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Middle Level IM-MS and CIU Experiments for Improved Therapeutic Immunoglobulin Subclass Fingerprinting ACS Paragon Plus Environment Analytical Chemistry T

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Middle Level IM-MS and CIU Experiments for Improved Therapeutic Immunoglobulin Subclass Fingerprinting ACS Paragon Plus Environment Analytical Chemistry T Middle level IM-MS and CIU experiments for improved therapeutic immunoglobulin subclass fingerprinting ACS Paragon Plus Environment Analytical Chemistry T. Botzanowski, O. Hernandez-Alba, M. Malissard, E. Wagner-Rousset, E. Desligniere, O. Colas, F. Haeuw J., A. Beck, S. Cianferani To cite this version: T. Botzanowski, O. Hernandez-Alba, M. Malissard, E. Wagner-Rousset, E. Desligniere, et al.. Middle level IM-MS and CIU experiments for improved therapeutic immunoglobulin subclass fingerprinting ACS Paragon Plus Environment Analytical Chemistry. Analytical Chemistry, American Chemical Society, 2020, 92 (13), pp.8827-8835. 10.1021/acs.analchem.0c00293. hal-02960844 HAL Id: hal-02960844 https://hal.archives-ouvertes.fr/hal-02960844 Submitted on 8 Oct 2020 HAL is a multi-disciplinary open access L’archive ouverte pluridisciplinaire HAL, est archive for the deposit and dissemination of sci- destinée au dépôt et à la diffusion de documents entific research documents, whether they are pub- scientifiques de niveau recherche, publiés ou non, lished or not. The documents may come from émanant des établissements d’enseignement et de teaching and research institutions in France or recherche français ou étrangers, des laboratoires abroad, or from public or private research centers. publics ou privés. Analytical Chemistry This document is confidential and is proprietary to the American Chemical Society and its authors. Do not copy or disclose without written permission. If you have received this item in error, notify the sender and delete all copies. Middle level IM-MS and CIU experiments for improved therapeutic immunoglobulin subclass fingerprinting Journal: Analytical Chemistry Manuscript ID ac-2020-00293w.R2 Manuscript Type: Article Date Submitted by the n/a Author: Complete List of Authors: Botzanowski, Thomas; IPHC Hernandez-Alba, Oscar; IPHC, Laboratoire de Spectrométrie de Masse Bio-Organique (LSMBO) Malissard, Martine; Centre d'Immunologie Pierre Fabre Wagner-Rousset, Elsa; Centre d'Immunologie Pierre Fabre, Physici- Chemistry Deslignière, Evolène; IPHC, Laboratoire de Spectrométrie de Masse Bio- Organique (LSMBO) Colas, Olivier; Centre d'Immunologie Pierre Fabre Haeuw, Jean-François; Centre d'Immunologie Pierre Fabre, Physico- Chemistry Beck, Alain; Centre d'Immunologie Pierre Fabre, Physico-Chemistry Cianférani, Sarah; IPHC, Laboratoire de Spectrométrie de Masse Bio- Organique (LSMBO) ACS Paragon Plus Environment Page 1 of 16 Analytical Chemistry 1 2 3 4 5 6 7 Middle level IM-MS and CIU experiments for improved therapeutic 8 immunoglobulin subclass fingerprinting 9 10 Thomas Botzanowski1¶, Oscar Hernandez-Alba1¶, Martine Malisssard2, Elsa Wagner-Rousset2, Evolène 11 Deslignière1, Olivier Colas2, Jean-François Haeuw2, Alain Beck2, Sarah Cianférani1* 12 13 1 Laboratoire de Spectrométrie de Masse BioOrganique, Université de Strasbourg, CNRS, IPHC UMR 7178, 67000 14 Strasbourg, France. 15 2 IRPF - Centre d’Immunologie Pierre-Fabre (CIPF), 74160 Saint-Julien-en-Genevois, France. 16 17 *Corresponding author: Sarah Cianférani. Email: [email protected] 18 ABSTRACT: Most of the current FDA and EMA approved therapeutic monoclonal antibodies (mAbs) are based on humanized or 19 human IgG1, 2 or 4 subclasses and engineered variants. On the structural side, these subclasses are characterized by specific inter- 20 chains disulfide bridge connections. Different analytical techniques have been reported to assess intact IgGs subclasses, with recently 21 special interest in native ion mobility (IM) and collision induced unfolding (CIU) mass spectrometry (MS). However, these two 22 techniques exhibit significant limitations to differentiate mAb subclasses at the intact level. In the present work, we aimed at developing a unique IM-MS-based approach for the characterization of mAb subclasses at the middle level. Upon IdeS-digestion, the 23 unfolding patterns of the F(ab’)2 and Fc domains were simultaneously analyzed in a single run to provide deeper structural insights 24 of the mAb scaffold. The unfolding patterns associated with the F(ab’) domains are completely different in terms of unfolding 25 2 energies and number of transitions. Thereby, F(ab’)2 regions are the diagnostic domain to provide specific unfolding signatures to 26 differentiate IgG subclasses and provide more confident subclass categorization than CIU on intact mAbs. In addition, the potential 27 of middle-level CIU was evaluated through the characterization of eculizumab, a hybrid therapeutic IgG2/4 mAb. The unfolding 28 signatures of both domains allowed to corroborate, within a single run, the hybrid nature of eculizumab as well as specific subclass 29 domain assignments to the F(ab’)2 and Fc regions. Altogether, our results confirm the suitability of middle-level CIU of F(ab’)2 30 domains for subclass categorization of canonical and more complex new generation engineered antibodies and related products. 31 32 33 INTRODUCTION disulfide bond, while the two heavy-chains can be linked either 34 During the last 20 years, monoclonal antibody (mAb) by two (for IgG1 and IgG4) or four (for IgG2) disulfide bonds 35 3 development and engineering have significantly evolved due to located in the hinge region of the antibody . In addition, mAbs 36 their therapeutic efficiency against many diseases such as global structure is also maintained with 12 intra-chain disulfide 37 cancer, and autoimmune diseases1. More than 80 antibody- bridges that connect two cysteines that belong to the same 38 based products are currently approved by regulatory agencies domain. The inter-chain disulfide bridges network, which is 39 (FDA and EMA), while ~600 others are in clinical studies, characteristic of each individual subclass, has an impact on 40 including more than 60 in phase III clinical trials2. different mAb properties (structure, stability, surface hydrophobicity, isoelectric point, etc.)4 and modulate their 41 Among the different post-translational modifications (PTMs) higher-order structure5-8. Thereby, mAbs from different 42 that can occur within the primary sequence of mAbs, subclasses will differ in their secondary immune functions9-10. glycosylation and inter-chain disulfide linkages strongly 43 In terms of mAb developability, there is a continuous interest contribute to the stabilization of the tertiary structure of these 44 for improvement of new analytical techniques to characterize proteins. Indeed, therapeutic mAbs can be classified into four 45 the impact of the different inter-chain disulfide patterns on subclasses (IgG1, IgG2, IgG3, and IgG4) with different inter- 46 therapeutic mAb structures and structure-function relationships. 47 and intra-chain disulfide connectivities. While human IgG3 subclass is usually not considered for therapeutic mAbs Ion mobility coupled to mass spectrometry (IM-MS), and its 48 engineering and production due to its limited potential collision induced unfolding (CIU) variant, have been used to 11-14 49 associated to its shorter half-life1, human IgG1, IgG2, and IgG4 characterize the structure and dynamics of proteins and 15-16 50 mAb subclasses represent the main classes of mAb-based protein complexes in the gas-phase. During the last 5 years, 51 therapeutics. One of the main structural differences between the CIU has been increasingly used in structural biology to 52 three therapeutic subclasses (IgG1, IgG2, and IgG4) is the characterize a wide range of biological systems and has 53 number (four for IgG1 and IgG4 and six for IgG2) and the integrated the analytical portfolio of international regulatory 17 54 connectivities of inter-chain disulfide bridges3 (Figure 1). The agencies . Although the CIU approach still remains as a 55 heavy and light chains of all subclasses are linked by one laborious and time-consuming process, significant efforts have 56 1 57 58 59 60 ACS Paragon Plus Environment Analytical Chemistry Page 2 of 16 been made to improve data acquisition18 and interpretation19-20. N-deglycosylated during 30 min at 37 °C with IgGZERO 1 CIU experiments allowed to circumvent in some cases the (Genovis). In the case of middle-level analysis, the 2 limitations associated to IM resolution to separate and deglycosylated mAbs were degraded with IdeS enzyme 3 differentiate mAbs with very similar global structure. Thereby, (immunoglobulin-degrading enzyme of Streptococcus 4 CIU afforded structural insights that led to the differentiation of pyogenes, FabRICATOR, Genovis). A 1 µg/unit ratio was used 20, 22 5 human non-therapeutic mAb subclasses , ADCs’ to achieve an efficient digestion and subsequently, the mixture 23-24 6 characterization , and stabilized vs wild-type therapeutic was incubated during 60 min at 37°C. After deglycosylation IgG4 mAbs among others25. More particularly, the group of and/or IdeS digestion, therapeutic mAbs were then desalted 7 Ruotolo reported that glycan moieties contribute to the against 100 mM ammonium acetate at pH 7.0 prior to native 8 stabilization of the mAb scaffold in the gas-phase, thus MS analysis, using about six to eight cycles of centrifugal 9 glycosylated mAbs require around 15% more energy to undergo concentrator (Vivaspin, 30 kDa cutoff, Sartorious, Göttingen, 10 unfolding compared to their non-glycosylated counterparts22. Germany). The concentration of each individual solution after 11 The same study also highlighted the role of inter-chain disulfide desalting process was measured by UV absorbance using a 12 linkage in mAb gas-phase stability, the latter being proposed as nanodrop spectrophotometer
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