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Properties, production, and applications of camelid single-domain antibody fragments
Open accessAbstract
Camelids produce functional antibodies devoid of light chains of which the single N-terminal domain is fully capable of antigen binding. These single-domain antibody fragments (VHHs or Nanobodies®) have several advantages for biotechnological applications. They are well expressed in microorganisms and have a high stability and solubility. Furthermore, they are well suited for construction of larger molecules and selection systems such as phage, yeast, or ribosome display. This minireview offers an overview of (1) their properties as compared to conventional antibodies, (2) their production in microorganisms, with a focus on yeasts, and (3) their therapeutic applications.
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“Given their high-affinity, solubility and stability also in absence of the partner VL domain, the camelid VH domains (VHH) [4] and the shark VH domains called V-NAR (New Antigen Receptor) [5], are currently used as templates to generate highly efficient and stable new antibody fragments collectively termed nanobodies [6,7,8].”
From Evolution of Escherichia coli Expression System in Producing Antibody Recombinant Fragments (2020) · cites this paper as [4]
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Naturally occurring antibodies devoid of light chains
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“Sequence analysis (Hamers-Casterman et al. 1993; Muyldermans et al. 1994; Vu et al. 1997; Harmsen et al. 2000) and elucidation of the crystal structure (Desmyter et al.”
BackgroundInfluentialRapid generation of functional human IgG antibodies derived from Fab-on-phage display libraries
Jostock, T., Vanhove, M., Brepoels, E., van Gool, R., Daukandt, M., Wehnert, A., van Hegelsom, R., Dransfield, D., Sexton, D., Devlin, M., et al. (2004) · Journal of Immunological Methods · doi:10.1016/j.jim.2004.03.014 · Cited by 2,572
Engineered antibody fragments and the rise of single domains
Holliger, P., & Hudson, P. J. (2005) · Nature Biotechnology · doi:10.1038/nbt1142 · Cited by 1,928 · cited 1×
“As compared to human VH domains, the VHH FRs show a high sequence homology of more than 80%, and their 3D structures can be superimposed (Muyldermans et al. 2001; Holliger and Hudson 2005).”
BackgroundWard, E. S., Güssow, D., Griffiths, A. D., Jones, P., & Winter, G. P. (1989) · Nature · doi:10.1038/341544a0 · Cited by 1,010 · cited 2×
“Although isolated antibody heavy (Utsumi and Karush 1964) and light chains (Yoo et al. 1967) can retain antigenbinding specificity, their affinity and solubility is often reduced (Ward et al. 1989).”
BackgroundGreenberg, A. S., Avila, D. W., Hughes, M. K., Hughes, A. L., McKinney, E. C., & Flajnik, M. F. (1995) · Nature · doi:10.1038/374168a0 · Cited by 783 · cited 2×
“Although single-domain antibodies later were also identified in particular cartilaginous fish (Greenberg et al. 1995), most research on the biotechnological application of singledomain antibodies was done using camelids because of Appl Microbiol Biotechnol (2007) 77:13–22”
BackgroundSelection and identification of single domain antibody fragments from camel heavy‐chain antibodies
Ghahroudi, M. A., Desmyter, A., Wyns, L., HAMERS, R., & Muyldermans, S. (1997) · FEBS Letters · doi:10.1016/s0014-5793(97)01062-4 · Cited by 775 · cited 1×
“Methods to isolate antigen-specific VHHs from immune ( Arbabi-Ghahroudi et al. 1997; Van der Linden et al. 2000a), nonimmune (Tanha et al. 2002; Yau et al. 2003; Verheesen et al. 2006), or semisynthetic (Goldman et al. 2006) libraries using phage, yeast, or ribosome display are now well established.”
BackgroundTargeting and tracing antigens in live cells with fluorescent nanobodies
Rothbauer, U., Zolghadr, K., Tillib, S. V., Nowak, D., Schermelleh, L., Gahl, A., Backmann, N., Conrath, K., Muyldermans, S., Cardoso, M. C., et al. (2006) · Nature Methods · doi:10.1038/nmeth953 · Cited by 715 · cited 1×
“Because of their stability, VHHs are especially suited for intrabody production because this requires expression in the reducing environment of the cytoplasm (Gueorguieva et al. 2006; Rothbauer et al. 2006).”
BackgroundMolecular basis for the preferential cleft recognition by dromedary heavy-chain antibodies
Genst, E. D., Silence, K., Decanniere, K., Conrath, K., Loris, R., Kinne, J., Muyldermans, S., & Wyns, L. (2006) · Proceedings of the National Academy of Sciences · doi:10.1073/pnas.0505379103 · Cited by 681 · cited 4×
“Occasionally, VHHs with affinity constants (KD) as low as 100 pM are isolated (Saerens et al. 2004; De Genst et al. 2006; Harmsen et al. 2006), which equals the affinity ceiling proposed for natural antibodies (Sundberg and Mariuzza 2002).”
BackgroundInfluentialSingle‐domain antibody fragments with high conformational stability
Dumoulin, M., Conrath, K., Meirhaeghe, A. V., Meersman, F., Heremans, K., Frenken, L. G. J., Muyldermans, S., Wyns, L., & Matagne, A. (2002) · Protein Science · doi:10.1110/ps.34602 · Cited by 641 · cited 4×
“VHHs are especially suited for oral immunotherapy because of their resistance against extremes of pH and the capacity to bind to the target at high concentrations of chaotropic agents (Dumoulin et al. 2002, 2003).”
BackgroundInfluentialStructure-Immunogenicity Relationships of Therapeutic Proteins
Hermeling, S., Crommelin, D. J. A., Schellekens, H., & Jiskoot, W. (2004) · Pharmaceutical Research · doi:10.1023/b:pham.0000029275.41323.a6 · Cited by 617 · cited 1×
“This could rely on their high sequence homology to conventional VH domains and on their high stability because aggregation of proteins is known to increase immunogenicity (Hermeling et al. 2004).”
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“To stabilize the enlarged CDRs, nanobodies often possess an additional disulfide bond between CDR1 and CDR3 in dromedaries, and CDR2 and CDR3 in llamas.(19) Nanobodies have been raised to numerous viruses (reviewed by Vanlandschoot et al.”
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“Clear advantages include the ability to recognize hidden antigenic sites that are inaccessible for conventional antibodies due to their structure; stability over a wide range of temperatures and pH; high solubility, as well as economical and facile expression and production in large quantities in microorganisms [15, 1…”
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“antigen receptor) from the respective HCAbs can be used to generate highly stable nanobodies of minimal size (Figure 4C) (11 - 15 kDa) [50].”
BackgroundBacterial transmembrane signalling systems and their engineering for biosensing
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“achieve binding affinities similar to conventional IgGs [49].”
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“Although the anti-EGFR1 nanobody was reported to have no immunogenicity in preclinical and clinical tests [30, 69], the risk of immunogenicity of MaAbNA still exists due to the Staphylococcus origin of the affibody molecules.”
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Toward Drug-Like Multispecific Antibodies by Design
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“The singular VHH domains of HCAbs are also referred to as nanobodies® (trademarked by Ablynx) or single domain antibodies [16,17] (Figure 1(e)).”
BackgroundSelection of specific nanobodies to develop an immuno-assay detecting Staphylococcus aureus in milk
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Pick a Tag and Explore the Functions of Your Pet Protein
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“Llama single domain antibody fragments have been abundantly studied and excellent reviews on the subject are available [6, 17 , 27, 28].”
BackgroundSurface display of a single-domain antibody library on Gram-positive bacteria
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“Moreover, they can readily be produced in many recombinant protein expression systems, including bacterial and yeast cells [5, 12].”
BackgroundA single-domain antibody inhibits SFTSV and mitigates virus-induced pathogenesis in vivo
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“currently known, which is also called nanobody or single-domain antibody (15, 16).”
BackgroundTakeuchi, T., Kawanishi, M., Nakanishi, M., Yamasaki, H., & Tanaka, Y. (2022) · Arthritis & Rheumatology · doi:10.1002/art.42273 · Cited by 63
“antibody naturally produced by llamas and other camelids (4,5).”
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Ultrasensitive and rapid colorimetric detection of paraquat via a high specific VHH nanobody
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A VHH That Neutralizes the Zinc Metalloproteinase Activity of Botulinum Neurotoxin Type A
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Cell Penetrable Humanized-VH/VHH That Inhibit RNA Dependent RNA Polymerase (NS5B) of HCV
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“It is now generally accepted that the VHH is a potent enzyme inhibitor [12].”
BackgroundReceptor signals come in waves
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“Although a putative additional disulfide bond has been observed in two llama VHH subfamilies, in most cases the llama VHH lacks such a bond [34, 35].”
BackgroundSingle-domain antibody fragments derived from heavy-chain antibodies: a review
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Nanobodies: The Future of Antibody-Based Immune Therapeutics
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“7 The heavy-chain-only antibody and conventional antibody differs in the light chains; the heavy-chain-only antibodies are devoid of the variable and constant light chain along with the CH1 domain 8 (Fig.”
Evaluation of a nanobody phage display library constructed from a Brucella-immunised camel
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Formatted single-domain antibodies can protect mice against infection with influenza virus (H5N2)
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“In the present study, we have chosen to design nanobody-PE38 immunotoxin for two reasons: 1) nanobody should have reduced immunogenicity, because most human-anti-mouse antibody responses (HAMA) are directed against the Fc-portion of whole antibodies [32] and nanobodies are weakly immunogenic in humans [33]; 2) it has…”
MethodPhage display antibodies for diagnostic applications
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“Newer formats such as human domain antibodies, camelid domain antibodies [13], single”
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Small Molecules That Target Protein Misfolding
Gavrin, L. K., Denny, R. A., & Saiah, E. (2012) · Journal of Medicinal Chemistry · doi:10.1021/jm301182j · Cited by 53
“Camel nanoantibody” is an efficient tool for research, diagnostics and therapy
Tillib, S. V. (2011) · Molecular Biology · doi:10.1134/s0026893311010134 · Cited by 52
Neutralizing Nanobodies Targeting Diverse Chemokines Effectively Inhibit Chemokine Function
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Hassani, M., Taheri, F. H., Sharifzadeh, Z., Arashkia, A., Hadjati, J., van Weerden, W. M., Modarressi, M. H., & Abolhassani, M. (2019) · Journal of Cellular Biochemistry · doi:10.1002/jcb.28370 · Cited by 55
“Due to the absence of an Fc‐domain, VHHs can be generated by Escherichia coli or yeast, which are time‐saving and cost‐effective.(18) In this report, we engineered a CARs to augment the efficacy of T cells combined with the specificity of the antibody.”
MethodFunctionalization of gold nanoparticles with nanobodies through physical adsorption
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Chemically Synthesized Molecules with the Targeting and Effector Functions of Antibodies
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Novel Therapy Based on Camelid Nanobodies
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In Vivo Neutralization of Botulinum Neurotoxins Serotype E with Heavy-chain Camelid Antibodies (VHH)
Bakherad, H., Gargari, S. L. M., Rasooli, I., Rajabibazl, M., Mohammadi, M. R., Ebrahimizadeh, W., Ardekani, L. S., & Zare, H. (2013) · Molecular Biotechnology · doi:10.1007/s12033-013-9669-1 · Cited by 49
“In conclusion, the recombinant VHH finds their applications in the diagnostic tools and treatment measures for their very stable, highly soluble, specific response and high affinity [19].”
BackgroundAymé, G., Adam, F., Legendre, P., Bazaa, A., Proulle, V., Denis, C. V., Christophe, O. D., & Lenting, P. J. (2017) · Arteriosclerosis Thrombosis and Vascular Biology · doi:10.1161/atvbaha.117.309319 · Cited by 49
Nanobodies - the new concept in antibody engineering
Deffar, K., Shi, H., Li, L., Wang, X., & Zhu, X. (2009) · AFRICAN JOURNAL OF BIOTECHNOLOGY · doi:10.5897/ajb09.353 · Cited by 48
SITE-SPECIFIC FUNCTIONALIZATION OF PROTEINS AND THEIR APPLICATIONS TO THERAPEUTIC ANTIBODIES
van Vught, R., Pieters, R. J., & Breukink, E. J. (2014) · Computational and Structural Biotechnology Journal · doi:10.5936/csbj.201402001 · Cited by 49
Chavanayarn, C., Thanongsaksrikul, J., Thueng-in, K., Bangphoomi, K., Sookrung, N., & Chaicumpa, W. (2012) · Toxins · doi:10.3390/toxins4070554 · Cited by 47
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Protective Effect of Different Anti-Rabies Virus VHH Constructs against Rabies Disease in Mice
Terryn, S., Francart, A., Lamoral, S., Hultberg, A., Rommelaere, H., Wittelsberger, A., Callewaert, F., Stöhr, T., Meerschaert, K., Ottevaere, I., et al. (2014) · PLoS ONE · doi:10.1371/journal.pone.0109367 · Cited by 46
“The single domain nature and the small size of VHH allow easy formatting by genetic fusion into multimeric constructs with multiple specificities [4–6].”
BackgroundMizukami, M., Tokunaga, H., Onishi, H., Ueno, Y., Hanagata, H., Miyazaki, N., Kiyose, N., Ito, Y., Ishibashi, M., Hagihara, Y., et al. (2014) · Protein Expression and Purification · doi:10.1016/j.pep.2014.09.017 · Cited by 46
Engineered IgG1‐Fc – one fragment to bind them all
Laurent, E., Traxlmayr, M. W., Obinger, C., & Hasenhindl, C. (2016) · Immunological Reviews · doi:10.1111/imr.12385 · Cited by 46
“the single-domain antigen-binding fragments of camelid heavy chain antibodies, which, for example, have the potential for application in oral immunotherapy due to the increased resistance to extreme pH and proteolytic digest as compared to conventional antibodies (11, 12).”
BackgroundExpanding the Scope of Protein-Detecting Electrochemical DNA “Scaffold” Sensors
Kang, D., Parolo, C., Sun, S., Ogden, N. E., Dahlquist, F. W., & Plaxco, K. W. (2018) · ACS Sensors · doi:10.1021/acssensors.8b00311 · Cited by 46
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“Primary PCR was performed using oligonucleotide primers designed to universally prime mammalian immunoglobulin genes in the CH2 domain and also at the 59 end of alpaca VHH genes within the signal sequence [37,42,42,43] [AlpCH2_Rev, 59 CGC CAT CAA GGT ACC AGT TGA: AlpLFw_VHH, 59 GGT GGT CCT GGC TGC].”
MethodGriffin, L. M., Snowden, J. R., Lawson, A. D. G., Wernery, U., Kinne, J., & BAKER, T. S. (2014) · Journal of Immunological Methods · doi:10.1016/j.jim.2014.01.003 · Cited by 45
Toxin Neutralization Using Alternative Binding Proteins
Jenkins, T. P., Fryer, T., Dehli, R. I., Jürgensen, J. A., Fuglsang-Madsen, A. J., Føns, S., & Laustsen, A. H. (2019) · Toxins · doi:10.3390/toxins11010053 · Cited by 48
Picomolar SARS-CoV-2 Neutralization Using Multi-Arm PEG Nanobody Constructs
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“25,26 Taken together, we conducted a phase II study to evaluate the feasibility and safety of envafolimab plus lenvatinib and TACE in uHCC.”
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“Derived from the Camelid heavy chain antibody repertoire, which completely lack light chains, their single Nterminal domain (VHH) is fully capable of antigen binding with affinities comparable with those of conventional antibodies [10,11].”
Multifunctional receptor-targeting antibodies for cancer therapy
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van Lith, S. A. M., van Duijnhoven, S. M. J., Navis, A. C., Leenders, W. P. J., Dolk, E., Wennink, J. W. H., van Nostrum, C. F., & van Hest, J. C. M. (2017) · Bioconjugate Chemistry · doi:10.1021/acs.bioconjchem.6b00638 · Cited by 44
High-level expression of Camelid nanobodies in Nicotiana benthamiana
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Ta, D. T., Redeker, E. S., Billen, B., Reekmans, G., Sikulu, J., Noben, J., Guedens, W., & Adriaensens, P. (2015) · Protein Engineering Design and Selection · doi:10.1093/protein/gzv032 · Cited by 43
Zhong, L., Huang, X., Rodrigues, E. D., Leijten, J., Verrips, T. C., Khattabi, M. E., Karperien, M., & Post, J. N. (2016) · Stem Cells and Development · doi:10.1089/scd.2016.0222 · Cited by 43
“Compared with conventional antibodies, using VHH has several advantages, including small size (15 kDa) and high binding specificity and affinity [38], simple and easy to clone, and subsequently to genetically modify, they can be produced in bacteria and yeast [38,39].”
Development of Radiotracers for Imaging of the PD-1/PD-L1 Axis
Krutzek, F., Kopka, K., & Stadlbauer, S. (2022) · Pharmaceuticals · doi:10.3390/ph15060747 · Cited by 44
“Nanobodies can be engineered from heavy-chain antibodies found in camelids (VHH fragments), cartilaginous fishes (VNAR fragments), or from IgG antibodies found in mice and humans using genetic engineering techniques [84,87,90].”
BackgroundHarmsen, M. M., van Solt, C. B., & Fijten, H. (2009) · Applied Microbiology and Biotechnology · doi:10.1007/s00253-009-2029-1 · Cited by 43
Self-citationTanaka, Y., Kawanishi, M., Nakanishi, M., Yamasaki, H., & Takeuchi, T. (2022) · Modern Rheumatology · doi:10.1093/mr/roac126 · Cited by 42
Gómez-Sebastián, S., Núñez, M. C., Garaicoechea, L., Alvarado, C., Mozgovoj, M., Lasa, R., Kahl, A., Wigdorovitz, A., Parreño, V. G., & Escribano, J. M. (2012) · BMC Biotechnology · doi:10.1186/1472-6750-12-59 · Cited by 42
“coli, yeast, plants and mammalian cells [1], and there is only one”
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Clercq, S. D., Boucherie, C., Vandekerckhove, J. S., Gettemans, J., & Guillabert, A. (2013) · PLoS ONE · doi:10.1371/journal.pone.0078108 · Cited by 42
“Nanobodies correspond with the antigen-binding domains of ‘‘heavy-chain only antibodies’’, which are found in Camelidae species and cartilaginous fish such as sharks [33,34].”
BackgroundRetractedMarcotte, H., & Hammarström, L. L. G. (2015) · Elsevier eBooks · doi:10.1016/b978-0-12-415847-4.00071-9 · Cited by 41
“Several VHH are currently being studied for use in various areas, including infectious diseases (Harmsen and De Haard, 2007) .”
InfluentialImmunodiagnostic reagents using llama single domain antibody–alkaline phosphatase fusion proteins
Swain, M. D., Anderson, G. P., Serrano-González, J., Liu, J. L., Zabetakis, D., & Goldman, E. R. (2011) · Analytical Biochemistry · doi:10.1016/j.ab.2011.06.012 · Cited by 41
Alzogaray, V., Danquah, W., Aguirre, A., Urrutia, M., Berguer, P. M., Véscovi, E. G., Haag, F., Koch‐Nolte, F., & Goldbaum, F. A. (2010) · The FASEB Journal · doi:10.1096/fj.10-162958 · Cited by 41
Secretion and functional display of fusion proteins through the curli biogenesis pathway
Gerven, N. V., Goyal, P., Vandenbussche, G., Kerpel, M. D., Jonckheere, W., Greve, H. D., & Remaut, H. K. (2014) · Molecular Microbiology · doi:10.1111/mmi.12515 · Cited by 41
Metadata
- Authors
- Harmsen, M. M., & De Haard, H. J.
- Affiliations
- Wageningen University & Research (NL)
- Ablynx (Belgium) (BE)
- Corresponding author
- Harmsen, M. M.
- Venue
- Applied Microbiology and Biotechnology
- Published
- 2007-08-18
- Volume
- 77
- Issue
- 1
- Pages
- 13-22
- ISSN
- 0175-7598 (ISSN-L)
- 1432-0614
- PMC
- PMC2039825
- OpenAlex
- W2147451568
- Cited by
- 809
- References
- 96
- Citations by year
- 2026: 31 · 2025: 43 · 2024: 48 · 2023: 41 · 2022: 41 · 2021: 65 · 2020: 57 · 2019: 49 · 2018: 53 · 2017: 42 · 2016: 46 · 2015: 48 · 2014: 53 · 2013: 40 · 2012: 52
- FWCI
- 2.67
- Type
- journal article
- Language
- en
- Open access
- hybrid
- doi.org
- Locations
- Applied Microbiology and Biotechnology (publishedVersion, cc-by)
- PubMed Central (publishedVersion, cc-by)
- PubMed (publishedVersion)
- Socio-Environmental Systems Modeling (acceptedVersion)
- Data Archiving and Networked Services (DANS) (submittedVersion, other-oa)
- Topics
- Life Sciences › Immunology and Microbiology › Immunology › Monoclonal and Polyclonal Antibodies Research
- Life Sciences › Biochemistry, Genetics and Molecular Biology › Molecular Biology › Protein purification and stability
- Life Sciences › Agricultural and Biological Sciences › Food Science › Animal Diversity and Health Studies
- Keywords
- single-domain antibody fragments, VHH, nanobodies, camelid antibodies, recombinant antibody production, yeast expression system, phage display, ribosome display, yeast surface display, therapeutic applications
- MeSH terms
- Animals, Camelids, New World, Immunoglobulin Fragments, Immunoglobulin Heavy Chains, Models, Biological
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