ArticleBiochemistry2009
Physical instability of a therapeutic Fc fusion protein: domain contributions to conformational and colloidal stability.
Article in Biochemistry, 2009. The graph could read no effect estimate from its abstract, so it casts no vote on the map. Cited by 21 papers.
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Who cites it
21 citing papers in PubMed, 89 citations in OpenAlex.
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- Impact of Weak Vibration Generated by a Refrigerator on Protein Aggregation.The AAPS journal · 2025Article
- In situ characterization of amine-forming enzymes shows altered oligomeric state.Protein science : a publication of the Protein Society · 2025Article
- Evolving strategies in the treatment of rheumatoid arthritis: a historical perspective.Reumatologia · 2025Review
- Strategies for overcoming protein and peptide instability in biodegradable drug delivery systems.Advanced drug delivery reviews · 2023Review
- Localization of drug biodistribution in a 3D-bioengineered subcutaneous neovascularized microenvironment.Materials today. Bio · 2022Article
- Temperature Down-Shift Modifies Expression of UPR-/ERAD-Related Genes and Enhances Production of a Chimeric Fusion Protein in CHO Cells.Biotechnology journal · 2021Article
- Investigating the trade-off between folding and function in a multidomain Y-family DNA polymerase.eLife · 2020Article
- Electron microscopy-based semi-automated characterization of aggregation in monoclonal antibody products.Computational and structural biotechnology journal · 2020Article
- Engineering of Fc Fragments with Optimized Physicochemical Properties Implying Improvement of Clinical Potentials for Fc-Based Therapeutics.Frontiers in immunology · 2017Review
- Nanotechnology for protein delivery: Overview and perspectives.Journal of controlled release : official journal of the Controlled Release Society · 2016Review
- Antibody Aggregation: Insights from Sequence and Structure.Antibodies (Basel, Switzerland) · 2016Review
- Stabilizing the CH2 Domain of an Antibody by Engineering in an Enhanced Aromatic Sequon.ACS chemical biology · 2016Article
- The neonatal Fc receptor, FcRn, as a target for drug delivery and therapy.Advanced drug delivery reviews · 2015Review
- Improving monoclonal antibody selection and engineering using measurements of colloidal protein interactions.Journal of pharmaceutical sciences · 2014Review
- Evaluation of near infrared fluorescent labeling of monoclonal antibodies as a tool for tissue distribution.Drug metabolism and disposition: the biological fate of chemicals · 2014Article
- Monomeric banana lectin at acidic pH overrules conformational stability of its native dimeric form.PloS one · 2013Article
Corrections and comments
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Authors and funding
4 authors at 2 institutions in 1 country.
Funding
Abstract
Protein therapeutics made up of artificially combined proteins or protein domains, so-called fusion proteins, are a novel and growing class of biopharmaceuticals. We have studied abatacept (Orencia), a fusion protein that is constructed of a modified IgG Fc domain and the soluble part of the T-cell receptor CTLA-4. In accelerated degradation studies conducted at 40 degrees C, a pH shift from 7.5 to 6.0 yields significantly faster aggregation kinetics, as measured by size-exclusion chromatography. To understand how the fusion domains and their interactions contribute to this result, we considered aggregation in light of the modified Lumry-Eyring reaction pathway. Protein conformational stabilities against chaotropes and temperature were measured. The structural consequences of these perturbations were observed by a variety of experimental techniques, including differential scanning calorimetry, circular dichroism, and intrinsic fluorescence. Abatacept's colloidal stability was studied by measuring zeta potentials and osmotic second virial coefficients, as well as by modeling electrostatic potentials on the protein's surface. The domains of abatacept exhibit different conformational stabilities that are highly pH dependent, whereas abatacept was weakly colloidally unstable at pH 6 or 7.5. These results are ascribed to conformational instability of the CTLA-4 and C(H)2 domains, which unfold to form a molten globule-like structure that is aggregation-prone. We suggest the instability against aggregation is determined by the least stable domains.
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Registered trials
Read under generation 80e0d062 · epoch 390. Bibliography from PubMed, PubMed Central and OpenAlex; grants from NIH RePORTER; trial links from ClinicalTrials.gov; estimates, votes and beliefs from the OpenQuestion graph.