Immunogenicity of Biotherapeutics: Causes and Association with Posttranslational Modifications

Table 1

Immunogenicity of FDA-approved biologics.

SI number	Biologic	Type/target	Indications	Immunogenicity (% patients)		Reference
				Binding antibodies	Neutralizing antibodies
()	Adalimumab	Human IgG1 antibody specific for TNF alpha	Rheumatoid arthritis, psoriasis	5%–89%	5%–89%	[24–27]
()	Alemtuzumab	Humanized monoclonal antibody which binds to CD52 on leukocytes	B cell chronic lymphocytic leukaemia	30%–70%	30%–70%	[28]
()	Belimumab	Human monoclonal antibody that inhibits the biologic activity of the soluble form of the essential B cell survival factor B-lymphocyte stimulator	Systemic lupus erythematosus	4.8%	3/11	[29]; European Medicines Agency Assessment Report (http://www.ema.europa.eu/docs/en_GB/document_library/EPAR_-_Public_assessment_report/human/002015/WC500110152.pdf)
()	Canakinumab	Human monoclonal antibody anti-IL-1β	Inflammatory diseases related to cryopyrin-associated periodic syndromes (familial cold autoinflammatory syndrome and Muckle-Wells syndrome)	0%	0%	[24, 30]
()	Cetuximab	Human/mouse chimeric monoclonal antibody that binds specifically to the extracellular domain of the human epidermal growth factor receptor	Colorectal cancer, squamous cell carcinoma of the head and neck	5%	Data not available	Drug label (http://pi.lilly.com/us/erbitux-uspi.pdf)
()	Denosumab	Human monoclonal antibody; RANK ligand inhibitor	Treatment of postmenopausal women with osteoporosis at high risk for fracture; To increase bone mass in men at high risk for fracture receiving androgen deprivation therapy for nonmetastatic prostate cancer; To increase bone mass in women at high risk for fracture receiving adjuvant aromatase inhibitor therapy for breast cancer	<1%	0%	Drug label (http://www.accessdata.fda.gov/drugsatfda_docs/label/2011/125320s5s6lbl.pdf)
()	Golimumab	Human monoclonal antibody anti-TNF-alpha	Rheumatoid arthritis, psoriatic arthritis, and ankylosing spondylitis	4%	Data not available	[31–33]
()	Infliximab	Chimeric monoclonal antibody TNF blocker	Crohn’s disease, ulcerative colitis, rheumatoid arthritis, ankylosing spondylitis, and psoriasis	Crohn’s Disease: 10%, psoriatic arthritis: 15% psoriasis: 36–51%	Data not available	Drug label (http://www.accessdata.fda.gov/drugsatfda_docs/label/2013/103772s5359lbl.pdf)
()	Ipilimumab	Human monoclonal antibody that binds to cytotoxic T-lymphocyte-associated antigen 4 (CTLA-4)	Melanoma	1.1% of 1024 evaluable patients tested positive for binding antibodies and 6.9% of 58 evaluable patients, who were treated with 0.3 mg/kg (dose cohort with the lowest trough levels) dose, tested positive for binding antibodies.	0%	Drug label (http://www.accessdata.fda.gov/drugsatfda_docs/label/2013/103772s5359lbl.pdf)
()	Natalizumab	Human monoclonal antibody, which works against the cell adhesion molecule α4-integrin	Multiple sclerosis and Crohn’s disease	9%	9%	Drug label (http://www.accessdata.fda.gov/drugsatfda_docs/label/2008/125104s033lbl.pdf)
()	Nivolumab	Human monoclonal antibody IgG4 PD-1 immune checkpoint inhibitor	Squamous non-small cell lung cancer, unresectable or metastatic melanoma, and disease progression following ipilimumab and, if BRAF V600 mutation positive, a BRAF inhibitor	8.5%	0.7%	[34] Drug label (http://www.accessdata.fda.gov/drugsatfda_docs/label/2014/125554lbl.pdf)
()	Ofatumumab	Human monoclonal antibody anti-CD20	Rheumatoid arthritis, chronic lymphocytic leukaemia	0%	0%	[24, 35]
()	Panitumumab	Human monoclonal antibody against the epidermal growth factor receptor	Colorectal carcinoma	1–4.6%	0.8–1.6%	[24, 36–38] Drug label (http://www.accessdata.fda.gov/drugsatfda_docs/label/2009/125147s080lbl.pdf)
()	Pembrolizumab	Human monoclonal antibody PD-1 blocking	Unresectable or metastatic melanoma and disease progression following ipilimumab and, if BRAF V600 mutation positive, a BRAF inhibitor, metastatic NSCLC whose tumors express PD-L1	0.3%	0.3%	[39] Drug label (http://www.accessdata.fda.gov/drugsatfda_docs/label/2015/125514s004s006lbl.pdf)
()	Ramucirumab	Human monoclonal antibody vascular endothelial growth factor receptor 2 antagonist	Gastric cancer	6%	1%	Drug label (http://www.accessdata.fda.gov/drugsatfda_docs/label/2014/125477s002lbl.pdf)
()	Rituximab	Chimeric monoclonal antibody that targets the CD20 molecule expressed on the surface of B cells	Non-Hodgkin’s lymphoma, rheumatoid arthritis	11%	Data not available	[40]
()	Secukinumab	Human monoclonal antibody against IL-17A	Plaque psoriasis	0.4%	3/10	[41] Drug information (http://www.fda.gov/downloads/AdvisoryCommittees/CommitteesMeetingMaterials/Drugs/DermatologicandOphthalmicDrugsAdvisoryCommittee/UCM419023.pdf)
()	Siltuximab	Chimeric monoclonal antibody anti-IL-6	Multicentric Castleman’s disease (a rare lymphoproliferative disorder) being human immunodeficiency virus-negative and human herpes virus-8-negative	0.2%	0%	Drug label (http://www.accessdata.fda.gov/drugsatfda_docs/label/2014/125496s000lbl.pdf)
()	Ustekinumab	Human monoclonal antibody that binds to the p40 protein subunit used by both the IL-12 and IL-23 cytokines.	Psoriasis	6.6%	Data not available	[42]
()	Vedolizumab	Humanised IgG1 monoclonal antibody that binds to the human α4β7 integrin	Ulcerative colitis and Crohn’s disease	4%	33/56	Drug label (http://www.accessdata.fda.gov/drugsatfda_docs/label/2014/125476s000lbl.pdf)

IgG: immunoglobulin G; IL: interleukin; TNF: tumour necrosis factor; CD: cluster of differentiation; RANK: receptor activator of nuclear factor kappa-B; PD-1: programmed cell death protein-1; PDL-1: programmed death ligand-1; NSCLC: non-small cell lung cancer.