) · Journal of Pharmaceutical Sciences · doi:10.1002/jps.24237 · Cited by 116 · see citing works
Mouse Models for Assessing Protein Immunogenicity: Lessons and Challenges
Jiskoot, W., Kijanka, G., Randolph, T. W., Carpenter, J. F., Koulov, A. V., Mahler, H., Joubert, M. K., Jawa, V., & Narhi, L. O. (2016) · Journal of Pharmaceutical Sciences · doi:10.1016/j.xphs.2016.02.031 · Cited by 115 · see citing works
Compatibility, Physical Stability, and Characterization of an IgG4 Monoclonal Antibody After Dilution into Different Intravenous Administration Bags
Kumru, O. S., Liu, J., Ji, J. A., Cheng, W., Wang, Y. J., Wang, T., Joshi, S. B., Middaugh, C. R., & Volkin, D. B. (2012) · Journal of Pharmaceutical Sciences · doi:10.1002/jps.23224 · Cited by 107 · see citing works
Multidimensional Methods for the Formulation of Biopharmaceuticals and Vaccines
Maddux, N. R., Joshi, S., Volkin, D., Ralston, J., & Middaugh, C. (2011) · Journal of Pharmacy and Science · doi:10.1002/jps.22618 · Cited by 105 · see citing works
Immunogenicity Challenges Associated with Subcutaneous Delivery of Therapeutic Proteins
Jarvi, N. L., & Balu‐Iyer, S. V. (2021) · BioDrugs · doi:10.1007/s40259-020-00465-4 · Cited by 105 · see citing works
Low immunogenicity of tocilizumab in patients with rheumatoid arthritis
Burmester, G., Choy, E., Kivitz, A., Ogata, A., Bao, M., Nomura, A., Lacey, S., Pei, J., Reiss, W., Pethoe-Schramm, A., et al. (2016) · Annals of the Rheumatic Diseases · doi:10.1136/annrheumdis-2016-210297 · Cited by 99 · see citing works
Characterization of Subvisible Particle Formation During the Filling Pump Operation of a Monoclonal Antibody Solution
Nayak, A., Colandene, J. D., Bradford, V., & Perkins, M. D. (2011) · Journal of Pharmaceutical Sciences · doi:10.1002/jps.22676 · Cited by 99 · see citing works
Biosimilars: an overview
Sekhon, B. S., & Saluja, V. (2011) · Biosimilars · doi:10.2147/bs.s16120 · Cited by 97 · see citing works
“Minimization of immunogenicity has to begin at the molecule design stage by reducing or eliminating antigenic epitopes and building in favorable physical and chemical properties.(79) Pharmacovigilance is important in the biosimilars market because of the limited ability to predict clinical consequences of seemingly in…”
Background
Biologic excipients: Importance of clinical awareness of inactive ingredients
Ionova, Y., & Wilson, L. (2020) · PLoS ONE · doi:10.1371/journal.pone.0235076 · Cited by 95 · see citing works
Predicting the Agitation-Induced Aggregation of Monoclonal Antibodies Using Surface Tensiometry
Shieh, I. C., & Patel, A. R. (2015) · Molecular Pharmaceutics · doi:10.1021/acs.molpharmaceut.5b00089 · Cited by 95 · see citing works
Biology drives the discovery of bispecific antibodies as innovative therapeutics
Nie, S., Wang, Z., Moscoso‐Castro, M., D'Souza, P., Lei, C., Xu, J., & Gu, J. (2020) · Antibody Therapeutics · doi:10.1093/abt/tbaa003 · Cited by 95 · see citing works
Pegylation and Its Impact on the Design of New Protein-Based Medicines
Ginn, C., Khalili, H., Lever, R., & Brocchini, S. (2014) · Future Medicinal Chemistry · doi:10.4155/fmc.14.125 · Cited by 93 · see citing works
Trace levels of the CHO host cell protease cathepsin D caused particle formation in a monoclonal antibody product
Bee, J. S., Liu, T., Johnson, D., Dimitrova, M. N., Jusino, K. C., & Afdahl, C. D. (2015) · Biotechnology Progress · doi:10.1002/btpr.2150 · Cited by 93 · see citing works
Toward aggregation-resistant antibodies by design
Lee, C. C., Perchiacca, J. M., & Tessier, P. M. (2013) · Trends in biotechnology · doi:10.1016/j.tibtech.2013.07.002 · Cited by 92 · see citing works
Monoclonal antibody and protein therapeutic formulations for subcutaneous delivery: high-concentration, low-volume vs. low-concentration, high-volume
Desai, M. G., Kundu, A., Hageman, M., Lou, H., & Boisvert, D. (2023) · mAbs · doi:10.1080/19420862.2023.2285277 · Cited by 92 · see citing works
Immunogenicity of Botulinum Toxin Formulations: Potential Therapeutic Implications
Carr, W. W., Jain, N., & Sublett, J. W. (2021) · Advances in Therapy · doi:10.1007/s12325-021-01882-9 · Cited by 89 · see citing works
“, host cell proteins, including bacterial flagellin) present in injected treatments, may stimulate the immune system and result in an increase in neutralizing antibodies against a biologic due to an unintended adjuvant effect [26, 36].”
Background
Formulation and Stability of Cytokine Therapeutics
Lipiäinen, T., Peltoniemi, M., Sarkhel, S., Yrjönen, T., Vuorela, H. J., Urtti, A. O., & Juppo, A. M. (2014) · Journal of Pharmaceutical Sciences · doi:10.1002/jps.24243 · Cited by 89 · see citing works
Therapeutic outcomes, assessments, risk factors and mitigation efforts of immunogenicity of therapeutic protein products
Yin, L., Chen, X., Vicini, P., Rup, B. J., & Hickling, T. P. (2015) · Cellular Immunology · doi:10.1016/j.cellimm.2015.03.002 · Cited by 88 · see citing works
Standardizing terms, definitions and concepts for describing and interpreting unwanted immunogenicity of biopharmaceuticals: recommendations of the Innovative Medicines Initiative ABIRISK consortium
Rup, B., Pallardy, M. J., Sikkema, D., Albert, T., Allez, M., Broët, P., Carini, C., Creeke, P. I., Davidson, J. E., de Vries, N., et al. (2015) · Clinical & Experimental Immunology · doi:10.1111/cei.12652 · Cited by 87 · see citing works
Coupling of aggregation and immunogenicity in biotherapeutics: T- and B-cell immune epitopes may contain aggregation-prone regions
Kumar, S., Singh, S. K., Wang, X., Rup, B., & Gill, D. (2011) · Pharmaceutical Research · doi:10.1007/s11095-011-0414-9 · Cited by 85 · see citing works
“From the perspective of product development, it is the molecular characteristics of the product that are important and can be controlled ( 4 ,7,10,12,14).”
BackgroundInfluentialSelf-citation
Physicochemical and biological characterization of SB2, a biosimilar of Remicade® (infliximab)
Hong, J. H., Lee, Y., Lee, C., Eo, S., Kim, S.-Y., Lee, N., Park, J.-M., Park, S.-K., Seo, D., Jeong, M., et al. (2016) · mAbs · doi:10.1080/19420862.2016.1264550 · Cited by 83 · see citing works
“Charge variants or glycosylation profile may directly or indirectly influence protein immunogenicity by inducing conformational changes that lead to new epitopes or the shielding of immunogenic epitopes.(43,44) To further evaluate the conformational similarity between SB2 and RP, an antibody conformational assay (enzy…”
Method
Site-Specific PEGylation at Histidine Tags
Cong, Y., Pawlisz, E., Bryant, P., Balan, S., Laurine, E., Tommasi, R., Ruchi, S., Dubey, S., Peciak, K., Bird, M., et al. (2012) · Bioconjugate Chemistry · doi:10.1021/bc200530x · Cited by 84 · see citing works
Unraveling the Effect of Immunogenicity on the PK/PD, Efficacy, and Safety of Therapeutic Proteins
Smith, A. M., Manoli, H., Jaw, S., Frutoz, K., Epstein, A. L., Khawli, L. A., & Theil, F. (2016) · Journal of Immunology Research · doi:10.1155/2016/2342187 · Cited by 80 · see citing works
“Antigenic impurities such as endotoxin contamination and detergents, aggregate formation, and variation in biologic activity must be kept to a minimum in order to ensure a safe and reliably efficacious product [79].”
Machine-designed biotherapeutics: opportunities, feasibility and advantages of deep learning in computational antibody discovery
Wilman, W., Wróbel, S., Bielska, W., Deszyński, P., Dudzic, P., Jaszczyszyn, I., Kaniewski, J., Młokosiewicz, J., Rouyan, A., Satława, T., et al. (2022) · Briefings in Bioinformatics · doi:10.1093/bib/bbac267 · Cited by 83 · see citing works
Advancements in High Throughput Biophysical Technologies: Applications for Characterization and Screening during Early Formulation Development of Monoclonal Antibodies
Samra, H. S., & He, F. (2012) · Molecular Pharmaceutics · doi:10.1021/mp200404c · Cited by 77 · see citing works
The Path Towards a Tailored Clinical Biosimilar Development
Schiestl, M., Ranganna, G. M., Watson, K., Jung, B., Roth, K., Capsius, B., Trieb, M., Bias, P., & Maréchal-Jamil, J. (2020) · BioDrugs · doi:10.1007/s40259-020-00422-1 · Cited by 72 · see citing works
Effect of pH and Light on Aggregation and Conformation of an IgG1 mAb
Mason, B. D., Schöneich, C., & Kerwin, B. A. (2012) · Molecular Pharmaceutics · doi:10.1021/mp2004719 · Cited by 71 · see citing works
Protein Adsorption, Desorption, and Aggregation Mediated by Solid-Liquid Interfaces
Perevozchikova, T., Nanda, H., Nesta, D. P., & Roberts, C. J. (2015) · Journal of Pharmaceutical Sciences · doi:10.1002/jps.24429 · Cited by 71 · see citing works
Interferon Beta: From Molecular Level to Therapeutic Effects
Abdolvahab, M. H., Mofrad, M. R. K., & Schellekens, H. (2016) · International review of cytology · doi:10.1016/bs.ircmb.2016.06.001 · Cited by 71 · see citing works
“Aggregation of IFNβ is a notable concern for effectiveness and safety of this therapeutic protein in patients due to its ability to elicit immunological responses (Rosenberg, 2006; Singh, 2011).”
Background
Adsorption behavior of a human monoclonal antibody at hydrophilic and hydrophobic surfaces
Couston, R. G., Skoda, M. W. A., Uddin, S., & van der Walle, C. F. (2013) · mAbs · doi:10.4161/mabs.22522 · Cited by 70 · see citing works
Detection of Innate Immune Response Modulating Impurities in Therapeutic Proteins
Haile, L. A., Puig, M., Kelley-Baker, L., & Verthelyi, D. I. (2015) · PLoS ONE · doi:10.1371/journal.pone.0125078 · Cited by 69 · see citing works
“Immune responses to protein therapeutic products, even those with high homology to human sequences are frequent and can significantly affect the safety and efficacy of therapeutic proteins and peptides [1–4].”
Background
Monoclonal Antibody Interfaces: Dilatation Mechanics and Bubble Coalescence
Kannan, A., Shieh, I. C., Leiske, D. L., & Fuller, G. G. (2017) · Langmuir · doi:10.1021/acs.langmuir.7b03790 · Cited by 69 · see citing works
Stability testing in monoclonal antibodies
Kaur, H. (2021) · Critical Reviews in Biotechnology · doi:10.1080/07388551.2021.1874281 · Cited by 69 · see citing works
Drug development: longer-lived proteins
Kontos, S., & Hubbell, J. A. (2012) · Chemical Society Reviews · doi:10.1039/c2cs15289d · Cited by 69 · see citing works
Ethosomal Gel for Improving Transdermal Delivery of Thymosin β-4
Fu, X., Shi, Y., Wang, H., Zhao, X., Sun, Q., Huang, Y., Qi, T., & Lin, G. (2019) · International Journal of Nanomedicine · doi:10.2147/ijn.s228863 · Cited by 69 · see citing works
“The phospholipids, CHOL and ethanol used in the preparation of ethosomal gel were mild, a finding consistent with the drug design principle of Quality by Design (QbD).(31)”
Result
Investigation of the Immunogenicity of Different Types of Aggregates of a Murine Monoclonal Antibody in Mice
Freitag, A., Shomali, M., Michalakis, S., Biel, M., Siedler, M., Kaymakcalan, Z., Carpenter, J. F., Randolph, T. W., Winter, G., & Engert, J. (2014) · Pharmaceutical Research · doi:10.1007/s11095-014-1472-6 · Cited by 68 · see citing works
Trends in industrialization of biotherapeutics: a survey of product characteristics of 89 antibody-based biotherapeutics
Martin, K., Grimaldi, C. M., Grempler, R., Hansel, S. B., & Kumar, S. (2023) · mAbs · doi:10.1080/19420862.2023.2191301 · Cited by 67 · see citing works
“26,109 Furthermore, the real-life experience on immunogenicity of a given antibody-based biotherapeutic product, outside of the clinical trial setting, may be different than the % ADAs reported in the package inserts or BLA reviews.”
Background
Analytical lessons learned from selected therapeutic protein drug comparability studies
Federici, M. M., Lubiniecki, A. S., Manikwar, P., & Volkin, D. B. (2012) · Biologicals · doi:10.1016/j.biologicals.2012.10.001 · Cited by 66 · see citing works
Comparative Binding of Disulfide-Bridged PEG-Fabs
Khalili, H., Godwin, A., Choi, J.-W., Lever, R., & Brocchini, S. (2012) · Bioconjugate Chemistry · doi:10.1021/bc300372r · Cited by 65 · see citing works
Improving Monoclonal Antibody Selection and Engineering using Measurements of Colloidal Protein Interactions
Geng, S. B., Cheung, J. K., Narasimhan, C. N., Shameem, M., & Tessier, P. M. (2014) · Journal of Pharmaceutical Sciences · doi:10.1002/jps.24130 · Cited by 65 · see citing works
N-Glycosylation of cholera toxin B subunit in Nicotiana benthamiana: impacts on host stress response, production yield and vaccine potential
Hamorsky, K. T., Kouokam, J. C., Jurkiewicz, J. M., Nelson, B. A., Moore, L. J., Husk, A. S., Kajiura, H., Fujiyama, K., & Matoba, N. (2015) · Scientific Reports · doi:10.1038/srep08003 · Cited by 65 · see citing works
Predicting the Development of Anti-Drug Antibodies against Recombinant alpha-Galactosidase A in Male Patients with Classical Fabry Disease
van der Veen, S. J., Vlietstra, W. J., van Dussen, L., Kuilenburg, A. B. P., Dijkgraaf, M. G. W., Lenders, M., Brand, E., Wanner, C., Hughes, D. A., Elliot, P. M., et al. (2020) · International Journal of Molecular Sciences · doi:10.3390/ijms21165784 · Cited by 64 · see citing works
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Impact of Aggregation on the Immunogenicity of Therapeutic Recombinant Biological Products
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Authors: Singh, S. K.
Affiliations: Pfizer (United States) (US)
Corresponding author: Singh, Satish Kumar
ORCID: Singh, Satish Kumar
Venue: Journal of Pharmaceutical Sciences
Publisher: Elsevier BV
Published: 2011-02
Volume: 100
Issue: 2
Pages: 354-387
ISSN: 0022-3549 (ISSN-L)
DOI: 10.1002/jps.22276
OpenAlex: W2008138329
Cited by: 350
References: 290
Citations by year: 2026: 9 · 2025: 12 · 2024: 17 · 2023: 16 · 2022: 10 · 2021: 33 · 2020: 25 · 2019: 21 · 2018: 27 · 2017: 21 · 2016: 24 · 2015: 38 · 2014: 24 · 2013: 26 · 2012: 35
FWCI: 1.86
Type: journal article
Language: en
Open access: closed
Licence: www.elsevier.com/tdm/userlicense/1.0/ (tdm)
Locations: Journal of Pharmaceutical Sciences (publishedVersion)
PubMed (publishedVersion)
Topics: Life Sciences › Immunology and Microbiology › Immunology › Biosimilars and Bioanalytical Methods
Life Sciences › Biochemistry, Genetics and Molecular Biology › Molecular Biology › Protein purification and stability
Health Sciences › Medicine › Radiology, Nuclear Medicine and Imaging › Monoclonal and Polyclonal Antibodies Research
Keywords: immunogenicity, biologic therapy, therapeutic proteins, aggregation, post-translational modification, container closure systems, degradation products, expression systems, antigenic determinants, immunomodulatory proteins
MeSH terms: Animals, Antibody Formation, Biotechnology, Humans, Protein Processing, Post-Translational, Proteins

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Impact of Product-Related Factors on Immunogenicity of Biotherapeutics

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