Next generation antibody drugs: Pursuit of the 'high-hanging fruit'

Nature Reviews Drug Discovery

Volumn 17, Issue 3, 2018, Pages 197-223

  Carter, Paul J ^a   Lazar, Greg A ^a  

^a GENENTECH INC   (United States)

Author keywords

[No Author keywords available]

Indexed keywords

ANTIBODY DRUG CONJUGATE; ATEZOLIZUMAB; AVELUMAB; BISPECIFIC ANTIBODY; BLINATUMOMAB; BRENTUXIMAB VEDOTIN; CETUXIMAB; DARATUMUMAB; DENOSUMAB; DINUTUXIMAB; DURVALUMAB; GEMTUZUMAB OZOGAMICIN; IBRITUMOMAB TIUXETAN; INOTUZUMAB OZOGAMICIN; IPILIMUMAB; MOGAMULIZUMAB; NECITUMUMAB; NIMOTUZUMAB; NIVOLUMAB; OBINUTUZUMAB; OFATUMUMAB; OLARATUMAB; PANITUMUMAB; PEMBROLIZUMAB; PERTUZUMAB; PRALIA; RANMARK; RITUXIMAB; TOSITUMOMAB; TRASTUZUMAB; TRASTUZUMAB EMTANSINE; UNINDEXED DRUG; ANTIBODY CONJUGATE; MONOCLONAL ANTIBODY;

ACUTE LYMPHOBLASTIC LEUKEMIA; ACUTE MYELOID LEUKEMIA; ANAPLASTIC LARGE CELL LYMPHOMA; ANTIBODY ENGINEERING; BONE METASTASIS; BREAST CANCER; CANCER IMMUNOTHERAPY; CHRONIC LYMPHATIC LEUKEMIA; COLORECTAL CANCER; DIMERIZATION; DRUG MECHANISM; DRUG RESEARCH; DRUG UPTAKE; ESOPHAGUS CANCER; EYE DISEASE; FOLLICULAR LYMPHOMA; GLIOMA; HEAD AND NECK CANCER; HODGKIN DISEASE; HUMAN; IMMUNOCOMPETENT CELL; LIVER CELL CARCINOMA; MELANOMA; MERKEL CELL CARCINOMA; MULTIPLE MYELOMA; NASOPHARYNX CANCER; NEUROBLASTOMA; NON SMALL CELL LUNG CANCER; NONHODGKIN LYMPHOMA; NONHUMAN; OSTEOPOROSIS; PANCREAS CANCER; PRIORITY JOURNAL; RENAL CELL CARCINOMA; REVIEW; RHEUMATOID ARTHRITIS; SOFT TISSUE SARCOMA; SOLID MALIGNANT NEOPLASM; SQUAMOUS CELL CARCINOMA; STOMACH CANCER; T CELL LEUKEMIA; T CELL LYMPHOMA; T LYMPHOCYTE; TRANSITIONAL CELL CARCINOMA; WEGENER GRANULOMATOSIS; IMMUNOLOGY; NEOPLASM; PROCEDURES; PROTEIN ENGINEERING;

ANTIBODIES, BISPECIFIC; ANTIBODIES, MONOCLONAL; HUMANS; IMMUNOCONJUGATES; NEOPLASMS; PROTEIN ENGINEERING;

EID: 85042640438     PISSN: 14741776     EISSN: 14741784     Source Type: Journal    
DOI: 10.1038/nrd.2017.227     Document Type: Review

References (370)

1. Nelson, A. L., Dhimolea, E. &Reichert, J. M. Development trends for human monoclonal antibody therapeutics. Nat. Rev. Drug Discov. 9, 767-774 (2010).
2. Reichert, J. M. Antibodies to watch in 2017. mAbs 9, 167-181 (2017). This study is a recent addition to a popular series that tracks recently approved antibody drugs plus those in late-stage clinical development.
3. Schuurman, J. &Parren, P. W. Editorial overview: special section: new concepts in antibody therapeutics: what's in store for antibody therapy? Curr. Opin. Immunol. 40, vii-xiii (2016).
4. Udpa, N. &Million, R. P. Monoclonal antibody biosimilars. Nat. Rev. Drug Discov. 15, 13-14 (2016).
5. Garrison, L. P. Jr Cost-effectiveness and clinical practice guidelines: have we reached a tipping point? An overview. Value Health 19, 512-515 (2016).
6. Jacobs, I. et al. Monoclonal antibody and fusion protein biosimilars across therapeutic areas: a systematic review of published evidence. BioDrugs 30, 489-523 (2016).
7. Rath, T. et al. Fc-fusion proteins and FcRn: structural insights for longer-lasting and more effective therapeutics. Crit. Rev. Biotechnol. 35, 235-254 (2015).
8. Neri, D. &Sondel, P. M. Immunocytokines for cancer treatment: past, present and future. Curr. Opin. Immunol. 40, 96-102 (2016).
9. Bootz, F. &Neri, D. Immunocytokines: a novel class of products for the treatment of chronic inflammation and autoimmune conditions. Drug Discov. Today 21, 180-189 (2016).
10. Sadelain, M., Rivière, I. &Riddell, S. Therapeutic T cell engineering. Nature 545, 423-431 (2017).
11. Chan, A. C. &Carter, P. J. Therapeutic antibodies for autoimmunity and inflammation. Nat. Rev. Immunol. 10, 301-316 (2010).
12. Ayyar, B. V., Arora, S. &O'Kennedy, R. Coming-of-age of antibodies in cancer therapeutics. Trends Pharmacol. Sci. 37, 1009-1028 (2016).
13. Redman, J. M., Hill, E. M., AlDeghaither, D. &Weiner, L. M. Mechanisms of action of therapeutic antibodies for cancer. Mol. Immunol. 67, 28-45 (2015).
14. Zhukovsky, E. A., Morse, R. J. &Maus, M. V. Bispecific antibodies and CARs: generalized immunotherapeutics harnessing T cell redirection. Curr. Opin. Immunol. 40, 24-35 (2016).
15. Polakis, P. Antibody drug conjugates for cancer therapy. Pharmacol. Rev. 68, 3-19 (2016).
16. Tolcher, A. W. Antibody drug conjugates: lessons from 20 years of clinical experience. Ann. Oncol. 27, 2168-2172 (2016).
17. Beck, A., Goetsch, L., Dumontet, C. &Corvaïa, N. Strategies and challenges for the next generation antibody-drug conjugates. Nat. Rev. Drug. Discov. 16, 315-337 (2017). This study is a comprehensive recent Review on antibody-drug conjugates.
18. Niwa, R. &Satoh, M. The current status and prospects of antibody engineering for therapeutic use: focus on glycoengineering technology. J. Pharm. Sci. 104, 930-941 (2015).
19. Staerz, U. D., Kanagawa, O. &Bevan, M. J. Hybrid antibodies can target sites for attack by T cells. Nature 314, 628-631 (1985).
20. Newman, M. J. &Benani, D. J. A review of blinatumomab, a novel immunotherapy. J. Oncol. Pharm. Pract. 22, 639-645 (2016).
21. Brinkmann, U. &Kontermann, R. E. The making of bispecific antibodies. mAbs 9, 182-212 (2017).
22. Chichili, G. R. et al. A CD3xCD123 bispecific DART for redirecting host T cells to myelogenous leukemia: preclinical activity and safety in nonhuman primates. Sci. Transl Med. 7, 289ra82 (2015).
23. Reusch, U. et al. A tetravalent bispecific TandAb (CD19/CD3), AFM11, efficiently recruits T cells for the potent lysis of CD19+ tumor cells. mAbs 7, 584-604 (2015).
24. Sun, L. L. et al. Anti-CD20/CD3 T cell-dependent bispecific antibody for the treatment of B cell malignancies. Sci. Transl Med. 7, 287ra70 (2015).
25. Klein, C., Schaefer, W. &Regula, J. T. The use of CrossMAb technology for the generation of bi-and multispecific antibodies. mAbs 8, 1010-1020 (2016).
26. Spiess, C., Zhai, Q. &Carter, P. J. Alternative molecular formats and therapeutic applications for bispecific antibodies. Mol. Immunol. 67, 95-106 (2015).
27. Jain, T. et al. Biophysical properties of the clinicalstage antibody landscape. Proc. Natl Acad. Sci. USA 114, 944-949 (2017). This study presents a developability assessment of 137 clinical stage antibodies to empirically define boundaries of drug-like behaviour.
28. Mabry, R. et al. Engineering of stable bispecific antibodies targeting IL-17A and IL-23. Protein Eng. Des. Sel. 23, 115-127 (2009).
29. Arvedson, T. L. et al. Generation of half-life extended anti-CD33 BiTE® antibody constructs compatible with once-weekly dosing [abstract]. Cancer Res. 77 (Suppl.), 55 (2017).
30. Schmidt, M. M. &Wittrup, K. D. A modeling analysis of the effects of molecular size and binding affinity on tumor targeting. Mol. Cancer Ther. 8, 2861-2871 (2009).
31. Locke, F. L. et al. Phase 1 results of ZUMA-1: a multicenter study of KTE-C19 anti-CD19 CAR T cell therapy in refractory aggressive lymphoma. Mol. Ther. 25, 285-295 (2017).
32. Frankel, S. R. &Baeuerle, P. A. Targeting T cells to tumor cells using bispecific antibodies. Curr. Opin. Chem. Biol. 17, 385-392 (2013).
33. Krupka, C. et al. Blockade of the PD-1/PD-L1 axis augments lysis of AML cells by the CD33/CD3 BiTE antibody construct AMG 330: reversing a T-cellinduced immune escape mechanism. Leukemia 30, 484-491 (2016).
34. Osada, T. et al. CEA/CD3-bispecific T cell-engaging (BiTE) antibody-mediated T lymphocyte cytotoxicity maximized by inhibition of both PD1 and PD-L1. Cancer Immunol. Immunother. 64, 677-688 (2015).
35. Oates, J., Hassan, N. J. &Jakobsen, B. K. ImmTACs for targeted cancer therapy: why, what, how, and which. Mol. Immunol. 67, 67-74 (2015).
36. Chang, A. Y. et al. Opportunities and challenges for TCR mimic antibodies in cancer therapy. Expert Opin. Biol. Ther. 16, 979-987 (2016).
37. Reusch, U. et al. A novel tetravalent bispecific TandAb (CD30/CD16A) efficiently recruits NK cells for the lysis of CD30+ tumor cells. mAbs 6, 728-739 (2014).
38. Jaiswal, S. et al. CD47 is upregulated on circulating hematopoietic stem cells and leukemia cells to avoid phagocytosis. Cell 138, 271-285 (2009).
39. Dheilly, E. et al. Selective blockade of the ubiquitous checkpoint receptor CD47 is enabled by dualtargeting bispecific antibodies. Mol. Ther. 25, 523-533 (2017).
40. Piccione, E. C. et al. A bispecific antibody targeting CD47 and CD20 selectively binds and eliminates dual antigen expressing lymphoma cells. mAbs 7, 946-956 (2015).
41. Moolten, F. L. &Cooperband, S. R. Selective destruction of target cells by diphtheria toxin conjugated to antibody directed against antigens on the cells. Science 169, 68-70 (1970).
42. Petersdorf, S. H. et al. A phase 3 study of gemtuzumab ozogamicin during induction and postconsolidation therapy in younger patients with acute myeloid leukemia. Blood 121, 4854-4860 (2013).
43. Castaigne, S. et al. Effect of gemtuzumab ozogamicin on survival of adult patients with de-novo acute myeloid leukaemia (ALFA-0701): a randomised, openlabel, phase 3 study. Lancet 379, 1508-1516 (2012).
44. Francisco, J. A. et al. cAC10-vcMMAE, an anti-CD30-monomethyl auristatin E conjugate with potent and selective antitumor activity. Blood 102, 1458-1465 (2003).
45. Younes, A. et al. Results of a pivotal phase II study of brentuximab vedotin for patients with relapsed or refractory Hodgkin's lymphoma. J. Clin. Oncol. 30, 2183-2189 (2012).
46. Carter, P. et al. Humanization of an anti-p185HER2 antibody for human cancer therapy. Proc. Natl Acad. Sci. USA 89, 4285-4289 (1992).
47. Lewis Phillips, G. D. et al. Targeting HER2-positive breast cancer with trastuzumab-DM1, an antibodycytotoxic drug conjugate. Cancer Res. 68, 9280-9290 (2008).
48. Krop, I. E. et al. Trastuzumab emtansine versus treatment of physician's choice for pretreated HER2-positive advanced breast cancer (TH3RESA): a randomised, open-label, phase 3 trial. Lancet Oncol. 15, 689-699 (2014).
49. Verma, S. et al. Trastuzumab emtansine for HER2-positive advanced breast cancer. N. Engl. J. Med. 367, 1783-1791 (2012).
50. Hamblett, K. J. et al. Effects of drug loading on the antitumor activity of a monoclonal antibody drug conjugate. Clin. Cancer Res. 10, 7063-7070 (2004).
51. Lyon, R. P. et al. Reducing hydrophobicity of homogeneous antibody-drug conjugates improves pharmacokinetics and therapeutic index. Nat. Biotechnol. 33, 733-735 (2015).
52. Yurkovetskiy, A. V. et al. A polymer-based antibodyvinca drug conjugate platform: characterization and preclinical efficacy. Cancer Res. 75, 3365-3372 (2015).
53. McDonagh, C. F. et al. Engineered antibody-drug conjugates with defined sites and stoichiometries of drug attachment. Protein Eng. Des. Sel. 19, 299-307 (2006).
54. Junutula, J. R. et al. Site-specific conjugation of a cytotoxic drug to an antibody improves the therapeutic index. Nat. Biotechnol. 26, 925-932 (2008). This study is the first demonstration that site-specific drug conjugation to an antibody can enhance the therapeutic index of the corresponding conjugate.
55. Shen, B. Q. et al. Conjugation site modulates the in vivo stability and therapeutic activity of antibodydrug conjugates. Nat. Biotechnol 30, 184-189 (2012).
56. Levengood, M. R. et al. Orthogonal cysteine protection enables homogeneous multi-drug antibodydrug conjugates. Angew. Chem. Int. Ed. 56, 733-737 (2017).
57. Li, J. Y. et al. A biparatopic HER2-targeting antibodydrug conjugate induces tumor regression in primary models refractory to or ineligible for HER2-targeted therapy. Cancer Cell 29, 117-129 (2016). This study presents a bivalent biparatopic anti-HER2 antibody-drug conjugate with tubulysin that shows exceptional in vivo antitumour efficacy compared with that achieved by a bivalent monospecific antibody-drug conjugate.
58. de Goeij, B. E. et al. Efficient payload delivery by a bispecific antibody-drug conjugate targeting HER2 and CD63. Mol. Cancer Ther. 15, 2688-2697 (2016).
59. DeVay, R. M. et al. Improved lysosomal trafficking can modulate the potency of antibody drug conjugates. Bioconjug. Chem. 28, 1102-1114 (2017).
60. Andreev, J. et al. Bispecific antibodies and antibodydrug conjugates (ADCs) bridging HER2 and prolactin receptor improve efficacy of HER2 ADCs. Mol. Cancer Ther. 16, 681-693 (2017).
61. Lehar, S. M. et al. Novel antibody-antibiotic conjugate eliminates intracellular S. aureus. Nature 527, 323-328 (2015). This study presents the first extension of the antibody-drug conjugate concept to an antibody-antibiotic conjugate for treatment of a bacterial infection.
62. Wang, R. E. et al. An immunosuppressive antibodydrug conjugate. J. Am. Chem. Soc. 137, 3229-3232 (2015).
63. Desjarlais, J. R. &Lazar, G. A. Modulation of antibody effector function. Exp. Cell Res. 317, 1278-1285 (2011).
64. Niwa, R. et al. Defucosylated chimeric anti-CC chemokine receptor 4 IgG1 with enhanced antibodydependent cellular cytotoxicity shows potent therapeutic activity to T-cell leukemia and lymphoma. Cancer Res. 64, 2127-2133 (2004).
65. Beck, A. &Reichert, J. M. Marketing approval of mogamulizumab: a triumph for glyco-engineering. mAbs 4, 419-425 (2012).
66. Mössner, E. et al. Increasing the efficacy of CD20 antibody therapy through the engineering of a new type II anti-CD20 antibody with enhanced direct and immune effector cell-mediated B-cell cytotoxicity. Blood 115, 4393-4402 (2010).
67. Kellner, C. et al. The Fc-engineered CD19 antibody MOR208 (XmAb5574) induces natural killer cellmediated lysis of acute lymphoblastic leukemia cells from pediatric and adult patients. Leukemia 27, 1595-1598 (2013).
68. Woyach, J. A. et al. A phase 1 trial of the Fc-engineered CD19 antibody XmAb5574 (MOR00208) demonstrates safety and preliminary efficacy in relapsed CLL. Blood 124, 3553-3560 (2014).
69. Caaveiro, J. M., Kiyoshi, M. &Tsumoto, K. Structural analysis of Fc/FcγR complexes: a blueprint for antibody design. Immunol. Rev. 268, 201-221 (2015).
70. Liu, Z. et al. Asymmetrical Fc engineering greatly enhances antibody-dependent cellular cytotoxicity (ADCC) effector function and stability of the modified antibodies. J. Biol. Chem. 289, 3571-3590 (2014).
71. Mimoto, F. et al. Novel asymmetrically engineered antibody Fc variant with superior FcγR binding affinity and specificity compared with afucosylated Fc variant. mAbs 5, 229-236 (2013). This study uses asymmetric Fc variants for exquisite tailoring of IgG specificity for FcγR.
72. Mimoto, F. et al. Engineered antibody Fc variant with selectively enhanced FcγRIIb binding over both FcγRIIaR131 and FcγRIIaH131. Protein Eng. Des. Sel. 26, 589-598 (2013).
73. Teeling, J. L. et al. Characterization of new human CD20 monoclonal antibodies with potent cytolytic activity against non-Hodgkin lymphomas. Blood 104, 1793-1800 (2004).
74. Saphire, E. O. et al. Crystal structure of a neutralizing human IGG against HIV-1: a template for vaccine design. Science 293, 1155-1159 (2001).
75. Wu, Y. et al. Structural basis for enhanced HIV-1 neutralization by a dimeric immunoglobulin G form of the glycan-recognizing antibody 2G12. Cell Rep. 5, 1443-1455 (2013).
76. Diebolder, C. A. et al. Complement is activated by IgG hexamers assembled at the cell surface. Science 343, 1260-1263 (2014). This study demonstrates that non-covalent interactions between Fc regions of IgG result in hexamerization after antigen-binding on cells. Fc point mutations were identified that increase IgG hexamerization and CDC activity.
77. Cook, E. M. et al. Antibodies that efficiently form hexamers upon antigen binding can induce complement-dependent cytotoxicity under complement-limiting conditions. J. Immunol. 197, 1762-1775 (2016).
78. Ayyar, B. V., Arora, S. &O'Kennedy, R. Coming-of-age of antibodies in cancer therapeutics. Trends Pharmacol. Sci. 37, 1009-1028 (2016).
79. Redman, J. M., Hill, E. M., AlDeghaither, D. &Weiner, L. M. Mechanisms of action of therapeutic antibodies for cancer. Mol. Immunol. 67, 28-45 (2015).
80. Zhukovsky, E. A., Morse, R. J. &Maus, M. V. Bispecific antibodies and CARs: generalized immunotherapeutics harnessing T cell redirection. Curr. Opin. Immunol. 40, 24-35 (2016).
81. Polakis, P. Antibody drug conjugates for cancer therapy. Pharmacol. Rev. 68, 3-19 (2016).
82. Tolcher, A. W. Antibody drug conjugates: lessons from 20 years of clinical experience. Ann. Oncol. 27, 2168-2172 (2016).
83. Beck, A., Goetsch, L., Dumontet, C. &Corvaïa, N. Strategies and challenges for the next generation antibody-drug conjugates. Nat. Rev. Drug. Discov. 16, 315-337 (2017). This study is a comprehensive recent Review on antibody-drug conjugates.
84. Niwa, R. &Satoh, M. The current status and prospects of antibody engineering for therapeutic use: focus on glycoengineering technology. J. Pharm. Sci. 104, 930-941 (2015).
85. Staerz, U. D., Kanagawa, O. &Bevan, M. J. Hybrid antibodies can target sites for attack by T cells. Nature 314, 628-631 (1985).
86. Newman, M. J. &Benani, D. J. A review of blinatumomab, a novel immunotherapy. J. Oncol. Pharm. Pract. 22, 639-645 (2016).
87. Brinkmann, U. &Kontermann, R. E. The making of bispecific antibodies. mAbs 9, 182-212 (2017).
88. Chichili, G. R. et al. A CD3xCD123 bispecific DART for redirecting host T cells to myelogenous leukemia: preclinical activity and safety in nonhuman primates. Sci. Transl Med. 7, 289ra82 (2015).
89. Reusch, U. et al. A tetravalent bispecific TandAb (CD19/CD3), AFM11, efficiently recruits T cells for the potent lysis of CD19+ tumor cells. mAbs 7, 584-604 (2015).
90. Sun, L. L. et al. Anti-CD20/CD3 T cell-dependent bispecific antibody for the treatment of B cell malignancies. Sci. Transl Med. 7, 287ra70 (2015).
91. Klein, C., Schaefer, W. &Regula, J. T. The use of CrossMAb technology for the generation of bi-and multispecific antibodies. mAbs 8, 1010-1020 (2016).
92. Spiess, C., Zhai, Q. &Carter, P. J. Alternative molecular formats and therapeutic applications for bispecific antibodies. Mol. Immunol. 67, 95-106 (2015).
93. Jain, T. et al. Biophysical properties of the clinicalstage antibody landscape. Proc. Natl Acad. Sci. USA 114, 944-949 (2017). This study presents a developability assessment of 137 clinical stage antibodies to empirically define boundaries of drug-like behaviour.
94. Mabry, R. et al. Engineering of stable bispecific antibodies targeting IL-17A and IL-23. Protein Eng. Des. Sel. 23, 115-127 (2009).
95. Arvedson, T. L. et al. Generation of half-life extended anti-CD33 BiTE® antibody constructs compatible with once-weekly dosing [abstract]. Cancer Res. 77 (Suppl.), 55 (2017).
96. Schmidt, M. M. &Wittrup, K. D. A modeling analysis of the effects of molecular size and binding affinity on tumor targeting. Mol. Cancer Ther. 8, 2861-2871 (2009).
97. Locke, F. L. et al. Phase 1 results of ZUMA-1: a multicenter study of KTE-C19 anti-CD19 CAR T cell therapy in refractory aggressive lymphoma. Mol. Ther. 25, 285-295 (2017).
98. Frankel, S. R. &Baeuerle, P. A. Targeting T cells to tumor cells using bispecific antibodies. Curr. Opin. Chem. Biol. 17, 385-392 (2013).
99. Krupka, C. et al. Blockade of the PD-1/PD-L1 axis augments lysis of AML cells by the CD33/CD3 BiTE antibody construct AMG 330: reversing a T-cellinduced immune escape mechanism. Leukemia 30, 484-491 (2016).
100. Osada, T. et al. CEA/CD3-bispecific T cell-engaging (BiTE) antibody-mediated T lymphocyte cytotoxicity maximized by inhibition of both PD1 and PD-L1. Cancer Immunol. Immunother. 64, 677-688 (2015).
101. Oates, J., Hassan, N. J. &Jakobsen, B. K. ImmTACs for targeted cancer therapy: why, what, how, and which. Mol. Immunol. 67, 67-74 (2015).
102. Chang, A. Y. et al. Opportunities and challenges for TCR mimic antibodies in cancer therapy. Expert Opin. Biol. Ther. 16, 979-987 (2016).
103. Reusch, U. et al. A novel tetravalent bispecific TandAb (CD30/CD16A) efficiently recruits NK cells for the lysis of CD30+ tumor cells. mAbs 6, 728-739 (2014).
104. Jaiswal, S. et al. CD47 is upregulated on circulating hematopoietic stem cells and leukemia cells to avoid phagocytosis. Cell 138, 271-285 (2009).
105. Dheilly, E. et al. Selective blockade of the ubiquitous checkpoint receptor CD47 is enabled by dualtargeting bispecific antibodies. Mol. Ther. 25, 523-533 (2017).
106. Piccione, E. C. et al. A bispecific antibody targeting CD47 and CD20 selectively binds and eliminates dual antigen expressing lymphoma cells. mAbs 7, 946-956 (2015).
107. Moolten, F. L. &Cooperband, S. R. Selective destruction of target cells by diphtheria toxin conjugated to antibody directed against antigens on the cells. Science 169, 68-70 (1970).
108. Petersdorf, S. H. et al. A phase 3 study of gemtuzumab ozogamicin during induction and postconsolidation therapy in younger patients with acute myeloid leukemia. Blood 121, 4854-4860 (2013).
109. Castaigne, S. et al. Effect of gemtuzumab ozogamicin on survival of adult patients with de-novo acute myeloid leukaemia (ALFA-0701): a randomised, openlabel, phase 3 study. Lancet 379, 1508-1516 (2012).
110. Francisco, J. A. et al. cAC10-vcMMAE, an anti-CD30-monomethyl auristatin E conjugate with potent and selective antitumor activity. Blood 102, 1458-1465 (2003).
111. Younes, A. et al. Results of a pivotal phase II study of brentuximab vedotin for patients with relapsed or refractory Hodgkin's lymphoma. J. Clin. Oncol. 30, 2183-2189 (2012).
112. Carter, P. et al. Humanization of an anti-p185HER2 antibody for human cancer therapy. Proc. Natl Acad. Sci. USA 89, 4285-4289 (1992).
113. Lewis Phillips, G. D. et al. Targeting HER2-positive breast cancer with trastuzumab-DM1, an antibodycytotoxic drug conjugate. Cancer Res. 68, 9280-9290 (2008).
114. Krop, I. E. et al. Trastuzumab emtansine versus treatment of physician's choice for pretreated HER2-positive advanced breast cancer (TH3RESA): a randomised, open-label, phase 3 trial. Lancet Oncol. 15, 689-699 (2014).
115. Verma, S. et al. Trastuzumab emtansine for HER2-positive advanced breast cancer. N. Engl. J. Med. 367, 1783-1791 (2012).
116. Hamblett, K. J. et al. Effects of drug loading on the antitumor activity of a monoclonal antibody drug conjugate. Clin. Cancer Res. 10, 7063-7070 (2004).
117. Lyon, R. P. et al. Reducing hydrophobicity of homogeneous antibody-drug conjugates improves pharmacokinetics and therapeutic index. Nat. Biotechnol. 33, 733-735 (2015).
118. Yurkovetskiy, A. V. et al. A polymer-based antibodyvinca drug conjugate platform: characterization and preclinical efficacy. Cancer Res. 75, 3365-3372 (2015).
119. McDonagh, C. F. et al. Engineered antibody-drug conjugates with defined sites and stoichiometries of drug attachment. Protein Eng. Des. Sel. 19, 299-307 (2006).
120. Junutula, J. R. et al. Site-specific conjugation of a cytotoxic drug to an antibody improves the therapeutic index. Nat. Biotechnol. 26, 925-932 (2008). This study is the first demonstration that site-specific drug conjugation to an antibody can enhance the therapeutic index of the corresponding conjugate.
121. Shen, B. Q. et al. Conjugation site modulates the in vivo stability and therapeutic activity of antibodydrug conjugates. Nat. Biotechnol 30, 184-189 (2012).
122. Levengood, M. R. et al. Orthogonal cysteine protection enables homogeneous multi-drug antibodydrug conjugates. Angew. Chem. Int. Ed. 56, 733-737 (2017).
123. Li, J. Y. et al. A biparatopic HER2-targeting antibodydrug conjugate induces tumor regression in primary models refractory to or ineligible for HER2-targeted therapy. Cancer Cell 29, 117-129 (2016). This study presents a bivalent biparatopic anti-HER2 antibody-drug conjugate with tubulysin that shows exceptional in vivo antitumour efficacy compared with that achieved by a bivalent monospecific antibody-drug conjugate.
124. de Goeij, B. E. et al. Efficient payload delivery by a bispecific antibody-drug conjugate targeting HER2 and CD63. Mol. Cancer Ther. 15, 2688-2697 (2016).
125. DeVay, R. M. et al. Improved lysosomal trafficking can modulate the potency of antibody drug conjugates. Bioconjug. Chem. 28, 1102-1114 (2017).
126. Andreev, J. et al. Bispecific antibodies and antibodydrug conjugates (ADCs) bridging HER2 and prolactin receptor improve efficacy of HER2 ADCs. Mol. Cancer Ther. 16, 681-693 (2017).
127. Lehar, S. M. et al. Novel antibody-antibiotic conjugate eliminates intracellular S. aureus. Nature 527, 323-328 (2015). This study presents the first extension of the antibody-drug conjugate concept to an antibody-antibiotic conjugate for treatment of a bacterial infection.
128. Wang, R. E. et al. An immunosuppressive antibodydrug conjugate. J. Am. Chem. Soc. 137, 3229-3232 (2015).
129. Desjarlais, J. R. &Lazar, G. A. Modulation of antibody effector function. Exp. Cell Res. 317, 1278-1285 (2011).
130. Niwa, R. et al. Defucosylated chimeric anti-CC chemokine receptor 4 IgG1 with enhanced antibodydependent cellular cytotoxicity shows potent therapeutic activity to T-cell leukemia and lymphoma. Cancer Res. 64, 2127-2133 (2004).
131. Beck, A. &Reichert, J. M. Marketing approval of mogamulizumab: a triumph for glyco-engineering. mAbs 4, 419-425 (2012).
132. Mössner, E. et al. Increasing the efficacy of CD20 antibody therapy through the engineering of a new type II anti-CD20 antibody with enhanced direct and immune effector cell-mediated B-cell cytotoxicity. Blood 115, 4393-4402 (2010).
133. Kellner, C. et al. The Fc-engineered CD19 antibody MOR208 (XmAb5574) induces natural killer cellmediated lysis of acute lymphoblastic leukemia cells from pediatric and adult patients. Leukemia 27, 1595-1598 (2013).
134. Woyach, J. A. et al. A phase 1 trial of the Fc-engineered CD19 antibody XmAb5574 (MOR00208) demonstrates safety and preliminary efficacy in relapsed CLL. Blood 124, 3553-3560 (2014).
135. Caaveiro, J. M., Kiyoshi, M. &Tsumoto, K. Structural analysis of Fc/FcγR complexes: a blueprint for antibody design. Immunol. Rev. 268, 201-221 (2015).
136. Liu, Z. et al. Asymmetrical Fc engineering greatly enhances antibody-dependent cellular cytotoxicity (ADCC) effector function and stability of the modified antibodies. J. Biol. Chem. 289, 3571-3590 (2014).
137. Mimoto, F. et al. Novel asymmetrically engineered antibody Fc variant with superior FcγR binding affinity and specificity compared with afucosylated Fc variant. mAbs 5, 229-236 (2013). This study uses asymmetric Fc variants for exquisite tailoring of IgG specificity for FcγR.
138. Mimoto, F. et al. Engineered antibody Fc variant with selectively enhanced FcγRIIb binding over both FcγRIIaR131 and FcγRIIaH131. Protein Eng. Des. Sel. 26, 589-598 (2013).
139. Teeling, J. L. et al. Characterization of new human CD20 monoclonal antibodies with potent cytolytic activity against non-Hodgkin lymphomas. Blood 104, 1793-1800 (2004).
140. Saphire, E. O. et al. Crystal structure of a neutralizing human IGG against HIV-1: a template for vaccine design. Science 293, 1155-1159 (2001).
141. Wu, Y. et al. Structural basis for enhanced HIV-1 neutralization by a dimeric immunoglobulin G form of the glycan-recognizing antibody 2G12. Cell Rep. 5, 1443-1455 (2013).
142. Diebolder, C. A. et al. Complement is activated by IgG hexamers assembled at the cell surface. Science 343, 1260-1263 (2014). This study demonstrates that non-covalent interactions between Fc regions of IgG result in hexamerization after antigen-binding on cells. Fc point mutations were identified that increase IgG hexamerization and CDC activity.
143. Cook, E. M. et al. Antibodies that efficiently form hexamers upon antigen binding can induce complement-dependent cytotoxicity under complement-limiting conditions. J. Immunol. 197, 1762-1775 (2016).
144. Tammen, A. et al. Monoclonal antibodies against epidermal growth factor receptor acquire an ability to kill tumor cells through complement activation by mutations that selectively facilitate the hexamerization of IgG on opsonized cells. J. Immunol. 198, 1585-1594 (2017).
145. DiLillo, D. J. &Ravetch, J. V. Differential Fc-receptor engagement drives an anti-tumor vaccinal effect. Cell 161, 1035-1045 (2015).
146. Tijink, B. M. et al. A phase I dose escalation study with anti-CD44v6 bivatuzumab mertansine in patients with incurable squamous cell carcinoma of the head and neck or esophagus. Clin. Cancer Res. 12, 6064-6072 (2006).
147. Mazor, Y. et al. Insights into the molecular basis of a bispecific antibody's target selectivity. mAbs 7, 461-469 (2015). This study demonstrates the dual targeting of two cell surface antigens by use of bispecific antibodies to increase targeting selectivity.
148. Mazor, Y. et al. Improving target cell specificity using a novel monovalent bispecific IgG design. mAbs 7, 377-389 (2015).
149. Mazor, Y. et al. Enhanced tumor-targeting selectivity by modulating bispecific antibody binding affinity and format valence. Sci. Rep. 7, 40098 (2017).
150. Zheng, S. et al. Cross-arm binding efficiency of an EGFR x c-Met bispecific antibody. mAbs 8, 551-561 (2016).
151. Desnoyers, L. R. et al. Tumor-specific activation of an EGFR-targeting probody enhances therapeutic index. Sci. Transl Med. 5, 207ra144 (2013). This study describes the development of an anti-EGFR antibody prodrug (probody) that is locally activated in the tumour microenvironment and has the potential to improve treatment safety.
152. Pardoll, D. M. The blockade of immune checkpoints in cancer immunotherapy. Nat. Rev. Cancer 12, 252-264 (2012).
153. Leach, D. R., Krummel, M. F. &Allison, J. P. Enhancement of antitumor immunity by CTLA-4 blockade. Science 271, 1734-1736 (1996). This study demonstrates that blockade of CTLA4 with an antibody can potentiate immune responses and lead to tumour eradication.
154. Wolchok, J. D. et al. Development of ipilimumab: a novel immunotherapeutic approach for the treatment of advanced melanoma. Ann. NY Acad. Sci. 1291, 1-13 (2013).
155. Peggs, K. S., Quezada, S. A., Chambers, C. A., Korman, A. J. &Allison, J. P. Blockade of CTLA-4 on both effector and regulatory T cell compartments contributes to the antitumor activity of anti-CTLA-4 antibodies. J. Exp. Med. 206, 1717-1725 (2009).
156. Hodi, F. S. et al. Improved survival with ipilimumab in patients with metastatic melanoma. N. Engl. J. Med. 363, 711-723 (2010). This study describes a randomized controlled phase III trial, demonstrating that an immunomodulatory antibody (anti-CTLA4) can lead to an overall survival benefit in patients with cancer (specifically, melanoma).
157. Maio, M. et al. Five-year survival rates for treatmentnaive patients with advanced melanoma who received ipilimumab plus dacarbazine in a phase III trial. J. Clin. Oncol. 33, 1191-1196 (2015).
158. Sharma, P. &Allison, J. P. The future of immune checkpoint therapy. Science 348, 56-61 (2015).
159. Garber, K. Industry 'road tests' new wave of immune checkpoints. Nat. Biotechnol. 35, 487-488 (2017).
160. Sharma, P. &Allison, J. P. Immune checkpoint targeting in cancer therapy: toward combination strategies with curative potential. Cell 161, 205-214 (2015).
161. Chen, D. S. &Mellman, I. Elements of cancer immunity and the cancer-immune set point. Nature 541, 321-330 (2017).
162. Le, D. T. et al. Mismatch repair deficiency predicts response of solid tumors to PD-1 blockade. Science 357, 409-413 (2017). This study presents clinical data that provide evidence for the benefit of PD1 blockade in the treatment of microsatellite instability-high solid tumours or mismatch repair-deficient solid tumours.
163. Horenstein, A. L. et al. Antibody mimicry, receptors and clinical applications. Hum. Antibodies 25, 75-85 (2017).
164. Leiber, D., Harbon, S., Guillet, J. G., Andre, C. &Strosberg, A. D. Monoclonal antibodies to purified muscarinic receptor display agonist-like activity. Proc. Natl Acad. Sci. USA 81, 4331-4334 (1984).
165. Bremer, E. Targeting of the tumor necrosis factor receptor superfamily for cancer immunotherapy. ISRN Oncol. 2013, 371854 (2013).
166. Walsh, G. Biopharmaceutical benchmarks 2014. Nat. Biotechnol. 32, 992-1000 (2014).
167. Li, J. et al. Thrombocytopenia caused by the development of antibodies to thrombopoietin. Blood 98, 3241-3248 (2001).
168. Casadevall, N. et al. Pure red-cell aplasia and antierythropoietin antibodies in patients treated with recombinant erythropoietin. N. Engl. J. Med. 346, 469-475 (2002).
169. Elliott, S., Lorenzini, T., Yanagihara, D., Chang, D. &Elliott, G. Activation of the erythropoietin (EPO) receptor by bivalent anti-EPO receptor antibodies. J. Biol. Chem. 271, 24691-24697 (1996).
170. Liu, Z. et al. A potent erythropoietin-mimicking human antibody interacts through a novel binding site. Blood 110, 2408-2413 (2007).
171. Schneider, H. et al. Homodimerization of erythropoietin receptor by a bivalent monoclonal antibody triggers cell proliferation and differentiation of erythroid precursors. Blood 89, 473-482 (1997).
172. Lacy, S. E. et al. The potency of erythropoietin-mimic antibodies correlates inversely with affinity. J. Immunol. Res. 181, 1282-1287 (2008).
173. Deng, B. et al. An agonist murine monoclonal antibody to the human c-Mpl receptor stimulates megakaryocytopoiesis. Blood 92, 1981-1988 (1998).
174. Kai, M. et al. Switching constant domains enhances agonist activities of antibodies to a thrombopoietin receptor. Nat. Biotechnol. 26, 209-211 (2008).
175. Orita, T. et al. A novel therapeutic approach for thrombocytopenia by minibody agonist of the thrombopoietin receptor. Blood 105, 562-566 (2005).
176. Sonoda, J., Chen, M. Z. &Baruch, A. FGF21-receptor agonists: an emerging therapeutic class for obesityrelated diseases. Horm. Mol. Biol. Clin. Investig. http://dx.doi.org/10.1515/hmbci-2017-0002 (2017).
177. Gaich, G. et al. The effects of LY2405319, an FGF21 analog, in obese human subjects with type 2 diabetes. Cell Metab. 18, 333-340 (2013).
178. Talukdar, S. et al. A long-acting FGF21 molecule, PF-05231023, decreases body weight and improves lipid profile in non-human primates and type 2 diabetic subjects. Cell Metab. 23, 427-440 (2016).
179. Foltz, I. N. et al. Treating diabetes and obesity with an FGF21-mimetic antibody activating the βKlotho/ FGFR1c receptor complex. Sci. Transl Med. 4, 162ra153 (2012).
180. Wu, A. L. et al. Antibody-mediated activation of FGFR1 induces FGF23 production and hypophosphatemia. PLoS ONE 8, e57322 (2013).
181. Kolumam, G. et al. Sustained brown fat stimulation and insulin sensitization by a humanized bispecific antibody agonist for fibroblast growth factor receptor 1/βKlotho complex. EBioMedicine 2, 730-743 (2015).
182. Kitazawa, T. et al. A bispecific antibody to factors IXa and X restores factor VIII hemostatic activity in a hemophilia A model. Nat. Med. 18, 1570-1574 (2012). This study presents an innovative antibody engineering approach that, together with REF. 122, led to the development of the bispecific antibody, emicizumab, for the treatment of haemophilia A.
183. Sampei, Z. et al. Non-antigen-contacting region of an asymmetric bispecific antibody to factors IXa/X significantly affects factor VIII-mimetic activity. mAbs 7, 120-128 (2015).
184. Sampei, Z. et al. Identification and multidimensional optimization of an asymmetric bispecific IgG antibody mimicking the function of factor VIII cofactor activity. PLoS ONE 8, e57479 (2013).
185. Witmer, C. &Young, G. Factor VIII inhibitors in hemophilia A: rationale and latest evidence. Ther. Adv. Hematol. 4, 59-72 (2013).
186. Oldenburg, J. et al. Emicizumab prophylaxis in hemophilia A with inhibitors. N. Engl. J. Med. 377, 809-818 (2017). This study shows that prophylaxis with the bispecific antibody, emicizumab, was associated with a significantly lower rate of bleeding events in a phase III clinical trial for the treatment of haemophilia A with factor VIII inhibitors.
187. Chu, S. Y. et al. Suppression of rheumatoid arthritis B cells by XmAb5871, an anti-CD19 antibody that coengages B cell antigen receptor complex and Fcγ receptor IIb inhibitory receptor. Arthritis Rheumatol. 66, 1153-1164 (2014).
188. Szili, D. et al. Suppression of innate and adaptive B cell activation pathways by antibody coengagement of FcγRIIb and CD19. mAbs 6, 991-999 (2014).
189. Chu, S. Y. et al. Reduction of total IgE by targeted coengagement of IgE B-cell receptor and FcγRIIb with Fc-engineered antibody. J. Allergy Clin. Immunol. 129, 1102-1115 (2012).
190. Merchant, M. et al. Monovalent antibody design and mechanism of action of onartuzumab, a MET antagonist with anti-tumor activity as a therapeutic agent. Proc. Natl Acad. Sci. USA 110, E2987-E2996 (2013).
191. Liu, L. et al. LY2875358, a neutralizing and internalizing anti-MET bivalent antibody, inhibits HGFdependent and HGF-independent MET activation and tumor growth. Clin. Cancer Res. 20, 6059-6070 (2014).
192. Wajant, H. Principles of antibody-mediated TNF receptor activation. Cell Death Differ. 22, 1727-1741 (2015).
193. Kaplan-Lefko, P. J. et al. Conatumumab, a fully human agonist antibody to death receptor 5, induces apoptosis via caspase activation in multiple tumor types. Cancer Biol. Ther. 9, 618-631 (2010).
194. Motoki, K. et al. Enhanced apoptosis and tumor regression induced by a direct agonist antibody to tumor necrosis factor-related apoptosis-inducing ligand receptor 2. Clin. Cancer Res. 11, 3126-3135 (2005).
195. Tamada, T. et al. TRAIL-R2 superoligomerization induced by human monoclonal agonistic antibody KMTR2. Sci. Rep. 5, 17936 (2015).
196. Ashkenazi, A. Targeting the extrinsic apoptotic pathway in cancer: lessons learned and future directions. J. Clin. Invest. 125, 487-489 (2015).
197. Chodorge, M. et al. A series of Fas receptor agonist antibodies that demonstrate an inverse correlation between affinity and potency. Cell Death Differ. 19, 1187-1195 (2012).
198. Komada, Y. et al. Epitopes and functional responses defined by a panel of anti-Fas (CD95) monoclonal antibodies. Hybridoma 18, 391-398 (1999).
199. Lukashev, M. et al. Targeting the lymphotoxin-β receptor with agonist antibodies as a potential cancer therapy. Cancer Res. 66, 9617-9624 (2006).
200. Aspeslagh, S. et al. Rationale for anti-OX40 cancer immunotherapy. Eur. J. Cancer 52, 50-66 (2016).
201. Linch, S. N., McNamara, M. J. &Redmond, W. L. OX40 agonists and combination immunotherapy: putting the pedal to the metal. Front. Oncol. 5, 34 (2015).
202. Nocentini, G., Ronchetti, S., Petrillo, M. G. &Riccardi, C. Pharmacological modulation of GITRL/ GITR system: therapeutic perspectives. Br. J. Pharmacol. 165, 2089-2099 (2012).
203. Ramakrishna, V. et al. Characterization of the human T cell response to in vitro CD27 costimulation with varlilumab. J. Immunother. Cancer 3, 37 (2015).
204. Martinez-Forero, I. et al. T cell costimulation with anti-CD137 monoclonal antibodies is mediated by K63-polyubiquitin-dependent signals from endosomes. J. Immunol. 190, 6694-6706 (2013).
205. Vonderheide, R. H. &Glennie, M. J. Agonistic CD40 antibodies and cancer therapy. Clin. Cancer Res. 19, 1035-1043 (2013).
206. Richman, L. P. &Vonderheide, R. H. Role of crosslinking for agonistic CD40 monoclonal antibodies as immune therapy of cancer. Cancer Immunol. Res. 2, 19-26 (2014).
207. Li, F. &Ravetch, J. V. Inhibitory Fcγ receptor engagement drives adjuvant and anti-tumor activities of agonistic CD40 antibodies. Science 333, 1030-1034 (2011).
208. Kim, J. M. &Ashkenazi, A. Fcγ receptors enable anticancer action of proapoptotic and immunemodulatory antibodies. J. Exp. Med. 210, 1647-1651 (2013).
209. Wilson, N. S. et al. An Fcγ receptor-dependent mechanism drives antibody-mediated target-receptor signaling in cancer cells. Cancer Cell 19, 101-113 (2011).
210. Bartkowiak, T. &Curran, M. A. 4-1BB agonists: multipotent potentiators of tumor immunity. Front. Oncol. 5, 117 (2015).
211. Chester, C., Ambulkar, S. &Kohrt, H. E. 4-1BB agonism: adding the accelerator to cancer immunotherapy. Cancer Immunol. Immunother. 65, 1243-1248 (2016).
212. Dahan, R. et al. Therapeutic activity of agonistic, human anti-CD40 monoclonal antibodies requires selective FcγR engagement. Cancer Cell 29, 820-831 (2016).
213. Tammen, A. et al. Monoclonal antibodies against epidermal growth factor receptor acquire an ability to kill tumor cells through complement activation by mutations that selectively facilitate the hexamerization of IgG on opsonized cells. J. Immunol. 198, 1585-1594 (2017).
214. DiLillo, D. J. &Ravetch, J. V. Differential Fc-receptor engagement drives an anti-tumor vaccinal effect. Cell 161, 1035-1045 (2015).
215. Tijink, B. M. et al. A phase I dose escalation study with anti-CD44v6 bivatuzumab mertansine in patients with incurable squamous cell carcinoma of the head and neck or esophagus. Clin. Cancer Res. 12, 6064-6072 (2006).
216. Mazor, Y. et al. Insights into the molecular basis of a bispecific antibody's target selectivity. mAbs 7, 461-469 (2015). This study demonstrates the dual targeting of two cell surface antigens by use of bispecific antibodies to increase targeting selectivity.
217. Mazor, Y. et al. Improving target cell specificity using a novel monovalent bispecific IgG design. mAbs 7, 377-389 (2015).
218. Mazor, Y. et al. Enhanced tumor-targeting selectivity by modulating bispecific antibody binding affinity and format valence. Sci. Rep. 7, 40098 (2017).
219. Zheng, S. et al. Cross-arm binding efficiency of an EGFR x c-Met bispecific antibody. mAbs 8, 551-561 (2016).
220. Desnoyers, L. R. et al. Tumor-specific activation of an EGFR-targeting probody enhances therapeutic index. Sci. Transl Med. 5, 207ra144 (2013). This study describes the development of an anti-EGFR antibody prodrug (probody) that is locally activated in the tumour microenvironment and has the potential to improve treatment safety.
221. Pardoll, D. M. The blockade of immune checkpoints in cancer immunotherapy. Nat. Rev. Cancer 12, 252-264 (2012).
222. Leach, D. R., Krummel, M. F. &Allison, J. P. Enhancement of antitumor immunity by CTLA-4 blockade. Science 271, 1734-1736 (1996). This study demonstrates that blockade of CTLA4 with an antibody can potentiate immune responses and lead to tumour eradication.
223. Wolchok, J. D. et al. Development of ipilimumab: a novel immunotherapeutic approach for the treatment of advanced melanoma. Ann. NY Acad. Sci. 1291, 1-13 (2013).
224. Peggs, K. S., Quezada, S. A., Chambers, C. A., Korman, A. J. &Allison, J. P. Blockade of CTLA-4 on both effector and regulatory T cell compartments contributes to the antitumor activity of anti-CTLA-4 antibodies. J. Exp. Med. 206, 1717-1725 (2009).
225. Hodi, F. S. et al. Improved survival with ipilimumab in patients with metastatic melanoma. N. Engl. J. Med. 363, 711-723 (2010). This study describes a randomized controlled phase III trial, demonstrating that an immunomodulatory antibody (anti-CTLA4) can lead to an overall survival benefit in patients with cancer (specifically, melanoma).
226. Maio, M. et al. Five-year survival rates for treatmentnaive patients with advanced melanoma who received ipilimumab plus dacarbazine in a phase III trial. J. Clin. Oncol. 33, 1191-1196 (2015).
227. Sharma, P. &Allison, J. P. The future of immune checkpoint therapy. Science 348, 56-61 (2015).
228. Garber, K. Industry 'road tests' new wave of immune checkpoints. Nat. Biotechnol. 35, 487-488 (2017).
229. Sharma, P. &Allison, J. P. Immune checkpoint targeting in cancer therapy: toward combination strategies with curative potential. Cell 161, 205-214 (2015).
230. Chen, D. S. &Mellman, I. Elements of cancer immunity and the cancer-immune set point. Nature 541, 321-330 (2017).
231. Le, D. T. et al. Mismatch repair deficiency predicts response of solid tumors to PD-1 blockade. Science 357, 409-413 (2017). This study presents clinical data that provide evidence for the benefit of PD1 blockade in the treatment of microsatellite instability-high solid tumours or mismatch repair-deficient solid tumours.
232. Horenstein, A. L. et al. Antibody mimicry, receptors and clinical applications. Hum. Antibodies 25, 75-85 (2017).
233. Leiber, D., Harbon, S., Guillet, J. G., Andre, C. &Strosberg, A. D. Monoclonal antibodies to purified muscarinic receptor display agonist-like activity. Proc. Natl Acad. Sci. USA 81, 4331-4334 (1984).
234. Bremer, E. Targeting of the tumor necrosis factor receptor superfamily for cancer immunotherapy. ISRN Oncol. 2013, 371854 (2013).
235. Walsh, G. Biopharmaceutical benchmarks 2014. Nat. Biotechnol. 32, 992-1000 (2014).
236. Li, J. et al. Thrombocytopenia caused by the development of antibodies to thrombopoietin. Blood 98, 3241-3248 (2001).
237. Casadevall, N. et al. Pure red-cell aplasia and antierythropoietin antibodies in patients treated with recombinant erythropoietin. N. Engl. J. Med. 346, 469-475 (2002).
238. Elliott, S., Lorenzini, T., Yanagihara, D., Chang, D. &Elliott, G. Activation of the erythropoietin (EPO) receptor by bivalent anti-EPO receptor antibodies. J. Biol. Chem. 271, 24691-24697 (1996).
239. Liu, Z. et al. A potent erythropoietin-mimicking human antibody interacts through a novel binding site. Blood 110, 2408-2413 (2007).
240. Schneider, H. et al. Homodimerization of erythropoietin receptor by a bivalent monoclonal antibody triggers cell proliferation and differentiation of erythroid precursors. Blood 89, 473-482 (1997).
241. Lacy, S. E. et al. The potency of erythropoietin-mimic antibodies correlates inversely with affinity. J. Immunol. Res. 181, 1282-1287 (2008).
242. Deng, B. et al. An agonist murine monoclonal antibody to the human c-Mpl receptor stimulates megakaryocytopoiesis. Blood 92, 1981-1988 (1998).
243. Kai, M. et al. Switching constant domains enhances agonist activities of antibodies to a thrombopoietin receptor. Nat. Biotechnol. 26, 209-211 (2008).
244. Orita, T. et al. A novel therapeutic approach for thrombocytopenia by minibody agonist of the thrombopoietin receptor. Blood 105, 562-566 (2005).
245. Sonoda, J., Chen, M. Z. &Baruch, A. FGF21-receptor agonists: an emerging therapeutic class for obesityrelated diseases. Horm. Mol. Biol. Clin. Investig. http://dx.doi.org/10.1515/hmbci-2017-0002 (2017).
246. Gaich, G. et al. The effects of LY2405319, an FGF21 analog, in obese human subjects with type 2 diabetes. Cell Metab. 18, 333-340 (2013).
247. Talukdar, S. et al. A long-acting FGF21 molecule, PF-05231023, decreases body weight and improves lipid profile in non-human primates and type 2 diabetic subjects. Cell Metab. 23, 427-440 (2016).
248. Foltz, I. N. et al. Treating diabetes and obesity with an FGF21-mimetic antibody activating the βKlotho/ FGFR1c receptor complex. Sci. Transl Med. 4, 162ra153 (2012).
249. Wu, A. L. et al. Antibody-mediated activation of FGFR1 induces FGF23 production and hypophosphatemia. PLoS ONE 8, e57322 (2013).
250. Kolumam, G. et al. Sustained brown fat stimulation and insulin sensitization by a humanized bispecific antibody agonist for fibroblast growth factor receptor 1/βKlotho complex. EBioMedicine 2, 730-743 (2015).
251. Kitazawa, T. et al. A bispecific antibody to factors IXa and X restores factor VIII hemostatic activity in a hemophilia A model. Nat. Med. 18, 1570-1574 (2012). This study presents an innovative antibody engineering approach that, together with REF. 122, led to the development of the bispecific antibody, emicizumab, for the treatment of haemophilia A.
252. Sampei, Z. et al. Non-antigen-contacting region of an asymmetric bispecific antibody to factors IXa/X significantly affects factor VIII-mimetic activity. mAbs 7, 120-128 (2015).
253. Sampei, Z. et al. Identification and multidimensional optimization of an asymmetric bispecific IgG antibody mimicking the function of factor VIII cofactor activity. PLoS ONE 8, e57479 (2013).
254. Witmer, C. &Young, G. Factor VIII inhibitors in hemophilia A: rationale and latest evidence. Ther. Adv. Hematol. 4, 59-72 (2013).
255. Oldenburg, J. et al. Emicizumab prophylaxis in hemophilia A with inhibitors. N. Engl. J. Med. 377, 809-818 (2017). This study shows that prophylaxis with the bispecific antibody, emicizumab, was associated with a significantly lower rate of bleeding events in a phase III clinical trial for the treatment of haemophilia A with factor VIII inhibitors.
256. Chu, S. Y. et al. Suppression of rheumatoid arthritis B cells by XmAb5871, an anti-CD19 antibody that coengages B cell antigen receptor complex and Fcγ receptor IIb inhibitory receptor. Arthritis Rheumatol. 66, 1153-1164 (2014).
257. Szili, D. et al. Suppression of innate and adaptive B cell activation pathways by antibody coengagement of FcγRIIb and CD19. mAbs 6, 991-999 (2014).
258. Chu, S. Y. et al. Reduction of total IgE by targeted coengagement of IgE B-cell receptor and FcγRIIb with Fc-engineered antibody. J. Allergy Clin. Immunol. 129, 1102-1115 (2012).
259. Merchant, M. et al. Monovalent antibody design and mechanism of action of onartuzumab, a MET antagonist with anti-tumor activity as a therapeutic agent. Proc. Natl Acad. Sci. USA 110, E2987-E2996 (2013).
260. Liu, L. et al. LY2875358, a neutralizing and internalizing anti-MET bivalent antibody, inhibits HGFdependent and HGF-independent MET activation and tumor growth. Clin. Cancer Res. 20, 6059-6070 (2014).
261. Wajant, H. Principles of antibody-mediated TNF receptor activation. Cell Death Differ. 22, 1727-1741 (2015).
262. Kaplan-Lefko, P. J. et al. Conatumumab, a fully human agonist antibody to death receptor 5, induces apoptosis via caspase activation in multiple tumor types. Cancer Biol. Ther. 9, 618-631 (2010).
263. Motoki, K. et al. Enhanced apoptosis and tumor regression induced by a direct agonist antibody to tumor necrosis factor-related apoptosis-inducing ligand receptor 2. Clin. Cancer Res. 11, 3126-3135 (2005).
264. Tamada, T. et al. TRAIL-R2 superoligomerization induced by human monoclonal agonistic antibody KMTR2. Sci. Rep. 5, 17936 (2015).
265. Ashkenazi, A. Targeting the extrinsic apoptotic pathway in cancer: lessons learned and future directions. J. Clin. Invest. 125, 487-489 (2015).
266. Chodorge, M. et al. A series of Fas receptor agonist antibodies that demonstrate an inverse correlation between affinity and potency. Cell Death Differ. 19, 1187-1195 (2012).
267. Komada, Y. et al. Epitopes and functional responses defined by a panel of anti-Fas (CD95) monoclonal antibodies. Hybridoma 18, 391-398 (1999).
268. Lukashev, M. et al. Targeting the lymphotoxin-β receptor with agonist antibodies as a potential cancer therapy. Cancer Res. 66, 9617-9624 (2006).
269. Aspeslagh, S. et al. Rationale for anti-OX40 cancer immunotherapy. Eur. J. Cancer 52, 50-66 (2016).
270. Linch, S. N., McNamara, M. J. &Redmond, W. L. OX40 agonists and combination immunotherapy: putting the pedal to the metal. Front. Oncol. 5, 34 (2015).
271. Nocentini, G., Ronchetti, S., Petrillo, M. G. &Riccardi, C. Pharmacological modulation of GITRL/ GITR system: therapeutic perspectives. Br. J. Pharmacol. 165, 2089-2099 (2012).
272. Ramakrishna, V. et al. Characterization of the human T cell response to in vitro CD27 costimulation with varlilumab. J. Immunother. Cancer 3, 37 (2015).
273. Martinez-Forero, I. et al. T cell costimulation with anti-CD137 monoclonal antibodies is mediated by K63-polyubiquitin-dependent signals from endosomes. J. Immunol. 190, 6694-6706 (2013).
274. Vonderheide, R. H. &Glennie, M. J. Agonistic CD40 antibodies and cancer therapy. Clin. Cancer Res. 19, 1035-1043 (2013).
275. Richman, L. P. &Vonderheide, R. H. Role of crosslinking for agonistic CD40 monoclonal antibodies as immune therapy of cancer. Cancer Immunol. Res. 2, 19-26 (2014).
276. Li, F. &Ravetch, J. V. Inhibitory Fcγ receptor engagement drives adjuvant and anti-tumor activities of agonistic CD40 antibodies. Science 333, 1030-1034 (2011).
277. Kim, J. M. &Ashkenazi, A. Fcγ receptors enable anticancer action of proapoptotic and immunemodulatory antibodies. J. Exp. Med. 210, 1647-1651 (2013).
278. Wilson, N. S. et al. An Fcγ receptor-dependent mechanism drives antibody-mediated target-receptor signaling in cancer cells. Cancer Cell 19, 101-113 (2011).
279. Bartkowiak, T. &Curran, M. A. 4-1BB agonists: multipotent potentiators of tumor immunity. Front. Oncol. 5, 117 (2015).
280. Chester, C., Ambulkar, S. &Kohrt, H. E. 4-1BB agonism: adding the accelerator to cancer immunotherapy. Cancer Immunol. Immunother. 65, 1243-1248 (2016).
281. Dahan, R. et al. Therapeutic activity of agonistic, human anti-CD40 monoclonal antibodies requires selective FcγR engagement. Cancer Cell 29, 820-831 (2016).
282. Roth, E. M. et al. Antidrug antibodies in patients treated with alirocumab. N. Engl. J. Med. 376, 1589-1590 (2017).
283. Hwang, W. Y. K. &Foote, J. Immunogenicity of engineered antibodies. Methods 36, 3-10 (2005).
284. van Schie, K. A., Wolbink, G. J. &Rispens, T. Crossreactive and pre-existing antibodies to therapeutic antibodies - effects on treatment and immunogenicity. mAbs 7, 662-671 (2015).
285. Rosenberg, A. S. &Sauna, Z. E. Immunogenicity assessment during the development of protein therapeutics. J. Pharm. Pharmacol.http://dx.doi. org/10.1111/jphp.12810 (2017).
286. Salazar-Fontana, L. I. et al. Approaches to mitigate the unwanted immunogenicity of therapeutic proteins during drug development. AAPS J. 19, 377-385 (2017).
287. Milling, L., Zhang, Y. &Irvine, D. J. Delivering safer immunotherapies for cancer. Adv. Drug Deliv. Rev. 114, 79-101 (2017).
288. Campbell, M. &Humphries, P. The blood-retina barrier: tight junctions and barrier modulation. Adv. Exp. Med. Biol. 763, 70-84 (2012).
289. Kim, Y. C., Chiang, B., Wu, X. &Prausnitz, M. R. Ocular delivery of macromolecules. J. Control. Release 190, 172-181 (2014).
290. Folkman, J. &Klagsbrun, M. Angiogenic factors. Science 235, 442-447 (1987).
291. Ferrara, N. &Adamis, A. P. Ten years of anti-vascular endothelial growth factor therapy. Nat. Rev. Drug Discov. 15, 385-403 (2016).
292. Chen, Y. et al. Selection and analysis of an optimized anti-VEGF antibody: crystal structure of an affinitymatured Fab in complex with antigen. J. Mol. Biol. 293, 865-881 (1999).
293. Brown, D. M. et al. Ranibizumab versus verteporfin for neovascular age-related macular degeneration. N. Engl. J. Med. 355, 1432-1444 (2006).
294. Rosenfeld, P. J. et al. Ranibizumab for neovascular age-related macular degeneration. N. Engl. J. Med. 355, 1419-1431 (2006).
295. Holash, J. et al. VEGF-Trap: a VEGF blocker with potent antitumor effects. Proc. Natl Acad. Sci. USA 99, 11393-11398 (2002).
296. Volz, C. &Pauly, D. Antibody therapies and their challenges in the treatment of age-related macular degeneration. Eur. J. Pharm. Biopharm. 95, 158-172 (2015).
297. Le, K. N. et al. Population pharmacokinetics and pharmacodynamics of lampalizumab administered intravitreally to patients with geographic atrophy. CPT Pharmacometr. Syst. Pharmacol. 4, 595-604 (2015).
298. Jager, R. D., Aiello, L. P., Patel, S. C. &Cunningham, E. T. Jr. Risks of intravitreous injection: a comprehensive review. Retina 24, 676-698 (2004).
299. Agrahari, V., Agrahari, V., Mandal, A., Pal, D. &Mitra, A. K. How are we improving the delivery to back of the eye? Advances and challenges of novel therapeutic approaches. Expert Opin. Drug Deliv. 14, 1145-1162 (2016).
300. Shatz, W. et al. Contribution of antibody hydrodynamic size to vitreal clearance revealed through rabbit studies using a species-matched Fab. Mol. Pharm. 13, 2996-3003 (2016).
301. Ghosh, J. G. et al. Long-acting protein drugs for the treatment of ocular diseases. Nat. Commun. 8, 14837 (2017).
302. Gadkar, K. et al. Design and pharmacokinetic characterization of novel antibody formats for ocular therapeutics. Invest. Ophthalmol. Vis. Sci. 56, 5390-5400 (2015).
303. Depreter, F., Pilcer, G. &Amighi, K. Inhaled proteins: challenges and perspectives. Int. J. Pharm. 447, 251-280 (2013).
304. Fellner, R. C., Terryah, S. T. &Tarran, R. Inhaled protein/peptide-based therapies for respiratory disease. Mol. Cell. Pediatr. 3, 16 (2016).
305. Wagener, J. S. &Kupfer, O. Dornase alfa (Pulmozyme). Curr. Opin. Pulm. Med. 18, 609-614 (2012).
306. Chan, J. &Cheng-Lai, A. Inhaled insulin: a clinical and historical review. Cardiol. Rev. 25, 140-146 (2017).
307. Hart, T. K. et al. Preclinical efficacy and safety of mepolizumab (SB-240563), a humanized monoclonal antibody to IL-5, in cynomolgus monkeys. J. Allergy Clin. Immunol. 108, 250-257 (2001).
308. Prince, G. A., Hemming, V. G., Horswood, R. L., Baron, P. A. &Chanock, R. M. Effectiveness of topically administered neutralizing antibodies in experimental immunotherapy of respiratory syncytial virus infection in cotton rats. J. Virol. 61, 1851-1854 (1987).
309. Hacha, J. et al. Nebulized anti-IL-13 monoclonal antibody Fab fragment reduces allergen-induced asthma. Am. J. Respir. Cell. Mol. Biol. 47, 709-717 (2012).
310. Maillet, A. et al. The airways, a novel route for delivering monoclonal antibodies to treat lung tumors. Pharm. Res. 28, 2147-2156 (2011).
311. Guilleminault, L. et al. Fate of inhaled monoclonal antibodies after the deposition of aerosolized particles in the respiratory system. J. Control. Release 196, 344-354 (2014).
312. Herve, V. et al. VEGF neutralizing aerosol therapy in primary pulmonary adenocarcinoma with K-ras activating-mutations. mAbs 6, 1638-1648 (2014).
313. Fahy, J. V. et al. Effect of aerosolized anti-IgE (E25) on airway responses to inhaled allergen in asthmatic subjects. Am. J. Respir. Crit. Care Med. 160, 1023-1027 (1999).
314. Freches, D. et al. PEGylation prolongs the pulmonary retention of an anti-IL-17A Fab antibody fragment after pulmonary delivery in three different species. Int. J. Pharm. 521, 120-129 (2017).
315. Koussoroplis, S. J. et al. PEGylation of antibody fragments greatly increases their local residence time following delivery to the respiratory tract. J. Control. Release 187, 91-100 (2014).
316. Burgess, G. et al. A randomised, double-blind, placebo-controlled, dose-escalation study to evaluate the safety, tolerability, pharmacodynamics and pharmacokinetics of single inhaled doses of VR942 (UCB4144) in healthy subjects and repeated doses in mild asthmatics [abstract]. Am. J. Respir. Crit. Care Med. 195, A4681 (2017).
317. Van Heeke, G. et al. Nanobodies® as inhaled biotherapeutics for lung diseases. Pharmacol. Ther. 169, 47-56 (2017).
318. Detalle, L. et al. Generation and characterization of ALX-0171, a potent novel therapeutic nanobody for the treatment of respiratory syncytial virus infection. Antimicrob. Agents Chemother. 60, 6-13 (2016). This study provides proof of concept that a small antibody fragment (anti-RSV nanobody) can be efficacious when delivered directly into the lungs of RSV-infected cotton rats.
319. Jasion, V. S. &Burnett, B. P. Survival and digestibility of orally-administered immunoglobulin preparations containing IgG through the gastrointestinal tract in humans. Nutr. J. 14, 22 (2015).
320. Moroz, E., Matoori, S. &Leroux, J. C. Oral delivery of macromolecular drugs: where we are after almost 100 years of attempts. Adv. Drug Deliv. Rev. 101, 108-121 (2016).
321. Hua, S., Marks, E., Schneider, J. J. &Keely, S. Advances in oral nano-delivery systems for colon targeted drug delivery in inflammatory bowel disease: selective targeting to diseased versus healthy tissue. Nanomedicine 11, 1117-1132 (2015).
322. Lakatos, P. L. &Miheller, P. Is there an increased risk of lymphoma and malignancies under anti-TNF therapy in IBD? Curr. Drug Targets 11, 179-186 (2010).
323. Ford, A. C. &Peyrin-Biroulet, L. Opportunistic infections with anti-tumor necrosis factor-α therapy in inflammatory bowel disease: meta-analysis of randomized controlled trials. Am. J. Gastroenterol. 108, 1268-1276 (2013).
324. Vandenbroucke, K. et al. Orally administered L. lactis secreting an anti-TNF nanobody demonstrate efficacy in chronic colitis. Mucosal Immunol. 3, 49-56 (2010).
325. Bhol, K. C. et al. AVX-470: a novel oral anti-TNF antibody with therapeutic potential in inflammatory bowel disease. Inflamm. Bowel Dis. 19, 2273-2281 (2013).
326. Harris, M. S. et al. AVX-470, an orally delivered antitumour necrosis factor antibody for treatment of active ulcerative colitis: results of a first-in-human trial. J. Crohns Colitis 10, 631-640 (2016).
327. Muzammil, S. et al. FcRn binding is not sufficient for achieving systemic therapeutic levels of immunoglobulin G after oral delivery of enteric-coated capsules in cynomolgus macaques. Pharmacol. Res. Perspect. 4, e00218 (2016).
328. Prince, M. et al. The global prevalence of dementia: a systematic review and metaanalysis. Alzheimers Dement. 9, 63-75.e2 (2013).
329. Ganrot, K. &Laurell, C. B. Measurement of IgG and albumin content of cerebrospinal fluid, and its interpretation. Clin. Chem. 20, 571-573 (1974).
330. Sevigny, J. et al. The antibody aducanumab reduces Aβ plaques in Alzheimer's disease. Nature 537, 50-56 (2016). This is an important early-stage clinical study that demonstrates that an antibody can reduce amyloid-β plaques in Alzheimer disease.
331. Abbott, A. &Dolgin, E. Failed Alzheimer's trial does not kill leading theory of disease. Nature 540, 15-16 (2016).
332. Selkoe, D. J. &Hardy, J. The amyloid hypothesis of Alzheimer's disease at 25 years. EMBO Mol. Med. 8, 595-608 (2016).
333. Doody, R. S. et al. Phase 3 trials of solanezumab for mild-to-moderate Alzheimer's disease. N. Engl. J. Med. 370, 311-321 (2014).
334. Salloway, S. et al. Two phase 3 trials of bapineuzumab in mild-to-moderate Alzheimer's disease. N. Engl. J. Med. 370, 322-333 (2014).
335. McDade, E. &Bateman, R. J. Stop Alzheimer's before it starts. Nature 547, 153-155 (2017).
336. Freskgård, P. O. &Urich, E. Antibody therapies in CNS diseases. Neuropharmacol 120, 38-55 (2017).
337. Pardridge, W. M. Re-engineering therapeutic antibodies for Alzheimer's disease as blood-brain barrier penetrating bi-specific antibodies. Expert Opin. Biol. Ther. 16, 1455-1468 (2016).
338. Pardridge, W. M. &Boado, R. J. Reengineering biopharmaceuticals for targeted delivery across the blood-brain barrier. Methods Enzymol. 503, 269-292 (2012).
339. Pardridge, W. M., Buciak, J. L. &Friden, P. M. Selective transport of an anti-transferrin receptor antibody through the blood-brain barrier in vivo. J. Pharmacol. Exp. Ther. 259, 66-70 (1991).
340. Zhou, Q. H., Boado, R. J., Lu, J. Z., Hui, E. K. &Pardridge, W. M. Monoclonal antibody-glial-derived neurotrophic factor fusion protein penetrates the blood-brain barrier in the mouse. Drug Metab. Dispos. 38, 566-572 (2010).
341. Zhou, Q. H., Boado, R. J., Lu, J. Z., Hui, E. K. &Pardridge, W. M. Re-engineering erythropoietin as an IgG fusion protein that penetrates the blood-brain barrier in the mouse. Mol. Pharm. 7, 2148-2155 (2010).
342. Yu, Y. J. et al. Boosting brain uptake of a therapeutic antibody by reducing its affinity for a transcytosis target. Sci. Transl Med. 3, 84ra44 (2011). This study demonstrates the use of a bispecific IgG that is monovalent for transferrin receptor and targets a protein linked to Alzheimer disease to increase delivery into the brain.
343. Yu, Y. J. et al. Therapeutic bispecific antibodies cross the blood-brain barrier in nonhuman primates. Sci. Transl Med. 6, 261ra154 (2014).
344. Couch, J. A. et al. Addressing safety liabilities of TfR bispecific antibodies that cross the blood-brain barrier. Sci. Transl Med. 5, 183ra57 (2013).
345. Niewoehner, J. et al. Increased brain penetration and potency of a therapeutic antibody using a monovalent molecular shuttle. Neuron 81, 49-60 (2014).
346. Zuchero, Y. J. et al. Discovery of novel blood-brain barrier targets to enhance brain uptake of therapeutic antibodies. Neuron 89, 70-82 (2016).
347. Kim, M. S. et al. A draft map of the human proteome. Nature 509, 575-581 (2014).
348. Santos, R. et al. A comprehensive map of molecular drug targets. Nat. Rev. Drug Discov. 16, 19-34 (2017).
349. Wang, X., Wang, R., Zhang, Y. &Zhang, H. Evolutionary survey of druggable protein targets with respect to their subcellular localizations. Genome Biol. Evol. 5, 1291-1297 (2013).
350. Choi, S. &Choi, K. Y. Screening-based approaches to identify small molecules that inhibit protein-protein interactions. Expert Opin. Drug Discov. 12, 293-303 (2017).
351. Stewart, M. P. et al. In vitro and ex vivo strategies for intracellular delivery. Nature 538, 183-192 (2016).
352. Liao, X., Rabideau, A. E. &Pentelute, B. L. Delivery of antibody mimics into mammalian cells via anthrax toxin protective antigen. Chembiochem 15, 2458-2466 (2014).
353. Verdurmen, W. P., Luginbuhl, M., Honegger, A. &Plückthun, A. Efficient cell-specific uptake of binding proteins into the cytoplasm through engineered modular transport systems. J. Control. Release 200, 13-22 (2015).
354. Verdurmen, W. P. R., Mazlami, M. &Plückthun, A. A quantitative comparison of cytosolic delivery via different protein uptake systems. Sci. Rep. 7, 13194 (2017). This study provides side-by-side comparison of different technologies for cytosolic delivery of proteins.
355. Choi, D. K. et al. A general strategy for generating intact, full-length IgG antibodies that penetrate into the cytosol of living cells. mAbs 6, 1402-1414 (2014).
356. Shin, S. M. et al. Antibody targeting intracellular oncogenic Ras mutants exerts anti-tumour effects after systemic administration. Nat. Commun. 8, 15090 (2017).
357. Wec, A. Z. et al. A "Trojan horse" bispecific antibody strategy for broad protection against ebolaviruses. Science 354, 350-354 (2016).
358. Corti, D. &Kearns, J. D. Promises and pitfalls for recombinant oligoclonal antibodies-based therapeutics in cancer and infectious disease. Curr. Opin. Immunol. 40, 51-61 (2016).
359. Swain, S. M. et al. Pertuzumab, trastuzumab, and docetaxel in HER2-positive metastatic breast cancer. N. Engl. J. Med. 372, 724-734 (2015). This study provides clinical validation of the antibody combination concept that led to the approval of a pair of antibodies.
360. Larkin, J. et al. Combined nivolumab and ipilimumab or monotherapy in untreated melanoma. N. Engl. J. Med. 373, 23-34 (2015). This study and REF 288 provide clinical validation of the antibody combination concept that led to the approval of pairs of antibodies.
361. Nowakowski, A. et al. Potent neutralization of botulinum neurotoxin by recombinant oligoclonal antibody. Proc. Natl Acad. Sci. USA 99, 11346-11350 (2002). This study provides a powerful demonstration of the superior in vivo potency of a three-antibody oligoclonal to botulinum neurotoxins as compared with that of component antibodies.
362. Nayak, S. U. et al. Safety and pharmacokinetics of XOMA 3AB, a novel mixture of three monoclonal antibodies against botulinum toxin A. Antimicrob. Agents Chemother. 58, 5047-5053 (2014).
363. Arena, S. et al. MM-151 overcomes acquired resistance to cetuximab and panitumumab in colorectal cancers harboring EGFR extracellular domain mutations. Sci. Transl Med. 8, 324ra14 (2016).
364. Kearns, J. D. et al. Enhanced targeting of the EGFR network with MM-151, an oligoclonal anti-EGFR antibody therapeutic. Mol. Cancer Ther. 14, 1625-1636 (2015).
365. Dienstmann, R. et al. Safety and activity of the first-in-class Sym004 anti-EGFR antibody mixture in patients with refractory colorectal cancer. Cancer Discov. 5, 598-609 (2015).
366. D'Souza, J. W. &Robinson, M. K. Oligoclonal antibodies to target the ErbB family. Expert Opin. Biol. Ther. 15, 1015-1021 (2015).
367. Nielsen, L. S. et al. Single-batch production of recombinant human polyclonal antibodies. Mol. Biotechnol. 45, 257-266 (2010).
368. Wilmes, G. M. et al. Non-viral adeno-associated virus-based platform for stable expression of antibody combination therapeutics. mAbs 6, 957-967 (2014).
369. Hutchings, C. J., Koglin, M., Olson, W. C. &Marshall, F. H. Opportunities for therapeutic antibodies directed at G-protein-coupled receptors. Nat. Rev. Drug Discov. 16, 661 (2017).
370. Wilkinson, T. C., Gardener, M. J. &Williams, W. A. Discovery of functional antibodies targeting ion channels. J. Biomol. Screen 20, 454-467 (2015).