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Engineering the Interactions Between a Plant-Produced HIV Antibody And Engineering the interactions between a plant-produced HIV antibody and human Fc receptors Szymon Stelter, Mathew Paul, Audreey Y.-H Teh, Melanie Grandits, Friedrich Altmann, Jessica Vanier, Muriel Bardor, Alexandra Castilho, Rachel Allen, Julian K-C Ma To cite this version: Szymon Stelter, Mathew Paul, Audreey Y.-H Teh, Melanie Grandits, Friedrich Altmann, et al.. En- gineering the interactions between a plant-produced HIV antibody and human Fc receptors. Plant Biotechnology Journal, Wiley, 2020, 18, pp.402-414. 10.1111/pbi.13207. hal-02276812 HAL Id: hal-02276812 https://hal-normandie-univ.archives-ouvertes.fr/hal-02276812 Submitted on 3 Sep 2019 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. Plant Biotechnology Journal (2019), pp. 1–13 doi: 10.1111/pbi.13207 Engineering the interactions between a plant-produced HIV antibody and human Fc receptors Szymon Stelter1,a, Mathew J. Paul1, Audrey Y.-H. Teh1, Melanie Grandits1, Friedrich Altmann2, Jessica Vanier3, Muriel Bardor3,4, Alexandra Castilho5, Rachel Louise Allen6 and Julian K-C. Ma1,* 1Hotung Molecular Immunology Unit, Institute for Infection and Immunity, St George’s University of London, London, UK 2Division of Biochemistry, University of Natural Resources and Life Sciences, Vienna, Austria 3UNIROUEN, Laboratoire Glycobiologie et Matrice Extracellulaire Veg etale EA, Normandie Univ, Rouen, France 4Institut Universitaire de France (I.U.F.), Paris Cedex 05, France 5Department of Applied Genetics and Cell Biology, University of Natural Resources and Life Sciences, Vienna, Austria 6Institute for Infection and Immunity, St George’s University of London, London, UK Received 12 March 2019; Summary revised 13 June 2019; Plants can provide a cost-effective and scalable technology for production of therapeutic accepted 9 July 2019. monoclonal antibodies, with the potential for precise engineering of glycosylation. Glycan *Correspondence: (Tel +44 208 725 5818; structures in the antibody Fc region influence binding properties to Fc receptors, which opens email [email protected]) opportunities for modulation of antibody effector functions. To test the impact of glycosylation aPresent address: Crescendo Biologics Ltd, in detail, on binding to human Fc receptors, different glycovariants of VRC01, a broadly Meditrina Building 260, Babraham Research Campus, Cambridge, CB22 3AT, UK. neutralizing HIV monoclonal antibody, were generated in Nicotiana benthamiana and characterized. These include glycovariants lacking plant characteristic a1,3-fucose and b1,2- xylose residues and glycans extended with terminal b1,4-galactose. Surface plasmon resonance- based assays were established for kinetic/affinity evaluation of antibody–FccR interactions, and revealed that antibodies with typical plant glycosylation have a limited capacity to engage FccRI, FccRIIa, FccRIIb and FccRIIIa; however, the binding characteristics can be restored and even Keywords: antibody, improved with targeted glycoengineering. All plant-made glycovariants had a slightly reduced glycoengineering, plant, molecular affinity to the neonatal Fc receptor (FcRn) compared with HEK cell-derived antibody. However, pharming, fucose, Fc receptor, CD64, this was independent of plant glycosylation, but related to the oxidation status of two CD16, FcRn, neonatal Fc receptor, methionine residues in the Fc region. This points towards a need for process optimization to methionine oxidation. control oxidation levels and improve the quality of plant-produced antibodies. Introduction composition can influence binding affinity and receptor-medi- ated activity (Jefferis, 2009b). Antibody-based therapeutics comprise a major segment of the An important feature of IgG antibodies is their long serum half- fast-growing biopharmaceutical market. There are currently life, which extends their therapeutic and protective effect (Ward more than 50 monoclonal antibodies approved for clinical use, et al., 2015). Rapid clearance of IgG from the circulation is and hundreds are in preclinical and clinical development (Ecker prevented by interaction with neonatal Fc receptor (FcRn), which et al., 2015). Most of these are IgG antibodies that target protects IgG antibodies from endosomal degradation (Junghans cancer and autoimmune disorders, although there is growing and Anderson, 1996). FcRn is a membrane heterodimer protein, interest in monoclonal antibodies to tackle infectious diseases which belongs to the MHC class I molecular family (Burmeister (Irani et al., 2015). Whilst binding to cognate antigen is the et al., 1994). Recent studies have demonstrated that efficacy of hallmark of antibody function, engagement of cell-surface Fc antibody therapy correlates with serum half-life and that receptors can activate immune cells to remove or neutralize engineering antibodies to prolong their lifespan in the blood antibody-coated targets via processes known collectively as extends their therapeutic effect (Ko et al., 2014; Zalevsky et al., antibody effector functions (Desjarlais and Lazar, 2011). There 2010). are six classical Fc receptors recognizing IgG: high-affinity FccRI The importance of Fc receptor interactions was recently (CD64) and low-affinity FccRIIa, FccRIIb, FccRIIc (CD32a-c), highlighted for broadly neutralizing antibodies (bNAbs) in FccRIIIa and FccRIIIb (CD16a and b); and their cooperation on protection against HIV infection (Gautam et al., 2016; Ward immune cells surface allows for a tailored cellular response et al., 2015). Various studies suggest that bNAbs can control against the target. Interaction of the antibody Fc region with persistent viral reservoirs, raising the possibility of their use for FccRs is influenced by glycans attached to a highly conserved treating infected individuals (Caskey et al., 2015; Chun et al., N-glycosylation site within the Fc fragment, and their 2014). Protective and therapeutic effects of antibodies are Please cite this article as: Stelter, S., Paul, M.J., Teh, A.Y.-H., Grandits, M., Altmann, F., Vanier, J., Bardor, M., Castilho, A., Allen, R.L., Ma, J.K-C. (2019) Engineering the interactions between a plant-produced HIV antibody and human Fc receptors. Plant Biotechnol. J., https://doi.org/10.1111/pbi.13207 ª 2019 The Authors. Plant Biotechnology Journal published by Society for Experimental Biology and The Association of Applied Biologists and John Wiley & Sons Ltd. 1 This is an open access article under the terms of the Creative Commons Attribution License, which permits use, distribution and reproduction in any medium, provided the original work is properly cited. 2 Szymon Stelter et al. largely dependent on the antibody Fc region, and were some (Forthal et al., 2010), but not all (Rosenberg et al., 2013), dramatically decreased when FcR-binding activities were engi- plant-produced antibodies. neered out of the antibodies (Bournazos et al., 2014). The mAb VRC01 expressed in plants demonstrated similar antigen role of FccRs in antibody-mediated protection against HIV binding and HIV neutralization activity to VRC01 produced in HEK infection was further emphasized in the RV144 vaccine trial, cells (Rosenberg et al., 2013; Teh et al., 2014). However, plant- where an estimated 30% of vaccinated individuals were derived VRC01 was cleared rapidly from the bloodstream in protected from acquiring HIV. Detailed analysis revealed that macaques (Rosenberg et al., 2013). The reason for the rapid the protective effect correlated with induction of IgG3 clearance observed for some plant-made antibodies is unknown, responses and high ADCC activity of the elicited antibodies and results are inconsistent (Khoudi et al., 1999; Lee et al., 2013; (Chung et al., 2014). Triguero et al., 2011). It has been suggested that distinct One of the first broadly neutralizing HIV antibodies discovered glycosylation of recombinant antibodies expressed in nonhuman using next-generation methods, VRC01 (Wu et al., 2010), has systems might have an indirect effect on FcRn binding (Jefferis, rapidly become an important clinical candidate for HIV prevention 2009a), even though human glycosylation does not affect and treatment (Ledgerwood et al., 2015). A single injection of binding of IgG to FcRn directly, because the receptor does not VRC01 antibody provided 8-week protection against HIV infec- come in close contact with the Fc glycans (Martin et al., 2001; tion in macaques, which was extended to 14.5 weeks by Nezlin and Ghetie, 2004). improving its binding to FcRn (Gautam et al., 2016). Moreover, In this study, the primary objective was to perform a compre- an engineered VRC01 demonstrated increased FcRn-mediated hensive analysis of the impact of glycosylation on mAb VRC01 delivery to gut mucosal tissue resulting in enhanced mucosal interactions with Fc receptors. Also, other post-translational localization and improved protection against SHIV challenge (Ko modifications, like methionine oxidation, were assessed in the et al., 2014). In humans, VRC01 has been the subject of context of FcRn binding. A panel of engineered glycovariants of numerous completed and current
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