Rask-Andersen, M., Masuram, S. & Schiöth, H. B. The druggable genome: evaluation of drug targets in clinical trials suggests major shifts in molecular class and indication. Annu. Rev. Pharmacol. Toxicol. 54, 9–26 (2014).
Attwood, M. M., Rask-Andersen, M. & Schiöth, H. B. Orphan drugs and their impact on pharmaceutical development. Trends Pharmacol. Sci. 39, 525–535 (2018).
Hopkins, A. L. & Groom, C. R. The druggable genome. Nat. Rev. Drug Discov. 1, 727–730 (2002).
Overington, J. P., Al-Lazikani, B. & Hopkins, A. L. How many drug targets are there? Nat. Rev. Drug Discov. 5, 993–996 (2006).
Santos, R. et al. A comprehensive map of molecular drug targets. Nat. Rev. Drug Discov. 16, 19–34 (2017).
Kesik-Brodacka, M. Progress in biopharmaceutical development. Biotechnol. Appl. Biochem. 65, 306–322 (2017).
Urquhart, L. Top drugs and companies by sales in 2018. Nat. Rev. Drug Discov. 18, 245–245 (2019).
Urquhart, L. Top companies and drugs by sales in 2019. Nat. Rev. Drug Discov. 19, 228–228 (2020).
Lu, R.-M. et al. Development of therapeutic antibodies for the treatment of diseases. J. Biomed. Sci. 27, 1 (2020).
Sullivan, L. A. & Brekken, R. A. The VEGF family in cancer and antibody-based strategies for their inhibition. MAbs 2, 165–175 (2010).
Shim, H. One target, different effects: a comparison of distinct therapeutic antibodies against the same targets. Exp. Mol. Med. 43, 539–549 (2011).
Giacca, M. & Zacchigna, S. VEGF gene therapy: therapeutic angiogenesis in the clinic and beyond. Gene Ther. 19, 622–629 (2012).
Suragani, R. N. V. S. et al. Transforming growth factor-β superfamily ligand trap ACE-536 corrects anemia by promoting late-stage erythropoiesis. Nat. Med. 20, 408–414 (2014).
Regula, J. T. et al. Targeting key angiogenic pathways with a bispecific CrossMAb optimized for neovascular eye diseases. EMBO Mol. Med. 8, 1265–1288 (2016).
Ricklin, D., Mastellos, D. C., Reis, E. S. & Lambris, J. D. The renaissance of complement therapeutics. Nat. Rev. Nephrol. 14, 26–47 (2018).
Monaco, C., Nanchahal, J., Taylor, P. & Feldmann, M. Anti-TNF therapy: past, present and future. Int. Immunol. 27, 55–62 (2015).
Apte, R. S., Chen, D. S. & Ferrara, N. VEGF in signaling and disease: beyond discovery and development. Cell 176, 1248–1264 (2019).
Amadio, M., Govoni, S. & Pascale, A. Targeting VEGF in eye neovascularization: what’s new?: a comprehensive review on current therapies and oligonucleotide-based interventions under development. Pharmacol. Res. 103, 253–269 (2016).
Bartlett, H. S. & Million, R. P. Targeting the IL-17–TH17 pathway. Nat. Rev. Drug Discov. 14, 11–12 (2015).
Hawkes, J. E., Yan, B. Y., Chan, T. C. & Krueger, J. G. Discovery of the IL-23/IL-17 signaling pathway and the treatment of psoriasis. J. Immunol. 201, 1605–1613 (2018).
FDA. FDA approves new treatment for osteoporosis in postmenopausal women at high risk of fracture. http://www.fda.gov/news-events/press-announcements/fda-approves-new-treatment-osteoporosis-postmenopausal-women-high-risk-fracture (2019).
Suen, P. K. & Qin, L. Sclerostin, an emerging therapeutic target for treating osteoporosis and osteoporotic fracture: a general review. J. Orthop. Translat. 4, 1–13 (2016).
Hoy, S. M. Fremanezumab: first global approval. Drugs 78, 1829–1834 (2018).
Lamb, Y. N. Galcanezumab: first global approval. Drugs 78, 1769–1775 (2018).
Dhillon, S. Eptinezumab: first approval. Drugs 80, 733–739 (2020).
Edvinsson, L. in Calcitonin Gene-Related Peptide (CGRP) Mechanisms: Focus on Migraine (eds Brain, S. D. & Geppetti, P.) 121–130 (Springer, 2019).
Edvinsson, L. The CGRP pathway in migraine as a viable target for therapies. Headache J. Head Face Pain 58, 33–47 (2018).
Goulet, D. R. & Atkins, W. M. Considerations for the design of antibody-based therapeutics. J. Pharm. Sci. 109, 74–103 (2019).
Igawa, T. et al. Engineering the variable region of therapeutic IgG antibodies. MAbs 3, 243–252 (2011).
Pineda, C., Castañeda Hernández, G., Jacobs, I. A., Alvarez, D. F. & Carini, C. Assessing the immunogenicity of biopharmaceuticals. BioDrugs 30, 195–206 (2016).
Chames, P., Regenmortel, M. V., Weiss, E. & Baty, D. Therapeutic antibodies: successes, limitations and hopes for the future. Br. J. Pharmacol. 157, 220–233 (2009).
Brezski, R. J. & Georgiou, G. Immunoglobulin isotype knowledge and application to Fc engineering. Curr. Opin. Immunol. 40, 62–69 (2016).
Sondermann, P. & Szymkowski, D. E. Harnessing Fc receptor biology in the design of therapeutic antibodies. Curr. Opin. Immunol. 40, 78–87 (2016).
Tridandapani, S. et al. Regulated expression and inhibitory function of FcγRIIb in human monocytic cells. J. Biol. Chem. 277, 5082–5089 (2002).
Jiang, X.-R. et al. Advances in the assessment and control of the effector functions of therapeutic antibodies. Nat. Rev. Drug Discov. 10, 101–111 (2011).
Rother, R. P., Rollins, S. A., Mojcik, C. F., Brodsky, R. A. & Bell, L. Discovery and development of the complement inhibitor eculizumab for the treatment of paroxysmal nocturnal hemoglobinuria. Nat. Biotechnol. 25, 1256–1264 (2007).
Kennedy, P. J., Oliveira, C., Granja, P. L. & Sarmento, B. Monoclonal antibodies: technologies for early discovery and engineering. Crit. Rev. Biotechnol. 38, 394–408 (2018).
Sheridan, D. et al. Design and preclinical characterization of ALXN1210: a novel anti-C5 antibody with extended duration of action. PLoS ONE 13, 0195909 (2018).
Dubois, E. A., Rissmann, R. & Cohen, A. F. Rilonacept and canakinumab. Br. J. Clin. Pharmacol. 71, 639–641 (2011).
Stewart, M. W. Aflibercept (VEGF Trap-eye): the newest anti-VEGF drug. Br. J. Ophthalmol. 96, 1157–1158 (2012).
Perkins, S. L. & Cole, S. W. Ziv-aflibercept (Zaltrap) for the treatment of metastatic colorectal cancer. Ann. Pharmacother. 48, 93–98 (2014).
Shah, D. K. & Betts, A. M. Antibody biodistribution coefficients. MAbs 5, 297–305 (2013).
Bates, A. & Power, C. A. David vs. Goliath: the structure, function, and clinical prospects of antibody fragments. Antibodies 8, 28 (2019).
Bannas, P., Hambach, J. & Koch-Nolte, F. Nanobodies and nanobody-based human heavy chain antibodies as antitumor therapeutics. Front Immunol 8, 1603 (2017).
FDA. FDA approved caplacizumab-yhdp. http://www.fda.gov/drugs/resources-information-approved-drugs/fda-approved-caplacizumab-yhdp (2019).
Haßel, S. K. & Mayer, G. Aptamers as therapeutic agents: has the initial euphoria subsided? Mol. Diagn. Ther. 23, 301–309 (2019).
Nimjee, S. M., White, R. R., Becker, R. C. & Sullenger, B. A. Aptamers as therapeutics. Annu. Rev. Pharmacol. Toxicol. 57, 61–79 (2017).
Ali, M. H., Elsherbiny, M. E. & Emara, M. Updates on aptamer research. Int. J. Mol. Sci. 20, 2511 (2019).
Ng, E. W. M. et al. Pegaptanib, a targeted anti-VEGF aptamer for ocular vascular disease. Nat. Rev. Drug Discov. 5, 123–132 (2006).
Maier, K. E. & Levy, M. From selection hits to clinical leads: progress in aptamer discovery. Mol. Ther. Methods Clin. Dev. 5, 16014 (2016).
Morita, Y., Leslie, M., Kameyama, H., Volk, D. E. & Tanaka, T. Aptamer therapeutics in cancer: current and future. Cancers 10, 80 (2018).
Yu, X., Yang, Y.-P., Dikici, E., Deo, S. K. & Daunert, S. Beyond antibodies as binding partners: the role of antibody mimetics in bioanalysis. Annu. Rev. Anal. Chem. 10, 293–320 (2017).
Simeon, R. & Chen, Z. In vitro-engineered non-antibody protein therapeutics. Protein Cell 9, 3–14 (2018).
Plückthun, A. Designed ankyrin repeat proteins (DARPins): binding proteins for research, diagnostics, and therapy. Annu. Rev. Pharmacol. Toxicol. 55, 489–511 (2015).
Stahl, A. et al. Highly potent VEGF-A-antagonistic DARPins as anti-angiogenic agents for topical and intravitreal applications. Angiogenesis 16, 101–111 (2013).
Frejd, F. Y. & Kim, K.-T. Affibody molecules as engineered protein drugs. Exp. Mol. Med. 49, e306 (2017).
Goswami, R. et al. Gene therapy leaves a vicious cycle. Front. Oncol. 9, 297 (2019).
Grishanin, R. et al. Preclinical evaluation of ADVM-022, a novel gene therapy approach to treating wet age-related macular degeneration. Mol. Ther. 27, 118–129 (2019).
Jiang, D. J., Xu, C. L. & Tsang, S. H. Revolution in gene medicine therapy and genome surgery. Genes 9, 575 (2018).
Guimaraes, T. A. C., de, Georgiou, M., Bainbridge, J. W. B. & Michaelides, M. Gene therapy for neovascular age-related macular degeneration: rationale, clinical trials and future directions. Br. J. Ophthalmol. https://doi.org/10.1136/bjophthalmol-2020-316195 (2020).
Anguela, X. M. & High, K. A. Entering the modern era of gene therapy. Annu. Rev. Med. 70, 273–288 (2019).
Hollingsworth, R. E. & Jansen, K. Turning the corner on therapeutic cancer vaccines. NPJ Vaccines 4, 1–10 (2019).
Nakagami, H. & Morishita, R. Recent advances in therapeutic vaccines to treat hypertension. Hypertension 72, 1031–1036 (2018).
Rosell, R. et al. Pathway targeted immunotherapy: rationale and evidence of durable clinical responses with a novel, EGF-directed agent for advanced NSCLC. J. Thorac. Oncol. 11, 1954–1961 (2016).
Bennett, C. F., Baker, B. F., Pham, N., Swayze, E. & Geary, R. S. Pharmacology of antisense drugs. Annu. Rev. Pharmacol. Toxicol. 57, 81–105 (2017).
Setten, R. L., Rossi, J. J. & Han, S. The current state and future directions of RNAi-based therapeutics. Nat. Rev. Drug Discov. 18, 421–446 (2019).
Rupaimoole, R. & Slack, F. J. MicroRNA therapeutics: towards a new era for the management of cancer and other diseases. Nat. Rev. Drug Discov. 16, 203–222 (2017).
Leavitt, B. et al. Discovery and early clinical development of ISIS-HTTRx, the first HTT-lowering drug to be tested in patients with Huntington’s disease (PL01.002). Neurology 86, PL01.002 (2016).
Chakraborty, C., Sharma, A. R., Sharma, G., Doss, C. G. P. & Lee, S.-S. Therapeutic miRNA and siRNA: moving from bench to clinic as next generation medicine. Mol. Ther. Nucleic Acids 8, 132–143 (2017).
Uijl, E. et al. A3941 long-lasting small interfering RNA targeting angiotensinogen induces a robust and durable antihypertensive effect. J. Hypertens. 36, e17 (2018).
Neilsen, P. M. et al. Mutant p53 drives invasion in breast tumors through up-regulation of miR-155. Oncogene 32, 2992–3000 (2013).
Querfeld, C. et al. Preliminary results of a phase 1 trial evaluating MRG-106, a synthetic microRNA antagonist (LNA antimiR) of microRNA-155, in patients with CTCL. Blood 128, 1829–1829 (2016).
Kim, J. W. & Cochran, J. R. Targeting ligand–receptor interactions for development of cancer therapeutics. Curr. Opin. Chem. Biol. 38, 62–69 (2017).
Sandercock, C. G. & Storz, U. Antibody specification beyond the target: claiming a later-generation therapeutic antibody by its target epitope. Nat. Biotechnol. 30, 615–618 (2012).
Nakayamada, S. & Tanaka, Y. BAFF- and APRIL-targeted therapy in systemic autoimmune diseases. Inflamm. Regen. 36, 6 (2016).
Matsumoto, H. et al. Membrane-bound and soluble Fas ligands have opposite functions in photoreceptor cell death following separation from the retinal pigment epithelium. Cell Death Dis. 6, e1986 (2015).
Genovese, M. C. et al. A phase II randomized study of subcutaneous ixekizumab, an anti-interleukin-17 monoclonal antibody, in rheumatoid arthritis patients who were naive to biologic agents or had an inadequate response to tumor necrosis factor inhibitors. Arthritis Rheumatol. 66, 1693–1704 (2014).
Martin, D. A. et al. A phase Ib multiple ascending dose study evaluating safety, pharmacokinetics, and early clinical response of brodalumab, a human anti-IL-17R antibody, in methotrexate-resistant rheumatoid arthritis. Arthritis Res. Ther. 15, R164 (2013).
Pavelka, K. et al. A study to evaluate the safety, tolerability, and efficacy of brodalumab in subjects with rheumatoid arthritis and an inadequate response to methotrexate. J. Rheumatol. 42, 912–919 (2015).
Beringer, A., Noack, M. & Miossec, P. IL-17 in chronic inflammation: from discovery to targeting. Trends Mol. Med. 22, 230–241 (2016).
FDA. FDA approves novel preventive treatment for migraine. http://www.fda.gov/news-events/press-announcements/fda-approves-novel-preventive-treatment-migraine (2019).
Przepiorka, D. et al. FDA approval: blinatumomab. Clin. Cancer Res. 21, 4035–4039 (2015).
Labrijn, A. F., Janmaat, M. L., Reichert, J. M. & Parren, P. W. H. I. Bispecific antibodies: a mechanistic review of the pipeline. Nat. Rev. Drug Discov. 18, 585–608 (2019).
Brinkmann, U. & Kontermann, R. E. The making of bispecific antibodies. MAbs 9, 182–212 (2017).
Mullard, A. Bispecific antibody pipeline moves beyond oncology. Nat. Rev. Drug Discov. 16, 666–668 (2017).
Jimeno, A. et al. A first-in-human phase 1a study of the bispecific anti-DLL4/anti-VEGF antibody navicixizumab (OMP-305B83) in patients with previously treated solid tumors. Invest. New Drugs 37, 461–472 (2019).
Egan, T. J. et al. Novel multispecific heterodimeric antibody format allowing modular assembly of variable domain fragments. MAbs 9, 68–84 (2016).
Levin, A. D., Wildenberg, M. E., Brink, V. D. & R, G. Mechanism of action of anti-TNF therapy in inflammatory bowel disease. J. Crohns Colitis 10, 989–997 (2016).
Sandborn, W. J. et al. Etanercept for active Crohn’s disease: a randomized, double-blind, placebo-controlled trial. Gastroenterology 121, 1088–1094 (2001).
Mitoma, H., Horiuchi, T., Tsukamoto, H. & Ueda, N. Molecular mechanisms of action of anti-TNF-α agents – comparison among therapeutic TNF-α antagonists. Cytokine 101, 56–63 (2018).
Kirchner, S., Holler, E., Haffner, S., Andreesen, R. & Eissner, G. Effect of different tumor necrosis factor (TNF) reactive agents on reverse signaling of membrane integrated TNF in monocytes. Cytokine 28, 67–74 (2004).
Scallon, B. J., Moore, M. A., Trinh, H., Knight, D. M. & Ghrayeb, J. Chimeric anti-TNF-α monoclonal antibody cA2 binds recombinant transmembrane TNF-α and activates immune effector functions. Cytokine 7, 251–259 (1995).
Xin, L. et al. Dual regulation of soluble tumor necrosis factor-α induced activation of human monocytic cells via modulating transmembrane TNF-α-mediated ‘reverse signaling’. Int. J. Mol. Med. 18, 885–892 (2006).
Ringheanu, M. et al. Effects of infliximab on apoptosis and reverse signaling of monocytes from healthy individuals and patients with Crohn’s disease. Inflamm. Bowel Dis. 10, 801–810 (2004).
Toedter, G. et al. Genes associated with intestinal permeability in ulcerative colitis: changes in expression following infliximab therapy. Inflamm. Bowel Dis. 18, 1399–1410 (2012).
Vos, A. C. W. et al. Regulatory macrophages induced by infliximab are involved in healing in vivo and in vitro. Inflamm. Bowel Dis. 18, 401–408 (2012).
Olesen, C. M., Coskun, M., Peyrin-Biroulet, L. & Nielsen, O. H. Mechanisms behind efficacy of tumor necrosis factor inhibitors in inflammatory bowel diseases. Pharmacol. Ther. 159, 110–119 (2016).
Yamazaki, H. et al. Certolizumab pegol for induction of remission in Crohn’s disease. Cochrane Database Syst. Rev. https://doi.org/10.1002/14651858.CD012893.pub2 (2019).
Ueda, N. et al. The cytotoxic effects of certolizumab pegol and golimumab mediated by transmembrane tumor necrosis factor α. Inflamm. Bowel Dis. 19, 1224–1231 (2013).
Tracey, D., Klareskog, L., Sasso, E. H., Salfeld, J. G. & Tak, P. P. Tumor necrosis factor antagonist mechanisms of action: a comprehensive review. Pharmacol. Ther. 117, 244–279 (2008).
Guo, Q. et al. Rheumatoid arthritis: pathological mechanisms and modern pharmacologic therapies. Bone Res. 6, 15 (2018).
Brennan, F. M. & McInnes, I. B. Evidence that cytokines play a role in rheumatoid arthritis. J. Clin. Invest. 118, 3537–3545 (2008).
Calmon-Hamaty, F., Combe, B., Hahne, M. & Morel, J. Lymphotoxin α stimulates proliferation and pro-inflammatory cytokine secretion of rheumatoid arthritis synovial fibroblasts. Cytokine 53, 207–214 (2011).
Devine, E. B., Alfonso-Cristancho, R. & Sullivan, S. D. Effectiveness of biologic therapies for rheumatoid arthritis: an indirect comparisons approach. Pharmacotherapy 31, 39–51 (2011).
Gartlehner, G., Hansen, R. A., Jonas, B. L., Thieda, P. & Lohr, K. N. The comparative efficacy and safety of biologics for the treatment of rheumatoid arthritis: a systematic review and metaanalysis. J. Rheumatol. 33, 2398–2408 (2006).
Yang, S., Zhao, J. & Sun, X. Resistance to anti-VEGF therapy in neovascular age-related macular degeneration: a comprehensive review. Drug Des. Devel. Ther. 10, 1857–1867 (2016).
Gaudreault, J., Fei, D., Rusit, J., Suboc, P. & Shiu, V. Preclinical pharmacokinetics of ranibizumab (rhuFabV2) after a single intravitreal administration. Invest. Ophthalmol. Vis. Sci. 46, 726–733 (2005).
Gaudreault, J. et al. Preclinical pharmacology and safety of ESBA1008, a single-chain antibody fragment, investigated as potential treatment for age related macular degeneration. Invest. Ophthalmol. Vis. Sci. 53, 3025–3025 (2012).
Schmid, M. K. et al. Efficacy and adverse events of aflibercept, ranibizumab and bevacizumab in age-related macular degeneration: a trade-off analysis. Br. J. Ophthalmol. 99, 141–146 (2015).
Zhang, Y., Chioreso, C., Schweizer, M. L. & Abràmoff, M. D. Effects of Aflibercept for neovascular age-related macular degeneration: a systematic review and meta-analysis of observational comparative studies. Invest. Ophthalmol. Vis. Sci. 58, 5616–5627 (2017).
Sharma, A., Kumar, N., Kuppermann, B. D., Loewenstein, A. & Bandello, F. Brolucizumab: is extended VEGF suppression on the horizon? Eye 34, 424–426 (2020).
Dugel, P. U. et al. HAWK and HARRIER: phase 3, multicenter, randomized, double-masked trials of brolucizumab for neovascular age-related macular degeneration. Ophthalmology 127, 72–84 (2020).
Bordet, T. & Behar-Cohen, F. Ocular gene therapies in clinical practice: viral vectors and nonviral alternatives. Drug Discov. Today https://doi.org/10.1016/j.drudis.2019.05.038 (2019).
Carter, P. J. & Lazar, G. A. Next generation antibody drugs: pursuit of the ‘high-hanging fruit’. Nat. Rev. Drug Discov. 17, 197–223 (2018).
Neves, V., Aires-da-Silva, F., Corte-Real, S. & Castanho, M. A. R. B. Antibody approaches to treat brain diseases. Trends Biotechnol. 34, 36–48 (2016).
Erdő, F., Bors, L. A., Farkas, D., Bajza, Á. & Gizurarson, S. Evaluation of intranasal delivery route of drug administration for brain targeting. Brain Res. Bull. 143, 155–170 (2018).
Crowe, J. S. et al. Preclinical development of a novel, orally-administered anti-tumour necrosis factor domain antibody for the treatment of inflammatory bowel disease. Sci. Rep. 8, 4941 (2018).
Burgess, G. et al. Randomized study of the safety and pharmacodynamics of inhaled interleukin-13 monoclonal antibody fragment VR942. EBioMedicine 35, 67–75 (2018).
Miller, A. H. & Raison, C. L. Are anti-inflammatory therapies viable treatments for psychiatric disorders?: Where the rubber meets the road. JAMA Psychiatry 72, 527–528 (2015).
Goldsmith, D., Rapaport, M. & Miller, B. A meta-analysis of blood cytokine network alterations in psychiatric patients: comparisons between schizophrenia, bipolar disorder and depression. Mol. Psychiatry 21, 1696–1709 (2016).
Wittenberg, G. M. et al. Effects of immunomodulatory drugs on depressive symptoms: a mega-analysis of randomized, placebo-controlled clinical trials in inflammatory disorders. Mol. Psychiatry 25, 1275–1285 (2020).
Vabret, N. et al. Immunology of COVID-19: current state of the science. Immunity https://doi.org/10.1016/j.immuni.2020.05.002 (2020).
Huang, C. et al. Clinical features of patients infected with 2019 novel coronavirus in Wuhan, China. Lancet 395, 497–506 (2020).
McGrath, N. A., Brichacek, M. & Njardarson, J. T. A graphical journey of innovative organic architectures that have improved our lives. J. Chem. Educ. 87, 1348–1349 (2010).
Oprea, T. I. et al. Unexplored therapeutic opportunities in the human genome. Nat. Rev. Drug Discov. 17, 317–332 (2018).
Malik, A. & Urquhart, L. EvaluatePharma World Preview 2018, outlook to 2024. http://info.evaluategroup.com/WP2018-EPV.html (2018).
Urquhart, L. FDA new drug approvals in Q2 2019. Nat. Rev. Drug Discov. 18, 575–575 (2019).
Harding, S. D. et al. The IUPHAR/BPS Guide to PHARMACOLOGY in 2018: updates and expansion to encompass the new guide to IMMUNOPHARMACOLOGY. Nucleic Acids Res. 46, D1091–D1106 (2018).
Igawa, T., Haraya, K. & Hattori, K. Sweeping antibody as a novel therapeutic antibody modality capable of eliminating soluble antigens from circulation. Immunol. Rev. 270, 132–151 (2016).
Rask-Andersen, M., Almén, M. S. & Schiöth, H. B. Trends in the exploitation of novel drug targets. Nat. Rev. Drug Discov. 10, 579–590 (2011).
Wishart, D. S. et al. DrugBank 5.0: a major update to the DrugBank database for 2018. Nucleic Acids Res. 46, D1074–D1082 (2018).