Treating paroxysmal nocturnal hemoglobinuria with humanized IgG 2/4 kappa antibody: understanding the ravulizumab structure

Authors

  • Yara Maria da Silva Pires
  • Thaís Humenhuk
  • Aline de Fátima Bonetti
  • Astrid Wiens

DOI:

https://doi.org/10.55905/oelv22n1-128

Keywords:

ravulizumab, eculizumab, therapeutic monoclonal antibody, paroxysmal nocturnal hemoglobinuria

Abstract

Background: Paroxysmal nocturnal hemoglobinuria (PNH) is a rare hematologic disease caused by somatic mutations in hematopoietic stem cells. As molecular studies are essential for a better understanding of new drugs, tools such as the international ImMunoGeneTics information system® are powerful approaches to better understanding the molecular conformations, arrangements, and orientations of two-dimensional (2D) structures of PNH treatments. This review aims to characterize the structure of Ravulizumab, describe its drug design process, and show its amino acid sequence through IGMT Colliers de Perles. Methods: The IMGT/mAb-DB interface was used to evaluate therapeutic antibodies and to clarify their immunological applications and pharmacological effects. Results: Ravulizumab binds to C5 and blocks its activation by complement pathway convertases, thereby preventing the release of the proinflammatory C5a and activation of the terminal pathway. The healthcare cost of PNH patients decreased because smaller doses of RAVUL could promote full complement blockage, maintaining the therapeutic effect. Choosing the epitope, hinge, and Fc region is crucial to balance efficacy and undesirable effects. The better intermolecular interactions of RAVUL with binding sites are due to its nanostructure design. Conclusion: These results bridge the gap between linear amino acid sequences and 3D structures. It may guide the development of new drugs for rare diseases.

References

Cella, D., Sarda, S.P., Hsieh, R., Fishman, J., Hakimi, Z., Hoffman, K., Al-Adhami, M., Nazir, J., Cutts, K., Lenderking, W.R., 2022. Changes in hemoglobin and clinical out-comes drive improvements in fatigue, quality of life, and physical function in patients with paroxysmal nocturnal hemoglobinuria: post hoc analyses from the phase III PE-GASUS study. Ann Hematol 101, 1905–1914. https://doi.org/10.1007/s00277-022-04887-8

Carmody, L.C., Blau, H., Danis, D. et al. Significantly different clinical phenotypes associated with mutations in synthesis and transamidase+remodeling glycosylphospha-tidylinositol (GPI)-anchor biosynthesis genes. Orphanet J Rare Dis 15, 40 (2020). https://doi.org/10.1186/s13023-020-1313-0

Kulasekararaj AG, Risitano AM, Maciejewski JP, Notaro R, Browett P, Lee JW, Huang M, Geffner M, Brodsky R, 2021. Phase 2 study of danicopan in patients with pa-roxysmal nocturnal hemoglobinuria with an inadequate response to eculizumab. Blood 138, 1928–1938. https://doi.org/10.1182/blood.2021011388

Fukuzawa T, Sampei Z, Haraya K, Ruike Y, Shida-Kawazoe M, Shimizu Y, Gan SW, Irie M, Tsuboi Y, Tai H, Sakiyama T, Sakamoto A, Ishii S, Maeda A, Iwayanagi Y, Shi-bahara N, Shibuya M, Nakamura G, Nambu T, Hayasaka A, Mimoto F, Okura Y, Hori Y, Habu K, Wada M, Miura T, Tachibana T, Honda K, Tsunoda H, Kitazawa T, Kawa-be Y, Igawa T, Hattori K, Nezu J. Long lasting neutralization of C5 by SKY59, a novel recycling antibody, is a potential therapy for complement-mediated diseases. Sci Rep. 2017 Apr 24;7(1):1080. doi: 10.1038/s41598-017-01087-7.

Lefranc MP, Lefranc G. IMGT ® Nomenclature of Engineered IGHG Variants Invol-ved in Antibody Effector Properties and Formats. Antibodies (Basel). 2022 Oct 18;11(4):65. doi: 10.3390/antib11040065. PMID: 36278618; PMCID: PMC9624366.

Vlachakis, D., Feidakis, C., Megalooikonomou, V., Kossida, S., 2013. IMGT/Collier-de-Perles: A two-dimensional visualization tool for amino acid domain sequences. Theor Biol Med Model 10. https://doi.org/10.1186/1742-4682-10-14

Poiron, C., Lefranc, M., 1995. AGENCE NATIONALE DE LA RECHERCHE Link to IMGT/2Dstructure-DB.

Lefranc, M.P., Giudicelli, V., Duroux, P., Jabado-Michaloud, J., Folch, G., Aouinti, S., Carillon, E., Duvergey, H., Houles, A., Paysan-Lafosse, T., Hadi-Saljoqi, S., Sasorith, S., Lefranc, G., Kossida, S., 2015. IMGT R, the international ImMunoGeneTics infor-mation system R 25 years on. Nucleic Acids Res 43, D413–D422. https://doi.org/10.1093/nar/gku1056

Pires, Y.M. da S., Bonetti, A. de F., Ciecilinsky, J.T., Souza, A.W., 2023. Efficacy and safety of current treatments for paroxysmal nocturnal hemoglobinuria: A systematic re-view. Clinical Immunology Communications 3, 37–41. https://doi.org/10.1016/j.clicom.2022.11.002

Shin, J.-H., Park, Y.-E., Kim, D.-S., 2021. Nomenclature of emerging therapeutics in neurology. Annals of Clinical Neurophysiology 23, 29–34. https://doi.org/10.14253/acn.2021.23.1.29

Sheridan, D., Yu, Z.X., Zhang, Y., Patel, R., Sun, F., Lasaro, M.A., Bouchard, K., An-drien, B., Marozsan, A., Wang, Y., Tamburini, P., 2018. Design and preclinical characte-rization of ALXN1210: A novel anti-C5 antibody with extended duration of action. PLoS One 13. https://doi.org/10.1371/journal.pone.0195909

Frazer-Abel, A., 2018. The effect on the immunology laboratory of the expansion in complement therapeutics. J Immunol Methods. https://doi.org/10.1016/j.jim.2018.08.001

FDA. US Food & Drug Administration. ULTOMIRIS ™ (ravulizumab-cwvz) injection, for intravenous use. HIGHLIGHTS OF PRESCRIBING INFORMATION, 2018. Ale-xion Pharma GmbH. https://www.accessdata.fda.gov/ Accessed 3 Jun 2023

Chiu, M.L.; Goulet, D.R.; Teplyakov, A.; Gilliland, G.L. Antibody Structure and Func-tion: The Basis for Engineering Therapeutics. Antibodies 2019, 8, 55. https://doi.org/10.3390/antib8040055

Stern RM, Connell NT. Ravulizumab: a novel C5 inhibitor for the treatment of pa-roxysmal nocturnal hemoglobinuria. Ther Adv Hematol. 2019 Sep 10. doi: 10.1177/2040620719874728.

Wong, E.K.S., Kavanagh, D., 2015. Anticomplement C5 therapy with eculizumab for the treatment of paroxysmal nocturnal hemoglobinuria and atypical hemolytic uremic syndrome. Translational Research. https://doi.org/10.1016/j.trsl.2014.10.010

Roopenian, D.C., Christianson, G.J., Sproule, T.J., Brown, A.C., Akilesh, S., Jung, N., Petkova, S., Avanessian, L., Choi, E.Y., Shaffer, D.J., Eden, P.A., Anderson, C.L., 2003. The MHC Class I-Like IgG Receptor Controls Perinatal IgG Transport, IgG Ho-meostasis, and Fate of IgG-Fc-Coupled Drugs. The Journal of Immunology 170, 3528–3533. https://doi.org/10.4049/jimmunol.170.7.3528

Vanoli, F., Mantegazza, R., 2023. Ravulizumab for the treatment of myasthenia gravis. Expert Opin Biol Ther 23, 235–241. https://doi.org/10.1080/14712598.2023.2185131

Ladwig, P.M., Willrich, M.A.V., 2021. Ravulizumab: Characterization and quantitation of a new C5 inhibitor using isotype specific affinity purification and high-resolution mass spectrometry. Journal of Mass Spectrometry and Advances in the Clinical Lab 21, 10–18. https://doi.org/10.1016/j.jmsacl.2021.08.002

Quist, S.W., Postma, A.J., Myrén, K.J., de Jong, L.A., Postma, M.J., 2023. Cost-effectiveness of ravulizumab compared with eculizumab for the treatment of paroxysmal nocturnal hemoglobinuria in the Netherlands. European Journal of Health Economics. https://doi.org/10.1007/s10198-022-01556-5

Boulard, P., Gouilleux-Gruart, V., Watier, H., 2022. Finding the Right Heavy Chains for Immunostimulatory Antibodies. Int J Mol Sci. https://doi.org/10.3390/ijms231810367

Kaas, Q., Ehrenmann, F., Lefranc, M.P., 2007. IG, TR and IgSF, MHC and MhcSF: What do we learn from the IMGT Colliers de Perles? Brief Funct Genomic Proteomic 6, 253–264. https://doi.org/10.1093/bfgp/elm032

Published

2024-01-22

How to Cite

Pires, Y. M. da S., Humenhuk, T., Bonetti, A. de F., & Wiens, A. (2024). Treating paroxysmal nocturnal hemoglobinuria with humanized IgG 2/4 kappa antibody: understanding the ravulizumab structure. OBSERVATÓRIO DE LA ECONOMÍA LATINOAMERICANA, 22(1), 2472–2483. https://doi.org/10.55905/oelv22n1-128

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