The global landscape of approved antibody therapies.

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.

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

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

*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

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

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

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).

Click here for additional data file.

Click here for additional data file.