Skip to main content

Laboratory SAXS was used to characterize monoclonal antibody in solution

Biotherapeutics, particularly monoclonal antibodies (mAbs), are well-established therapies recognized for their high specificity and adaptability in targeting various diseases, including cancers and autoimmune disorders [1, 2]. Detailed structural characterization is crucial for ensuring the stability, efficacy, and safety of mAbs throughout the drug development process [3-6]. Maintaining structural integrity under varying conditions—such as concentration, ionic strength, and formulation changes—is essential, as instability can lead to aggregation, degradation, or reduced binding affinity, thereby compromising therapeutic potential [5-7].

Optimizing antibody formulations and storage conditions requires a thorough understanding of their behavior in different physicochemical environments [8]. Factors such as concentration and ionic strength significantly influence conformational stability, intermolecular interactions, and aggregation tendencies [6, 8]. Addressing these challenges early in the development process is key to achieving long-term stability and therapeutic efficacy.

Small-Angle X-ray Scattering (SAXS) is a well-established technique that provides detailed insights into the size, shape, structure, stability, flexibility, oligomeric state, folding states, and interparticle interactions of samples in a near-native environment [9, 10].  Unlike traditional light scattering methods, which primarily measure particle size and polydispersity, SAXS offers specific structural insights into conformational states and flexibility, making it particularly valuable for studying complex proteins like antibodies. Additionally, SAXS’s high-throughput capabilities enable rapid data acquisition and analysis, making it an efficient tool for structural and biophysical characterization, as well as for validating models from crystallography, NMR, and computational predictions [11, 12].

Author: Sanaullah Khan
Measurements and Data Analysis: Sanaullah Khan
Scientific reviewers: S. Skou, A. Kikhney, A. Tutueanu.
References
[1] Y. Xu, D. Wang, B. Mason, T. Rossomando, N. Li et al., Structure, heterogeneity and developability assessment of therapeutic antibodies, mAbs, 11(2), 239–264 (2018). DOI: 10.1080/19420862.2018.1553476.
[2] X. Wang, Q. Li, and M. Davies, Development of antibody arrays for monoclonal antibody Higher Order Structure analysis, Front. Pharmacol 4, 103 (2013). DOI: 10.3389/fphar.2013.00103.
[3] P. Carter and G. Lazar, Next-generation antibody drugs: pursuit of the ‘high-hanging fruit’, Nat Rev Drug Discov 17, 197–223 (2018). DOI: 10.1038/nrd.2017.227.
[4] R. M. Lu, Y. C. Hwang, I. J. Liu, C. C. Lee, H. Z. Tsai et al., Development of therapeutic antibodies for the treatment of diseases, J. Biomed. Sci. 27 (2020). DOI: 10.1186/s12929-019-0592-z.
[5] Y. Tokunaga and K. Takeuchi, Role of NMR in high ordered structure characterization of monoclonal antibodies,Int. J. Mol. Sci. 22, 46 (2021). DOI: 10.3390/ijms22010046.
[6] W. Zhang, H. Wang, N. Feng, Y. Li, J. Gu, and Z. Wang, Developability assessment at early-stage discovery to enable development of antibody-derived therapeutics, Antibody Therapeutics 6, 13–29, (2022). DOI: 10.1093/abt/tbac029
[7] A. Y. Xu, M. M. Castellanos, K. Mattison, S. Krueger, and J. E. Curtis, Studying Excipient Modulated Physical Stability and Viscosity of Monoclonal Antibody Formulations Using Small-Angle Scattering, Molecular Pharmaceutics 16, 10, 4319–4338 (2019). DOI: 10.1021/acs.molpharmaceut.9b00687.
[8] H. L. Svilenov and G. Winter, Formulations That Suppress Aggregation During Long-Term Storage of a Bispecific Antibody are Characterized by High Refoldability and Colloidal Stability, J. Pharm. Sci., 109, 6, 2048–2058 (2020). DOI: 10.1016/j.xphs.2020.03.011
[9] P. Bernadó and D. I. Svergun, Structural analysis of intrinsically disordered proteins by small-angle X-ray scattering, Mol. Biosyst. 8, 151 (2012). DOI: 10.1039/C1MB05275F.
[10] A. G. Kikhney, D. I. Svergun, A Practical Guide to Small Angle X-Ray Scattering (SAXS) of Flexible and Intrinsically Disordered Proteins, FEBS Letters 589, 19 (2015). DOI: 10.1016/j.febslet.2015.08.027.
[11] G. L. Hura, A. L. Menon, M. Hammel, R. P. Rambo, F. L. Poole II et al., Robust, high-throughput solution structural analyses by small angle X-ray scattering (SAXS), Nat. Methods, 6, 606–612, (2009). DOI: 10.1038/nmeth.1353.
[12] H. D. T. Mertens and D. I. Svergun, Combining NMR and small angle X-ray scattering for the study of biomolecular structure and dynamics, Arch Biochem Biophys 628, 33 (2017). DOI: 10.1016/j.abb.2017.05.005.