Phage Display Libraries: From Binders to Targeted Drug Delivery and Human Therapeutics

  • Mouldy SioudEmail author


The application of repertoire selection technologies for the study and characterization of tumor heterogeneity is an area of great interest in the field of tumor biology and immunotherapy. Among the most promising approaches, phage display has been successfully used to select peptides and antibody fragments to a variety of different targets, including cancer cells, immune cells and cytokines. Peptides selected from phage display have been used to guide the delivery of lytic peptides, cytotoxic drugs, and nanoparticles to cancer cells with the aim to obtain more efficient and less toxic therapeutics. Additionally, antibodies developed through phage display are being used in the treatment of autoimmune diseases and in some cases metastatic cancers. This review provides a short description of how phage libraries are designed, and highlights the conversion of the isolated binders into human therapeutics and use in targeted therapies.


Phage display Affinity selection Peptides Antibodies Targeted therapies Drug delivery Immunotherapy Biomarkers 



Complementary DNA


Complementarity-determining region


Epidermal growth factor


Antigen-binding fragment


Food and drug administration




monoclonal antibody


Non-small cell lung cancer


Single-chain variable fragment


Tumor necrosis factor


Vascular endothelial growth factor


Variable heavy chain


Variable light chain



This work was supported by the Norwegian Cancer Society (Grant No. 182593).

Compliance with Ethical Standards

Conflict of interest

The author has no potential conflict of interest.


  1. 1.
    Smith, G. P. (1985). Filamentous fusion phage: Novel expression vectors that display cloned antigens on the virion surface. Science, 228, 1315–1317.CrossRefPubMedGoogle Scholar
  2. 2.
    Smith, G. P., & Petrenko, V. A. (1997). Phage display. Chemical Reviews, 97, 391–410.CrossRefPubMedGoogle Scholar
  3. 3.
    Nixon, A. E., Sexton, D. J., & Ladner, R. C. (2014). Drugs derived from phage display: From candidate identification to clinical practice. MAbs, 6, 73–85.CrossRefPubMedGoogle Scholar
  4. 4.
    Kennedy, P. J., Oliveira, C., Granda, P. L., & Samento, B. (2018). Monoclonal antibodies: Technologies for early discovery and engineering. Critical Reviews in Biotechnology, 38, 394–408.CrossRefPubMedGoogle Scholar
  5. 5.
    Barbas, C. F. 3rd, Kang, A. S., Lerner, R. A., & Benkovic, S. J. (1991). Assembly of combinatorial antibody libraries on phage surfaces: The gene III site. Proceedings of the National Academy of Sciences of the United States of America, 88, 7978–7982.CrossRefPubMedPubMedCentralGoogle Scholar
  6. 6.
    Cherf, G. M., & Cochran, J. R. (2015). Applications of yeast surface display for protein engineering. Methods in Molecular Biology, 1319, 155–175.CrossRefPubMedGoogle Scholar
  7. 7.
    Yan, X., & Xu, Z. (2006). Ribosome-display technology: Applications for directed evolution of functional proteins. Drug Discovery Today, 11, 911–916.CrossRefPubMedGoogle Scholar
  8. 8.
    Ohashi, H., Ishizaka, M., Hirai, N., & Miyamoto-Sato, E. (2013). Efficiency of puromycin-based technologies mediated by release factors and a ribosome recycling factor. Protein Engineering, Design and Selection, 26, 533–537.CrossRefPubMedPubMedCentralGoogle Scholar
  9. 9.
    Gray, B. P., & Brown, K. C. (2014). Combinatorial peptide libraries: Mining for cell-binding peptides. Chemical Reviews, 114, 1020–1081.CrossRefPubMedGoogle Scholar
  10. 10.
    Shadidi, M., & Sioud, M. (2003). Selective targeting of cancer cells using synthetic peptides. Drug Resistance Updates, 6, 363–371.CrossRefPubMedGoogle Scholar
  11. 11.
    Frenzel, A., Schirrmann, T., & Hust, M. (2016). Phage display-derived human antibodies in clinical development and therapy. MAbs, 8, 1177–1194.CrossRefPubMedPubMedCentralGoogle Scholar
  12. 12.
    Straus, S. K., & Bo, H. E. (2018). Filamentous bacteriophage proteins and assembly. Subcellular Biochemistry, 88, 261–279.CrossRefPubMedGoogle Scholar
  13. 13.
    Qi, H., Lu, H., Qiu, H. J., Petrenko, V., & Liu, A. (2012). Phagemid vectors for phage display: Properties, characteristics and construction. Journal of Molecular Biology, 417, 129–143.CrossRefPubMedGoogle Scholar
  14. 14.
    Enshell-Seijffers, D., Smelyanski, L., & Gershoni, J. M. (2001). The rational design of a ‘type 88’ genetically stable peptide display vector in the filamentous bacteriophage fd. Nucleic Acids Research, 29, E50–E50.CrossRefPubMedPubMedCentralGoogle Scholar
  15. 15.
    Hoogenboom, H. R., Griffiths, A. D., Johnson, K. S., et al. (1991). Multi-subunit proteins on the surface of filamentous phage: Methodologies for displaying antibody (Fab) heavy and light chains. Nucleic Acids Research, 19, 4133–4137.CrossRefPubMedPubMedCentralGoogle Scholar
  16. 16.
    Krumpe, L. R., Atkinson, A. J., Smythers, G. W., et al. (2006). T7 lytic phage-displayed peptide libraries exhibit less sequence bias than M13 filamentous phage-displayed peptide libraries. Proteomics, 6, 4210–4222.CrossRefPubMedGoogle Scholar
  17. 17.
    Matsumoto, Y., Shindo, Y., Takakusagi, Y., et al. (2011). Screening of a library of T7 phage-displayed peptides identifies alphaC helix in 14-3-3 protein as a CBP501-binding site. Bioorganic & Medicinal Chemistry, 19, 7049–7056.CrossRefGoogle Scholar
  18. 18.
    Cwirla, S. E., Peters, E. A., Barrett, R. W., & Dower, W. J. (1990). Peptide on phage: A vast library of peptides for identifying ligands. Proceedings of National Academy of Sciences of the United States of America, 87, 6378–6382.CrossRefGoogle Scholar
  19. 19.
    Sioud, M., Førre, Ø, & Dybwad, A. (1996). Selection of ligands for polyclonal antibodies from random peptide libraries: Potential identification of autoantigens that may trigger B and T cell responses in autoimmune diseases. Clinical Immuology and Immunopathology, 79, 105–114.CrossRefGoogle Scholar
  20. 20.
    Bonnycastle, L. L., Mehroke, J. S., Rashed, M., Gong, X., & Scott, J. K. (1996). Probing the basis of antibody reactivity with a panel of constrained peptide libraries displayed by filamentous phage. Journal of Molecular Biology, 258(5), 747–762.CrossRefPubMedGoogle Scholar
  21. 21.
    Deyle, K., Kong, X.-D., & Heinis, C. (2017). Phage selection of cyclic peptides for application in research and drug development. Accounts of Chemical Research, 50, 1866–1874.CrossRefPubMedGoogle Scholar
  22. 22.
    Ladner, R. C. (1995). Constrained peptides as binding entities. TIBTECH, 13, 426–430.CrossRefGoogle Scholar
  23. 23.
    Teesalu, T., Sugahara, K. N., & Ruoslahti, E. (2012). Mapping of vascular ZIP codes by phage display. Methods in Enzymology, 503, 35–56.CrossRefPubMedGoogle Scholar
  24. 24.
    Deramchia, K., Jacobin-Valat, M. J., Vallet, A., et al. (2012). In vivo phage display to identify new human antibody fragments homing to atherosclerotic endothelial and subendothelial tissues. The American Journal of Pathology, 180(6), 2576–2589.CrossRefPubMedGoogle Scholar
  25. 25.
    Felici, F., Castagnoli, L., Musacchio, A., Jappelli, R., & Cesareni, G. (1991). Selection of antibody ligands from a large library of oligopeptides expressed on a multivalent exposition vector. Journal of Molecular Biology, 222(2), 301–310.CrossRefPubMedGoogle Scholar
  26. 26.
    Fack, F., Hügle-Dörr, B., Song, D., et al. (1997). Epitope mapping by phage display: Random versus gene-fragment libraries. Journal of Immunological Methods, 206, 43–52.CrossRefPubMedGoogle Scholar
  27. 27.
    Dybwad, A., Bogen, B., Natvig, J. B., Førre, O., & Sioud, M. (1995). Peptide phage libraries can be an efficient tool for identifying antibody ligands for polyclonal antisera. Clinical & Experimental Immunology, 102, 438–442.CrossRefGoogle Scholar
  28. 28.
    Sun, Y., Kang, C., Liu, F., et al. (2017). RGD peptide-based target drug delivery of doxorubicin nanomedicine. Drug Development Research, 78, 283–291.CrossRefPubMedGoogle Scholar
  29. 29.
    Koivunen, E., Wang, E., & Ruoslahti, E. (1995). Phage libraries displaying cyclic peptides with different ring sizes: Ligands specificities of the RGD-directed integrins. Biotechnology, 13, 265–270.PubMedGoogle Scholar
  30. 30.
    Arap, W., Pasqualini, R., & Ruoslahti, E. (1998). Cancer treatment by targeted drug delivery to tumor vasculature in a mouse model. Science, 279, 377–380.CrossRefPubMedGoogle Scholar
  31. 31.
    Kibria, G., Hatakeyama, H., Ohga, N., Hida, K., & Harashima, H. (2013). The effect of liposomal size on the targeted delivery of doxorubicin to integrin αvβ3-expressing tumor endothelial cells. Biomaterials, 34, 5617–5627.CrossRefPubMedGoogle Scholar
  32. 32.
    Pasqualini, R., Koivunen, E., Kain, R., et al. (2000). Aminopeptidase N is a receptor for tumor-homing peptides and a target for inhibiting angiogenesis. Cancer Research, 60(3), 722–727.PubMedPubMedCentralGoogle Scholar
  33. 33.
    Laakkonen, P., Porkka, K., Hoffman, J. A., & Ruoslahti, E. (2002). A tumor-homing peptide with a targeting specificity related to lymphatic vessels. Nature Medicine, 8(7), 751–755.CrossRefPubMedGoogle Scholar
  34. 34.
    Shadidi, M., & Sioud, M. (2003). Identification of novel carrier peptides for the specific delivery of therapeutics into cancer cells. The FASEB Journal, 17, 256–258.CrossRefPubMedGoogle Scholar
  35. 35.
    Lee, S. M., Lee, E. J., Hong, H. Y., et al. (2007). Targeting bladder tumor cells in vivo and in the urine with a peptide identified by phage display. Molecular Cancer Research, 5, 11–19.CrossRefPubMedGoogle Scholar
  36. 36.
    Pandya, H., Gibo, D. M., Garg, S., Kridel, S., & Debinski, W. (2012). An interleukin 13 receptor α 2-specific peptide homes to human glioblastoma multiforme xenografts. Neuro-Oncology, 14, 6–18.CrossRefPubMedGoogle Scholar
  37. 37.
    Oyama, T., Sykes, K. F., Samli, K. N., et al. (2003). Isolation of lung tumor specific peptides from a random peptide library: Generation of diagnostic and cell-targeting reagents. Cancer Letters, 202(2), 219–230.CrossRefPubMedGoogle Scholar
  38. 38.
    McGuire, M. J., Gray, B. P., Li, S., et al. (2014). Identification and characterization of a suite of tumor targeting peptides for non-small cell lung cancer. Scientific Reports, 4, 4480.CrossRefPubMedPubMedCentralGoogle Scholar
  39. 39.
    Chang, D. K., Lin, C. T., Wu, C. H., & Wu, H. C. (2009). A novel peptide enhances therapeutic efficacy of liposomal anti-cancer drugs in mice models of human lung cancer. PLoS ONE, 4(1), e4171.CrossRefPubMedPubMedCentralGoogle Scholar
  40. 40.
    Chi, Y.-H., Hsiao, J.-K., Lin, M.-H., et al. (2017). Lung cancer-targeting peptides with multi-subtype indication for combinational drug delivery and molecular imaging. Theranostics, 7, 1612–1632.CrossRefPubMedPubMedCentralGoogle Scholar
  41. 41.
    Hong, F. D., & Clayman, G. L. (2000). Isolation of a peptide for targeted drug delivery into human head and neck solid tumors. Cancer Research, 60, 6551–6556.PubMedGoogle Scholar
  42. 42.
    Jiang, Y.-Q., Wang, H.-R., Li, H.-P., et al. (2006). Targeting of hapeatoma cell and suppression of tumor growth by a novel 12mer peptide fused to superantigen TSST-1. Molecular Medicine, 12, 81–87.CrossRefPubMedPubMedCentralGoogle Scholar
  43. 43.
    Nishimura, S., Takahashi, S., Kamikatahira, H., et al. (2008). Combinatorial targeting of the macropinocytotic pathway in leukemia and lymphoma cells. Journal of Biological Chemistry, 283, 11752–11762.CrossRefPubMedGoogle Scholar
  44. 44.
    Kim, Y., Lillo, A. M., Steiniger, S. C. J., et al. (2006). Targeting heat shock proteins on cancer cells: Selection, characterization, and cell-penetrating properties of a peptidic GRP78 ligand. Biochemistry, 45, 9434–9444.CrossRefPubMedGoogle Scholar
  45. 45.
    Zhang, J., Spring, H., & Schwab, M. (2001). Neuroblastoma tumor cell-binding peptides identified through random peptide phage display. Cancer Letters, 171, 153–164.CrossRefPubMedGoogle Scholar
  46. 46.
    Zitzmann, S., Mier, W., Schad, A., et al. (2005). A new prostate carcinoma binding peptide (DUP-1) for tumor imaging and therapy. Clinical Cancer Research, 1, 139–146.Google Scholar
  47. 47.
    Sugahara, K. N., Teesalu, T., Karmali, P. P., et al. (2009). Tissue-penetrating delivery of compounds and nanoparticles into tumors. Cancer Cell, 16, 510–520.CrossRefPubMedPubMedCentralGoogle Scholar
  48. 48.
    Karasseva, N. G., Glinsky, V. V., Chen, N. X., Komatireddy, R., & Quinn, T. P. (2002). Identification and characterization of peptides that bind human ErbB-2 selected from a bacteriophage display library. Journal of Protein Chemistry, 21, 287–296.CrossRefPubMedGoogle Scholar
  49. 49.
    Li, Z., Zhao, R., Wu, X., et al. (2005). Identification and characterization of a novel peptide ligand of epidermal growth factor receptor for targeted delivery of therapeutics. The FASEB Journal, 19, 1978–1985.CrossRefPubMedGoogle Scholar
  50. 50.
    Qin, X., Wan, Y., Li, M., et al. (2007). Identification of a novel peptide ligand of human vascular endothelia growth factor receptor 3 for targeted tumour diagnosis and therapy. Journal of Biochemistry, 142, 79–85.CrossRefPubMedGoogle Scholar
  51. 51.
    Koivunen, E., Arap, W., Valtanen, H., et al. (1999). Tumor targeting with a selective gelatinase inhibitor. Nature Biotechnology, 17(8), 768–774.CrossRefPubMedGoogle Scholar
  52. 52.
    Umlauf, B. J., Mercedes, J. S., Chung, C. Y., & Brown, K. C. (2014). Identification of a novel lysosomal trafficking peptide using phage display biopanning coupled with endocytic selection pressure. Bioconjugate Chemistry, 25(10), 1829–1837.CrossRefPubMedPubMedCentralGoogle Scholar
  53. 53.
    Jubb, A. M., Strickland, L. A., Liu, S. D., et al. (2012). Neuropilin-1 expression in cancer and development. The Journal of Pathology, 226, 50–60.CrossRefPubMedGoogle Scholar
  54. 54.
    Li, Z. J., Wu, W. K., Ng, S. S., et al. (2010). A novel peptide specifically targeting the vasculature of orthotopic colorectal cancer for imaging detection and drug delivery. Journal of Controlled Release, 148, 292–302.CrossRefPubMedGoogle Scholar
  55. 55.
    Nohara, S., Kato, K., Fujiwara, D., et al. (2016). Aminopeptidase N (APN/CD13) as a target molecule for scirrhous gastric cancer. Clinics and Research in Hepatology and Gastroenterology, 40, 494–503.CrossRefPubMedGoogle Scholar
  56. 56.
    Pastorino, F., Brignole, C., Marimpietri, D., et al. (2003). Vascular damage and anti-angiogenic effects of tumor vessel-targeted liposomal chemotherapy. Cancer Research, 63(21), 7400–7409.PubMedGoogle Scholar
  57. 57.
    Herringson, T. P., & Altin, J. G. (2011). Effective tumor targeting and enhanced anti-tumor effect of liposomes engrafted with peptides specific for tumor lymphatics and vasculature. International Journal of Pharmaceutics, 411(1–2), 206–214.CrossRefPubMedGoogle Scholar
  58. 58.
    Karmali, P. P., Kotamraju, V. R., Kastantin, M., et al. (2009). Targeting of albumin-embedded paclitaxel nanoparticles to tumors. Nanomedicine, 5, 73–82.CrossRefPubMedGoogle Scholar
  59. 59.
    Jung, H. K., Kim, S., Park, R. W., et al. (2016). Bladder tumor-targeted delivery of pro-apoptotic peptide for cancer therapy. Journal of Controlled Release, 235, 259–267.CrossRefPubMedGoogle Scholar
  60. 60.
    Leuschner, C., & Hansel, W. (2004). Membrane disrupting lytic peptides for cancer treatments. Current Pharmaceutical Design, 10, 2299–2310.CrossRefPubMedGoogle Scholar
  61. 61.
    Sioud, M., Skorstad, G., Mobergslien, A., & Sæbøe-Larssen, S. (2013). A novel peptide carrier for efficient targeting of antigens and nucleic acids to dendritic cells. The FASEB Journal, 27, 3272–3283.CrossRefPubMedGoogle Scholar
  62. 62.
    Neo, S. H., Lew, Q. J., Koh, S. M., et al. (2016). Use of a novel cytotoxic HEXIM1 peptide in the directed breast cancer therapy. Oncotarget, 7, 5483–5494.CrossRefPubMedGoogle Scholar
  63. 63.
    Wang, X. F., Birringer, M., Dong, L. F., et al. (2007). A peptide conjugate of vitamin E succinate targets breast cancer cells with high ErbB2 expression. Cancer Research, 67, 3337–3344.CrossRefPubMedGoogle Scholar
  64. 64.
    Luo, H., Yang, J., Jin, H., et al. (2011). Tetrameric far-red fluorescent protein as a scaffold to assemble an octavalent peptide nanoprobe for enhanced tumor targeting and intracellular uptake in vivo. The FASEB Journal, 25, 1–9.CrossRefGoogle Scholar
  65. 65.
    Moreno, M., Zurita, E., & Giralt, E. (2014). Delivering wasp venom for cancer therapy. Journal of Controlled Release, 182, 13–21.CrossRefPubMedGoogle Scholar
  66. 66.
    Sioud, M., & Mobergslien, A. (2012). Selective killing of cancer cells by peptide-targeted delivery of an anti-microbial peptide. Biochemistry Pharmacology, 84, 1123–1132.CrossRefGoogle Scholar
  67. 67.
    Koller, C. M., Kim, Y., & Schmidt-Wolf, I. G. (2013). Targeting renal cancer with a combination of WNT inhibitors and a bi-functional peptide. Anticancer Research, 33, 2435–2440.PubMedGoogle Scholar
  68. 68.
    Sigismund, S., Avanzato, D., & Lanzetti, L. (2018). Emerging functions of the EGFR in cancer. Molecular Oncology, 12(1), 3–20.CrossRefPubMedGoogle Scholar
  69. 69.
    Song, S., Liu, D., Peng, J., et al. (2008). Peptide ligand-mediated liposome distribution and targeting to EGFR expressing tumor in vivo. International Journal of Pharmaceutics, 363, 155–161.CrossRefPubMedGoogle Scholar
  70. 70.
    Kohno, M., Horibe, T., Haramoto, M., et al. (2011). A novel hybrid peptide targeting EGFR-expressing cancers. European Journal of Cancer, 47, 773–783.CrossRefPubMedGoogle Scholar
  71. 71.
    Carmeliet, P. (2005). VEGF as a key mediator of angiogenesis in cancer. Oncology, 69(Suppl 3), 4–10.CrossRefPubMedGoogle Scholar
  72. 72.
    Shay, G., Lynch, C. C., & Fingleton, B. (2015). Moving targets: Emerging roles for MMPs in cancer progression and metastasis. Matrix Biology, 44–46, 200–206.CrossRefPubMedGoogle Scholar
  73. 73.
    Medina, O. P., Söderlund, T., Laakkonen, L. J., et al. (2001). Binding of novel peptide inhibitors of type IV collagenases to phospholipid membranes and use in liposome targeting to tumor cells in vitro. Cancer Research, 61(10), 3978–3985.PubMedGoogle Scholar
  74. 74.
    Mäkelä, A. R., Enbäck, J., Laakkonen, J. P., et al. (2008). Tumor targeting of baculovirus displaying a lymphatic homing peptide. The Journal of Gene Medicine, 10, 1019–1031.CrossRefPubMedGoogle Scholar
  75. 75.
    Osuka, S., & Van Meir, E. G. (2017). Overcoming therapeutic resistance in glioblastoma: The way forward. The Journal of Clinical Investigation, 127(2), 415–426.CrossRefPubMedPubMedCentralGoogle Scholar
  76. 76.
    Siegel, R. L., Miller, K. D., & Jemal, A. (2016). Cancer statistics. CA: A Cancer Journal of Clinicians, 66, 7–30.Google Scholar
  77. 77.
    App, C., Knop, J., Huff, T., et al. (2014). Peptide labeling with photoactivatable trifunctional cadaverine derivative and identification of interacting partners by biotin transfer. Analytical Biochemistry, 456, 14–21.CrossRefPubMedGoogle Scholar
  78. 78.
    Bhogal, M. S., Lanyon-Hogg, T., Johnston, K. A., Warriner, S. L., & Baker, A. (2016). Covalent label transfer between peroxisomal importomer components reveals export-driven import interactions. Journal of Biological Chemistry, 291, 2460–2468.CrossRefPubMedGoogle Scholar
  79. 79.
    Otvos, L. Jr., & Wade, J. D. (2014). Current challenges in peptide-based drug discovery. Frontiers in Chemistry, 2, 62.PubMedPubMedCentralGoogle Scholar
  80. 80.
    Katsara, T., Selios, T., Deraos, S., et al. (2006). Round and round we go: Cyclic peptides in disease. Current Medicinal Chemistry, 13, 2221–2232.CrossRefPubMedGoogle Scholar
  81. 81.
    Li, S., McGuire, M. J., Lin, M., et al. (2009). Synthesis and characterization of a high-affinity αvβ6-specific ligand for in vitro and in vivo applications. Molecular Cancer Therapeutics, 8, 1239–1249.CrossRefPubMedPubMedCentralGoogle Scholar
  82. 82.
    Erbas, B., & Tuncel, M. (2016). Renal function assessment during peptide receptor radionuclide therapy. Seminars in Nuclear Medicine, 6, 462–478.CrossRefGoogle Scholar
  83. 83.
    Mero, A., Clementi, C., Veronese, F. M., & Pasut, G. (2011). Covalent conjugation of poly(ethylene glycol) to proteins and peptides: Strategies and methods. Methods in Molecular Biology, 751, 95–129.CrossRefPubMedGoogle Scholar
  84. 84.
    Ehrlich, G. K., Michel, H., Truitt, T., et al. (2013). Preparation and characterization of albumin conjugates of a truncated peptide YY analogue for half-life extension. Bioconjugate Chemistry, 24, 2015–2024.CrossRefPubMedGoogle Scholar
  85. 85.
    Roopenian, D. C., & Akilesh, S. (2007). FcRn: The neonatal Fc receptor comes of age. Nature Reviews Immunology, 7, 715–725.CrossRefPubMedGoogle Scholar
  86. 86.
    Unverdorben, F., Richter, F., Hurt, M., et al. (2015). Pharmacokinetic properties of IgG and various Fc fusion proteins in mice. MAbs, 8, 120–128.CrossRefPubMedCentralGoogle Scholar
  87. 87.
    Strohl, W. R. (2015). Fusion proteins for half-life extension of biologics as a strategy to make biobeters. BioDrugs, 29, 215–239.CrossRefPubMedPubMedCentralGoogle Scholar
  88. 88.
    Sioud, M., Westby, P., Olsen, J. K., & Mobergslien, A. (2015). Generation of new peptide-Fc fusion proteins that mediate antibody-dependent cellular cytotoxicity against different types of cancer cells. Molecular Therapy-Methods & Clinical Development, 4, 2:e15043.CrossRefGoogle Scholar
  89. 89.
    Mobergslien, A., Peng, Q., Vasovic, V., & Sioud, M. (2016). Cancer cell-binding peptide fused Fc domain activates immune effector cells and blocks tumor growth. Oncotarget, 15, 75940–75953.Google Scholar
  90. 90.
    Qin, H., Lerman, B., Sakamaki, I., et al. (2014). Generation of a new therapeutic peptide that depletes myeloid-derived suppressor cells in tumor-bearing mice. Nature Medicine, 20, 676–681.CrossRefPubMedPubMedCentralGoogle Scholar
  91. 91.
    Tracy, D., Klareskog, L., Sasso, E. H., Salfeld, J. G., & Tak, P. P. (2008). Tumour necrosis factor antagonist mechanisms of action: A comprehensive review. Pharmacology & Therapeutics, 117, 244–279.CrossRefGoogle Scholar
  92. 92.
    Klareskog, L., van der Heijde, D., de Jager, J. P., et al. (2004). Therapeutic effect of the combination of etanercept and methotrexate compared with each treatment alone in patients with rheumatoid arthritis: Double-blind randomised controlled trial. The Lancet, 363, 675–681.CrossRefGoogle Scholar
  93. 93.
    Molineux, G., & Newland, A. (2010). Development of romiplostim for the treatment of patients with chronic immune thrombocytopenia: From bench to bedside. British Journal of Haematology, 150, 9–20.PubMedGoogle Scholar
  94. 94.
    Herbst, R. S., Hong, D., Chap, L., et al. (2009). Safety, pharmacokinetics, and antitumor activity of AMG 386, a selective angiopoietin inhibitor, in adult patients with advanced solid tumors. Journal of Clinical Oncology, 27, 3557–3565.CrossRefPubMedGoogle Scholar
  95. 95.
    Karlan, B. Y., Oza, A. M., Richardson, G. E., et al. (2012). Randomized, double-blind, placebo-controlled phase II study of AMG 386 combined with weekly paclitaxel in patients with recurrent ovarian cancer. Journal of Clinical Oncology, 30, 362–371.CrossRefPubMedGoogle Scholar
  96. 96.
    McCafferty, J., Griffiths, A. D., Winter, G., & Chiswell, D. J. (1990). Phage antibodies: Filamentous phage displaying antibody variable domains. Nature, 348, 552–554.CrossRefPubMedGoogle Scholar
  97. 97.
    Alt, F. W., Yancopoulos, G. D., Blackwell, T. K., et al. (1984). Ordered rearrangement of immunoglobulin heavy chain variable region segments. The EMBO Journal, 3, 1209–1219.CrossRefPubMedPubMedCentralGoogle Scholar
  98. 98.
    Tonegawa, S. (1983). Somatic generation of antibody diversity. Nature, 302, 575–581.CrossRefPubMedGoogle Scholar
  99. 99.
    Köhler, G., & Milstein, C. (1975). Continuous cultures of fused cells secreting antibody of predefined specificity. Nature, 256, 495–497.CrossRefPubMedGoogle Scholar
  100. 100.
    Tjandra, J. J., Ramadi, L., & McKenzie, I. C. (1990). Development of human anti-murine antibody (HAMA) response in patients. Immunology and Cell Biology, 68, 367–375.CrossRefPubMedGoogle Scholar
  101. 101.
    He, X. Y., Xu, Z., Melrose, J., et al. (1998). Humanization and pharmacokinetics of a monoclonal antibody with specificity for both E- and P-selectin. The Journal of Immunology, 160, 1029–1035.PubMedGoogle Scholar
  102. 102.
    Marks, J. D., Hoogenboom, H. R., Bonnert, T. P., et al. (1991). By-passing immunization: Human antibodies from V-gene libraries displayed on phage. Journal of Molecular Biology, 222, 581–597.CrossRefPubMedGoogle Scholar
  103. 103.
    Lerner, R. (2016). Combinatorial antibody libraries: New advances, new immunological insights. Nature Reviews Immunology, 16, 498–508.CrossRefPubMedGoogle Scholar
  104. 104.
    Winter, G., Griffiths, A. D., Hawkins, R. E., & Hoogenboom, H. R. (1994). Making antibodies by phage display technology. Annual Review of Immunology, 12, 433–455.CrossRefPubMedGoogle Scholar
  105. 105.
    Hammers, C. M., & Stanley, J. R. (2014). Antibody phage display: Technique and applications. The Journal of Investigative Dermatology, 134, 1–5.CrossRefPubMedGoogle Scholar
  106. 106.
    Unkauf, T., Miethe, S., Fühner, V., et al. (2016). Generation of recombinant antibodies against toxins and viruses by phage display for diagnostics and therapy. Advances in Experimental Medicine and Biology, 917, 55–76.CrossRefPubMedGoogle Scholar
  107. 107.
    Hoogenboom, H. R. (2005). Selecting and screening recombinant antibody libraries. Nature Biotechnology, 23, 1105–1116.CrossRefPubMedGoogle Scholar
  108. 108.
    Wu, H., Beuerlein, G., Nie, Y., et al. (1998). Stepwise in vitro affinity maturation of vitaxin, an alpha v beta 3-specific humanized mAb. Proceedings of the National Academy of Sciences of the United States of America, 95, 6037–6042.CrossRefPubMedPubMedCentralGoogle Scholar
  109. 109.
    Ho, M., Kreitman, R. J., Onda, M., & Pastan, I. (2005). In vitro antibody evolution targeting germline host spots to increase activity of an anti-CD22 immunotoxin. Journal of Biological Chemistry, 280, 607–617.CrossRefPubMedGoogle Scholar
  110. 110.
    Beerli, R. R., & Rader, C. (2010). Mining human antibody repertoires. MAbs, 2, 365–378.CrossRefPubMedGoogle Scholar
  111. 111.
    Ohlin, M., & Borrebaeck, C. A. (1996). Characterization of human antibody repertoire following active immune responses in vivo. Molecular Immunology, 33, 583–592.CrossRefPubMedGoogle Scholar
  112. 112.
    Graus, Y. E., de Baets, M. H., Parren, P. W., et al. (1997). Human anti-nicotinic acelylcholine receptor recombinant Fab fragments isolated from thymus-derived phage display libraries from myasthenia gravis patients reflect predominant specificities in serum and block the action of pathogenic serum antibodies. The Journal of Immunology, 158(4), 1919–1929.PubMedGoogle Scholar
  113. 113.
    Rahumatullah, A., Ahmad, A., Noordin, R., & Lim, T. S. (2015). Delineation of BmSXP antibody V-gene usage from a lymphatic filariasis based immune scFv antibody library. Molecular Immunology, 67(2 Pt B):512–523. Scholar
  114. 114.
    Hamidon, N. H., Suraiya, S., Sarmiento, M. E., et al. (2018). Immune TB antibody phage display library as a tool To study B cell immunity in TB infections. Applied Biochemistry and Biotechnology, 184(3), 852–868. Scholar
  115. 115.
    Scott, A., Walper, B., Lee, P. S., Anderson, G. P., & Goldman, E. R. (2013). Selection and characterization of single domain antibodies specific for Bacillus anthracis spore proteins. Antibodies, 2, 152–167.CrossRefGoogle Scholar
  116. 116.
    Knappik, A., Ge, L., Honegger, A., et al. (2000). Fully synthetic human combinatorial antibody libraries (HuCAL) based on modular consensus frameworks and CDRs randomized with trinucleotides. Journal of Molecular Biology, 296(1), 57–86.CrossRefPubMedGoogle Scholar
  117. 117.
    Tiller, T., Schuster, I., Deppe, D., et al. (2013). A fully synthetic human Fab antibody library based on fixed VH/VL framework pairings with favorable biophysical properties. MAbs, 5(3), 445–470.CrossRefPubMedPubMedCentralGoogle Scholar
  118. 118.
    Barbas, C. F., Bain, J. D., Hoekstra, D. M., & Lerner, R. (1992). Semi synthetic combinatorial libraries: A chemical solution to the diversity problem. Proceedings of National Academy of Sciences of the United States of America, 89, 4457–4461.CrossRefGoogle Scholar
  119. 119.
    Benhar, I. (2007). Design of synthetic antibody libraries. Expert Opinion on Biological Therapy, 7, 763–779.CrossRefPubMedGoogle Scholar
  120. 120.
    Hoogenboom, H. R., & Winter, G. (1992). By-passing immunisation. Human antibodies from synthetic repertoires of germline VH gene segments rearranged in vitro. Journal of Molecular Biology, 227, 3–8.CrossRefGoogle Scholar
  121. 121.
    Beck, A., Wurch, T., Bailly, C., & Corvaia, N. (2010). Strategies and challenges for the next generation of therapeutic antibodies. Nature Review Immunology, 10(5), 345–352.CrossRefGoogle Scholar
  122. 122.
    Beck, A., & Reichert, J. M. (2012). Marketing approval of mogamulizumab: A triumph for glycol-engineering. MAbs, 4, 419–425.CrossRefPubMedPubMedCentralGoogle Scholar
  123. 123.
    Lee, C. C., Perchiacca, J. M., & Tessier, P. M. (2013). Toward aggregation-resistant antibodies by design. Trends in Biotechnology, 31, 612–620.CrossRefPubMedGoogle Scholar
  124. 124.
    Roy, A., Nair, S., Sen, N., Soni, N., & Maddhusudhan, M. S. (2017). In silico methods for design of biological therapeutics. Methods, 131, 33–65.CrossRefPubMedGoogle Scholar
  125. 125.
    Kiyoshi, M., Caaveiro, J. M., Miura, E., et al. (2014). Affinity improvement of a therapeutic antibody by structure-based computational design: Generation of electrostatic interactions in the transition state stabilizes the antibody-antigen complex. PLoS ONE, 9(1), e87099. Scholar
  126. 126.
    Lippow, S. M., Wittrup, K. D., & Tidor, B. (2007). Computational design of antibody-affinity improvement beyond in vivo maturation. Nature Biotechnology, 25(10), 1171–1176.CrossRefPubMedPubMedCentralGoogle Scholar
  127. 127.
    Morse, R. J., & Maus, M. V. (2016). Bispecific antibodies and CARs: Generalized immunotherapeutics harnessing T cell redirection. Current Opinion in Immunology, 40, 24–35.CrossRefPubMedPubMedCentralGoogle Scholar
  128. 128.
    Alibakhshi, A., Abarghooi Kahaki, F., Ahangarzadeh, S., et al. (2017). Targeted cancer therapy through antibody fragments-decorated nanomedicines. Journal of Controlled Release, 268, 323–334.CrossRefPubMedGoogle Scholar
  129. 129.
    Green, L. L. (1999). Antibody engineering via genetic engineering of the mouse: XenoMouse strains are a vehicle for the facile generation of therapeutic human monoclonal antibodies. Journal of Immunological Methods, 231, 11–23.CrossRefPubMedGoogle Scholar
  130. 130.
    Halpern, W. G., Lappin, P., Zanardi, T., et al. (2006). Chronic administration of belimumab, a BLyS antagonist, decreases tissue and peripheral blood B-lymphocyte populations in cynomolgus monkeys: Pharmacokinetics, pharmacodynamics, and toxicologic effects. Toxicological Sciences, 91, 586–599.CrossRefPubMedGoogle Scholar
  131. 131.
    Mazumdar, S. (2009). Raxibacumab. MAbS 1, 531–538.CrossRefPubMedPubMedCentralGoogle Scholar
  132. 132.
    Steinbrook, R. (2006). The price of sight—ranibizumab, bevacizumab, and the treatment of macular degeneration. New England Journal of Medicine, 355, 1409–1412.CrossRefPubMedGoogle Scholar
  133. 133.
    Spratlin, J. L., Cohen, R. B., Eadens, M., et al. (2010). Phase I pharmacologic and biologic study of ramucirumab (IMC-1121B), a fully human immunoglobulin G1 monoclonal antibody targeting the vascular endothelial growth factor receptor-2. Journal of Clinical Oncology, 28, 780–787.CrossRefPubMedPubMedCentralGoogle Scholar
  134. 134.
    de Haard, H. J., van Neer, N., Reurs, A., et al. (1999). A large non-immunized human Fab fragment phage library that permits rapid isolation and kinetic analysis of high affinity antibodies. Journal of Molecular Chemistry, 274, 18218–18230.Google Scholar
  135. 135.
    Hotte, S. J., Hirte, H. W., et al. (2008). A phase 1 study of mapatumumab in patients with advanced solid malignacies. Clinical Cancer Research, 14, 3450–3455.CrossRefPubMedGoogle Scholar
  136. 136.
    Weickhardt, A., Doebele, R., Oton, A., et al. (2012). A phase I/II study of erlotinib in combination with the anti-insulin-like growth factor-1 receptor monoclonal antibody IMC-A12 (cixutumumab) in patients with advanced non-small cell lung cancer. Journal of Thoracic Oncology, 7, 419–426.CrossRefPubMedPubMedCentralGoogle Scholar
  137. 137.
    Adams, C., Totpal, K., Lawrence, D., et al. (2008). Structural and functional analysis of the interaction between the agonistic monoclonal antibody Apomab and the proapoptotic receptor DR5. Cell Death and Differentiation, 15(4), 751–761.CrossRefPubMedGoogle Scholar
  138. 138.
    Kaymakcalan, Z., Sakorafas, P., Bose, S., et al. (2009). Comparisons of affinities, activities, and complement activation of adalimumab, infliximab, and etanercept in binding to soluble and membrane tumor necrosis factor. Clinical Immunology, 131, 308–316.CrossRefPubMedGoogle Scholar
  139. 139.
    Welch, B. (2008). Adalimumab (Humira) for the treatment of rheumatoid arthritis. American Family Physician, 78, 1406–1408.Google Scholar
  140. 140.
    Mackay, F., & Browning, J. L. (2002). BAFF: A fundamental survival factor for B cells. Nature Reviews Immunology, 2, 465–475.CrossRefPubMedGoogle Scholar
  141. 141.
    Stohl, W. (2017). Inhibition of B cell activating factor (BAFF) in the management of systemic lupus erythematosus (SLE). Expert Review in Clinical Immunology, 13, 623–633.CrossRefPubMedGoogle Scholar
  142. 142.
    Witsch, E., Sela, M., & Yarden, Y. (2010). Roles for growth factors in cancer progression. Physiology, 25, 85–101.CrossRefPubMedGoogle Scholar
  143. 143.
    McMahon, G. (2000). VEGF receptor signaling in tumor angiogenesis. The Oncologist, 5(Suppl 1), 3–10.CrossRefPubMedGoogle Scholar
  144. 144.
    Chen, Y., Wiesmann, C., Fuh, G., et al. (1999). Selection and analysis of an optimized anti VEGF antibody: Crystal structure of an affinity-matured Fab in complex with antigen. Journal of Molecular Biology, 293, 865–881.CrossRefPubMedGoogle Scholar
  145. 145.
    Oude Munnink, T. H., Arjaans, M. E., Timmer-Bosscha, H., et al. (2011). PET with the 89Zr-labeled transforming growth factor-beta antibody fresolimumab in tumor models. Journal of Nuclear Medicine, 52, 2001–2008.CrossRefPubMedGoogle Scholar
  146. 146.
    Mérino, D., Lalaoui, N., Morizot, A., Solary, E., & Micheau, O. (2007). TRAIL in cancer therapy: Present and future challenges. Expert Opinion on Therapeutic Targets, 11, 1299–1314.CrossRefPubMedPubMedCentralGoogle Scholar
  147. 147.
    von Karstedt, S., Montinaro, A., & Walczak, H. (2017). Exploring the TRAILs less travelled: TRAIL in cancer biology and therapy. Nature Reviews Cancer, 17, 352–366.CrossRefGoogle Scholar
  148. 148.
    Liu, S., Moayeri, M., & Leppla, S. H. (2014). Anhrax lethal and edema toxins in anthrax pathogenesis. Trends in Microbiology, 22, 317–325.CrossRefPubMedPubMedCentralGoogle Scholar
  149. 149.
    Kramer, R. A., Marissen, W. E., Goudsmit, J., et al. (2005). The human antibody repertoire specific for rabies virus glycoproteins as selected from immune libraries. European Journal of Immunology, 35, 2131–2145.CrossRefPubMedGoogle Scholar
  150. 150.
    Sioud, M., Westby, P., Vasovic, V., Fløisand, Y., & Peng, Q. (2018). Development of a new high-affinity human antibody with antitumor activity against solid and blood malignancies. The FASEB Journal, 32(9), 5063–5077.CrossRefPubMedGoogle Scholar
  151. 151.
    Reichert, J. M. (2017). Antibodies to watch in 2017. MAbs, 9,167–181.CrossRefPubMedGoogle Scholar
  152. 152.
    Sioud, M., & Hansen, M. H. (2001). Profiling the immune response in patients with breast cancer by phage-displayed cDNA libraries. European Journal of Immunology, 31(3), 716–725.CrossRefPubMedGoogle Scholar
  153. 153.
    Sioud, M., Hansen, M., & Dybwad, A. (2000). Profiling the immune responses in patient sera with peptide and cDNA display libraries. International Journal of Molecular Medicine, 6(2), 123–128.PubMedGoogle Scholar
  154. 154.
    Zantow, J., Just, S., Lagkouvardos, I., et al. (2016). Mining gut microbiome oligopeptides by functional metaproteome display. Scientific Reports, 6, 34337.CrossRefPubMedPubMedCentralGoogle Scholar
  155. 155.
    Dybwad, A., Førre, O., Natvig, J. B., & Sioud, M. (1995). Structural characterization of peptides that bind synovial fluid antibodies from RA patients: A novel strategy for identification of disease-related epitopes using a random peptide library. Clinical Immunology and Immunopathology, 75, 45–50.CrossRefPubMedGoogle Scholar

Copyright information

© Springer Science+Business Media, LLC, part of Springer Nature 2019

Authors and Affiliations

  1. 1.Department of Cancer ImmunologyOslo University Hospital, The Norwegian Radium Hospital, MontebelloOsloNorway

Personalised recommendations