Antibody Fragments Produced by Recombinant and Proteolytic Methods

  • Gregory P. Adams

Summary

While monoclonal antibodies provide the means to specifically target radioisotopes to tumors, the initial clinical radioimmunotherapy trials were largely unsuccessful. In the past decade, the field of molecular biology has matured to the point where we can re-engineer antibodies to overcome the limitations that were likely responsible for the early failures of radioimmunotherapy. In this chapter the wide variety of engineered and proteolytically produced antibody fragments are described along with their potential benefits for radioimmunotherapy.

Keywords

Permeability Toxicity Filtration Albumin Recombination 

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References

  1. 1.
    Kohler, G. and Milstein, C. Continuous cultures of fused cells secreting antibody of predefined specificity. Nature, 256: 495-497, 1975.CrossRefPubMedGoogle Scholar
  2. 2.
    Holechek, M. J. Glomerular filtration: an overview. Nephrol Nurs J, 30: 285-290; quiz 291-282, 2003.Google Scholar
  3. 3.
    Schier, R., Bye, J., Apell, G., McCall, A., Adams, G. P., Malmqvist, M., Weiner, L. M., and Marks, J. D. Isolation of high-affinity monomeric human anti-c-erbB-2 single chain Fv using affinity-driven selection. J Mol Biol, 255: 28-43, 1996.CrossRefPubMedGoogle Scholar
  4. 4.
    Schier, R., McCall, A., Adams, G. P., Marshall, K. W., Merritt, H., Yim, M., Crawford, R. S., Weiner, L. M., Marks, C., and Marks, J. D. Isolation of picomolar affinity anti-c-erbB-2 singlechain Fv by molecular evolution of the complementarity determining regions in the center of the antibody binding site. J Mol Biol, 263: 551-567, 1996.CrossRefPubMedGoogle Scholar
  5. 5.
    Ghetie, V. and Ward, E. S. Multiple roles for the major histocompatibility complex class Irelated receptor FcRn. Annu Rev Immunol, 18: 739-766, 2000.CrossRefPubMedGoogle Scholar
  6. 6.
    Kortt, A. A., Lah, M., Oddie, G. W., Gruen, C. L., Burns, J. E., Pearce, L. A., Atwell, J. L., McCoy, A. J., Howlett, G. J., Metzger, D. W., Webster, R. G., and Hudson, P. J. Single-chain Fv fragments of anti-neuraminidase antibody NC10 containing five- and ten-residue linkers form dimers and with zero-residue linker a trimer. Protein Eng, 10: 423-433, 1997.CrossRefPubMedGoogle Scholar
  7. 7.
    Bird, R. E., Hardman, K. D., Jacobson, J. W., Johnson, S., Kaufman, B. M., Lee, S. M., Lee, T., Pope, S. H., Riordan, G. S., and Whitlow, M. Single-chain antigen-binding proteins. Science, 242: 423-426, 1988.CrossRefPubMedGoogle Scholar
  8. 8.
    Huston, J. S., Levinson, D., Mudgett-Hunter, M., Tai, M. S., Novotny, J., Margolies, M. N., Ridge, R. J., Bruccoleri, R. E., Haber, E., Crea, R., et al. Protein engineering of antibody binding sites: recovery of specific activity in an anti-digoxin single-chain Fv analogue produced in Escherichia coli. Proc Natl Acad Sci USA, 85: 5879-5883, 1988.CrossRefPubMedGoogle Scholar
  9. 9.
    Marks, J. D., Hoogenboom, H. R., Bonnert, T. P., McCafferty, J., Griffiths, A. D., and Winter, G. By-passing immunization. Human antibodies from V-gene libraries displayed on phage. J Mol Biol, 222: 581-597, 1991.CrossRefPubMedGoogle Scholar
  10. 10.
    Ward, E. S., Gussow, D., Griffiths, A. D., Jones, P. T., and Winter, G. Binding activities of a repertoire of single immunoglobulin variable domains secreted from Escherichia coli. Nature, 341: 544-546, 1989.CrossRefPubMedGoogle Scholar
  11. 11.
    Adams, G. P., McCartney, J. E., Tai, M. S., Oppermann, H., Huston, J. S., Stafford, W. F., 3rd, Bookman, M. A., Fand, I., Houston, L. L., and Weiner, L. M. Highly specific in vivo tumor targeting by monovalent and divalent forms of 741F8 anti-c-erbB-2 single-chain Fv. Cancer Res, 53: 4026-4034, 1993.PubMedGoogle Scholar
  12. 12.
    Beresford, G. W., Pavlinkova, G., Booth, B. J., Batra, S. K., and Colcher, D. Binding characteristics and tumor targeting of a covalently linked divalent CC49 single-chain antibody. Int J Cancer, 81: 911-917, 1999.CrossRefPubMedGoogle Scholar
  13. 13.
    Robinson, M. K., Hodge, K., Sundberg, A. L., Russeva, M., Horak, E., Shaller, C., von Mehren, M., Simmons, H. H., Marks, J. D., and Adams, G. P. Targeting ErbB2 and ErbB3 with a bispecific-single chain Fv enhances targeting selectivity and induces a therapeutic effect in vitro. Br J Cancer Unpublished data, 2008.Google Scholar
  14. 14.
    Goldenberg, D. M., Chatal, J. F., Barbet, J., Boerman, O., and Sharkey, R. M. Cancer imaging and therapy with bispecific antibody pretargeting. Update Cancer Ther, 2: 19-31, 2007.CrossRefPubMedGoogle Scholar
  15. 15.
    Adams, G. P., Schier, R., McCall, A. M., Crawford, R. S., Wolf, E. J., Weiner, L. M., and Marks, J. D. Prolonged in vivo tumour retention of a human diabody targeting the extracellular domain of human HER2/neu. Br J Cancer, 77: 1405-1412, 1998.PubMedGoogle Scholar
  16. 16.
    Holliger, P., Prospero, T., and Winter, G. ‘Diabodies’: small bivalent and bispecific antibody fragments. Proc Natl Acad Sci, 90: 6444-6448, 1993.CrossRefPubMedGoogle Scholar
  17. 17.
    Yazaki, P. J., Wu, A. M., Tsai, S. W., Williams, L. E., Ikler, D. N., Wong, J. Y., Shively, J. E., and Raubitschek, A. A. Tumor targeting of radiometal labeled anti-CEA recombinant T84.66 diabody and t84.66 minibody: comparison to radioiodinated fragments. Bioconjug Chem, 12: 220-228, 2001.CrossRefPubMedGoogle Scholar
  18. 18.
    Adams, G. P., Shaller, C. C., Dadachova, E., Simmons, H. H., Horak, E. M., Tesfaye, A., Klein-Szanto, A. J., Marks, J. D., Brechbiel, M. W., and Weiner, L. M. A single treatment of yttrium-90-labeled CHX-A”-C6.5 diabody inhibits the growth of established human tumor xenografts in immunodeficient mice. Cancer Res, 64: 6200-6206, 2004.CrossRefPubMedGoogle Scholar
  19. 19.
    Robinson, M. K., Shaller, C., Garmestani, K., Plascjak, P. S., Hodge, K. M., Yuan, Q. A., Marks, J. D., Waldmann, T. A., Brechbiel, M. W., and Adams, G. P. Effective treatment of established human breast tumor xenografts in immunodeficient mice with a single dose of the alpha-emitting radioisotope astatine-211 conjugated to anti-HER2/neu diabodies. Clin Cancer Res, 14: 875-882, 2008.CrossRefPubMedGoogle Scholar
  20. 20.
    Lawrence, L. J., Kortt, A. A., Iliades, P., Tulloch, P. A., and Hudson, P. J. Orientation of antigen binding sites in dimeric and trimeric single chain Fv antibody fragments. FEBS Lett, 425: 479-484, 1998.CrossRefPubMedGoogle Scholar
  21. 21.
    Le Gall, F., Kipriyanov, S. M., Moldenhauer, G., and Little, M. Di-, tri- and tetrameric single chain Fv antibody fragments against human CD19: effect of valency on cell binding. FEBS Lett, 453: 164-168, 1999.CrossRefPubMedGoogle Scholar
  22. 22.
    Pei, X. Y., Holliger, P., Murzin, A. G., and Williams, R. L. The 2.0-A resolution crystal structure of a trimeric antibody fragment with noncognate VH-VL domain pairs shows a rearrangement of VH CDR3. Proc Natl Acad Sci USA, 94: 9637-9642, 1997.CrossRefPubMedGoogle Scholar
  23. 23.
    Hu, S., Shively, L., Raubitschek, A., Sherman, M., Williams, L. E., Wong, J. Y., Shively, J. E., and Wu, A. M. Minibody: A novel engineered anti-carcinoembryonic antigen antibody fragment (single-chain Fv-CH3) which exhibits rapid, high-level targeting of xenografts. Cancer Res, 56: 3055-3061, 1996.PubMedGoogle Scholar
  24. 24.
    Wu, A. M. and Yazaki, P. J. Designer genes: recombinant antibody fragments for biological imaging. Q J Nucl Med, 44: 268-283, 2000.PubMedGoogle Scholar
  25. 25.
    Kenanova, V., Olafsen, T., Williams, L. E., Ruel, N. H., Longmate, J., Yazaki, P. J., Shively, J. E., Colcher, D., Raubitschek, A. A., and Wu, A. M. Radioiodinated versus radiometallabeled anti-carcinoembryonic antigen single-chain Fv-Fc antibody fragments: optimal pharmacokinetics for therapy. Cancer Res, 67: 718-726, 2007.CrossRefPubMedGoogle Scholar
  26. 26.
    Powers, D. B., Amersdorfer, P., Poul, M., Nielsen, U. B., Shalaby, M. R., Adams, G. P., Weiner, L. M., and Marks, J. D. Expression of single-chain Fv-Fc fusions in Pichia pastoris. J Immunol Methods, 251: 123-135, 2001.CrossRefPubMedGoogle Scholar
  27. 27.
    Mueller, B. M., Reisfeld, R. A., and Gillies, S. D. Serum half-life and tumor localization of a chimeric antibody deleted of the CH2 domain and directed against the disialoganglioside GD2. Proc Natl Acad Sci USA, 87: 5702-5705, 1990.CrossRefPubMedGoogle Scholar
  28. 28.
    Lu, D., Shen, J., Vil, M. D., Zhang, H., Jimenez, X., Bohlen, P., Witte, L., and Zhu, Z. Tailoring in vitro selection for a picomolar-affinity human antibody directed against VEGF receptor 2 for enhanced neutralizing activity. J Biol Chem, 2003.Google Scholar
  29. 29.
    Green, L. L. Antibody engineering via genetic engineering of the mouse: XenoMouse strains are a vehicle for the facile generation of therapeutic human monoclonal antibodies. J Immunol Methods, 231: 11-23, 1999.CrossRefPubMedGoogle Scholar
  30. 30.
    Clackson, T., Hoogenboom, H. R., Griffiths, A. D., and Winter, G. Making antibody fragments using phage display libraries. Nature, 352: 624-628, 1991.CrossRefPubMedGoogle Scholar
  31. 31.
    Winter, G., Griffiths, A. D., Hawkins, R. E., and Hoogenboom, H. R. Making antibodies by phage display technology. Annu Rev Immunol, 12: 433-455, 1994.CrossRefPubMedGoogle Scholar
  32. 32.
    Feldhaus, M. J. and Siegel, R. W. Yeast display of antibody fragments: a discovery and characterization platform. J Immunol Methods, 290: 69-80, 2004.CrossRefPubMedGoogle Scholar
  33. 33.
    Swers, J. S., Kellogg, B. A., and Wittrup, K. D. Shuffled antibody libraries created by in vivo homologous recombination and yeast surface display. Nucleic Acids Res, 32: e36, 2004.CrossRefPubMedGoogle Scholar
  34. 34.
    Hanes, J. and Pluckthun, A. In vitro selection and evolution of functional proteins by using ribosome display. Proc Natl Acad Sci USA, 94: 4937-4942, 1997.CrossRefPubMedGoogle Scholar
  35. 35.
    Harvey, B. R., Georgiou, G., Hayhurst, A., Jeong, K. J., Iverson, B. L., and Rogers, G. K. Anchored periplasmic expression, a versatile technology for the isolation of high-affinity antibodies from Escherichia coli-expressed libraries. Proc Natl Acad Sci USA, 101: 9193-9198, 2004.CrossRefPubMedGoogle Scholar
  36. 36.
    Davies Cde, L., Berk, D. A., Pluen, A., and Jain, R. K. Comparison of IgG diffusion and extracellular matrix composition in rhabdomyosarcomas grown in mice versus in vitro as spheroids reveals the role of host stromal cells. Br J Cancer, 86: 1639-1644, 2002.CrossRefPubMedGoogle Scholar
  37. 37.
    Halin, C., Niesner, U., Villani, M. E., Zardi, L., and Neri, D. Tumor-targeting properties of antibody-vascular endothelial growth factor fusion proteins. Int J Cancer, 102: 109-116, 2002.CrossRefPubMedGoogle Scholar
  38. 38.
    Carnemolla, B., Borsi, L., Balza, E., Castellani, P., Meazza, R., Berndt, A., Ferrini, S., Kosmehl, H., Neri, D., and Zardi, L. Enhancement of the antitumor properties of interleukin-2 by its targeted delivery to the tumor blood vessel extracellular matrix. Blood, 99: 1659-1665, 2002.CrossRefPubMedGoogle Scholar
  39. 39.
    Halin, C., Gafner, V., Villani, M. E., Borsi, L., Berndt, A., Kosmehl, H., Zardi, L., and Neri, D. Synergistic therapeutic effects of a tumor targeting antibody fragment, fused to interleukin 12 and to tumor necrosis factor alpha. Cancer Res, 63: 3202-3210, 2003.PubMedGoogle Scholar
  40. 40.
    Wochner, R. D., Strober, W., and Waldmann, T. A. The role of the kidney in the catabolism of Bence Jones proteins and immunoglobulin fragments. J Exp Med, 126: 207-221, 1967.CrossRefPubMedGoogle Scholar
  41. 41.
    Tarburton, J. P., Halpern, S. E., Hagan, P. L., Sudora, E., Chen, A., Fridman, D. M., and Pfaff, A. E. Effect of acetylation on monoclonal antibody ZCE-025 Fab’: distribution in normal and tumor-bearing mice. J Biol Response Mod, 9: 221-230, 1990.PubMedGoogle Scholar
  42. 42.
    Pavlinkova, G., Beresford, G., Booth, B. J., Batra, S. K., and Colcher, D. Charge-modified single chain antibody constructs of monoclonal antibody CC49: generation, characterization, pharmacokinetics, and biodistribution analysis. Nucl Med Biol, 26: 27-34, 1999.CrossRefPubMedGoogle Scholar
  43. 43.
    Dennis, M. S., Zhang, M., Meng, Y. G., Kadkhodayan, M., Kirchhofer, D., Combs, D., and Damico, L. A. Albumin binding as a general strategy for improving the pharmacokinetics of proteins. J Biol Chem, 277: 35035-35043, 2002.CrossRefPubMedGoogle Scholar
  44. 44.
    Huston, J. S., George, A. J., Adams, G. P., Stafford, W. F., Jamar, F., Tai, M. S., McCartney, J. E., Oppermann, H., Heelan, B. T., Peters, A. M., Houston, L. L., Bookman, M. A., Wolf, E. J., and Weiner, L. M. Single-chain Fv radioimmunotargeting. Q J Nucl Med, 40: 320-333, 1996.PubMedGoogle Scholar
  45. 45.
    Kang, N., Hamilton, S., Odili, J., Wilson, G., and Kupsch, J. In vivo targeting of malignant melanoma by 125Iodine- and 99mTechnetium-labeled single-chain Fv fragments against high molecular weight melanoma-associated antigen. Clin Cancer Res, 6: 4921-4931, 2000.PubMedGoogle Scholar
  46. 46.
    Fang, J., Jin, H. B., and Song, J. D. Construction, expression and tumor targeting of a singlechain Fv against human colorectal carcinoma. World J Gastroenterol, 9: 726-730, 2003.PubMedGoogle Scholar
  47. 47.
    Weiner, L. M., Houston, L. L., Houston, J. C., McCartney, J. E., Tai, M. S., Apell, G., Stafford, W. F., Bookman, M. A., Gallo, J., and Adams, G. P. Improving the tumor-selectve delivery of single-chain Fv molecules. Tumor Targeting: 51-60, 1995.Google Scholar
  48. 48.
    Adams, G. P., Tai, M. S., McCartney, J. E., Marks, J. D., Stafford, W. F., 3rd, Houston, L. L., Huston, J. S., and Weiner, L. M. Avidity-mediated enhancement of in vivo tumor targeting by single-chain Fv dimers. Clin Cancer Res, 12: 1599-1605, 2006.CrossRefPubMedGoogle Scholar
  49. 49.
    Goel, A., Colcher, D., Baranowska-Kortylewicz, J., Augustine, S., Booth, B. J., Pavlinkova, G., and Batra, S. K. Genetically engineered tetravalent single-chain Fv of the pancarcinoma monoclonal antibody CC49: improved biodistribution and potential for therapeutic application. Cancer Res, 60: 6964-6971, 2000.PubMedGoogle Scholar
  50. 50.
    Milenic, D. E., Yokota, T., Filpula, D. R., Finkelman, M. A., Dodd, S. W., Wood, J. F., Whitlow, M., Snoy, P., and Schlom, J. Construction, binding properties, metabolism, and tumor targeting of a single-chain Fv derived from the pancarcinoma monoclonal antibody CC49. Cancer Res, 51: 6363-6371, 1991.PubMedGoogle Scholar
  51. 51.
    Slavin-Chiorini, D. C., Horan Hand, P. H., Kashmiri, S. V., Calvo, B., Zaremba, S., and Schlom, J. Biologic properties of a CH2 domain-deleted recombinant immunoglobulin. Int J Cancer, 53: 97-103, 1993.CrossRefPubMedGoogle Scholar

Copyright information

© Springer Science + Business Media B.V 2008

Authors and Affiliations

  • Gregory P. Adams
    • 1
  1. 1.Department of Medical OncologyFox Chase Cancer CenterPhiladelphiaUSA

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