Development of therapeutic antibodies for the treatment of ...

1 REVIEWOpen AccessDevelopment of therapeutic antibodies forthe treatment of diseasesRuei-Min Lu1, Yu-Chyi Hwang1, I-Ju Liu1 , Chi-Chiu Lee1 , Han-Zen Tsai1 , Hsin-Jung Li1and Han-Chung Wu1,2*AbstractIt has been more than three decades since the first monoclonal antibody was approved by the United States Foodand drug Administration (US FDA) in 1986, and during this time, antibody engineering has dramatically antibody drugs have increasingly fewer adverse effects due to their high specificity. As a result, therapeuticantibodies have become the predominant class of new drugs developed in recent years. Over the past five years, antibodies have become the best-selling drugs in the pharmaceutical market, and in 2018, eight of the top tenbestselling drugs worldwide were biologics. The global therapeutic monoclonal antibody market was valued atapproximately US$ billion in 2018 and is expected to generate revenue of $150 billion by the end of 2019 and$300 billion by 2025.

2 Thus, the market for therapeutic antibody drugs has experienced explosive growth as newdrugs have been approved for treating various human diseases, including many cancers, autoimmune, metabolicand infectious diseases. As of December 2019, 79 therapeutic mAbs have been approved by the US FDA, but thereis still significant growth potential. This review summarizes the latest market trends and outlines the preeminentantibody engineering technologies used in the Development of therapeutic antibody drugs, such as humanizationof monoclonal antibodies , phage display, the human antibody mouse, single B cell antibody technology, andaffinity maturation. Finally, future applications and perspectives are also : therapeutic antibody, Antibody market, Humanized antibody, Phage display, Human antibody mouse,Single B cell antibody technology, Affinity maturationBackgroundMonoclonal antibodies (mAbs) are produced by B cellsand specifically target antigens.

3 The hybridoma tech-nique introduced by K hler and Milstein in 1975 [1] hasmade it possible to obtain pure mAbs in large amounts,greatly enhancing the basic research and potential fortheir clinical use. Other scientific and technological ad-vances have also enabled the successful translation ofmAbs to the clinic. Around the world, at least 570 thera-peutic mAbs have been studied in clinical trials by com-mercial companies [2], and 79 therapeutic mAbs havebeen approved by the United States Food and drug Ad-ministration (US FDA) and are currently on the market[3], including 30 mAbs for the treatment of cancer(Table1).The increasing importance of therapeutic mAbs is ap-parent ( ), as mAbs have become the predominanttreatment modality for various diseases over the past 25years. During this time, major technological advanceshave made the discovery and Development of mAb ther-apies quicker and more efficient.

4 Since 2008, 48 newmAbs have been approved, contributing to a total globalmarket of 61 mAbs in clinical use at the end of 2017, ac-cording to the US FDA. Strikingly, a total of 18 newantibodies were granted approval by the US FDA from2018 to 2019 this number was tallied from informa-tion contained on various websites, including the anti-body society [3], the database of therapeutic antibodies [4], and company pipelines and press releases. A list ofantibody-based drugs approved by the US FDA is shownin first therapeutic mAb, muromonab-CD3 (Ortho-clone OKT3), was approved by the US FDA in 1986 [5]and comprises a murine mAb against T cell-expressedCD3 that functions as an immunosuppressant for the The Author(s). 2020 Open AccessThis article is distributed under the terms of the Creative Commons Attribution License ( ), which permits unrestricted use, distribution, andreproduction in any medium, provided you give appropriate credit to the original author(s) and the source, provide a link tothe Creative Commons license, and indicate if changes were made.

5 The Creative Commons Public Domain Dedication waiver( ) applies to the data made available in this article, unless otherwise stated.* I-Ju Liu, Chi-Chiu Lee and Han-Zen Tsai contributed equally to this of Cellular and Organismic Biology, Academia Sinica, Taipei 115,Taiwan2128 Academia Rd., Section 2, Nankang, Taipei 11529, TaiwanLuet al. Journal of Biomedical Science (2020) 27:1 1US FDA-approved monoclonal antibody on the marketmAbBrandnameCompanyTargetFormatTec hnology Indication&US#ApprovalMuromonab-CD3 OrthocloneOKT3 Centocor Ortho Biotech IgG2aHybridoma/JanssenBiotech, IncKidney transplantrejection1986*AbciximabReoproC entocor Lilly/JanssenBiotech IgG1 FabHybridoma Prevention of bloodclots in angioplasty1994 RituximabMabThera,RituxanBiogen , F. Hoffmann-LaRoche IgG1 Hybridoma Non-Hodgkinlymphoma1997 PalivizumabSynagisMedImmune/AbbVie IgG1 Hybridoma Prevention ofrespiratory syncytialvirus infection1998 InfliximabRemicade Janssen Biotech Chimeric IgG1 Hybridoma Crohn s disease1998 TrastuzumabHerceptin Roche, F.

6 Hoffmann-La Roche, IgG1 Hybridoma Breast cancer1998 Alemtuzumab Campath,LemtradaBerlex Pharmaceuticals IgG1 Hybridoma Chronic myeloidleukemia2001 AdalimumabHumiraAbbVie Human IgG1 PhagedisplayRheumatoid arthritis 2002 IbritumomabtiuxetanZevalinBiogen AG/SpectrumPharmaceuticals IgG1 Hybridoma Non-Hodgkinlymphoma2002 OmalizumabXolairRoche, F. Hoffmann-La Roche, Pharma-ceuticals IgG1 Hybridoma Asthma2003 CetuximabErbituxBristol-Myers Squibb/Merck & Lilly/ImClone Systems IgG1 Hybridoma Colorectal cancer2004 BevacizumabAvastinRoche, F. Hoffmann-La Roche, IgG1 Hybridoma Colorectal cancer2004 NatalizumabTysabriBiogen PharmaceuticalsInternational, IgG4 Hybridoma Multiple sclerosis2004 Panitumumab VectibixAmgenEGFRH uman IgG2 TransgenicmiceColorectal cancer2006 RanibizumabLucentisRoche, F. Hoffmann-La Roche Pharma-ceuticals IgG1 FabHybridoma Macular degeneration 2006 EculizumabSolirisAlexion Pharmaceuticals Paroxysmal nocturnalhemoglobinuria2007 CertolizumabpegolCimziaCelltech, Humanized Fab,pegylatedHybridoma Crohn s disease2008 UstekinumabStelaraMedarex/Centocor Ortho Biotech IgG1 TransgenicmicePsoriasis2009 CanakinumabIlarisNovartis Pharmaceuticals Human IgG1 TransgenicmiceMuckle-Wellssyndrome2009 GolimumabSimponiCentocor Ortho Biotech Biotech Human IgG1 TransgenicmiceRheumatoid andpsoriatic arthritis,ankylosing spondylitis2009 OfatumumabArzerraGenmab A/S / IgG1 TransgenicmiceChronic lymphocyticleukemia2009 TocilizumabRoActemra,ActemraChugai Pharmaceutical Co.

7 , , F. Hoffmann-La Roche. IgG1 Hybridoma Rheumatoid arthritis 2010 DenosumabXgeva,ProliaAmgenRANKLH uman IgG2 TransgenicmiceBone loss2010 BelimumabBenlystaGlaxoSmithKline /Human GenomeSciences IgG1 PhagedisplaySystemic lupuserythematosus2011 IpilimumabYervoyBristol-Myers Squibb/MedarexCTLA-4 Human IgG1 Transgenic Metastatic melanoma 2011 Luet al. Journal of Biomedical Science (2020) 27:1 Page 2 of 30 Table 1US FDA-approved monoclonal antibody on the market(Continued)mAbBrandnameCompanyTarg etFormatTechnology Indication&US#ApprovalmiceBrentuximabved otinAdcetrisSeattle genetics Co., IgG1;ADCH ybridoma Hodgkin lymphoma,systemic anaplasticlarge cell lymphoma2011 PertuzumabPerjetaRoche, F. Hoffmann-La Roche, IgG1 Hybridoma Breast Cancer2012 TrastuzumabemtansineKadcylaRoche, F. Hoffmann-La Roche ; ADCH ybridoma Breast cancer2012 RaxibacumabAbthraxGlaxoSmithKline /Human GenomeSciences Inc.

8 (HGSI)B. anthrasisPAHuman IgG1 TransgenicmiceAnthrax infection2012 Obinutuzumab Gazyva,GazyvaroBiogen , F. Hoffmann-LaRoche, IgG1 GlycoengineeredHybridoma Chronic lymphocyticleukemia2013 SiltuximabSylvantCentocor Biotech International NVIL-6 Chimeric IgG1 Hybridoma Castleman disease2014 RamucirumabCyramzaEli Lilly/ImClone Systems IgG1 PhagedisplayGastric cancer2014 VedolizumabEntyvioGenentech Inc. 4 7integrinHumanized IgG1 Hybridoma Ulcerative colitis,Crohn disease2014 Blinatumomab BlincytoAmgenCD19, CD3 Murine bispecifictandem scFvHybridoma Acute lymphoblasticleukemia2014 NivolumabOpdivoBristol-Myers Squibb/OnoPharmaceutical Co., IgG4 TransgenicmiceMelanoma, non-smallcell lung cancer2014 Pembrolizumab KeytrudaMerck & Co. IgG4 Hybridoma Melanoma2014 IdarucizumabPraxbindBoehringer IngelheimPharmaceuticalsDabigatran Humanized Fab Hybridoma Reversal ofdabigatran-inducedanticoagulation2015 Necitumumab PortrazzaEli Lilly/ImClone Systems IgG1 PhagedisplayNon-small cell lungcancer2015 DinutuximabUnituxinUnited Therapeutics CorporationGD2 Chimeric IgG1 Hybridoma Neuroblastoma2015 SecukinumabCosentyxNovartis Pharmaceuticals Human IgG1 TransgenicmicePsoriasis2015 MepolizumabNucalaCentocor IgG1 Hybridoma Severe eosinophilicasthma2015 AlirocumabPraluentRegeneron Pharmaceuticals IgG1 TransgenicmiceHigh cholesterol2015 EvolocumabRepathaAmgen/Amgen Astellas IgG2 TransgenicmiceHigh cholesterol2015 Daratumumab DarzalexGenmab A/S/Janssen Biotech Inc.

9 CD38 Human IgG1 TransgenicmiceMultiple myeloma2015 ElotuzumabEmplicitiBristol-Myers Squibb/AbbVie IgG1 Hybridoma Multiple myeloma2015 IxekizumabTaltzEli LillyIL-17 Humanized IgG4 Hybridoma Psoriasis2016 ReslizumabCinqaero,CinqairCelltech, UCB/Schering-Plough/TevaPharmaceutical Industries, IgG4 Hybridoma Asthma2016 OlaratumabLartruvoEli Lilly/ImClone Systems Human IgG1 TransgenicmiceSoft tissue sarcoma2016 Bezlotoxumab ZinplavaMerck & Co. IgG1 TransgenicmicePrevention ofClostridium difficileinfection recurrence2016 AtezolizumabTecentriq Roche, F. Hoffmann-La Roche, IgG1 Hybridoma Bladder cancer2016 Obiltoxaximab AnthimElusys Therapeutics anthrasisChimeric IgG1 Hybridoma Prevention of2016 Luet al. Journal of Biomedical Science (2020) 27:1 Page 3 of 30 Table 1US FDA-approved monoclonal antibody on the market(Continued)mAbBrandnameCompanyTarg etFormatTechnology Indication&US#ApprovalPAinhalational anthraxInotuzumabozogamicinBesponsa Wyeth IgG4 Hybridoma Acute lymphoblasticleukemia2017 BrodalumabSiliq,LumicefMedImmune/Amgen/K yowa HakkoKirin /AstraZeneca/ValeantPharmaceuticals International IgG2 TransgenicmicePlaque psoriasis2017 GuselkumabTremfyaMorphoSys/Janssen Biotech p19 Human IgG1 PhagedisplayPlaque psoriasis2017 DupilumabDupixentRegeneron Pharmaceuticals Human IgG4 TransgenicmiceAtopic dermatitis2017 SarilumabKevzaraRegeneron Pharmaceuticals IgG1 TransgenicmiceRheumatoid arthritis 2017 AvelumabBavencioMerck Serono International IgG1 PhagedisplayMerkel cell carcinoma 2017 OcrelizumabOcrevusBiogen , F.

10 Hoffmann-LaRoche, Industrie Farmaceutiche Riu-nite IgG1 Hybridoma Multiple sclerosis2017 EmicizumabHemlibraChugai Pharmaceutical Co., , F. Hoffmann-La Roche, IXa,XHumanizedIgG4, bispecificHybridoma Hemophilia A2017 BenralizumabFasenraMedImmune/Kyowa Hakko Kirin/AstraZenecaIL-5R Humanized IgG1 Hybridoma Asthma2017 GemtuzumabozogamicinMylotargPfizerCD33 HumanizedIgG4; ADCH ybridoma Acute myeloidleukemia2017 DurvalumabImfinziMedImmune/AstraZenecaPD -L1 Human IgG1 TransgenicmiceBladder cancer2017 BurosumabCrysvitaKyowa Hakko Kirin/UltragenyxPharmaceutical IgG1 TransgenicmiceX-linkedhypophosphatemia20 18 LanadelumabTakhzyroDyax IgG1 PhagedisplayHereditaryangioedema attacks2018 Mogamulizumab Poteligeo Kyowa Hakko KirinCCR4 Humanized IgG1 Hybridoma Mycosis fungoides orS zary syndrome2018 ErenumabAimovigNovartisCGRPRH uman IgG2 TransgenicmiceMigraine prevention 2018 Galcanezumab EmgalityEli LillyCGRPH umanized IgG4 Hybridoma Migraine prevention 2018 TildrakizumabIlumyaMerck & Co.