Advertisement

Molecular Biology

, Volume 51, Issue 6, pp 772–781 | Cite as

Engineering Antibodies as Drugs: Principles and Practice

  • A. A. Lugovskoy
Current Trends in the Application of Monoclonal Antibodies Special Issue

Abstract

Over the last forty years, recombinant antibodies have been transformed from an unproven experimental approach to a therapeutic modality with multiple success stories in the treatment of cancer, inflammation, infections and cardiometabolic diseases. Owing to their high affinity and selectivity for the target antigen, their multimodal tunable mode of action, their modular nature and long half-life, antibodies now hold prominent positions in the pipelines of major biopharmaceutical companies. In this brief report, I aim to highlight the themes that have shaped the therapeutic antibody engineering as it exists today and to offer a personal perspective on its future developments. Distinct antibody engineering history, developments and trends in Russian Federation will not be discussed since they are detailed elsewhere in this journal issue.

Keywords

antibody antibody engineering antibody-drug conjugates immunooncology effector function multispecific antibodies and mixtures 

Preview

Unable to display preview. Download preview PDF.

Unable to display preview. Download preview PDF.

References

  1. 1.
    Köhler G., Milstein C. 1975. Continuous cultures of fused cells secreting antibody of predefined specificity. Nature. 256, 495–197.PubMedCrossRefGoogle Scholar
  2. 2.
    Hooks M.A., Wade C.S., Millikan W.J. 1991. Muromonab CD-3: A review of its pharmacology, pharmacokinetics, and clinical use in transplantation. Pharmacotherapy. 11, 26–37.PubMedGoogle Scholar
  3. 3.
    Chatenoud L., Baudrihaye M.F., Chkoff N., et al. 1986. Restriction of the human in vivo immune response against the mouse monoclonal antibody OKT3. J. Immunol. 137, 830–838.PubMedGoogle Scholar
  4. 4.
    Mountain A., Adair J.R. 1992. Engineering antibodies for therapy. Biotechnol. Genet. Eng. Rev. 10, 1–142.PubMedCrossRefGoogle Scholar
  5. 5.
    Queen C., Schneider W.P., Selick H.E., et al. 1989. A humanized antibody that binds to the interleukin 2 receptor. Proc. Natl. Acad. Sci. U. S. A. 86, 10029–10033.PubMedPubMedCentralCrossRefGoogle Scholar
  6. 6.
    Mendez M.J., Green L.L., Corvalan J.R., et al. 1997. Functional transplant of megabase human immunoglobulin loci recapitulates human antibody response in mice. Nat. Genet. 15, 146–156.PubMedCrossRefGoogle Scholar
  7. 7.
    Taylor L.D., Carmack C.E., Schramm S.R., et al. 1992. A transgenic mouse that expresses a diversity of human sequence heavy and light chain immunoglobulins. Nucleic Acids Res. 20, 6287–6295.PubMedPubMedCentralCrossRefGoogle Scholar
  8. 8.
    Murphy A.J., Macdonald L.E., Stevens S., et al. 2014. Mice with megabase humanization of their immunoglobulin genes generate antibodies as efficiently as normal mice. Proc. Natl. Acad. Sci. U. S. A. 111, 5153–5158.PubMedPubMedCentralCrossRefGoogle Scholar
  9. 9.
    McCafferty J., Griffiths A.D., Winter G., et al. 1990. Phage antibodies: Filamentous phage displaying antibody variable domains. Nature. 348, 552–554.PubMedCrossRefGoogle Scholar
  10. 10.
    Barbas C.F., Kang A.S., Lerner R.A., et al. 1991. Assembly of combinatorial antibody libraries on phage surfaces: The gene III site. Proc. Natl. Acad. Sci. U. S. A. 88, 7978–7982.PubMedPubMedCentralCrossRefGoogle Scholar
  11. 11.
    Boder E.T., Wittrup K.D. 1997. Yeast surface display for screening combinatorial polypeptide libraries. Nat. Biotechnol. 15, 553–557.PubMedCrossRefGoogle Scholar
  12. 12.
    Chao G., Lau W.L., Hackel B.J., et al. 2006. Isolating and engineering human antibodies using yeast surface display. Nat. Protoc. 1, 755–768.PubMedCrossRefGoogle Scholar
  13. 13.
    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, 445–470.PubMedPubMedCentralCrossRefGoogle Scholar
  14. 14.
    Jain T., Sun T., Durand S., et al. 2017. Biophysical properties of the clinical-stage antibody landscape. Proc. Natl. Acad. Sci. U. S. A. 114, 944–949.PubMedPubMedCentralCrossRefGoogle Scholar
  15. 15.
    Smietana K., Siatkowski M., Møller M. 2016. Trends in clinical success rates. Nat. Rev. Drug Discov. 15, 379–380.PubMedCrossRefGoogle Scholar
  16. 16.
    Hay M., Thomas D.W., Craighead J.L., et al. 2014. Clinical development success rates for investigational drugs. Nat. Biotechnol. 32, 40–51.PubMedCrossRefGoogle Scholar
  17. 17.
    Schulze U., Ringel M. 2013. What matters most in commercial success: First-in-class or best-in-class? Nat. Rev. Drug Discov. 12, 419–420.PubMedCrossRefGoogle Scholar
  18. 18.
    Bruhns P. 2012. Properties of mouse and human IgG receptors and their contribution to disease models. Blood. 119, 5640–5649.PubMedCrossRefGoogle Scholar
  19. 19.
    Cartron G., Dacheux L., Salles G., et al. 2002. Therapeutic activity of humanized anti-CD20 monoclonal antibody and polymorphism in IgG Fc receptor FcgammaRIIIa gene. Blood. 99, 754–758.PubMedCrossRefGoogle Scholar
  20. 20.
    Desjarlais J.R., Lazar G.A., Zhukovsky E.A., Chu S.Y. 2007. Optimizing engagement of the immune system by anti-tumor antibodies: An engineer’s perspective TL-12. Drug Discov. Today. 12 VN-r, 898–910.PubMedCrossRefGoogle Scholar
  21. 21.
    Shields R.L., Namenuk A.K., Hong K., et al. 2001. High resolution mapping of the binding site on human IgG1 for FcγRI, FcγRII, FcγRIII, and FcRn and design of IgG1 variants with improved binding to the FcγR. J. Biol. Chem. 276, 6591–6604.PubMedCrossRefGoogle Scholar
  22. 22.
    Richards J.O., Karki S., Lazar G.A., et al. 2008. Optimization of antibody binding to FcgammaRIIa enhances macrophage phagocytosis of tumor cells. Mol. Cancer Ther. 7, 2517–2527.PubMedCrossRefGoogle Scholar
  23. 23.
    Presta L.G. 2008. Molecular engineering and design of therapeutic antibodies. Curr. Opin. Immunol. 20, 460–470.PubMedCrossRefGoogle Scholar
  24. 24.
    Stavenhagen J.B., Gorlatov S., Tuaillon N., et al. 2007. Fc optimization of therapeutic antibodies enhances their ability to kill tumor cells in vitro and controls tumor expansion in vivo via low-affinity activating Fc receptors. Cancer Res. 67, 8882–8890.PubMedCrossRefGoogle Scholar
  25. 25.
    Ferrara C., Brünker P., Suter T., et al. 2006. Modulation of therapeutic antibody effector functions by glycosylation engineering: Influence of Golgi enzyme localization domain and co-expression of heterologous β1, 4-N-acetylglucosaminyltransferase III and Golgi α-mannosidase II. Biotechnol. Bioeng. 93, 851–861.PubMedCrossRefGoogle Scholar
  26. 26.
    Niwa R., Hatanaka S., Shoji-Hosaka E., et al. 2004. Enhancement of the antibody-dependent cellular cytotoxicity of low-fucose IgG1 Is independent of FcgammaRIIIa functional polymorphism. Clin. Cancer Res. 10, 6248–6255.PubMedCrossRefGoogle Scholar
  27. 27.
    Popma J.J., Satler L.F. 1994. Early and late clinical outcome following coronary angioplasty performed with platelet glycoprotein IIb/IIIa receptor inhibition: The EPIC Trial results. J. Invasive Cardiol. 6 (Suppl. A), 19A–28A; discussion 45A–50A.PubMedGoogle Scholar
  28. 28.
    An Z., Forrest G., Moore R., et al. 2009. IgG2m4, an engineered antibody isotype with reduced Fc function. MAbs. 1, 572–579.PubMedPubMedCentralCrossRefGoogle Scholar
  29. 29.
    Angal S., King D.J., Bodmer M.W., et al. 1993. A single amino acid substitution abolishes the heterogeneity of chimeric mouse/human (IgG4) antibody. Mol. Immunol. 30, 105–108.PubMedCrossRefGoogle Scholar
  30. 30.
    Brambell F.W., Hemmings W., Morris I.G. 1964. Theoretical model of gamma-globulin catabolism. Nature. 203, 1352–1354.PubMedCrossRefGoogle Scholar
  31. 31.
    Roopenian D.C., Akilesh S. 2007. FcRn: The neonatal Fc receptor comes of age. Nat. Rev. Immunol. 7, 715–725.PubMedCrossRefGoogle Scholar
  32. 32.
    Dall’Acqua W.F., Kiener P.A., Wu H. 2006. Properties of human IgG1s engineered for enhanced binding to the neonatal Fc receptor (FcRn). J. Biol. Chem. 281, 23514–23524.PubMedCrossRefGoogle Scholar
  33. 33.
    Vaccaro C., Zhou J., Ober R.J., Ward E.S. 2005. Engineering the Fc region of immunoglobulin G to modulate in vivo antibody levels. Nat. Biotechnol. 23, 1283–1288.PubMedCrossRefGoogle Scholar
  34. 34.
    Hinton P.R., Johlfs M.G., Xiong J.M., et al. 2003. Engineered human IgG antibodies with longer serum half-lives in primates. J. Biol. Chem. 279, 6213–6216.PubMedCrossRefGoogle Scholar
  35. 35.
    Yeung Y.A., Leabman M.K., Marvin J.S., et al. 2009. Engineering human IgG1 affinity to human neonatal Fc receptor: Impact of affinity improvement on pharmacokinetics in primates. J. Immunol. 182, 7663–7671.PubMedCrossRefGoogle Scholar
  36. 36.
    Zalevsky J., Chamberlain A.K., Horton H.M., et al. 2010. Enhanced antibody half-life improves in vivo activity. Nat. Biotechnol. 28, 157–159.PubMedPubMedCentralCrossRefGoogle Scholar
  37. 37.
    Lobo E.D., Hansen R.J., Balthasar J.P. 2004. Antibody pharmacokinetics and pharmacodynamics. J. Pharm. Sci. 93, 2645–2668.PubMedCrossRefGoogle Scholar
  38. 38.
    Rosengren S., Dychter S.S., Printz M.A., et al. 2015. Clinical immunogenicity of rHuPH20, a hyaluronidase enabling subcutaneous drug administration. AAPS J. 17, 1144–1156.PubMedPubMedCentralCrossRefGoogle Scholar
  39. 39.
    Melichar B., Študentová H., Kalábová H., Vitásková D. 2014. Role of subcutaneous formulation of trastuzumab in the treatment of patients with HER2-positive breast cancer. Immunotherapy. 6, 811–819.PubMedCrossRefGoogle Scholar
  40. 40.
    Stewart R., Hammond S.A., Oberst M., Wilkinson R.W. 2014. The role of Fc gamma receptors in the activity of immunomodulatory antibodies for cancer. J. Immunother. Cancer. 2, 29.CrossRefGoogle Scholar
  41. 41.
    Mahne A.E., Mauze S., Joyce-Shaikh B., et al. 2017. Dual roles for regulatory T-cell depletion and costimulatory signaling in agonistic GITR targeting for tumor immunotherapy. Cancer Res. 77, 1108–1118.PubMedCrossRefGoogle Scholar
  42. 42.
    Byers V.S., Rodvien R., Grant K., et al. 1989. Phase I study of monoclonal antibody-ricin A chain immunotoxin XomaZyme-791 in patients with metastatic colon cancer. Cancer Res. 49, 6153–6160.PubMedGoogle Scholar
  43. 43.
    LoRusso P.M., Lomen P.L., Redman B.G., et al. 1995. Phase I study of monoclonal antibody-ricin A chain immunoconjugate Xomazyme-791 in patients with metastatic colon cancer. Am. J. Clin. Oncol. 18, 307–312.PubMedCrossRefGoogle Scholar
  44. 44.
    Kuan C.T., Pai L.H., Pastan I. 1995. Immunotoxins containing Pseudomonas exotoxin that target LeY damage human endothelial cells in an antibody-specific mode: Relevance to vascular leak syndrome. Clin. Cancer Res. 1, 1589–1594.PubMedGoogle Scholar
  45. 45.
    Lynch T.J., Lambert J.M., Coral F., et al. 1997. Immunotoxin therapy of small-cell lung cancer: A phase I study of N901-blocked ricin. J. Clin. Oncol. 15, 723–734.PubMedCrossRefGoogle Scholar
  46. 46.
    Giantonio B.J., Alpaugh R.K., Schultz J., et al. 1997. Superantigen-based immunotherapy: A phase I trial of PNU-214565, a monoclonal antibody-staphylococcal enterotoxin A recombinant fusion protein, in advanced pancreatic and colorectal cancer. J. Clin. Oncol. 15, 1994–2007.PubMedCrossRefGoogle Scholar
  47. 47.
    Trail P.A., Willner D., Lasch S.J., et al. 1993. Cure of xenografted human carcinomas by BR96-doxorubicin immunoconjugates. Science. 261, 212–215.PubMedCrossRefGoogle Scholar
  48. 48.
    Tolcher A.W., Sugarman S., Gelmon K.A., et al. 1999. Randomized phase II study of BR96-doxorubicin conjugate in patients with metastatic breast cancer. J. Clin. Oncol. 17, 478–478.PubMedCrossRefGoogle Scholar
  49. 49.
    Saleh M.N., Sugarman S., Murray J., et al. 2000. Phase I trial of the anti-Lewis Y drug immunoconjugate BR96–doxorubicin in patients with Lewis Y-expressing epithelial tumors. J. Clin. Oncol. 18, 2282–2292.PubMedCrossRefGoogle Scholar
  50. 50.
    Hamann P.R., Hinman L.M., Hollander I., et al. 2002. Gemtuzumab ozogamicin, a potent and selective anti-CD33 antibody–calicheamicin conjugate for treatment of acute myeloid leukemia. Bioconjug. Chem. 13, 47–58.PubMedCrossRefGoogle Scholar
  51. 51.
    Ducry L., Stump B. 2010. Antibody–drug conjugates: Linking cytotoxic payloads to monoclonal antibodies. Bioconjug. Chem. 21, 5–13.PubMedCrossRefGoogle Scholar
  52. 52.
    Petersdorf S.H., Kopecky K.J., Slovak M., et al. 2013. A phase 3 study of gemtuzumab ozogamicin during induction and postconsolidation therapy in younger patients with acute myeloid leukemia. Blood. 121, 4854–4860. doi 10.1182/blood-2013-01-466706PubMedPubMedCentralCrossRefGoogle Scholar
  53. 53.
    Davies A.J. 2007. Radioimmunotherapy for B-cell lymphoma: Y90 ibritumomab tiuxetan and I131 tositumomab. Oncogene. 26, 3614–3628.PubMedCrossRefGoogle Scholar
  54. 54.
    Srivastava S.C. 1996. Criteria for the selection of radionuclides for targeting nuclear antigens for cancer radioimmunotherapy. Cancer Biother. Radiopharm. 11, 43–50.PubMedCrossRefGoogle Scholar
  55. 55.
    Larson S.M., Carrasquillo J.A., Cheung N.-K., Press O.W. 2015. Radioimmunotherapy of human tumours. Nat. Rev. Cancer. 15, 347–360.PubMedPubMedCentralCrossRefGoogle Scholar
  56. 56.
    Buchegger F., Larson S.M., Mach J.P., et al. 2013. Radioimmunotherapy combined with maintenance anti-CD20 antibody may trigger long-term protective T cell immunity in follicular lymphoma patients. Clin. Dev. Immunol. 2013, 875343. doi 10.1155/2013/875343PubMedPubMedCentralCrossRefGoogle Scholar
  57. 57.
    Ychou M., Azria D., Menkarios C., et al. 2008. Adjuvant radioimmunotherapy trial with iodine-131-labeled anti-carcinoembryonic antigen monoclonal antibody F6 F (ab')2 after resection of liver metastases from colorectal cancer. Clin. Cancer Res. 14, 3487–3493.PubMedPubMedCentralCrossRefGoogle Scholar
  58. 58.
    Lee H., Shields A.F., Siegel B.A., et al. 2017. 64Cu-MM-302 positron emission tomography quantifies variability of enhanced permeability and retention of nanoparticles in relation to treatment response in patients with metastatic breast cancer. Clin. Cancer Res. 23 (15), 4190–4202. doi 10.1158/1078-0432.CCR-16-3193PubMedCrossRefGoogle Scholar
  59. 59.
    Jagoda E.M., Lang L., Bhadrasetty V., et al. 2012. Immuno-PET of the hepatocyte growth factor receptor Met using the 1-armed antibody onartuzumab. J. Nucl. Med. 53, 1592–1600.PubMedPubMedCentralCrossRefGoogle Scholar
  60. 60.
    Younes A., Bartlett N.L., Leonard J.P., et al. 2010. Brentuximab vedotin (SGN-35) for relapsed CD30-positive lymphomas. N. Engl. J. Med. 363, 1812–1821.PubMedCrossRefGoogle Scholar
  61. 61.
    Verma S., Miles D., Gianni L., et al. 2012. Trastuzumab emtansine for HER2-positive advanced breast cancer. N. Engl. J. Med. 367, 1783–1791.PubMedPubMedCentralCrossRefGoogle Scholar
  62. 62.
    Donaghy H. 2016. Effects of antibody, drug and linker on the preclinical and clinical toxicities of antibodydrug conjugates. MAbs. 8, 659–671.PubMedPubMedCentralCrossRefGoogle Scholar
  63. 63.
    Kim E.G., Kim K.M. 2015. Strategies and advancement in antibody–drug conjugate optimization for targeted cancer therapeutics. Biomol. Ther. (Seoul). 23, 493–509.PubMedPubMedCentralCrossRefGoogle Scholar
  64. 64.
    Erickson H.K., Lambert J.M. 2012. ADME of antibody–maytansinoid conjugates. AAPS J. 14, 799–805.PubMedPubMedCentralCrossRefGoogle Scholar
  65. 65.
    Miller K., Cortes J., Hurvitz S.A., et al. 2016. HERMIONE: A randomized Phase 2 trial of MM-302 plus trastuzumab versus chemotherapy of physician’s choice plus trastuzumab in patients with previously treated, anthracycline-naïve, HER2-positive, locally advanced/metastatic breast cancer. BMC Cancer. 16, 352.PubMedPubMedCentralCrossRefGoogle Scholar
  66. 66.
    Geddie M.L., Kohli N., Kirpotin D.B., et al. 2017. Improving the developability of an anti-EphA2 singlechain variable fragment for nanoparticle targeting. MAbs. 9, 58–67.PubMedCrossRefGoogle Scholar
  67. 67.
    Huehls A.M., Coupet T.A., Sentman C.L. 2015. Bispecific T-cell engagers for cancer immunotherapy. Immunol. Cell Biol. 93, 290–296.PubMedCrossRefGoogle Scholar
  68. 68.
    Kantarjian H., Stein A., Gökbuget N., et al. 2017. Blinatumomab versus chemotherapy for advanced acute lymphoblastic leukemia. N. Engl. J. Med. 376, 836–847.PubMedCrossRefGoogle Scholar
  69. 69.
    Buie L.W., Pecoraro J.J., Horvat T.Z., Daley R.J. 2015. Blinatumomab. Ann. Pharmacother. 49, 1057–1067.PubMedCrossRefGoogle Scholar
  70. 70.
    Eavarone D.A., Prendergast J., Rao P.E., et al. 2017. Novel humanized anti-Sialyl-Tn, anti-CD3 bispecific antibodies demonstrate tumor and T-cell specificity for immune activation at the tumor site. In: Assoc. Cancer Res. Annu. Meet. 3640/13.Google Scholar
  71. 71.
    Stamova S., Koristka S., Keil J., et al. 2012. Cancer immunotherapy by retargeting of immune effector cells via recombinant bispecific antibody constructs. Antibodies. 1, 172–198.CrossRefGoogle Scholar
  72. 72.
    Klein C., Waldhauer I., Nicolini V.G., et al. 2017. Cergutuzumab amunaleukin (CEA-IL2v), a CEA-targeted IL-2 variant-based immunocytokine for combination cancer immunotherapy: Overcoming limitations of aldesleukin and conventional IL-2-based immunocytokines. Oncoimmunology. 6, e1277306.PubMedPubMedCentralCrossRefGoogle Scholar
  73. 73.
    Del Bano J., Chames P., Baty D., Kerfelec B. 2015. Taking up cancer immunotherapy challenges: Bispecific antibodies, the path forward? Antibodies. 5, 1.CrossRefGoogle Scholar
  74. 74.
    Weidle U.H., Kontermann R.E., Brinkmann U. 2014. Tumor-antigen-binding bispecific antibodies for cancer treatment. Semin. Oncol. 41, 653–660.PubMedCrossRefGoogle Scholar
  75. 75.
    Gross G., Gorochov G., Waks T., Eshhar Z. 1989. Generation of effector T cells expressing chimeric T cell receptor with antibody type-specificity. Transplant. Proc. 21, 127–130.PubMedGoogle Scholar
  76. 76.
    Thistlethwaite F., Mansoor W., Gilham D.E., Hawkins R.E. 2005. Engineering T-cells with antibodybased chimeric receptors for effective cancer therapy. Curr. Opin. Mol. Ther. 7, 48–55.PubMedGoogle Scholar
  77. 77.
    Porter D.L., Levine B.L., Kalos M., et al. 2011. Chimeric antigen receptor-modified T cells in chronic lymphoid leukemia. N. Engl. J. Med. 365, 725–733.PubMedPubMedCentralCrossRefGoogle Scholar
  78. 78.
    Grupp S.A., Kalos M., Barrett D., et al. 2013. Chimeric antigen receptor-modified T cells for acute lymphoid leukemia. N. Engl. J. Med. 368, 1509–1518.PubMedPubMedCentralCrossRefGoogle Scholar
  79. 79.
    Maude S.L., Frey N., Shaw P.A., et al. 2014. Chimeric antigen receptor T cells for sustained remissions in leukemia. N. Engl. J. Med. 371, 1507–1517.PubMedPubMedCentralCrossRefGoogle Scholar
  80. 80.
    Kalos M., Levine B.L., Porter D.L., et al. 2011. T cells with chimeric antigen receptors have potent antitumor effects and can establish memory in patients with advanced leukemia. Sci. Transl. Med. 3, 95ra73.CrossRefGoogle Scholar
  81. 81.
    Walker A., Johnson R. 2016. Commercialization of cellular immunotherapies for cancer. Biochem. Soc. Trans. 44, 329–332.PubMedCrossRefGoogle Scholar
  82. 82.
    Hu Y., Sun J., Wu Z., et al. 2016. Predominant cerebral cytokine release syndrome in CD19-directed chimeric antigen receptor-modified T cell therapy. J. Hematol. Oncol. 9, 70. doi 10.1186/s13045-016-0299-5PubMedPubMedCentralCrossRefGoogle Scholar
  83. 83.
    Sotillo E., Sun J., Wu Z., et al. 2015. Convergence of acquired mutations and alternative splicing of CD19 enables resistance to CART-19 immunotherapy. Cancer Discov. 5, 1282–1295.PubMedPubMedCentralCrossRefGoogle Scholar
  84. 84.
    Torikai H., Reik A., Liu P.Q., et al. 2012. A foundation for universal T-cell based immunotherapy: T cells engineered to express a CD19-specific chimeric-antigen-receptor and eliminate expression of endogenous TCR. Blood. 119, 5697–5705.PubMedPubMedCentralCrossRefGoogle Scholar
  85. 85.
    Gargett T., Brown M.P. 2014. The inducible caspase-9 suicide gene system as a “safety switch” to limit on-target, off-tumor toxicities of chimeric antigen receptor T cells. Front. Pharmacol. 5, 235.PubMedPubMedCentralCrossRefGoogle Scholar
  86. 86.
    Topalian S.L., Weiner G.J., Pardoll D.M. 2011. Cancer immunotherapy comes of age. J. Clin. Oncol. 29, 4828–4836.PubMedPubMedCentralCrossRefGoogle Scholar
  87. 87.
    Hegde P.S., Karanikas V., Evers S. 2016. The where, the when, and the how of immune monitoring for cancer immunotherapies in the era of checkpoint inhibition. Clin. Cancer Res. 22, 1865–1874. doi 10.1158/1078-0432PubMedCrossRefGoogle Scholar
  88. 88.
    Tol J., Koopman M., Cats A., et al. 2009. Chemotherapy, bevacizumab, and cetuximab in metastatic colorectal cancer. N. Engl. J. Med. 360 (6), 563–572. doi 10.1056/NEJMoa0808268PubMedCrossRefGoogle Scholar
  89. 89.
    Robak T., Windyga J., Trelinski J., et al. 2012. Rozrolimupab, a mixture of 25 recombinant human monoclonal RhD antibodies, in the treatment of primary immune thrombocytopenia. Blood. 120, 3670–3676.PubMedCrossRefGoogle Scholar
  90. 90.
    Sánchez-Martin F.J., Bellosillo B., Gelabert-Baldrich M., et al. 2016. The first-in-class anti-EGFR antibody mixture Sym004 overcomes Cetuximab resistance mediated by EGFR extracellular domain mutations in colorectal cancer. Clin. Cancer Res. 22, 3260–3267.PubMedCrossRefGoogle Scholar
  91. 91.
    Kearns J.D., Bukhalid R., Sevecka M., et al. 2015. Enhanced targeting of the EGFR network with MM-151, an oligoclonal anti-EGFR antibody therapeutic. Mol. Cancer Ther. 14, 1625–1636.PubMedCrossRefGoogle Scholar
  92. 92.
    Baselga J., Cortés J., Kim S.B., et al. 2012. Pertuzumab plus Trastuzumab plus Docetaxel for metastatic breast cancer. N. Engl. J. Med. 366, 109–119.PubMedCrossRefGoogle Scholar
  93. 93.
    Larkin J., Chiarion-Sileni V., Gonzalez R., et al. 2015. Combined Nivolumab and Ipilimumab or monotherapy in untreated melanoma. N. Engl. J. Med. 373, 23–34.PubMedPubMedCentralCrossRefGoogle Scholar
  94. 94.
    Henricks L.M., Schellens J.H.M., Huitema A.D.R., Beijnen J.H. 2015. The use of combinations of monoclonal antibodies in clinical oncology. Cancer Treat. Rev. 41, 859–867.PubMedCrossRefGoogle Scholar
  95. 95.
    Fitzgerald J.B., Schoeberl B., Nielsen U.B., Sorger P.K. 2006. Systems biology and combination therapy in the quest for clinical efficacy. Nat. Chem. Biol. 2, 458–466.PubMedCrossRefGoogle Scholar
  96. 96.
    Albanell J., Codony J., Rovira A., et al. 2003. Mechanism of action of anti-HER2 monoclonal antibodies: Scientific update on trastuzumab and 2C4. Adv. Exp. Med. Biol. 532, 253–268.PubMedCrossRefGoogle Scholar
  97. 97.
    Weidle U.H., Kontermann R.E., Brinkmann U. 2014. Tumor-antigen-binding bispecific antibodies for cancer treatment. Semin. Oncol. 41, 653–660.PubMedCrossRefGoogle Scholar
  98. 98.
    Harms B.D., Kearns J.D., Iadevaia S., Lugovskoy A.A. 2014. Understanding the role of cross-arm binding efficiency in the activity of monoclonal and multispecific therapeutic antibodies. Methods. 65, 95–104.PubMedCrossRefGoogle Scholar
  99. 99.
    Fitzgerald J., Lugovskoy A.A. 2011. Rational engineering of antibody therapeutics targeting multiple oncogene pathways. MAbs. 3, 299–309.PubMedPubMedCentralCrossRefGoogle Scholar
  100. 100.
    Gu J., Yang J., Chang Q., et al. 2015. Identification of anti-EGFR and anti-ErbB3 dual variable domains immunoglobulin (DVD-Ig. proteins with unique activities. PLoS ONE. 10, e0124135.PubMedGoogle Scholar
  101. 101.
    Fitzgerald J.B., Johnson B.W., Baum J., et al. 2014. MM-141, an IGF-IR- and ErbB3-directed bispecific antibody, overcomes network adaptations that limit activity of IGF-IR inhibitors. Mol. Cancer Ther. 13, 410–425.PubMedCrossRefGoogle Scholar
  102. 102.
    Michaelson J.S., Demarest S.J., Miller B., et al. 2009. Anti-tumor activity of stability-engineered IgG-like bispecific antibodies targeting TRAIL-R2 and LTbetaR. MAbs. 1, 128–141.PubMedPubMedCentralCrossRefGoogle Scholar
  103. 103.
    Schuhmacher A., Gassmann O., Hinder M. 2016. Changing R&D models in research-based pharmaceutical companies. J. Transl. Med. 14, 105.PubMedPubMedCentralCrossRefGoogle Scholar
  104. 104.
    McIntyre D. 2017. Institute for Protein Innovation Release: New research institute promises to transform protein science and drug discovery. BioSpace. http://www.bioportfolio.com/news/article/3135921/.Google Scholar

Copyright information

© Pleiades Publishing, Inc. 2017

Authors and Affiliations

  1. 1.Morphic TherapeuticWalthamUSA

Personalised recommendations