Molecules and Cells

  • 제40권9호
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  • Pages.655-666
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  • 2017
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  • 1016-8478(pISSN)
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  • 0219-1032(eISSN)
한국분자세포생물학회 (Korean Society for Molecular and Cellular Biology)
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Generation, Diversity Determination, and Application to Antibody Selection of a Human Naïve Fab Library

  • Kim, Sangkyu (Department of Systems Immunology, College of Biomedical Science, Kangwon National University) ;
  • Park, Insoo (Therapeutic Antibody Research Center, Korea Research Institute of Bioscience and Biotechnology) ;
  • Park, Seung Gu (Department of Medical Biotechnology, College of Biomedical Science, Kangwon National University) ;
  • Cho, Seulki (Therapeutic Antibody Research Center, Korea Research Institute of Bioscience and Biotechnology) ;
  • Kim, Jin Hong (Therapeutic Antibody Research Center, Korea Research Institute of Bioscience and Biotechnology) ;
  • S.Ipper, Nagesh (Institute of Bioscience and Biotechnology, Kangwon National University) ;
  • Choi, Sun Shim (Department of Medical Biotechnology, College of Biomedical Science, Kangwon National University) ;
  • Lee, Eung Suk (Scripps Korea Antibody Institute) ;
  • Hong, Hyo Jeong (Department of Systems Immunology, College of Biomedical Science, Kangwon National University)
  • 투고 : 2017.06.27
  • 심사 : 2017.08.06
  • 발행 : 2017.09.30
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초록

We constructed a large $na{\ddot{i}}ve$ human Fab library ($3{\times}10^{10}$ colonies) from the lymphocytes of 809 human donors, assessed available diversities of the heavy-chain variable (VH) and ${\kappa}$ light-chain variable (VK) domain repertoires, and validated the library by selecting Fabs against 10 therapeutically relevant antigens by phage display. We obtained a database of unique 7,373 VH and 41,804 VK sequences by 454 pyrosequencing, and analyzed the repertoires. The distribution of VH and VK subfamilies and germline genes in our antibody repertoires slightly differed from those in earlier published natural antibody libraries. The frequency of somatic hypermutations (SHMs) in heavy-chain complementarity determining region (HCDR)1 and HCDR2 are higher compared with the natural IgM repertoire. Analysis of position-specific SHMs in CDRs indicates that asparagine, threonine, arginine, aspartate and phenylalanine are the most frequent non-germline residues on the antibody-antigen interface and are converted mostly from the germline residues, which are highly represented in germline SHM hotspots. The amino acid composition and length-dependent changes in amino acid frequencies of HCDR3 are similar to those in previous reports, except that frequencies of aspartate and phenylalanine are a little higher in our repertoire. Taken together, the results show that this antibody library shares common features of natural antibody repertoires and also has unique features. The antibody library will be useful in the generation of human antibodies against diverse antigens, and the information about the diversity of natural antibody repertoires will be valuable in the future design of synthetic human antibody libraries with high functional diversity.

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참고문헌

  1. Barbie, V., and Lefranc, M.P. (1998). The human immunoglobulin kappa variable (IGKV) genes and joining (IGKJ) segments. Exp. Clin. Immunogenet. 15, 171-183. https://doi.org/10.1159/000019068
  2. Boder, E.T., and Wittrup, K.D. (1997). Yeast surface display for screening combinatorial polypeptide libraries. Nat. Biotechnol. 15, 553-557. https://doi.org/10.1038/nbt0697-553
  3. Bruggemann, M., Osborn, M.J., Ma, B., Hayre, J., Avis, S., Lundstrom, B., and Buelow, R. (2015). Human antibody production in transgenic animals. Arch. Immunol. Ther. Exp. (Warsz.) 63, 101-108. https://doi.org/10.1007/s00005-014-0322-x
  4. Burkovitz, A., Sela-Culang, I., and Ofran, Y. (2014). Large-scale analysis of somatic hypermutations in antibodies reveals which structural regions, positions and amino acids are modified to improve affinity. The FEBS journal 281, 306-319. https://doi.org/10.1111/febs.12597
  5. Chaplin, D.D. (2003). 1. Overview of the immune response. J. Allergy Clin. Immunol. 111, S442-459. https://doi.org/10.1067/mai.2003.125
  6. Cho, S., Park, I., Kim, H., Jeong, M.S., Lim, M., Lee, E.S., Kim, J.H., Kim, S., and Hong, H.J. (2016). Generation, characterization and preclinical studies of a human anti-L1CAM monoclonal antibody that cross-reacts with rodent L1CAM. mAbs 8, 414-425. https://doi.org/10.1080/19420862.2015.1125067
  7. Clark, L.A., Ganesan, S., Papp, S., and van Vlijmen, H.W. (2006). Trends in antibody sequence changes during the somatic hypermutation process. J. Immunol. 177, 333-340. https://doi.org/10.4049/jimmunol.177.1.333
  8. Coomber, D.W. (2002). Panning of antibody phage-display libraries. Standard protocols. Methods Mol. Biol. 178, 133-145.
  9. Cox, J.P., Tomlinson, I.M., and Winter, G. (1994). A directory of human germ-line V kappa segments reveals a strong bias in their usage. Eur. J. Immunol. 24, 827-836. https://doi.org/10.1002/eji.1830240409
  10. Ecker, D.M., Jones, S.D., and Levine, H.L. (2015). The therapeutic monoclonal antibody market. mAbs 7, 9-14. https://doi.org/10.4161/19420862.2015.989042
  11. Geng, X., Kong, X., Hu, H., Chen, J., Yang, F., Liang, H., Chen, X., and Hu, Y. (2015). Research and development of therapeutic mAbs: An analysis based on pipeline projects. Hum. Vaccin. Immunother. 11, 2769-2776. https://doi.org/10.1080/21645515.2015.1074362
  12. Glanville, J., Zhai, W., Berka, J., Telman, D., Huerta, G., Mehta, G.R., Ni, I., Mei, L., Sundar, P.D., Day, G.M., et al. (2009). Precise determination of the diversity of a combinatorial antibody library gives insight into the human immunoglobulin repertoire. Proc. Natl. Acad. Sci. USA. 106, 20216-20221. https://doi.org/10.1073/pnas.0909775106
  13. Gram, H., Marconi, L.A., Barbas, C.F., 3rd, Collet, T.A., Lerner, R.A., and Kang, A.S. (1992). In vitro selection and affinity maturation of antibodies from a naive combinatorial immunoglobulin library. Proc. Natl. Acad. Sci. USA. 89, 3576-3580. https://doi.org/10.1073/pnas.89.8.3576
  14. Hanes, J., and Pluckthun, A. (1997). In vitro selection and evolution of functional proteins by using ribosome display. Proc. Natl. Acad. Sci. USA. 94, 4937-4942. https://doi.org/10.1073/pnas.94.10.4937
  15. Hoet, R.M., Cohen, E.H., Kent, R.B., Rookey, K., Schoonbroodt, S., Hogan, S., Rem, L., Frans, N., Daukandt, M., Pieters, H., et al. (2005). Generation of high-affinity human antibodies by combining donorderived and synthetic complementarity-determining-region diversity. Nat. Biotechnol. 23, 344-348. https://doi.org/10.1038/nbt1067
  16. Hoogenboom, H.R. (2005). Selecting and screening recombinant antibody libraries. Nat. Biotechnol. 23, 1105-1116. https://doi.org/10.1038/nbt1126
  17. Jackson, K.J., Wang, Y., and Collins, A.M. (2014). Human immunoglobulin classes and subclasses show variability in VDJ gene mutation levels. Immunol. Cell Biol. 92, 729-733. https://doi.org/10.1038/icb.2014.44
  18. Jung, E., Lee, J., Hong, H.J., Park, I., and Lee, Y. (2014). RNA recognition by a human antibody against brain cytoplasmic 200 RNA. RNA 20, 805-814. https://doi.org/10.1261/rna.040899.113
  19. Kawasaki, K., Minoshima, S., Nakato, E., Shibuya, K., Shintani, A., Schmeits, J.L., Wang, J., and Shimizu, N. (1997). One-megabase sequence analysis of the human immunoglobulin lambda gene locus. Genome Res. 7, 250-261. https://doi.org/10.1101/gr.7.3.250
  20. Kim, S.J., and Hong, H.J. (2012). Humanization by guided selections. Methods Mol. Biol. 907, 247-257.
  21. Kugler, J., Wilke, S., Meier, D., Tomszak, F., Frenzel, A., Schirrmann, T., Dubel, S., Garritsen, H., Hock, B., Toleikis, L., et al. (2015). Generation and analysis of the improved human HAL9/10 antibody phage display libraries. BMC Biotechnol. 15, 10. https://doi.org/10.1186/s12896-015-0125-0
  22. Lloyd, C., Lowe, D., Edwards, B., Welsh, F., Dilks, T., Hardman, C., and Vaughan, T. (2009). Modelling the human immune response: performance of a 1011 human antibody repertoire against a broad panel of therapeutically relevant antigens. Protein Eng. Des. Sel. 22, 159-168.
  23. Market, E., and Papavasiliou, F.N. (2003). V(D)J recombination and the evolution of the adaptive immune system. PLoS Biol. 1, E16. https://doi.org/10.1371/journal.pbio.0000016
  24. Matsuda, F., and Honjo, T. (1996). Organization of the human immunoglobulin heavy-chain locus. Adv. Immunol. 62, 1-29.
  25. McCafferty, J., Griffiths, A.D., Winter, G., and Chiswell, D.J. (1990). Phage antibodies: filamentous phage displaying antibody variable domains. Nature 348, 552-554. https://doi.org/10.1038/348552a0
  26. Muramatsu, M., Sankaranand, V.S., Anant, S., Sugai, M., Kinoshita, K., Davidson, N.O., and Honjo, T. (1999). Specific expression of activation-induced cytidine deaminase (AID), a novel member of the RNA-editing deaminase family in germinal center B cells. J. Biol. Chem. 274, 18470-18476. https://doi.org/10.1074/jbc.274.26.18470
  27. Muramatsu, M., Kinoshita, K., Fagarasan, S., Yamada, S., Shinkai, Y., and Honjo, T. (2000). Class switch recombination and hypermutation require activation-induced cytidine deaminase (AID), a potential RNA editing enzyme. Cell 102, 553-563. https://doi.org/10.1016/S0092-8674(00)00078-7
  28. Oh, M.S., Kim, K.S., Jang, Y.K., Maeng, C.Y., Min, S.H., Jang, M.H., Yoon, S.O., Kim, J.H., and Hong, H.J. (2003). A new epitope tag from hepatitis B virus preS1 for immunodetection, localization and affinity purification of recombinant proteins. J. Immunol. Methods 283, 77-89. https://doi.org/10.1016/j.jim.2003.08.010
  29. Pallares, N., Frippiat, J.P., Giudicelli, V., and Lefranc, M.P. (1998). The human immunoglobulin lambda variable (IGLV) genes and joining (IGLJ) segments. Exp. Clin. Immunogenet. 15, 8-18. https://doi.org/10.1159/000019054
  30. Perelson, A.S., and Oster, G.F. (1979). Theoretical studies of clonal selection: minimal antibody repertoire size and reliability of self-nonself discrimination. J. Theor. Biol. 81, 645-670. https://doi.org/10.1016/0022-5193(79)90275-3
  31. Ponsel, D., Neugebauer, J., Ladetzki-Baehs, K., and Tissot, K. (2011). High affinity, developability and functional size: the holy grail of combinatorial antibody library generation. Molecules 16, 3675-3700. https://doi.org/10.3390/molecules16053675
  32. Raghunathan, G., Smart, J., Williams, J., and Almagro, J.C. (2012). Antigen-binding site anatomy and somatic mutations in antibodies that recognize different types of antigens. J. Mol. Recognit. 25, 103-113. https://doi.org/10.1002/jmr.2158
  33. Rothlisberger, D., Honegger, A., and Pluckthun, A. (2005). Domain interactions in the Fab fragment: a comparative evaluation of the single-chain Fv and Fab format engineered with variable domains of different stability. J. Mol. Biol. 347, 773-789. https://doi.org/10.1016/j.jmb.2005.01.053
  34. Schatz, D.G. (2004). V(D)J recombination. Immunol. Rev. 200, 5-11. https://doi.org/10.1111/j.0105-2896.2004.00173.x
  35. Schwimmer, L.J., Huang, B., Giang, H., Cotter, R.L., Chemla-Vogel, D.S., Dy, F.V., Tam, E.M., Zhang, F., Toy, P., Bohmann, D.J., et al. (2013). Discovery of diverse and functional antibodies from large human repertoire antibody libraries. J. Immunol. Methods 391, 60-71. https://doi.org/10.1016/j.jim.2013.02.010
  36. Selsted, M.E., and Ouellette, A.J. (2005). Mammalian defensins in the antimicrobial immune response. Nat. Immunol. 6, 551-557. https://doi.org/10.1038/ni1206
  37. Sharma, S., Byrne, H., and O'Kennedy, R.J. (2016). Antibodies and antibody-derived analytical biosensors. Essays Biochem. 60, 9-18. https://doi.org/10.1042/EBC20150002
  38. Tiller, T., Schuster, I., Deppe, D., Siegers, K., Strohner, R., Herrmann, T., Berenguer, M., Poujol, D., Stehle, J., Stark, Y., et al. (2013). A fully synthetic human Fab antibody library based on fixed VH/VL framework pairings with favorable biophysical properties. mAbs 5, 445-470. https://doi.org/10.4161/mabs.24218
  39. Tomlinson, I.M., Walter, G., Marks, J.D., Llewelyn, M.B., and Winter, G. (1992). The repertoire of human germline VH sequences reveals about fifty groups of VH segments with different hypervariable loops. J. Mol. Biol. 227, 776-798. https://doi.org/10.1016/0022-2836(92)90223-7
  40. Tomlinson, I.M., Walter, G., Jones, P.T., Dear, P.H., Sonnhammer, E.L., and Winter, G. (1996). The imprint of somatic hypermutation on the repertoire of human germline V genes. J. Mol. Biol. 256, 813-817. https://doi.org/10.1006/jmbi.1996.0127
  41. Tonegawa, S. (1983). Somatic generation of antibody diversity. Nature 302, 575-581. https://doi.org/10.1038/302575a0
  42. Trepel, F. (1974). Number and distribution of lymphocytes in man. A critical analysis. Klin. Wochenschr. 52, 511-515. https://doi.org/10.1007/BF01468720
  43. Vargas-Madrazo, E., Lara-Ochoa, F., Ramirez-Benites, M.C., and Almagro, J.C. (1997). Evolution of the structural repertoire of the human V(H) and Vkappa germline genes. Int. Immunol. 9, 1801- 1815. https://doi.org/10.1093/intimm/9.12.1801
  44. Wei, C.H., Lee, E.S., Jeon, J.Y., Heo, Y.S., Kim, S.J., Jeon, Y.H., Kim, K.H., Hong, H.J., and Ryu, S.E. (2011). Structural mechanism of the antigen recognition by the L1 cell adhesion molecule antibody A10- A3. FEBS Lett. 585, 153-158. https://doi.org/10.1016/j.febslet.2010.11.028
  45. Williams, S.C., Frippiat, J.P., Tomlinson, I.M., Ignatovich, O., Lefranc, M.P., and Winter, G. (1996). Sequence and evolution of the human germline V lambda repertoire. J. Mol. Biol. 264, 220-232. https://doi.org/10.1006/jmbi.1996.0636
  46. Wu, T.T., and Kabat, E.A. (1970). An analysis of the sequences of the variable regions of Bence Jones proteins and myeloma light chains and their implications for antibody complementarity. J. Exp. Med. 132, 211-250. https://doi.org/10.1084/jem.132.2.211
  47. Yoon, S.O., Lee, T.S., Kim, S.J., Jang, M.H., Kang, Y.J., Park, J.H., Kim, K.S., Lee, H.S., Ryu, C.J., Gonzales, N.R., et al. (2006). Construction, affinity maturation, and biological characterization of an anti-tumorassociated glycoprotein-72 humanized antibody. J. Biol. Chem. 281, 6985-6992. https://doi.org/10.1074/jbc.M511165200
  48. Zemlin, M., Klinger, M., Link, J., Zemlin, C., Bauer, K., Engler, J.A., Schroeder, H.W., Jr., and Kirkham, P.M. (2003). Expressed murine and human CDR-H3 intervals of equal length exhibit distinct repertoires that differ in their amino acid composition and predicted range of structures. J. Mol. Biol. 334, 733-749. https://doi.org/10.1016/j.jmb.2003.10.007
  49. Zhai, W., Glanville, J., Fuhrmann, M., Mei, L., Ni, I., Sundar, P.D., Van Blarcom, T., Abdiche, Y., Lindquist, K., Strohner, R., et al. (2011). Synthetic antibodies designed on natural sequence landscapes. Journal of molecular biology 412, 55-71. https://doi.org/10.1016/j.jmb.2011.07.018
  50. Zhu, Z., and Dimitrov, D.S. (2009). Construction of a large naive human phage-displayed Fab library through one-step cloning. Methods Mol. Biol. 525, 129-142, xv.

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