Skip to main content
NCBI home page
Antibody Therapeutics logoLink to Antibody Therapeutics
. 2022 Sep 6;5(4):233–257. doi: 10.1093/abt/tbac021

The global landscape of approved antibody therapies

Xiaochen Lyu 1,#, Qichao Zhao 2,#, Julia Hui 3, Tiffany Wang 4, Mengyi Lin 5, Keying Wang 6, Jialing Zhang 7, Jiaqian Shentu 8, Paul A Dalby 9, Hongyu Zhang 10,11,✉, Bo Liu 12,✉
PMCID: PMC9535261  PMID: 36213257

Abstract

Antibody therapies have become an important class of therapeutics in recent years as they have exhibited outstanding efficacy and safety in the treatment of several major diseases including cancers, immune-related diseases, infectious disease and hematological disease. There has been significant progress in the global research and development landscape of antibody therapies in the past decade. In this review, we have collected available data from the Umabs Antibody Therapies Database (Umabs-DB, https://umabs.com) as of 30 June 2022. The Umabs-DB shows that 162 antibody therapies have been approved by at least one regulatory agency in the world, including 122 approvals in the US, followed by 114 in Europe, 82 in Japan and 73 in China, whereas biosimilar, diagnostic and veterinary antibodies are not included in our statistics. Although the US and Europe have been at the leading position for decades, rapid advancement has been witnessed in Japan and China in the past decade. The approved antibody therapies include 115 canonical antibodies, 14 antibody-drug conjugates, 7 bispecific antibodies, 8 antibody fragments, 3 radiolabeled antibodies, 1 antibody-conjugate immunotoxin, 2 immunoconjugates and 12 Fc-Fusion proteins. They have been developed against 91 drug targets, of which PD-1 is the most popular, with 14 approved antibody-based blockades for cancer treatment in the world. This review outlined the global landscape of the approved antibody therapies with respect to the regulation agencies, therapeutic targets and indications, aiming to provide an insight into the trends of the global development of antibody therapies.

Keywords: antibody format, antibody targets, global regulatory agency, approved antibody, antibody therapies

Statement of Significance: This article gives a comprehensive review of the global approved antibody therapies on their approval statistics in each country/region, types of engineering formats, targets and therapeutic indications, aiming to provide an insight into the trends of the global development of antibody therapies.

INTRODUCTION

Antibody therapy is a form of targeted treatment that uses antibody-based molecules to treat human diseases [1]. Monoclonal antibodies (mAbs) are immunoglobulins produced by plasma B cells as stimulated by a specific antigen. Antibodies can perform several roles in the human immune system, such as facilitating humoral and cellular immune responses to a wide range of antigens with high specificity and long-term efficacy. Thus, it has emerged as a major class of therapeutics since the approval of the first mAb, anti-CD3 OKT3 (also known as muromonab-CD3), by the United States Food and Drug Administration (US FDA) in 1986 [2]. The number of approved and marketed antibody therapies has reached 162 as of 30 June 2022, targeting a wide range of diseases including cancers, immune-related disease, infectious disease and hematological disease. The benefits of using antibody therapies stem from their high selectivity and optimal binding affinity. In addition, the safety and efficacy of antibody therapies are closely related to the characteristics of their therapeutic targets, such as expression patterns and the role they perform in the progression of disease [3]. Targets in cancers and immune-related diseases are well characterized, such as PD-1/PD-L1, CD20, tumor necrosis factor (TNF)-alpha, HER2 and CD3. As a result, the approved antibody therapies are mostly developed for the treatment of these indications, although a broader range of diseases have also been investigated [4]. Moreover, SARS-CoV-2 spike protein in COVID-19 infectious disease and calcitonin gene-related peptide (CGRP) in the central nervous system (CNS) disorders, have aroused broad interest in recent years [5, 6].

The global antibody therapies market was merely 0.3 billion USD in 1997 and rapidly increased to 186 billion USD in 2021. However, there are thousands of ongoing clinical trials and preclinical studies, and so the market is estimated to reach 445 billion USD by 2028, with a compound annual growth rate (CAGR) of 13.2% from 2022 to 2028 [7]. The market of antibody therapies has been growing fast and shows great market potential in the overall healthcare industry in the US, Europe, Japan and China. Companies with the largest number of approved antibodies and greatest share of the market are mostly located in the US due to their long-term investment into R&D. The market position of the US is followed by Europe, whereas there has been a rapid growth in the number of companies and approved antibodies in China and Japan over the past 5 years [8].

In this review, we collected data from the Umabs Antibody Therapies Database (Umabs-DB) [9], to make a statistical analysis of the antibodies approved by at least one drug regulatory agency of the world, excluding biosimilar, diagnostic and veterinary antibodies. We firstly inspected the number of antibody therapies approved by drug regulatory agencies for each year, which shows the trend of the approval of antibody therapies in different regions. Then, the format of antibody therapies on the year of their first approval is presented, showing the historical map to the development of new antibody formats. Targets and indications of antibody therapies in each historical period are presented to show the progress of global R&D. Lastly, approvals from companies in different countries and regions are analyzed to predict the future trend in the development of antibody therapies.

GLOBAL LANDSCAPE OF ANTIBODY THERAPIES APPROVAL

As of 30 June 2022, we reviewed a total of 162 antibody therapies approved by at least one drug regulatory agency in the world, including nine that were later withdrawn. Biosimilar, diagnostic and veterinary antibodies were not included for the analysis. An overview on the number of antibody therapies approved in each year and in different regions is presented in Fig. 1 and Table 1.

Figure 1.

Figure 1

Open in a new tab

The number of antibody therapies approved by different regulatory agencies each year is based on the Umabs-DB data available as of 30 June 2022. Only the first approval is included for each regulatory agency. Biosimilar, diagnostic, and veterinary antibodies are not included, whereas withdrawn antibodies are included in the analysis.

Table 1.

Globally approved antibody

Antibody name Brand name Target Antibody type Approved indication Approval
Muromonab Orthoclone OKT3 CD3 Canonical antibody; Rodent 1.Heart transplant rejection EMA Europe:1986*
2.Liver transplant rejection FDA US:1986*
3.Renal transplant rejection
IOR-T3 IOR-T3, aioushan CD3 Canonical antibody; Rodent 1.Organ transplant rejection CECMED Cuba:1989
NMPA China:1999
Nebacumab Centoxin Lipid A region of endotoxin Canonical antibody; Human 1.Sepsis EMA Europe:1991*
Abciximab ReoPro, Clotinab Integrin alpha IIb beta 3 (Integrin αIIbβ3) Fab fragment; Chimeric 1.Unstable angina FDA US:1994
2.Restenosis EMA Europe:1995
Edrecolomab Panorex Epithelial cell adhesion molecule (EpCAM) Canonical antibody; Rodent 1.Colorectal cancer EMA Europe:1995*
Daclizumab Zenapax, Zinbryta CD25 Canonical antibody; Humanized 1.Organ transplant rejection FDA US:1997*
2.Multiple sclerosis EMA Europe:1999*
Rituximab Rituxan, MabThera CD20 Canonical antibody; Chimeric 1.Rheumatoid arthritis FDA US:1997
2.Chronic lymphocytic leukemia EMA Europe:1998
3.Follicular lymphoma PMDA Japan:2001
4.Non-Hodgkin’s lymphoma NMPA China:2000/3/15
5.Lymphoproliferative disorders
6.Microscopic polyangiitis
7.Nephrotic syndrome
8.Pemphigus
9.Idiopathic thrombocytopenic purpura
10.Wegener’s granulomatosis
11.Granulomatosis with polyangiitis
12.Systemic scleroderma
13.Thrombotic thrombocytopenic purpura
Infliximab Remicade Tumor necrosis factor-alpha (TNF-α) Canonical antibody; Chimeric 1.Ankylosing spondylitis FDA US:1998
2.Psoriatic arthritis EMA Europe:1998
3.Rheumatoid arthritis PMDA Japan:2002
4.Behcet’s disease NMPA China:2006
5.Ulcerative colitis
6.Crohn’s disease
7.Kawasaki disease
8.Plaque psoriasis
9.Psoriasis
Trastuzumab Herceptin Human epidermal growth factor receptor 2 (HER2) Canonical antibody; Humanized 1.Breast cancer FDA US:1998
2.Gastric cancer EMA Europe:1998
Palivizumab Synagis Respiratory syncytial virus F protein (RSV-F) Canonical antibody; Humanized 1.Respiratory syncytial virus prophylaxis FDA US:1998
EMA Europe:1999
Basiliximab Simulect CD25 Canonical antibody; Chimeric 1.Organ transplant rejection FDA US:1998
2.Renal transplant rejection EMA Europe:1998
PMDA Japan:2002
NMPA China:2004
Etanercept Enbrel Tumor necrosis factor-alpha (TNF-α) Fc-Fusion protein 1.Ankylosing spondylitis FDA US:1998
2.Psoriatic arthritis EMA Europe:2000
3.Rheumatoid arthritis4.Plaque psoriasis PMDA Japan:2005
5.Juvenile rheumatoid arthritis NMPA China:2010
Gemtuzumab ozogamicin Mylotarg CD33 Antibody-drug conjugate; Humanized 1.Acute myelogenous leukemia FDA US: 2000
PMDA Japan:2005
EMA Europe:2018
Alemtuzumab Lemtrada, Campath CD52 Canonical antibody; Humanized 1.Chronic lymphocytic leukemia FDA US:2001
2.Multiple sclerosis EMA Europe:2001
PMDA Japan:2014
Wut3 Shudankang CD3 Canonical antibody; Rodent 1.Graft versus host disease NMPA China:2010
2.Organ transplant rejection
Adalimumab Humira Tumor necrosis factor-alpha (TNF-α) Canonical antibody; Human 1.Ankylosing spondylitis FDA US:2002
2.Juvenile rheumatoid arthritis EMA Europe:2003
3.Psoriatic arthritis PMDA Japan:2008
4.Rheumatoid arthritis NMPA China:2010
5.Behcet’s disease
6.Ulcerative colitis
7.Crohn’s disease
8.Hidradenitis suppurativa
9.Inflammatory bowel disease
10.Plaque psoriasis
11.Generalized pustular psoriasis
12.Pyoderma gangrenosum
13.Uveitis
Ibritumomab tiuxetan Zevalin, Zevaman CD20 Canonical antibody; Rodent 1.Non-Hodgkin’s lymphoma FDA US:2002
EMA Europe:2004
Omalizumab Xolair Immunoglobulin E (IgE) Canonical antibody; Humanized 1.Allergic asthma FDA USA:2003
3.Urticaria NMPA China:2017
Efalizumab Raptiva, Xanelim Integrin subunit alpha L (ITGAL) Canonical antibody; Humanized 1.Psoriasis FDA US:2003*
EMA Europe:2004*
Anti human interleukin-8 monoclonal antibody Enboke Interleukin 8 (IL-8) Canonical antibody; Rodent 1.Atopic dermatitis NMPA China:2003
2.Generalized pustular psoriasis
Alefacept Amevive CD2 Fc-Fusion protein 1.Psoriasis FDA US:2003*
Iodine 131 tositumomab Bexxar CD20 Radiolabeled antibody; Rodent 1.Non-Hodgkin’s lymphoma FDA US:2003*
EMA Europe:2003*
Cetuximab Erbitux Epidermal growth factor receptor (EGFR) Canonical antibody; Chimeric 1.Colorectal cancer FDA US:2004
2.Head and Neck cancer EMA Europe:2004
PMDA Japan:2008
NMPA China:2005
Bevacizumab Avastin Vascular endothelial growth factor A (VEGF-A) Canonical antibody; Humanized 1.Breast cancer FDA US:2004
2.Cervical cancer EMA Europe:2005
3.Colorectal cancer PMDA Japan:2007
4.Glioblastoma NMPA China:2010
5.Liver cancer
6.Non-small cell lung cancer
7.Ovarian cancer
8.Glioma
9.Renal cell carcinoma
Natalizumab Tysabri, Antegren Integrin subunit alpha 4 (ITGA4) Canonical antibody; Humanized 1.Crohn’s disease FDA US:2004
2.Multiple sclerosis EMA Europe:2006
PMDA Japan:2014
Tocilizumab Actemra, RoActemra Interleukin 6 receptor (IL-6R) Canonical antibody; Humanized 1.Juvenile rheumatoid arthritis FDA US:2010
2.Rheumatoid arthritis EMA Europe:2009
3.Castleman’s disease PMDA Japan:2005
4.Drug hypersensitivity NMPA China:2013
5.Giant cell arteritis
6.Severe acute respiratory syndrome coronavirus 2
7.Systemic scleroderma
8.Adult-onset Still’s disease
9.Vasculitis
Abatacept Orencia CD80, CD86 Fc-Fusion protein 1.Psoriatic arthritis FDA US:2005
2.Graft versus host disease EMA Europe:2007
3.Rheumatoid arthritis pain PMDA Japan:2010
4.Juvenile rheumatoid arthritis NMPA China:2020
Panitumumab Vectibix Epidermal growth factor receptor (EGFR) Canonical antibody; Human 1.Colorectal cancer FDA US:2006
EMA Europe:2007
PMDA Japan:2010
Iodine 131 derlotuximab biotin Cotara, Vivatuxin DNA/Histone H1 Radiolabeled antibody; Chimeric 1.Lung cancer NMPA China:2006
Iodine 131 metuximab Licartin CD147 Radiolabeled antibody; Chimeric 1.Liver cancer NMPA China:2006
Nimotuzumab Taixinsheng, TheraCIM, Theraloc, CIMAher, BIOMAb EGFR Epidermal growth factor receptor (EGFR) Canonical antibody; Humanized 1.Anaplastic astrocytoma CECMED Cuba:2006
2.Brain cancer NMPA China:2012
3.Esophageal cancer
4.Glioblastoma
5.Head and neck cancer
6.Nasopharyngeal cancer
7.Glioma
Ranibizumab Lucentis Vascular endothelial growth factor A (VEGF-A) Fab fragment; Humanized 1.Choroidal neovascularization FDA US:2006
2.Degenerative myopia EMA Europe:2007
3.Diabetic macular edema PMDA Japan:2009
4.Diabetic retinopathy NMPA China:2011
5.Retinal edema
6.Wet age-related macular degeneration
7.Retinopathy of prematurity
Eculizumab Soliris Complement C5 (C5) Canonical antibody; Humanized 1.Hemolytic uremic syndrome FDA US:2007
2.Myasthenia gravis EMA Europe:2007
3.Neuromyelitis optica PMDA Japan:2010
4.Paroxysmal nocturnal hemoglobinuria NMPA China:2018
Racotumomab Vaxira Ganglioside GM3 (GM3) Canonical antibody; Rodent 1.Non-small cell lung cancer CECMED Cuba:2008
Rilonacept Arcalyst Interleukin 1 alpha, Interleukin 1 beta (IL-1α, IL-1 β) Fc-Fusion protein 1.Cryopyrin-associated periodic syndrome FDA US:2008
2.Inborn genetic diseases
3.Pericarditis
Certolizumab pegol Cimzia Tumor necrosis factor-alpha (TNF-α) Fab fragment; Humanized 1.Ankylosing spondylitis FDA US:2008
2.Psoriatic arthritis EMA Europe:2009
3.Rheumatoid arthritis PMDA Japan:2012
4.Crohn’s disease NMPA China:2019
5.Plaque psoriasis
6.Axial spondyloarthritis
Romiplostim Nplate, Romiplate Thrombopoietin receptor (TPOR) Fc-Fusion protein 1.Idiopathic thrombocytopenic purpura FDA US:2008
2.Acute radiation syndrome EMA Europe:2009
3.Aplastic anemia PMDA Japan:2011
NMPA China:2022
Canakinumab Ilaris Interleukin 1 beta (IL-1 β) Canonical antibody; Human 1.Adult-onset Still’s disease FDA US:2009
2.Gouty arthritis EMA Europe:2009
3.Juvenile rheumatoid arthritis PMDA Japan:2011
4.Rheumatoid arthritis
5.Chronic obstructive pulmonary disease
6.Cryopyrin-associated periodic syndrome
7.Familial Mediterranean fever
8.Familial periodic fever
9.Peroxisomal disorder
Catumaxomab Removab CD3, Epithelial cell adhesion molecule (CD3, EpCAM) Bispecific antibody; Rodent 1.Gastric cancer EMA Europe:2009*
Ustekinumab Stelara Interleukin 12, Interleukin 23 (IL-12, IL- 23) Canonical antibody; Human 1.Psoriatic arthritis EMA Europe:2009
2.Ulcerative colitis FDA US:2009
3.Crohn’s disease PMDA Japan:2011
4.Plaque psoriasis NMPA China:2017
5.Psoriasis
Ofatumumab Arzerra, Kesimpta CD20 Canonical antibody; Human 1.Chronic lymphocytic leukemia FDA US:2009
2.Multiple sclerosis EMA Europe:2010
PMDA Japan:2013
NMPA China:2021
Golimumab Simponi Tumor necrosis factor-alpha (TNF-α) Canonical antibody; Human 1.Ankylosing spondylitis FDA US:2009
2.Juvenile rheumatoid arthritis EMA Europe:2009
3.Psoriatic arthritis PMDA Japan:2011
4.Rheumatoid arthritis NMPA China:2017
5.Ulcerative colitis
6.Axial spondyloarthritis
Denosumab Prolia, Ranmark, Xgeva Receptor activator of nuclear factor kappaB ligand (RANKL) Canonical antibody; Human 1.Corticosteroid-induced osteoporosis FDA US:2010
2.Rheumatoid arthritis EMA Europe:2020
3.Bone Metastases PMDA Japan:2012
4.Bone cancer NMPA China:2019
5.Bone disorder
6.Male osteoporosis
7.Malignant hypercalcaemia
8.Osteopetrosis
9.Postmenopausal Osteoporosis
Brentuximab vedotin Adcetris CD30 Antibody-drug conjugate; Chimeric 1.Hodgkin’s lymphoma FDA US:2011
2.T-cell lymphoma EMA Europe:2012
3.Peripheral T-cell lymphoma NMPA China:2020
4.Anaplastic large cell lymphoma PMDA Japan:2014
5.Sezary syndrome
6.Mycosis fungoides
7.Primary cutaneous anaplastic large cell lymphoma
Belatacept Nulojix CD80, CD86 Fc-Fusion protein 1.Renal transplant rejection FDA US:2011
EMA Europe:2011
Aflibercept Zaltrap, Eylea Vascular endothelial growth factor (VEGF) Fc-Fusion protein 1.Branch retinal vein occlusion FDA US:2011
2.Colorectal cancer EMA Europe:2012
3.Central retinal vein occlusion PMDA Japan:2012
4.Choroidal neovascularization NMPA China:2018
5.Diabetic macular edema
6.Diabetic retinopathy
7.Glaucoma
8.Wet age-related macular degeneration
9.Macular edema
Belimumab Benlysta, LymphoStat-B B cell activating factor (BAFF) Canonical antibody; Human 1.Lupus nephritis FDA US:2011
2.Systemic lupus erythematosus EMA Europe:2011
PMDA Japan:2017
NMPA China:2022
Ipilimumab Yervoy Cytotoxic T-lymphocyte antigen 4 (CTLA4) Canonical antibody; Human 1.Liver cancer FDA US:2011
2.Non-small cell lung cancer EMA Europe:2011
3.Mesothelioma PMDA Japan:2015
4.Malignant melanoma NMPA China:2021
5.Renal cell carcinoma
Pertuzumab Perjeta Human epidermal growth factor receptor 2 (HER2) Canonical antibody; Humanized 1.Breast cancer FDA US:2012
EMA Europe:2013
PMDA Japan:2013
NMPA China:2018
Raxibacumab Abthrax Bacillus anthracis protective antigen (B. anthracis PA) Canonical antibody; Human 1.Anthrax infection FDA US:2012
Mogamulizumab Poteligeo C–C chemokine receptor type 4 (CCR4) Canonical antibody; Humanized 1.Adult T-cell leukemia/lymphoma PMDA Japan:2012
2.Cutaneous T-cell lymphoma FDA US:2018
3.Peripheral T-cell lymphoma EMA Europe:2018
4.Mycosis fungoides
5.Sezary syndrome
Trastuzumab emtansine Kadcyla Human epidermal growth factor receptor 2 (HER2) Antibody-drug conjugate; Humanized 1.Breast cancer FDA US:2013
EMA Europe:2013
PMDA Japan:2013
NMPA China:2020
Obinutuzumab Gazyvaro, Gazyva CD20 Canonical antibody; Humanized 1.Chronic lymphocytic leukemia FDA US:2013
2.Follicular lymphoma EMA Europe:2014
3.Non-Hodgkin’s lymphoma PMDA Japan:2018
NMPA China:2021
Conbercept Langmu, Lumitin Vascular endothelial growth factor (VEGF) Fc-Fusion protein 1.Wet age-related macular degeneration NMPA China:2013
Itolizumab Alzumab CD6 Canonical antibody; Humanized 1.Cytokine release syndrome CDSCO India:2013
2.Plaque psoriasis
3.Severe acute respiratory syndrome coronavirus 2
Blinatumomab Blincyto CD19, CD3 Bispecific antibody; Rodent 1.B-cell acute lymphoblastic leukemia FDA US:2014
EMA Europe:2015
PMDA Japan:2018
NMPA China:2020
Pembrolizumab Keytruda Programmed cell death 1 (PD-1) Canonical antibody; Humanized 1.Breast cancer FDA US:2014
2.Cervical cancer EMA Europe:2015
3.Colorectal cancer PMDA Japan:2016
4.Esophageal cancer NMPA China:2018
5.Gastric cancer
6.Head and neck cancer
7.Liver cancer
8.Non-small cell lung cancer
9.Diffuse large B-cell lymphoma
10.Hodgkin’s lymphoma
11.Pancreatic cancer
12.Squamous cell carcinoma
13.Urogenital cancer
14.Malignant melanoma
Eftrenonacog alfa Alprolix Factor VIII Fc-Fusion protein 1.Hemophilia B FDA US:2014
PMDA Japan:2014
EMA Europe:2016
NMPA China:2021
Vedolizumab Entyvio, Kynteles Integrin alpha4 beta7 (Integrin α4β7) Canonical antibody; Humanized 1.Ulcerative colitis FDA US:2014
2.Crohn’s disease EMA Europe:2014
PMDA Japan:2018
Secukinumab Cosentyx, Scapho Interleukin 17A (IL-17A) Canonical antibody; Human 1.Ankylosing spondylitis PMDA Japan:2014
2.Psoriatic arthritis FDA US:2015
3.Non-radiographic axial spondyloarthritis EMA Europe:2015
4.Plaque psoriasis NMPA China:2019
5.Generalized pustular psoriasis
Ramucirumab Cyramza Vascular endothelial growth factor receptor 2 (VEGFR-2) Canonical antibody; Human 1.Colorectal cancer FDA US:2014
2.Gastric cancer EMA Europe:2014
3.Liver cancer PMDA Japan:2015
4.Non-small cell lung cancer NMPA China:2022
Efmoroctocog alfa Elocta, Eloctate Factor IX Fc-Fusion protein 1.Hemophilia A FDA US:2014
PMDA Japan:2014
EMA Europe:2015
Siltuximab Sylvant Interleukin 6 (IL-6) Canonical antibody; Chimeric 1.Castleman’s disease FDA US:2014
EMA Europe:2014
NMPA China:2021
Nivolumab Opdivo Programmed cell death 1 (PD-1) Canonical antibody; Human 1.Colorectal cancer PMDA Japan:2014
2.Esophageal cancer FDA US:2014
3.Gastric cancer EMA Europe:2015
4.Head and neck cancer NMPA China:2019
5.Non-small cell lung cancer
6.Hodgkin’s lymphoma
7.Mesothelioma
8.Squamous cell carcinoma
9.Urogenital cancer
10.Malignant melanoma
11.Renal cell carcinoma
Elotuzumab Empliciti SLAM family member 7 (SLAMF7) Canonical antibody; Humanized 1.Multiple myeloma FDA US:2015
EMA Europe:2016
PMDA Japan:2016
Alirocumab Praluent Proprotein convertase subtilisin/kexin Type 9 (PCSK9) Canonical antibody; Human 1.Hypercholesterolemia FDA US:2015
2.Hyperlipoproteinemia Type IIa EMA Europe:2015
PMDA Japan:2016
Mepolizumab Nucala
Interleukin 5 (IL-5)		 Canonical antibody; Humanized 1.Asthma FDA US:2015
EMA Europe:2015
PMDA Japan:2016
NMPA China:2021
Necitumumab Portrazza Epidermal growth factor receptor (EGFR) Canonical antibody; Human 1.Non-small cell lung cancer FDA US:2015
EMA Europe:2016
PMDA Japan:2019
Idarucizumab Praxbind Dabigatran Fab fragment; Humanized 1.Blood coagulation disorders FDA US:2015
EMA Europe:2015
PMDA Japan:2016
NMPA China:2018
Dinutuximab Unituxin, Qarziba GD2 ganglioside (GD2) Canonical antibody; Chimeric 1.Nephroblastoma FDA US:2015
EMA Europe:2015
PMDA Japan:2021
NMPA China:2021
Daratumumab Darzalex CD38 Canonical antibody; Human 1.Multiple myeloma FDA US:2015
EMA Europe:2016
PMDA Japan:2017
NMPA China:2019
Evolocumab Repatha Proprotein convertase subtilisin/kexin Type 9 (PCSK9) Canonical antibody; Human 1.Coronary artery disease FDA US:2015
2.Hypercholesterolemia EMA Europe:2015
3.Hyperlipoproteinemia Type Iia PMDA Japan:2016
4.Myocardial infarction NMPA China:2018
5.Stroke
Atezolizumab Tecentriq Programmed cell death 1 ligand 1 (PD-L1) Canonical antibody; Humanized 1.Breast cancer FDA US:2016
2.Liver cancer EMA Europe:2017
3.Non-small cell lung cancer PMDA Japan:2018
4.Small cell lung cancer NMPA China:2020
5.Urogenital cancer
6.Malignant melanoma
Olaratumab Lartruvo Platelet-derived growth factor receptor alpha (PDGFRA) Canonical antibody; Human 1.Soft tissue sarcoma FDA US:2016*
EMA Europe:2016*
Bezlotoxumab Zinplava Clostridium difficile Toxin B Canonical antibody; Human 1.C. difficile infection FDA US:2016
EMA Europe:2017
PMDA Japan:2017
Brodalumab Siliq, Kyntheum, Lumicef Interleukin 17 receptor alpha (IL-17 RA) Canonical antibody; Human 1.Ankylosing spondylitis PMDA Japan:2016
2.Psoriatic arthritis FDA US:2017
3.Erythrodermic psoriasis EMA Europe:2017
4.Plaque psoriasis NMPA China:2020
5.Psoriasis
6.Axial spondyloarthritis
7.Generalized pustular psoriasis
Ixekizumab Taltz Interleukin 17A (IL-17A) Canonical antibody; Humanized 1.Ankylosing spondylitis FDA US:2016
2.Psoriatic arthritis EMA Europe:2016
3.Erythrodermic psoriasis PMDA Japan:2016
4.Plaque psoriasis NMPA China:2019
5.Generalized pustular psoriasis
6.Non-radiographic axial spondyloarthritis
SII rmab Rabishield Rabies virus glycoprotein (Rabies virus GP) Canonical antibody; Human 1.Rabies virus infection CDSCO India:2016
Reslizumab Cinqair, Cinqaero Interleukin 5 (IL-5) Canonical antibody; Humanized 1.Asthma FDA US:2016
EMA Europe:2016
Obiltoxaximab Anthim B. anthracis Protective antigen (B. anthracis PA) Canonical antibody; Chimeric 1.Anthrax infection FDA US:2016
EMA Europe:2020
Inotuzumab ozogamicin Besponsa CD22 Antibody-drug conjugate; Humanized 1.B-cell acute lymphoblastic leukemia EMA Europe:2017
FDA US:2017
PMDA Japan:2018
NMPA China:2021
Sarilumab Kevzara Interleukin 6 receptor (IL-6R) Canonical antibody; Human 1.Rheumatoid arthritis HC Canada:2017
FDA US:2017
EMA Europe:2017
PMDA Japan:2017
Dupilumab Dupixent Interleukin 4 receptor alpha (IL-4RA) Canonical antibody; Human 1.Asthma FDA US:2017
2.Atopic dermatitis EMA Europe:2017
3.Nasal polyps PMDA Japan:2018
4.Eosinophilic esophagitis NMPA China:2020
Durvalumab Imfinzi Programmed cell death 1 ligand 1 (PD-L1) Canonical antibody; Human 1.Non-small cell lung cancer FDA US:2017
2.Small cell lung cancer PMDA Japan:2018
EMA Europe:2018
NMPA China:2019
Avelumab Bavencio Programmed cell death 1 ligand 1 (PD-L1) Canonical antibody; Human 1.Merkel cell carcinoma FDA US:2017
2.Urogenital cancer EMA Europe:2017
3.Renal cell carcinoma PMDA Japan:2017
Emicizumab Hemlibra Coagulation factor IX, Coagulation factor X (Factor IX, Factor X) Bispecific antibody; Humanized 1.Hemophilia A FDA US:2017
EMA Europe:2018
PMDA Japan:2018
NMPA China:2018
Benralizumab Fasenra Interleukin 5 receptor subunit alpha (IL-5RA) Canonical antibody; Humanized 1.Asthma FDA US:2017
EMA Europe:2018
PMDA Japan:2018
Ocrelizumab Ocrevus CD20 Canonical antibody; Humanized 1.Multiple sclerosis FDA US:2017
EMA Europe:2018
Guselkumab Tremfya Interleukin 23 p19 (IL-23p19) Canonical antibody; Human 1.Psoriatic arthritis FDA US:2017
2.Erythrodermic psoriasis EMA Europe:2017
3.Plaque psoriasis PMDA Japan:2018
4.Palmoplantar pustulosis NMPA China:2019
5.Generalized pustular psoriasis
Erenumab Aimovig Calcitonin gene-related peptide receptor (CGRP-R) Canonical antibody; Human 1.Migraine FDA US:2018
EMA Europe:2018
PMDA Japan:2021
Moxetumomab pasudotox Lumoxiti CD22 Immunotoxin; Rodent 1.Hairy cell leukemia FDA US:2018
EMA Europe:2021
Ravulizumab Ultomiris Complement C5 (C5) Canonical antibody; Humanized 1.Haemolytic uraemic syndrome FDA US:2018
2.Myasthenia gravis PMDA Japan:2019
3.Paroxysmal nocturnal hemoglobinuria EMA Europe:2019
Fremanezumab Ajovy Calcitonin gene-related peptide (CGRP) Canonical antibody; Humanized 1.Migraine FDA US:2018
EMA Europe:2019
PMDA Japan:2021
Sintilimab Tyvyt, Daboshu Programmed cell death 1 (PD-1) Canonical antibody; Human 1.Gastric cancer NMPA China:2018
2.Esophageal cancer
3.Liver cancer
4.Non-small cell lung cancer
5.Hodgkin’s lymphoma
Ibalizumab Trogarzo CD4 Canonical antibody; Humanized 1.HIV infection FDA US:2018
EMA Europe:2019
Galcanezumab Emgality Calcitonin gene-related peptide (CGRP) Canonical antibody; Humanized 1.Cluster headache FDA US:2018
2.Migraine EMA Europe:2018
PMDA Japan:2021
Tildrakizumab Ilumetri, Ilumya Interleukin 23 p19 (IL-23p19) Canonical antibody; Humanized 1.Plaque psoriasis FDA US:2018
EMA Europe:2018
PMDA Japan:2020
Emapalumab Gamifant Interferon gamma (IFN-γ) Canonical antibody; Human 1.Hemophagocytic Lymphohistiocytosis FDA US:2018
NMPA China:2022
EMA Europe:2021
Cemiplimab Libtayo Programmed cell death 1 (PD-1) Canonical antibody; Human 1.Basal cell carcinoma FDA US:2018
2.Non-small cell lung cancer EMA Europe:2019
3.Squamous cell carcinoma
Toripalimab Tuoyi Programmed cell death 1 (PD-1) Canonical antibody; Humanized 1.Nasopharyngeal cancer NMPA China:2018
2.Urogenital cancer
3.Malignant melanoma
Caplacizumab Cablivi von Willebrand Factor (vWF) VHH-VHH, Humanized 1.Thrombotic thrombocytopenic purpura EMA Europe:2018
FDA US:2019
Lanadelumab Takhzyro Kallikrein Canonical antibody; Human 1.Hereditary angioedema FDA US:2018
EMA Europe:2018
NMPA China:2020
PMDA Japan:2022
Burosumab Crysvita Fibroblast growth factor 23 (FGF23) Canonical antibody; Human 1.Osteomalacia EMA Europe:2018
2.X-linked hypophosphatemia FDA US:2018
PMDA Japan:2019
NMPA China:2021
Tislelizumab Baizean Programmed cell death 1 (PD-1) Canonical antibody; Humanized 1.Liver cancer NMPA China:2019
2.Non-small cell lung cancer
3.Hodgkin’s lymphoma
4.Nasopharyngeal cancer
5.Squamous cell carcinoma
6.Urogenital cancer
Risankizumab Skyrizi Interleukin 23 p19 (IL-23p19) Canonical antibody; Humanized 1.Psoriatic arthritis PMDA Japan:2019
2.Plaque psoriasis FDA US:2019
3.Psoriasis EMA Europe:2019
4.Crohn’s disease
Trastuzumab deruxtecan Enhertu Human epidermal growth factor receptor 2 (HER2) Antibody-drug conjugate; Humanized 1.Breast cancer FDA US:2019
2.Gastric cancer PMDA Japan:2020
EMA Europe:2021
Brolucizumab Beovu Vascular endothelial growth factor A (VEGF-A) ScFv fragment; Humanized 1.Wet age-related macular degeneration FDA US:2019
EMA Europe:2020
PMDA Japan:2020
Crizanlizumab Adakveo P-selectin Canonical antibody; Humanized 1.Vaso-occlusive crisis FDA US:2019
EMA Europe:2020
Enfortumab vedotin Padcev Nectin Cell Adhesion Molecule 4 (Nectin 4) Antibody-drug conjugate; Human 1.Urogenital cancer FDA US:2019
PMDA Japan:2021
EMA Europe:2022
Romosozumab Evenity Sclerostin Canonical antibody; Humanized 1.Male osteoporosis PMDA Japan:2019
2.Postmenopausal osteoporosis FDA US:2019
EMA Europe:2019
Efgartigimod alfa Vyvgart Neonatal Fc Receptor (FcRn) Fc fragment; Human 1.Myasthenia gravis EMA Europe:2019
FDA US:2021
PMDA Japan:2022
Camrelizumab Airuika Programmed cell death 1 (PD-1) Canonical antibody; Humanized 1.Esophageal cancer NMPA China:2019
2.Non-small cell lung cancer
3.Hodgkin’s lymphoma
4.Nasopharyngeal cancer
5.Liver cancer
Polatuzumab vedotin Polivy CD79b Antibody-drug conjugate; Humanized 1.Diffuse large B-cell lymphoma FDA US:2019
EMA Europe:2020
PMDA Japan:2021
Luspatercept Reblozyl Transforming growth factor-beta (TGF-β) Fc-Fusion protein 1.Beta-thalassemia FDA US:2019
2.Myelodysplastic syndrome EMA Europe:2020
NMPA China:2022
Rabimabs Twinrab Rabies virus glycoprotein (Rabies virus GP) Canonical antibody; Rodent 1.Rabies virus infection CDSCO India:2019
Netakimab Efleira Interleukin 17A (IL-17A) Canonical antibody; Humanized 1.Plaque psoriasis Minzdrav Russia:2019
2.Ankylosing spondylitis
3.Psoriatic arthritis
Inebilizumab Uplizna CD19 Canonical antibody; Humanized 1.Neuromyelitis optica FDA US:2020
PMDA Japan:2021
NMPA China:2022
EMA Europe:2022
Teprotumumab Tepezza Insulin-like growth factor 1 receptor (IGF-1R) Canonical antibody; Human 1.Graves’ ophthalmopathy FDA US:2020
Sacituzumab govitecan Trodelvy Tumor-associated calcium signal transducer 2 (TACSTD-2) Antibody-drug conjugate; Humanized 1.Breast cancer FDA US:2020
2.Urogenital cancer EMA Europe:2021
NMPA China:2022
Atoltivimab + Odesivimab + Maftivimab Inmazeb Ebola virus Glycoprotein Canonical antibody; Human 1.Ebola virus infection FDA US:2020
Cetuximab sarotalocan Akalux Epidermal growth factor receptor (EGFR) Antibody-drug conjugate; Chimeric 1.Head and neck cancer PMDA Japan:2020
Isatuximab Sarclisa CD38 Canonical antibody; Chimeric 1.Multiple myeloma FDA US:2020
EMA Europe:2020
PMDA Japan:2020
Belantamab mafodotin Blenrep B cell maturation antigen (BCMA) Antibody-drug conjugate; Humanized 1.Multiple myeloma FDA US:2020
EMA Europe:2020
Levilimab Ilsira Interleukin 6 receptor (IL-6R) Canonical antibody; Human 1.Rheumatoid arthritis Minzdrav Russia:2020
2.Severe acute respiratory syndrome coronavirus 2
Margetuximab Margenza Human epidermal growth factor receptor 2 (HER2) Canonical antibody; Chimeric 1.Breast cancer FDA US:2020
Satralizumab Enspryng Interleukin 6 receptor (IL-6R) Canonical antibody; Humanized 1.Neuromyelitis optica HC Canada:2020
PMDA Japan:2020
FDA US:2020
EMA Europe:2021
NMPA China:2021
Tafasitamab Monjuvi CD19 Canonical antibody; Humanized 1.Diffuse large B-cell lymphoma FDA US:2020
EMA Europe:2021
Naxitamab Danyelza GD2 ganglioside (GD2) Canonical antibody; Humanized 1.Neuroblastoma FDA US:2020
Ansuvimab Ebanga Ebola virus glycoprotein Canonical antibody; Human 1.Ebola virus infection FDA US:2020
Eptinezumab Vyepti Calcitonin gene-related peptide (CGRP) Canonical antibody; Humanized 1.Migraine FDA US:2020
EMA Europe:2022
Prolgolimab Forteca Programmed cell death 1 (PD-1) Antibody-drug conjugate; Humanized 1.Melanoma Minzdrav Russia:2020
Olokizumab Artlegia Interleukin 6 (IL-6) Canonical antibody; Humanized 1.Rheumatoid arthritis Minzdrav Russia:2020
2.Severe acute respiratory syndrome coronavirus 2
Penpulimab Annike Programmed cell death 1 (PD-1) Canonical antibody; Humanized 1.Non-small cell lung cancer NMPA China:2021
2.Hodgkin’s lymphoma
3.Nasopharyngeal cancer
Dostarlimab Jemperli Programmed cell death 1 (PD-1) Canonical antibody; Humanized 1.Endometrial cancer EMA Europe:2021
2.Solid cancer FDA US:2021
Evinacumab Evkeeza Angiopoietin-like protein 3 (ANGPTL3) Canonical antibody; Human 1.Hyperlipoproteinemia Type IIa FDA US:2021
EMA Europe:2021
Sugemalimab Cejemly Programmed cell death 1 ligand 1 (PD-L1) Canonical antibody; Human 1.Non-small cell lung cancer NMPA China:2021
Envafolimab enweida Programmed cell death 1 ligand 1 (PD-L1) Fc-Fusion VHH; Humanized 1.Solid cancer NMPA China:2021
Telitacicept Taiai B cell activating factor (BAFF), A proliferation-inducing ligand (APRIL) Fc-Fusion protein 1.Systemic lupus erythematosus NMPA China:2021
Regdanvimab Regkirona SARS-Cov-2 spike protein (SARS-Cov-2 S protein) Canonical antibody; Human 1.Severe acute respiratory syndrome coronavirus 2 ANVISA Brazil:2021
EMA Europe:2021
Amubarvimab + Romlusevimab SARS-Cov-2 spike protein (SARS-Cov-2 S protein) Canonical antibody; Human 1.Severe acute respiratory syndrome coronavirus 2 NMPA China:2021
Amivantamab Rybrevant Epidermal growth factor receptor, C-Met (EGFR, cMet) Bispecific antibody; Human 1.Non-small cell lung cancer FDA US:2021
Zimberelimab Yutuo Programmed cell death 1 (PD-1) Canonical antibody; Human 1.Hodgkin’s lymphoma NMPA China:2021
Bimekizumab Bimzelx Interleukin 17A, Interleukin 17F (IL-17A, IL-17F) Canonical antibody; Humanized 1.Erythrodermic psoriasis EMA Europe:2021
2.Plaque psoriasis PMDA Japan:2022
3.Generalized pustular psoriasis
Loncastuximab tesirine Lonca, Zynlonta CD19 Antibody-drug conjugate; Chimeric 1.Diffuse large B-cell lymphoma FDA US:2021
Tisotumab vedotin Tivdak Tissue factor (TF) Antibody-drug conjugate; Human 1.Cervical cancer FDA US:2021
Tralokinumab Adtralza, Adbry Interleukin 13 (IL-13) Canonical antibody; Human 1.Atopic dermatitis EMA Europe:2021
FDA US:2021
Tezepelumab Tezspire Thymic stromal lymphopoietin (TSLP) Canonical antibody; Human 1.Asthma FDA US:2021
Aducanumab Aduhelm Amyloid beta Canonical antibody; Human 1.Alzheimer’s disease FDA US:2021
Disitamab vedotin Aidixi Human epidermal growth factor receptor 2 (HER2) Antibody-drug conjugate; Humanized 1.Gastric cancer NMPA China:2021
2.Urothelial carcinoma
Sotrovimab Xevudy SARS-Cov-2 spike protein (SARS-Cov-2 S protein) Canonical antibody; Human 1.Severe acute respiratory syndrome coronavirus 2 PMDA Japan:2021
EMA Europe:2021
Pabinafusp alfa Izcargo Transferrin receptor protein 1 (TFR1) Immunoconjugate; Humanized 1.Mucopolysaccharidosis II PMDA Japan:2021
Anifrolumab Saphnelo Interferon alpha receptor 1 (IFNAR-1) Canonical antibody; Human 1.Systemic lupus erythematosus FDA US:2021
PMDA Japan:2021
EMA Europe:2022
Ormutivimab Xunke Rabies virus glycoprotein (Rabies virus GP) Canonical antibody; Human 1.Rabies virus prophylaxis NMPA China:2022
Faricimab Vabysmo Vascular endothelial growth factor A, Angiopoietin 2 (VEGF-A, ANG-2) Bispecific antibody; Humanized 1.Diabetic macular edema FDA US:2022
2.Wet age-related macular degeneration PMDA Japan:2022
Sutimlimab Enjaymo Complement C1s (C1s) Canonical antibody; Humanized 1.Autoimmune hemolytic anemia FDA US:2022
2.Cold agglutinin disease
Mosunetuzumab Lunsumio CD3, CD20 Bispecific antibody; Humanized 1.Follicular lymphoma EMA Europe:2022
Cadonilimab Kaitanni Cytotoxic T-lymphocyte antigen 4, Programmed Cell Death 1 (CTLA4, PD-1) Bispecific antibody; Humanized 1.Cervical cancer NMPA China:2022
Nemolizumab Mitchga Interleukin 31 receptor subunit alpha (IL-31RA) Canonical antibody; Humanized 1.Atopic dermatitis PMDA Japan:2022
Relatlimab + Nivolumab Opdualag Lymphocyte activation gene 3, Programmed cell death 1 (LAG-3, PD-1) Canonical antibody; Human 1.Melanoma FDA US:2022
Tixagevimab + Cilgavimab Evusheld SARS-Cov-2 spike protein (SARS-Cov-2 S protein) Canonical antibody; Human 1.Severe acute respiratory syndrome coronavirus 2 prophylaxis EMA Europe:2022
Serplulimab Hansizhuang Programmed cell death 1 (PD-1) Canonical antibody; Humanized 1.Non-small cell lung cancer NMPA China:2022
2.Small cell lung cancer
3.Solid cancer
Tebentafusp Kimmtrak CD3, Glycoprotein 100 (CD3, GP100) Immunoconjugate; Humanized 1.Uveal melanoma FDA US:2022
EMA Europe:2022
Open in a new tab

*indicates the antibody therapy was withdrawn.

Counting the number of global approvals, around 93% of approved antibody therapies were first approved by only four major drug regulatory agencies, which are the FDA in the US, the European Medicines Agency (EMA) in Europe, the Pharmaceuticals and Medical Devices Agency (PMDA) in Japan, and the National Medical Products Administration (NMPA) in China (Supplementary Fig. 1). The remaining 7% of antibody therapies were first approved in Canada, Brazil, Cuba, India and Russia. Historically, the FDA, EMA, NMPA, and PMDA started to give antibody therapies market approval in the 1990s. For the 162 approved antibody therapies to date, the FDA has approved 122, the EMA has approved 114 (including 4 approved by European countries prior to the formal establishment of the EMA), the NMPA has approved 73, and the PMDA has approved 82. In this review, we mainly focus on the approvals by these four drug regulatory agencies. If one antibody was first approved by one of the other agencies, the first approval information was given but the approvals in other countries were not specifically listed.

Our data show that the US has had the greatest number of approvals, and is far ahead of other countries and regions. After the first antibody therapy (OKT3) was approved by the FDA in 1986, it took another 8 years to approve the second antibody therapy in 1994. This was Abciximab, a treatment of cardiovascular disease which acts by binding to the αIIbβ3 integrin to prevent clotting [10, 11]. Since 2000, there has been at least one antibody therapy approved by the FDA every year. This has led the US to dominate the number of antibody therapy approvals for more than two decades.

The first antibody therapy approved in Europe was Nebacumab in 1991, which was an anti-endotoxin antibody for the treatment of sepsis [12]. Although Nebacumab was withdrawn in 1993 because it failed to reduce mortality in the following clinical performance, it was the only approved human IgM antibody to date [13]. The second antibody therapy approved in Europe in 1995 was Edrecolomab, a murine antibody targeting EpCAM for the treatment of colorectal cancer [14]. Between 1995 and 2014, the EMA only approved less than five antibodies annually, but since 2015, the number of annual approvals has increased to around 10.

Japan and China are about 10 years behind the US and Europe in terms of the number of approvals and clinical trials. However, Japan and China have witnessed rapid development in antibody therapies over the past decade. The first antibody approved in Japan was the anti-CD52 Alemtuzumab in 2001 [15], which was a humanized antibody developed by Sanofi Genzyme for the treatment of leukemia. The first locally developed antibody approved in Japan was Tocilizumab in 2005, which was a humanized antibody targeting the interleukin 6 receptor (IL-6R) for the treatment of arthritis [16]. Since then, the number of approvals in Japan has steadily increased, especially after 2014. As for China, the first antibody therapy was approved by the NMPA in 1999. This was a murine anti-CD3 antibody IOR-T3 developed by a Cuban company, for the treatment of organ transplant rejection [17]. In 2002, a locally developed antibody called Wut3, which was also a murine anti-CD3 antibody for the treatment of transplant rejection, was approved in China. Until 2017, the number of antibody therapies approved in China was <5 for each year. But since 2018, the annual approvals have increased to > 10, and even reached 18 in 2021. Although a total of 73 antibody therapies were approved by the NMPA in China for a wide range of indications, only 18 antibodies were developed by local companies. However, very recently, there was a first-in-class anti-PD-1/CTLA-4 bispecific antibody, Cadonilimab, approved by the NMPA for the treatment of metastatic cervical cancer [18]. Cadonilimab, the first bispecific antibody with dual immune checkpoint inhibition approved in the world, could signal a future increase in innovative antibody therapy development in China.

ANTIBODY DISCOVERY AND ENGINEERING IN APPROVED ANTIBODIES

In 1975, Georges Köhler and César Milstein established the hybridoma platform based on the fusion of murine B cell and myeloma cells, which enables the in vitro production of a large amount of pure mAbs [19]. Subsequently, chimeric antibodies formed by domain recombination, and then humanized antibodies, obtained primarily by complementary-determining region (CDR) grafting, have been enabled for mAb production [20]. Furthermore, fully human antibodies have been developed from phage display [21, 22], yeast display [23], mammalian cell display [24], transgenic animals [25, 26] and human blood samples [27, 28]. It is noted that the phage display developed antibodies are not naturally occurring human antibodies as their heavy chain and light chain sequences were not from the same B cells. More recently, glycoengineering has become a powerful tool to optimize the pharmacodynamic and pharmacokinetic properties of an antibody [29, 30]. For example, Fc core fucosylation has been shown to enhance FcγRIIIa binding and antibody-dependent cellular cytotoxicity (ADCC) activity of antibodies [31]. Meanwhile, an antibody lacking core fucosylation (afucosylated) increased ADCC activity through highly increased IgG-Fc receptor IIIa (FcγRIIIa) affinity [32]. There are currently four approved afucosylated antibodies: Obinutuzumab, Mogamulizumab Benralizumab and Inebilizumab.

The total number of rodent antibody therapies is only 11, out of which four have been withdrawn. In 1986, the first antibody therapy based on this technique, OKT3, was a murine mAb against CD3 expressed on the T cell surface, acting as an immunosuppressor in organ transplant rejection [2, 33]. No more murine antibody therapies have been approved since Rabimabs, which was approved in India for the treatment of rabies in 2019 [34]. For those approved non-humanized antibodies, anti-CD3/EpCAM Catumaxomab is a mouse-rat hybrid bispecific antibody, first approved by the EMA for the treatment of gastric cancer in 2009. This was also the first bispecific antibody to gain regulatory approval despite being withdrawn due to commercial failure [35, 36]. Moxetumomab pasudotox is the only murine antibody-conjugate immunotoxin and was approved by the FDA in 2018 for the treatment of hairy cell leukemia (HCL) [37].

There are risks and disadvantages of murine mAbs or mAbs from other animals for human administration. For example, patients would produce a rapid immune response through generation of human anti-mouse antibody (HAMA) against the murine antibodies, which greatly shortens the serum half-life of the therapy [38]. In addition, the ability of the murine Fc region to elicit ADCC in patients is limited [39]. To overcome these problems of murine mAbs, several engineering techniques have been developed to make their sequence more similar to the human antibody while maintaining binding affinity and specificity. The first technique developed was to create a chimeric antibody, which recombined the murine variable domains with a human constant region (Fig. 2A) [11, 40]. There are a total of 16 approved chimeric antibody therapies which are in multiple formats, including naked whole IgGs, fragments, and antibody drug conjugates (ADCs). The first murine antibody therapy, Abciximab [10, 11], was first approved in Cuba. A chimeric fragment antibody radiolabeled with Iodine 131, denoted as Iodine 131 Metuximab, was also approved by the NMPA in 2006 for the treatment of liver cancer [41]. In addition, in 2021, there was a chimeric ADC, loncastuximab tesirine, approved by the FDA for the treatment of large B-cell lymphoma. This indicates that the chimeric antibody is still popular for some applications [42].

Figure 2.

Figure 2

Open in a new tab

Antibody discovery and engineering for approved antibodies. A: Antibody therapies of different degree of humanization: a: the non-human antibody; b: the chimeric antibody, where the variable region (green region) is from a non-human animal, and the other domains (blue region) are from human; c: humanized antibody, where only the hypervariable region fragment is non-human; d: full human antibody. B: Different engineering formats of approved antibody therapies: a. canonical antibodies; b. fragments: including Fab fragment, single-chain variable fragment (scFv), Fc fragment, the variable regions of camelid heavy-chain-only antibodies (VHH) fused with human Fc fragment or with another VHH; c. antibody drug conjugates (ADCs): monoclonal antibody conjugate with cytotoxic small molecule drug payloads; d. bispecifics: including heterodimeric bispecific antibody, scFv–scFV bispecific antibody such as bispecific T-cell engager (BiTE) and IgG-scFv-based tetravalent; e. others: including antibody-conjugate immunotoxin, radiolabeled canonical antibody, radiolabeled Fab fragment, Fc-fusion protein, a scFv fused with a soluble T-cell receptor (TCR), and an IgG fused with an enzyme. C: The number of different formats of antibody therapies for the year that they were first approved (Fc-fusion proteins are not included).

Later, researchers set out to humanize an antibody mainly by grafting the CDR regions from mice into a human framework sequence [20]. After humanization, antibody therapies show much less immunogenicity but are often associated with loss of affinity. Therefore, a variety of methods have been innovated to restore and increase antibody affinity and specificity [43, 44]. As an important method of antibody engineering, 66 humanized antibodies from a diverse range of animals with multiple formats have been approved. The first humanized antibody therapy, anti-CD25 Daclizumab, was approved by the FDA in 1997 for the treatment of transplant rejection [45, 46]. Since then, humanized antibody therapies accounted for a high proportion of the approved antibody therapies each year (Fig. 2C).

In 1990, Gregory P. Winter introduced phage display of antibody fragments, in which exogenous human antibody genetic sequences can be incorporated into the filamentous bacteriophage genome and expressed on the phage surface for further specificity and affinity screening [21, 22]. Transgenic animals provided another powerful technique for the development of fully human antibodies, and was developed in 1994 by creating two transgenic mouse models that were genetically engineered to have human immunoglobulin genes, thus allowing the mice to express fully human antibodies after immunization [26]. In addition, the single B cell technique was developed to directly isolate antigen-specific B cells from human blood for the generation of human natural antibodies [47–49]. A total of 55 fully human antibody therapies have been approved so far. The first fully human antibody therapy, the IgM antibody Nebacumab, was approved in 1991 [13]. The first human whole IgG antibody therapy Adalimumab was approved by the FDA in 2002, which was developed by phage display to target against TNF-alpha for the treatment of rheumatic diseases [50]. The technique to isolate antigen-specific B cells directly from human blood has been successfully applied to discover antiviral antibodies [51, 52] such as REGN-EB3 targeting Ebola viral surface glycoprotein approved by the FDA in 2020 [53], and Evusheld targeting SARS-CoV-2 spike protein and first approved by the EMA in 2022 [54].

In addition, the recent advances in Next Generation Sequencing (NGS) make it a useful tool in rapid antibody discovery [55–57]. With the ever-progressing antibody discovery technologies, we believe there will likely be another wave of clinical trials and approvals for antibody therapies discovered from such innovative platforms.

Engineering of antibodies has evolved through a few stages whereby at first naked whole animal IgG antibodies were used directly as therapeutics, followed by recombination, humanization and affinity maturation. However, today we see more engineered antibody formats in a variety of shapes and sizes (Fig. 2B). We have categorized all approved antibody therapies into five classes: canonical antibody, fragment of antibody, ADC, bispecific antibody and other formats (Fig. 2C). Canonical antibodies have the whole antibody structure, consisting of two full-length heavy chains and two light chains. Of all approved antibodies, there are 115 canonical antibodies, 114 of which are IgGs and the other one is IgM (Nebacumab) [13]. Antibody fragments are composed of a few domains of the whole antibody structure but can act as therapies themselves. This format includes Fab fragments, single-chain variable fragments (scFvs), Fc fragments, and the variable regions of the camelid heavy chain of heavy-chain-only antibodies (VHH), which was fused with a human Fc fragment or with another VHH. There has been a total of eight fragment antibody therapies approved so far. The only scFv is the anti-vascular endothelial growth factor (VEGF)-A Brolucizumab for the treatment of wet age-related macular degeneration, approved by the FDA in 2019 [58]. Four Fab fragments have been approved so far, of which the first approved Fab fragment antibody therapy was Abciximab [10, 11]. There has also been one PEGylated Fab fragment, Certolizumab Pegol, approved in 2008 for the treatment of autoimmune-related diseases [59, 60]. ScFv is a small-sized antibody, which fuses only the variable regions of the heavy and light chain of the whole antibody, making it easier to penetrate the tissues [61–63]. The only Fc fragment antibody therapy, Efgartigimod alfa, was first approved by the FDA in 2021, targeting neonatal Fc Receptor (FcRn) for the treatment of myasthenia gravis [64]. There are two antibody therapies composed of VHH, Caplacizumab and Envafolimab, which were first approved by the EMA in 2018 and the NMPA in 2021, respectively. Caplacizumab is a bivalent single domain antibody with VHH–VHH format, whereas Envafolimab is a VHH-Fc fusion.

ADCs are composed of a monoclonal antibody chemically linked to a small molecule drug as a payload. There have been 14 ADCs approved so far. Meanwhile, bispecifics are engineered antibodies or antibody fragments designed to combine two or more different antigen-binding domains in an integrated structure. There have been seven bispecific antibodies approved to date. The structures of bispecific antibodies include the heterodimeric bispecific antibody (Catumaxomab, Emicizumab, Amivantamab, Faricimab, Mosunetuzumab), scFv-based bispecific antibody such as bispecific T-cell engager (BiTE) (Blinatumomab), and IgG-scFv-based tetravalent (Cadonilimab). As for other special formats of antibody therapies, we have classified them into the “others” group, which includes antibody-conjugate immunotoxin (with a bacterial toxin, moxetumomab pasudotox), radiolabeled antibodies (Iodine 131 derlotuximab biotin, Iodine 131 Tositumomab), radiolabeled Fab fragments (Iodine 131 Metuximab), Fc-fusion proteins, an scFv fused with a TCR (Tebentafusp), and an antibody fused with an enzyme (Pabinafusp alfa).

LANDSCAPES OF TARGETS AND INDICATIONS OF APPROVED ANTIBODY THERAPIES

 

There are several effects when an antibody binds to its targets, including blocking of a ligand, blocking receptor dimerization, mediating receptor internalization, antibody-dependent cellular phagocytosis, ADCC, and complement-dependent cytotoxicity [65].

Validation of a therapeutic target takes considerable research input, rendering the number of targets for clinical development very limited. There are 91 targets involved in the 162 approved antibody therapies. Some targets have been extensively studied, such as PD-1, CD3, CD20, EGFR,VEGF, and HER2, such that a large proportion of approved antibody therapies have been based on these targets, which are all cancer and immune-related disease targets [66–70]. It is notable that CD3 is used as a target for T cell-dependent bispecific antibodies, rather than as a direct tumor target for cancer treatment. Furthermore, other targets emerged recently such as the SARS-CoV-2 spike protein for SARS-CoV-2 infections since the Covid-19 pandemic (antibody therapy Regdanvimab, Amubarvimab + Romlusevimab cocktail, Sotrovimab, and Evusheld) and the CGRP for CNS diseases (antibody Fremanezumab, Galcanezumab, and Eptinezumab) (Fig. 3A).

Figure 3.

Figure 3

Open in a new tab

The landscape of targets and indications of approved antibody therapies based on the Umabs-DB data are available as of 30 June 2022. A: Statistics of the top 20 approved antibody targets by their first approval year; B: Top 20 targets and their related indications approved by different agencies; C: The proportion of different therapeutic areas of approved antibody therapies; D: Approval antibodies over indications and year of approval.

For approved antibody therapies, 112 have been developed against 30 targets, and the remaining 61 targets are associated with the 63 antibody therapies. Of those antibody therapies against the 30 targets, seven are bispecific antibodies, one is a combination therapy (Relatlimab + Nivolumab), two are canonical antibodies (Ustekinumab and Bimekizumab), two are Fc-Fusion proteins (Abatacept and Belatacept) and one is an immunoconjugate (Tebentafusp) developed against two targets (thus counted twice), resulting in significant research and market competition on these popular targets. The most popular 20 targets are mainly applied to the treatment of cancers (PD-1/PD-L1, CD20 [71, 72], VEGF [69], EGFR [67, 73], HER2 [70], CD3 [74], CD19 [75], CD22 [76], GD2 [77]), immune-related diseases (TNF-alpha [59], IL-6R [78], IL-23 [79], IL-17A [80], IL-1 [81]), infectious diseases (SARS-CoV-2 spike protein [82], Rabies virus GP [83]), CNS diseases (CGRP [5]), and hematological disease (C5 [84], Factor IX [85]). Approval agencies of these antibodies and their targets are also presented showing different healthcare demands in these countries or regions (Fig. 3B).

Choices of therapeutic targets have progressed over time. Among the top 20 targets, there are some “new” targets (PD-1/PD-L1, CD19, SARS-CoV-2 spike protein, CGPR, Rabies virus GP, and IL-6R) with antibodies approved only after 2011. In contrast, the target TNF-alpha has no antibodies approved after 2010, showing that it has been thoroughly developed and left no market space. In 2018, the Nobel Prize for Physiology or Medicine was awarded to the discovery of the immune checkpoint PD-1, which acts as a “brake” for activated T cells in the tumor microenvironment and is considered to be a key target for the treatment of many cancers [86]. With the global pandemics of COVID-19, there came an emerging focus on the discovery of neutralizing antibodies for the prevention or treatment of respiratory syndromes from COVID-19, for which a total of four antibody therapies have been approved so far.

With respect to the indications of the approved antibodies, we have categorized seven classes based on their pathology. It can be easily interpreted that nearly half (42.6%) of the antibody therapies are for cancers, 37% for immune-related diseases, 11% for infectious diseases, and 7.4% for hematological diseases, whereas antibodies for other indications only account for < 3% (Fig. 3C). Likewise, interests on indications have changed over time. Cancers have always been the largest indication for antibody therapies, enabled by the extensive characterization of several key therapeutic targets, as discussed before. The first antibody therapy for the treatment of cancer, Rituximab, was a chimeric IgG1 mAb targeting CD20 and was approved for non-Hodgkin’s lymphoma in 1997 by the FDA [87, 88]. Rituximab worked well in the clinic as a chimeric antibody, as it caused prompt and nearly complete depletion of peripheral B cells, which alleviated the immunogenic concern introduced by the administration of a chimeric antibody. Antibody therapies have revolutionized the treatment of immune-related diseases due to their efficacy, specificity, speed of onset, and tolerability. It should be noted that CNS diseases have been an emerging therapeutic area for antibody therapies since 2016, in which antibodies could lead to some breakthrough treatments (Fig. 3D).

COMPANIES/ORGANIZATIONS

Scrutinizing the companies with at least one approved antibody, there are a total of 82 companies. The number of companies that have had their antibody therapies first approved by the FDA is 33. For the EMA, it is 15 companies, for the NMPA it is 17, for the PDMA it is 7, and for other agencies it is 10 (Fig. 4A and Table 1). The number of companies suggests that the US is in a leading position in antibody therapy as it also dominates the research and clinical development in the field. For the companies in the FDA group, most approvals occurred between 2016 and 2020, which is similar to the first approvals by the EMA, PMDA, and agencies in the other group. However, the year 2021 saw a peak (8 companies) in the number of companies that had first approvals by the NMPA (Fig. 4A). This suggests an enormous scale of research funding and capital was put into the field over the past decade in China.

Figure 4.

Figure 4

Open in a new tab

A. Companies with their first approval by different regulatory agencies (the MHRA from the UK is included in the Others group). B. Top 10 companies ranking by the number of approved antibody therapies.

For the top 10 companies with the greatest number of approved antibodies, their product portfolio shows different R&D focuses of therapeutic areas (Fig. 4B and Supplementary Table 1) such as cancer, immune-related disease, infectious disease, hematological disease, and CNS disease. GSK, BMS, Amgen, and Eli Lilly show a stronger historical interest in cancer antibody therapies as they possess 5, 4, 3, and 3 approvals, respectively. In comparison, they possess 2, 2, 2, and 1 approvals in immune-related diseases, which are their second largest therapeutic field. Johnson & Johnson, AstraZeneca and Novartis show higher achievement in immune-related disease antibody therapies, as they possess 6, 3 and 3 approvals, which outnumber their approvals in cancer. Roche, Sanofi and Regeneron show a balanced output in antibody therapy for cancer (8, 2, and 2 approvals) and immune-related disease (8, 2 and 2 approvals). Hematological disorder has been more explored by AstraZeneca and Sanofi (2 and 2 approvals). Similarly, antibody therapy of infectious disease is characteristic to GSK and AstraZeneca (2 and 2 approvals), whereas therapy of eye-related diseases has only successfully been developed by Roche and Novartis (2 and 1 approvals).

CONCLUSION AND PERSPECTIVE

Antibody therapies have become the leading treatment for a range of human diseases. More than 160 antibody therapies have been approved in the world, but this is just a start. The emerging discovery technologies play an important role in speeding up R&D that will make more antibody candidates available for clinical development. Several antibody discovery technologies are widely applicable today, including hybridoma, in vitro display (phage display, yeast display and mammalian cell display, etc.) and single B cell technology. During the COVID-19 pandemic, several neutralizing antibodies that were discovered by characterizing single B cells in patients’ blood have been approved. Bamlanivimab (LY-CoV555) was the first antibody receiving FDA emergency use authorization to treat COVID-19 infection [89]. It only took a few months to complete the early discovery of neutralizing antibodies by the combination of single B cells characterization, NGS, and a machine learning algorithm. Furthermore, NGS, bioinformatics, and artificial intelligence are advancing antibody discovery to find and generate new antibody molecules that have better pharmacological properties. We believe further advancements in the fields of NGS, bioinformatics, and data-driven technology will continue to accelerate antibody discovery. Antibody discovery advancement and the discovery of new antibody targets will also combine to benefit the development of new antibody therapies.

The past decade has witnessed that the immunotherapeutic PD-1/PD-L1 blockade revolutionized the treatment of many types of cancer. The success of anti-PD-1/PD-L1 antibodies catalyzed the development of cancer immunotherapy. So far, the global regulatory authority has approved 12 antibodies targeting PD-1 (Pembrolizumab, Nivolumab, Sintilimab, Cemiplimab, Toripalimab, Tislelizumab, Camrelizumab, Prolgolimab, Penpulimab, Dostarlimab, Zimberelimab, and Serplulimab) and five antibodies targeting PD-L1 (Atezolizumab, Durvalumab, Avelumab, Sugemalimab, and Envafolimab). In addition, a bispecific antibody targeting CTLA-4 and PD-1 (Cadonilimab) and a two-antibody cocktail targeting LAG-3 and PD-1 (Relatlimab + Nivolumab) were approved this year. However, among the immune checkpoint antibodies, only anti-CTLA-4 and anti-LAG-3 antibodies have shown promising efficacy in combination with anti-PD-1/PD-L1 antibodies; it may help overcome the limitations seen in prior treatments. Apart from PD-1/PD-L1 antibodies, the limited efficacy of the immune checkpoint antibodies encouraged the discovery of novel targets for cancer immunotherapy.

Over the past four decades, there has been a significant change in the spectrum of antibody modalities. Traditional modalities of antibody therapies are protein-based molecules including canonical antibodies, ADCs, bispecific antibodies, and antibody fragments. Recently, the Chinese Antibody Society (CAS) introduced a new concept of AntibodyPlus™ for future antibody therapies. The AntibodyPlus™ therapies contain an antibody component and/or other modalities in medicine such as cell and mRNA expressing antibody therapies. There is no doubt that CAR-T cell therapy is getting more attention in such AntibodyPlus™ therapies. The FDA has already approved five CAR-T cell therapies (Abecma [90], Breyanzi [91], Kymriah [92], Tecartus [93], and Yescarta [94]) to treat hematological malignancies. With the novel strategies introduced to enhance the efficacy of CAR-T cell therapies, we will see a breakthrough for the treatment of solid tumors soon. In addition, one more interesting modality of antibody therapies is mRNA-encoded antibodies. The mRNA-encoded antibody circumvents the problems of complex production and purification processes, aberrant post-translational modifications inherent in protein-based antibodies. In addition, a mixture of mRNA sequences can simplify the manufacturing of antibody cocktails [95, 96]. The potential of mRNA-based antibody therapies is one of the most attractive aspects of next-generation antibody therapies.

In spite of these advancements, antibody therapies are still one of the fastest growing therapeutic forms in the world. This is achieved by consistent investment in R&D and the maturation of emerging markets. The global antibody therapy industry and its market will be substantially larger in the future.

FUNDING STATEMENT

None.

CONFLICT OF INTEREST STATEMENT

Xiaochen Lyu, Qichao Zhao and Hongyu Zhang are current employees of Zhanyuan Therapeutics ltd., and Bo Liu is a current employee of Umabs Therapeutics Inc. Hongyu Zhang holds the position of Assistant Editor for Antibody Therapeutics and is blinded from reviewing or making decisions for the manuscript.

ETHICS AND CONSENT STATEMENT

The consent is not required.

ANIMAL ETHICS STATEMENT

Not applicable.

DATA AVAILABILITY STATEMENT

All relevant data are available in Umabs Antibody Therapies Database (Umabs-DB, https://umabs.com).

Supplementary Material

figure1_suppl_tbac021
Click here for additional data file. (1,016.5KB, jpeg)
suppl_table1_tbac021
Click here for additional data file. (9.8KB, xlsx)

Contributor Information

Xiaochen Lyu, Big Data and Bioinformatics, Zhanyuan Therapeutics Ltd, Hangzhou, Zhejiang 310000, China.

Qichao Zhao, Research and Development, Zhanyuan Therapeutics Ltd, Hangzhou, Zhejiang 310000, China.

Julia Hui, Big Data and Discovery, Umabs Therapeutics Inc., Salem, NH 03079, USA.

Tiffany Wang, Department of Applied Mathematics, Harvard College, Cambridge, MA 02138, USA.

Mengyi Lin, Big Data and Bioinformatics, Zhanyuan Therapeutics Ltd, Hangzhou, Zhejiang 310000, China.

Keying Wang, Big Data and Bioinformatics, Zhanyuan Therapeutics Ltd, Hangzhou, Zhejiang 310000, China.

Jialing Zhang, Big Data and Bioinformatics, Zhanyuan Therapeutics Ltd, Hangzhou, Zhejiang 310000, China.

Jiaqian Shentu, Big Data and Bioinformatics, Zhanyuan Therapeutics Ltd, Hangzhou, Zhejiang 310000, China.

Paul A Dalby, Department of Biochemical Engineering, University College London, London WC1E 6BT, UK.

Hongyu Zhang, Big Data and Bioinformatics, Zhanyuan Therapeutics Ltd, Hangzhou, Zhejiang 310000, China; Research and Development, Zhanyuan Therapeutics Ltd, Hangzhou, Zhejiang 310000, China.

Bo Liu, Big Data and Discovery, Umabs Therapeutics Inc., Salem, NH 03079, USA.

References

  • 1. NCI dictionary of Cancer Terms . In: National Cancer Institute. 2 Feb 2011. [cited 1 Jul 2022]. Available: https://www.cancer.gov/publications/dictionaries/cancer-terms/def/antibody-therapy
  • 2. Van Wauwe, JP, De Mey, JR, Goossens, JG. OKT3: a monoclonal anti-human T lymphocyte antibody with potent mitogenic properties. J Immunol 1980; 124: 2708–13. [PubMed] [Google Scholar]
  • 3. Reichert, JM, Valge-Archer, VE. Development trends for monoclonal antibody cancer therapeutics. Nat Rev Drug Discov 2007; 6: 349–56. [DOI] [PubMed] [Google Scholar]
  • 4. Mullard, A. FDA approves 100th monoclonal antibody product. Nat Rev Drug Discov 2021; 20: 491–5. [DOI] [PubMed] [Google Scholar]
  • 5. Edvinsson, L, Haanes, KA, Warfvinge, Ket al. CGRP as the target of new migraine therapies - successful translation from bench to clinic. Nat Rev Neurol 2018; 14: 338–50. [DOI] [PubMed] [Google Scholar]
  • 6. Edvinsson, L. The CGRP pathway in migraine as a viable target for therapies. Headache 2018; 58: 33–47. [DOI] [PubMed] [Google Scholar]
  • 7.Ugalmugale, S, Swain, R. Antibody Therapy Market Size by Type, by End-Use, Industry Analysis Report, Regional Outlook, Growth Potential, COVID-19 Impact Analysis, Price Trends, Competitive Market Share & Forecast, 2022–2028. Global Market Insights Inc.; 2022 Feb. [cited 26 Jun 2022] Available: https://www.gminsights.com/industry-analysis/antibody-therapy-market [Google Scholar]
  • 8. Ecker, DM, Jones, SD, Levine, HL. The therapeutic monoclonal antibody market. MAbs 2015; 7: 9–14. [DOI] [PMC free article] [PubMed] [Google Scholar]
  • 9. UmabsDB - the antibody therapies database. [cited 26 Jun 2022]. Available: https://umabs.com/
  • 10. Kastrati, A, Mehilli, J, Schühlen, Het al. A clinical trial of abciximab in elective percutaneous coronary intervention after pretreatment with clopidogrel. N Engl J Med 2004; 350: 232–8. [DOI] [PubMed] [Google Scholar]
  • 11. Foster, W, Markham, A. Abciximab: an updated review of its use in ischaemic heart disease. Drugs 1998; 56: 629. [DOI] [PubMed] [Google Scholar]
  • 12. Reichert, JM. Marketed therapeutic antibodies compendium. MAbs 2012; 4: 413–5. [DOI] [PMC free article] [PubMed] [Google Scholar]
  • 13. Derkx, B, Wittes, J, Mc Closkey, Ret al. Randomized, placebo-controlled trial of HA-1A, a human monoclonal antibody to endotoxin, in children with meningococcal septic shock. Clin Infect Dis 1999; 28 770–7. 10.1086/515184 [DOI] [PubMed] [Google Scholar]
  • 14. Braun, S, Hepp, F, Kentenich, CRet al. Monoclonal antibody therapy with edrecolomab in breast cancer patients: monitoring of elimination of disseminated cytokeratin-positive tumor cells in bone marrow. Clin Cancer Res 1999; 5: 3999–4004. [PubMed] [Google Scholar]
  • 15. Hu, Y, Turner, MJ, Shields, Jet al. Investigation of the mechanism of action of alemtuzumab in a human CD52 transgenic mouse model. Immunology 2009; 128: 260–70. [DOI] [PMC free article] [PubMed] [Google Scholar]
  • 16. Venkiteshwaran, A. Tocilizumab. MAbs 2009; 1: 432–8. [DOI] [PMC free article] [PubMed] [Google Scholar]
  • 17. Amador-Perez, RB. Immunologic monitoring of renal allografted patients treated with the IOR-T3 (anti-CD3) monoclonal antibody. Effects on CD markers and its Inmunologia. [cited 9 Jul 2022]. Available:https://pascal-francis.inist.fr/vibad/index.php?action=getRecordDetail&idt=4020664
  • 18. Akeso, Inc . Akeso’s Cadonilimab (PD-1/CTLA-4), the First Dual Immune Checkpoint Inhibitor To Treat Cancer, Approved For Marketing in China. In: PR Newswire [Internet]. 29 Jun 2022 [cited 9 Jul 2022]. Available:https://www.prnewswire.com/news-releases/akesos-cadonilimab-pd-1ctla-4-the-first-dual-immune-checkpoint-inhibitor-to-treat-cancer-approved-for-marketing-in-china-301577866.html
  • 19. Kohler, G. Continuous cultures of fused cells secreting antibody of predefined specificity. Nature 1975; 256: 495–7. https://ci.nii.ac.jp/naid/10021259092/ [DOI] [PubMed] [Google Scholar]
  • 20. Jones, PT, Dear, PH, Foote, Jet al. Replacing the complementarity-determining regions in a human antibody with those from a mouse. Nature 1986; 321: 522–5. [DOI] [PubMed] [Google Scholar]
  • 21. McCafferty, J, Griffiths, AD, Winter, Get al. Phage antibodies: filamentous phage displaying antibody variable domains. Nature 1990; 348: 552–4. [DOI] [PubMed] [Google Scholar]
  • 22. Smith, GP. Filamentous fusion phage: novel expression vectors that display cloned antigens on the virion surface. Science 1985; 228: 1315–7. [DOI] [PubMed] [Google Scholar]
  • 23. Xu, Y, Roach, W, Sun, Tet al. Addressing polyspecificity of antibodies selected from an in vitro yeast presentation system: a FACS-based, high-throughput selection and analytical tool. Protein Eng Des Sel 2013; 26: 663–70. [DOI] [PubMed] [Google Scholar]
  • 24. Beerli, RR, Bauer, M, Buser, RBet al. Isolation of human monoclonal antibodies by mammalian cell display. Proc Natl Acad Sci U S A 2008; 105: 14336–41. [DOI] [PMC free article] [PubMed] [Google Scholar]
  • 25. Lonberg, N, Taylor, LD, Harding, FAet al. Antigen-specific human antibodies from mice comprising four distinct genetic modifications. Nature 1994; 368: 856–9. [DOI] [PubMed] [Google Scholar]
  • 26. Mendez, MJ, Green, LL, Corvalan, JRet al. Functional transplant of megabase human immunoglobulin loci recapitulates human antibody response in mice. Nat Genet 1997; 15: 146–56. [DOI] [PubMed] [Google Scholar]
  • 27. Küppers, R, Zhao, M, Hansmann, MLet al. Tracing B cell development in human germinal centres by molecular analysis of single cells picked from histological sections. EMBO J 1993; 12: 4955–67. [DOI] [PMC free article] [PubMed] [Google Scholar]
  • 28. Smith, K, Garman, L, Wrammert, Jet al. Rapid generation of fully human monoclonal antibodies specific to a vaccinating antigen. Nat Protoc 2009; 4: 372–84. [DOI] [PMC free article] [PubMed] [Google Scholar]
  • 29. Li, S, AJ, MC, Gardner, RAet al. Glycoengineering of therapeutic antibodies with small molecule inhibitors. Antibodies (Basel) 2021; 10: 44. 10.3390/antib10040044. [DOI] [PMC free article] [PubMed] [Google Scholar]
  • 30. Mastrangeli, R, Palinsky, W, Bierau, H. Glycoengineered antibodies: towards the next-generation of immunotherapeutics. Glycobiology 2019; 29: 199–210. [DOI] [PubMed] [Google Scholar]
  • 31. Pereira, NA, Chan, KF, Lin, PCet al. The “less-is-more” in therapeutic antibodies: afucosylated anti-cancer antibodies with enhanced antibody-dependent cellular cytotoxicity. MAbs 2018; 10: 693–711. [DOI] [PMC free article] [PubMed] [Google Scholar]
  • 32. Dammen-Brower, K, Epler, P, Zhu, Set al. Strategies for glycoengineering therapeutic proteins. Front Chem 2022; 10: 863118. [DOI] [PMC free article] [PubMed] [Google Scholar]
  • 33. A randomized clinical trial of OKT3 monoclonal antibody for acute rejection of cadaveric renal transplants. N Engl J Med 1985; 313: 337–42. [DOI] [PubMed] [Google Scholar]
  • 34. Kaplon, H, Muralidharan, M, Schneider, Zet al. Antibodies to watch in 2020. MAbs 2020; 12: 1703531. [DOI] [PMC free article] [PubMed] [Google Scholar]
  • 35. Linke, R, Klein, A, Seimetz, D. Catumaxomab: clinical development and future directions. MAbs 2010; 2: 129–36. [DOI] [PMC free article] [PubMed] [Google Scholar]
  • 36. digiONE, Coder . Neovii completes marketing authorisation withdrawal of Removab® in EU. [cited 9 Jul 2022]. Available: https://neovii.com/neovii-completes-marketing-authorisation-withdrawal-of-removab-in-the-european-union/
  • 37. Center for Drug Evaluation, Research . FDA approves moxetumomab pasudotox-tdfk for hairy cell leukemia. In: U.S. Food and Drug Administration. [cited 9 Jul 2022]. Available: https://www.fda.gov/drugs/resources-information-approved-drugs/fda-approves-moxetumomab-pasudotox-tdfk-hairy-cell-leukemia [Google Scholar]
  • 38. Legouffe, E, Liautard, J, Gaillard, JPet al. Human anti-mouse antibody response to the injection of murine monoclonal antibodies against IL-6. Clin Exp Immunol 1994; 98: 323–9. [DOI] [PMC free article] [PubMed] [Google Scholar]
  • 39. van der Horst, HJ, Nijhof, IS, Mutis, Tet al. Fc-engineered antibodies with enhanced fc-effector function for the treatment of B-cell malignancies. Cancer 2020; 12: 3041. 10.3390/cancers12103041. [DOI] [PMC free article] [PubMed] [Google Scholar]
  • 40. Morrison, SL, Johnson, MJ, Herzenberg, LAet al. Chimeric human antibody molecules: mouse antigen-binding domains with human constant region domains. Proc Natl Acad Sci U S A 1984; 81: 6851–5. [DOI] [PMC free article] [PubMed] [Google Scholar]
  • 41. Chen, Z-N, Mi, L, Xu, Jet al. Targeting radioimmunotherapy of hepatocellular carcinoma with iodine (131I) metuximab injection: clinical phase I/II trials. Int J Radiat Oncol Biol Phys 2006; 65: 435–44. [DOI] [PubMed] [Google Scholar]
  • 42. Caimi, PF, Ai, W, Alderuccio, JPet al. Loncastuximab tesirine in relapsed or refractory diffuse large B-cell lymphoma (LOTIS-2): a multicentre, open-label, single-arm, phase 2 trial. Lancet Oncol 2021; 22: 790–800. [DOI] [PubMed] [Google Scholar]
  • 43. Safdari, Y, Farajnia, S, Asgharzadeh, Met al. Antibody humanization methods – a review and update. Biotechnol Genet Eng Rev 2013; 175–86. 10.1080/02648725.2013.801235. [DOI] [PubMed] [Google Scholar]
  • 44. Kuramochi, T, Igawa, T, Tsunoda, Het al. Humanization and simultaneous optimization of monoclonal antibody. Methods Mol Biol 2019; 1060: 213–30. 10.1007/978-1-4939-8958-4_9. [DOI] [PubMed] [Google Scholar]
  • 45. Fisher . Genetically Engineered Drug Approved for Kidney Transplants. NY Times. [cited 9 Jul 2022]. Available: https://repository.library.georgetown.edu/handle/10822/532092 [Google Scholar]
  • 46. Bell, J, Colaneri, J. Zenapax: transplant’s first humanized monoclonal antibody. ANNA J 1998; 25: 429–30. [PubMed] [Google Scholar]
  • 47.Lopez, C, Roizman, B. The Herpesviruses: Immunobiology and Prophylaxis of Human Herpesvirus Infections. Berlin, German. Springer Science & Business Media; 2012. Editors: Carlos Lopez, Ryoichi Mori, Bernard Roizman, Richard J. Whitley. [Google Scholar]
  • 48. Traggiai, E, Becker, S, Subbarao, Ket al. An efficient method to make human monoclonal antibodies from memory B cells: potent neutralization of SARS coronavirus. Nat Med 2004; 10: 871–5. [DOI] [PMC free article] [PubMed] [Google Scholar]
  • 49. Bonsignori, M, Hwang, K-K, Chen, Xet al. Analysis of a clonal lineage of HIV-1 envelope V2/V3 conformational epitope-specific broadly neutralizing antibodies and their inferred unmutated common ancestors. J Virol 2011; 85: 9998–10009. [DOI] [PMC free article] [PubMed] [Google Scholar]
  • 50. Frenzel, A, Schirrmann, T, Hust, M. Phage display-derived human antibodies in clinical development and therapy. MAbs 2016; 8: 1177–94. [DOI] [PMC free article] [PubMed] [Google Scholar]
  • 51. Woda, M, Friberg, H, Currier, JRet al. Dynamics of dengue virus (DENV)-specific B cells in the response to DENV serotype 1 infections, using flow cytometry with labeled virions. J Infect Dis 2016; 214: 1001–9. [DOI] [PMC free article] [PubMed] [Google Scholar]
  • 52. Cox, KS, Tang, A, Chen, Zet al. Rapid isolation of dengue-neutralizingantibodies from single cell-sorted human antigen-specific memory B-cellcultures. MAbs 2016; 8:129–40. 10.1080/19420862.2015.1109757. [DOI] [PMC free article] [PubMed] [Google Scholar]
  • 53. Markham, A. REGN-EB3: first approval. Drugs 2021; 81: 175–8. [DOI] [PMC free article] [PubMed] [Google Scholar]
  • 54. Benotmane, I, Velay, A, Thaunant, Oet al. Pre-exposure prophylaxis with Evusheld™ elicits limited neutralizing activity against the omicron variant in kidney transplant patients. bioRxiv. 2022. 10.1101/2022.03.21.22272669. [DOI] [PMC free article] [PubMed]
  • 55. Goldstein, LD, Chen, Y-JJ, Wu, Jet al. Massively parallel single-cell B-cell receptor sequencing enables rapid discovery of diverse antigen-reactive antibodies. Commun Biol 2019; 2: 304. [DOI] [PMC free article] [PubMed] [Google Scholar]
  • 56. Mathew, NR, Jayanthan, JK, Smirnov, IVet al. Single-cell BCR and transcriptome analysis after influenza infection reveals spatiotemporal dynamics of antigen-specific B cells. Cell Rep 2021; 35: 109286. [DOI] [PMC free article] [PubMed] [Google Scholar]
  • 57. Cao, Y, Su, B, Guo, Xet al. Potent neutralizing antibodies against SARS-CoV-2 identified by high-throughput single-cell sequencing of convalescent patients’ B cells. Cell 2020; 182: 73–84.e16. 10.1016/j.cell.2020.05.025. [DOI] [PMC free article] [PubMed] [Google Scholar]
  • 58. Dugel, PU, Koh, A, Ogura, Yet al. HAWK and HARRIER: phase 3, multicenter, randomized, double-masked trials of Brolucizumab for Neovascular age-related macular degeneration. Ophthalmology 2020; 127: 72–84. [DOI] [PubMed] [Google Scholar]
  • 59. Esposito, E, Cuzzocrea, S. TNF-alpha as a therapeutic target in inflammatory diseases, ischemia-reperfusion injury and trauma. Curr Med Chem 2009; 16: 3152–67. [DOI] [PubMed] [Google Scholar]
  • 60. Goel, N, Stephens, S. Certolizumab pegol. MAbs 2010; 2: 137–47. [DOI] [PMC free article] [PubMed] [Google Scholar]
  • 61. Brolucizumab . In: Drugs.com. [cited 18 Jul 2022]. Available: https://www.drugs.com/monograph/brolucizumab.html
  • 62. Huston, JS, Levinson, D, Mudgett-Hunter, Met al. Protein engineering of antibody binding sites: recovery of specific activity in an anti-digoxin single-chain Fv analogue produced in Escherichia coli. Proc Natl Acad Sci U S A 1988; 85: 5879–83. [DOI] [PMC free article] [PubMed] [Google Scholar]
  • 63. Ahmad, ZA, Yeap, SK, Ali, AMet al. scFv antibody: principles and clinical application. Clin Dev Immunol 2012; 2012: 980250. [DOI] [PMC free article] [PubMed] [Google Scholar]
  • 64. Efgartigimod alfa (Vyvgart) for myasthenia gravis. Med Lett Drugs Ther 2022; 64: 62–3. [PubMed] [Google Scholar]
  • 65. Strohl, WR, Strohl, LM (eds). 8 - Monoclonal antibody targets and mechanisms of action. In: William R. Strohl and Lila M. Strohl. (eds), Therapeutic Antibody Engineering. Sawston, Cambridge. Woodhead Publishing, 2012, 163–595. [Google Scholar]
  • 66. Beers, SA, Chan, CHT, French, RRet al. CD20 as a target for therapeutic type I and II monoclonal antibodies. Semin Hematol 2010; 47: 107–14. [DOI] [PubMed] [Google Scholar]
  • 67. Paez, D, Paré, L, Espinosa, Iet al. Immunoglobulin G fragment C receptor polymorphisms and KRAS mutations: are they useful biomarkers of clinical outcome in advanced colorectal cancer treated with anti-EGFR-based therapy? Cancer Sci 2010; 101: 2048–53. [DOI] [PMC free article] [PubMed] [Google Scholar]
  • 68. Kuhn, C, Weiner, HL. Therapeutic anti-CD3 monoclonal antibodies: from bench to bedside. Immunotherapy 2016; 8: 889–906. [DOI] [PubMed] [Google Scholar]
  • 69. Ferrara, N, Mass, RD, Campa, Cet al. Targeting VEGF-A to treat cancer and age-related macular degeneration. Annu Rev Med 2007; 58: 491–504. [DOI] [PubMed] [Google Scholar]
  • 70.Zwick E, Wallasch C, Ullrich A. HER2/neu: a target forbreast cancer therapy. Breast Disease 2000; 11: 7–18. [DOI] [PubMed] [Google Scholar]
  • 71. Alduaij, W, Illidge, TM. The future of anti-CD20 monoclonal antibodies: are we making progress? Blood 2011; 117: 2993–3001. [DOI] [PubMed] [Google Scholar]
  • 72. Alduaij, W, Ivanov, A, Honeychurch, Jet al. Novel type II anti-CD20 monoclonal antibody (GA101) evokes homotypic adhesion and actin-dependent, lysosome-mediated cell death in B-cell malignancies. Blood 2011; 117: 4519–29. [DOI] [PMC free article] [PubMed] [Google Scholar]
  • 73. Patel, D, Guo, X, Ng, Set al. IgG isotype, glycosylation, and EGFR expression determine the induction of antibody-dependent cellular cytotoxicity in vitro by cetuximab. Hum Antibodies 2010; 19: 89–99. [DOI] [PubMed] [Google Scholar]
  • 74. Adams, AB, Ford, M, Larsen, CP. Transplantation immunobiology and immunosuppression. Sabiston Textbook of Surgery: The Biological Basis of Modern Surgical Practice 20th edPhiladelphia, PA: Elsevier. 2017. Editor: Robertson-Poth. [Google Scholar]
  • 75. Zalevsky, J, Leung, IWL, Karki, Set al. The impact of fc engineering on an anti-CD19 antibody: increased Fcγ receptor affinity enhances B-cell clearing in nonhuman primates. Blood 2009; 113: 3735–43. [DOI] [PubMed] [Google Scholar]
  • 76. Sullivan-Chang, L, O’Donnell, RT, Tuscano, JM. Targeting CD22 in B-cell malignancies: current status and clinical outlook. BioDrugs 2013; 27: 293–304. [DOI] [PubMed] [Google Scholar]
  • 77. Fleurence, J, Fougeray, S, Bahri, Met al. Targeting O-acetyl-GD2 ganglioside for cancer immunotherapy. J Immunol Res 2017; 2017: 1–16. [DOI] [PMC free article] [PubMed] [Google Scholar]
  • 78. Yousefi, H, Momeny, M, Ghaffari, SHet al. IL-6/IL-6R pathway is a therapeutic target in chemoresistant ovarian cancer. Tumori 2019; 105: 84–91. [DOI] [PubMed] [Google Scholar]
  • 79. Tang, C, Chen, S, Qian, Het al. Interleukin-23: as a drug target for autoimmune inflammatory diseases. Immunology 2012; 135: 112–24. [DOI] [PMC free article] [PubMed] [Google Scholar]
  • 80. Kellner, H. Targeting interleukin-17 in patients with active rheumatoid arthritis: rationale and clinical potential. Ther Adv Musculoskelet Dis 2013; 5: 141–52. [DOI] [PMC free article] [PubMed] [Google Scholar]
  • 81. Klein, AL, Imazio, M, Cremer, Pet al. Phase 3 trial of Interleukin-1 trap Rilonacept in recurrent pericarditis. N Engl J Med 2021; 384: 31–41. [DOI] [PubMed] [Google Scholar]
  • 82. Huang, Y, Yang, C, Xu, X-Fet al. Structural and functional properties of SARS-CoV-2 spike protein: potential antivirus drug development for COVID-19. Acta Pharmacol Sin 2020; 41: 1141–9. [DOI] [PMC free article] [PubMed] [Google Scholar]
  • 83. Kramer, RA, Marissen, WE, Goudsmit, Jet al. The human antibody repertoire specific for rabies virus glycoprotein as selected from immune libraries. Eur J Immunol 2005; 35: 2131–45. [DOI] [PubMed] [Google Scholar]
  • 84. Hawksworth, OA, Li, XX, Coulthard, LGet al. New concepts on the therapeutic control of complement anaphylatoxin receptors. Mol Immunol 2017; 89: 36–43. [DOI] [PubMed] [Google Scholar]
  • 85. Orlova, NA, Kovnir, SV, Vorobiev, IIet al. Coagulation factor IX for hemophilia B therapy. Acta Naturae 2012; 4: 62–73. [PMC free article] [PubMed] [Google Scholar]
  • 86. Tumeh, PC, Harview, CL, Yearley, JHet al. PD-1 blockade induces responses by inhibiting adaptive immune resistance. Nature 2014; 515: 568–71. [DOI] [PMC free article] [PubMed] [Google Scholar]
  • 87. Maloney, DG, Grillo-López, AJ, White, CAet al. IDEC-C2B8 (rituximab) anti-CD20 monoclonal antibody therapy in patients with relapsed low-grade non-Hodgkin’s lymphoma. Blood 1997; 90: 2188–95. [PubMed] [Google Scholar]
  • 88. Maloney, DG, Grillo-López, AJ, Bodkin, DJet al. IDEC-C2B8: results of a phase I multiple-dose trial in patients with relapsed non-Hodgkin’s lymphoma. J Clin Oncol 1997; 15: 3266–74. [DOI] [PubMed] [Google Scholar]
  • 89. Gottlieb, RL, Nirula, A, Chen, Pet al. Effect of Bamlanivimab as monotherapy or in combination with Etesevimab on viral load in patients with mild to moderate COVID-19: a randomized clinical trial. JAMA 2021; 325: 632–44. [DOI] [PMC free article] [PubMed] [Google Scholar]
  • 90. Wire, B. US Food and Drug Administration approves Bristol Myers Squibb’s and Bluebird Bio's Abecma (idecabtagene vicleucel), the first anti-Bcma car T cell therapy for …. Abecma is a first-in-class BCMA-directed personalized. 2021. [cited 18 Jul 2022]. Available:https://www.myelomacanada.ca/pixms/uploads/serve/ckeditor/032621_abecma_fda_approval_release.pdf
  • 91.Center for Biologics Evaluation, Research. BREYANZI (lisocabtagene maraleucel). In: U.S. Food and Drug Administration [Internet]. FDA; [cited 16 Sep 2022]. Available:https://www.fda.gov/vaccines-blood-biologics/cellular-gene-therapy-products/breyanzi-lisocabtagene-maraleucel [Google Scholar]
  • 92. Philippidis, A. Kymriah, First CAR-T Cancer Immunotherapy Approved by FDA. 2017. [cited 18 Jul 2022]. Available: 10.1089/clinomi.04.05.09 [DOI]
  • 93.Center for Biologics Evaluation, Research. TECARTUS (brexucabtagene autoleucel). In: U.S. Food and Drug Administration [Internet]. FDA; [cited 16 Sep 2022]. Available: https://www.fda.gov/vaccines-blood-biologics/cellular-gene-therapy-products/tecartus-brexucabtagene-autoleucel
  • 94. Fala, L. Yescarta (axicabtagene ciloleucel) second CAR T-cell therapy approved for patients with certain types of large B-cell lymphoma. 2018 [cited 14 Jul 2022]. Available:https://jons-online.com/browse-by-topic/fda-approvals-news-updates/1829-yescarta-axicabtagene-ciloleucel-second-car-t-cell-therapy-approved-for-patients-with-certain-types-of-large-b-cell-lymphoma
  • 95. Deal, CE, Carfi, A, Plante, OJ. Advancements in mRNA encoded antibodies for passive immunotherapy. Vaccine 2021; 9: 108. 10.3390/vaccines9020108. [DOI] [PMC free article] [PubMed] [Google Scholar]
  • 96. Van Hoecke, L, Roose, K. How mRNA therapeutics are entering the monoclonal antibody field. J Transl Med 2019; 17: 54. [DOI] [PMC free article] [PubMed] [Google Scholar]

Associated Data

This section collects any data citations, data availability statements, or supplementary materials included in this article.

Supplementary Materials

figure1_suppl_tbac021
Click here for additional data file. (1,016.5KB, jpeg)
suppl_table1_tbac021
Click here for additional data file. (9.8KB, xlsx)

Data Availability Statement

All relevant data are available in Umabs Antibody Therapies Database (Umabs-DB, https://umabs.com).

Articles from Antibody Therapeutics are provided here courtesy of Oxford University Press

RESOURCES