Current status and prospects of IL-6–targeting therapy

Figures & data

Figure 1. IL-6, its receptor system, and inhibitors at each stage of receptor complex formation. IL-6 has a four-bundle (from A to D) structure, interacting with the IL-6 receptor (IL-6 R) at site I and with gp130 at site II and site III. First, IL-6 binds to IL-6 R, the IL-6/IL-6 R complex binds to gp130, and finally a hexamer structure is formed. IL-6 signaling via membrane IL-6 R or soluble IL-6 R is called classic signaling or trans-signaling, respectively. Red arrows indicate signal transduction. Antibodies that inhibit the binding of IL-6 to IL-6 R, sgp130-Fc that inhibits the binding of IL-6/sIL-6 R complex to gp130, and antibodies that inhibit hexamer formation are surrounded by black squares. The antibodies listed in bold letters are approved for a variety of diseases.

Table 1. Comparison of congenital loss of IL-6 receptor with IL-6 receptor inhibition therapy.

	Congenital loss of IL-6 R(from two cases)	IL-6 R inhibition therapy(from clinical trial data)
acute phase response	no response	almost no response
infectious diseases	recurrent skin and lung infections	4.7–9.1/100 patient-years
allergic diseases	asthma, atopic dermatitis	uncommon
neutrophil	reduced	mildly reduced – normal
eosinophil	high	normal
lymphocytes	normal count in CD3, CD4, CD8, and CD19 cells, but increase in Th2 and Treg cells and decrease in memory B cells.	no change in CD4, CD8, or CD19 cells, but increase in Treg, NK, and naïve B cells and decrease in memory B cells.
IgG, IgA, IgM	mildly reduced	mildly reduced – normal
IgE	remarkably high	reduced
IL-6 level	high	high
reference	[88]	[46,81,84,85,94]

Table 2. Indications for IL-6–targeting therapy, approved diseases, phases of clinical trials, and case reports. Case reports excluded approved diseases and diseases for which randomized trials or case series showed the efficacy of IL-6–targeting therapy. TCZ: tocilizumab (anti–IL-6 R mAb); SAR: sarilumab (anti–IL-6 R mAb); STZ: satralizumab (anti–IL-6 R mAb); STX: siltuximab (anti–IL-6 mAb); SRK: sirukumab (anti–IL-6 mAb); CLZ: clazakizumab (anti–IL-6 mAb); OKZ: olokizumab; (anti–IL-6 mAb); OLA: olamkicept (soluble gp130-Fc fusion protein. TJ301); NMDAR; N-methyl-d-aspartate receptor; GVHD: graft-versus-host disease.

Diseases approved for the use of IL-6–inhibitory biologics (biologics: approved country and year)
Castleman disease	TCZ: Japan in 2005; STX: USA and EU in 2014.
rheumatoid arthritis	TCZ: Japan in 2008, EU in 2009, and USA in 2010; SAR: Japan, EU, and USA in 2017.
juvenile idiopathic arthritis	TCZ: Japan in 2008, EU and USA in 2011.
giant cell arteritis	TCZ: USA, Japan, and EU in 2017.
Takayasu arteritis	TCZ: Japan in 2017.
cytokine release syndrome in CAR-T cell therapy	TCZ: USA in 2017, EU in 2018, Japan in 2019.
adult-onset Still’s disease	TCZ: Japan in 2019.
neuromyelitis optica spectrum disorder	STZ: Japan and USA in 2020, EU in 2021.
systemic sclerosis-induced interstitial lung disease	TCZ: USA in 2021.
COVID-19	TCZ: USA and EU in 2021, Japan in 2022.
Diseases for which IL-6–inhibitory biologics have shown efficacy in phase 2 or phase 3 trials
Graves’ ophthalmopathy	TCZ: phase 3 [119]
myocardial infarction	TCZ: phase 2 [134]
polymyalgia rheumatica	TCZ: phase 2/3 [137]
graft inflammation with renal transplantation	TCZ: phase 2 [138]
depression	OKZ: phase 3, SRK, STX: phase 2 [56,142]
Case series showing the efficacy of IL-6–inhibitory biologics
Rheumatic diseases	amyloid A amyloidosis [143]
	Behçet’s disease [144]
	relapsing polychondritis [145]
Neuropsychiatric disorder	pediatric NMDAR antibody encephalitis [123]
	MOG antibody disease [148]
Transplantation	pre-engraftment syndrome after unrelated cord blood transplantation [147]
Immune-related adverse event (irAE)	steroid refractory immune-mediated adverse events secondary to immune checkpoint inhibitors [146]
Diseases for which phase 2 or phase 3 trials of IL-6–inhibitory biologics are ongoing (by ClinicalTrials.gov)
Rheumatic diseases	granulomatosis with polyangiitis (TCZ: phase 2)
	idiopathic retroperitoneal fibrosis (TCZ: phase 4)
Hematological disorder	hemophagocytic lymphohistiocytosis (TCZ: phase 2)
	indolent systemic mastocytosis (SAR: phase 2)
Respiratory disease	rapid progressive interstitial lung diseases (TCZ: phase 2)
	asthma (CLZ: phase 2)
Neuropsychiatric disorder	myasthenia gravis, generalized (TCZ: phase 2)
	major depressive disorder (TCZ: phase 2)
Transplantation	Ab-mediated rejection in kidney transplant (TCZ: phase 3, CLZ: phase 3)
	heart transplant (TCZ: phase 2)
	kidney transplantation graft failure (TCZ: phase 2)
	hematologic malignancy bone marrow transplant (TCZ: phase 2)
	leukemia graft-versus-host-disease (TCZ: phase 2)
Cancer	lung cancer, non-small cell (TCZ: phase 1b-2)
	melanoma (TCZ: phase 2)
	prostate cancer (TCZ: phase 2)
	breast metastatic triple negative cancer (SAR: phase 2)
	immune-related adverse events (TCZ: phase 2)
	irAE ipilimumab, and nivolumab (TCZ: phase 2)
	pyrexia due to cancer therapy (TCZ: phase 2)
	squamous cell carcinoma of the head and neck with atezolizumab (TCZ: phase 2)
	adamantinomatous craniopharyngioma (TCZ: phase 2)
	stromal activation in esophageal adenocarcinoma (TCZ: phase 2)
	diffuse astrocytoma IDH-wild type recurrent glioblastoma (TCZ: phase 2)
Diseases in which case reports show the effectiveness of tocilizumab
Rheumatic disease; Musculoskeletal inflammation		polymyositis	dermatomyositis
		anti-synthetase syndrome	febrile myalgia syndrome
		sciatica with lumbar spinal stenosis.
Rheumatic disease; Arthritis		reactive arthritis	SAPHO syndrome
		Felty’s syndrome	RS3PE syndrome
		gout	calcium pyrophosphate deposition disease
Rheumatic disease; Vasculitis		rheumatoid vasculitis	isolated aortitis
		polyarteritis nodosa	cutaneous polyarteritis nodosa
		microscopic polyangiitis	cryoglobulinemia vasculitis
		central nervous system vasculitis	Cogan’s syndrome
Systemic inflammatory disease		Cryopyrin-associated periodic syndrome	familial Mediterranean fever
		mevalonate kinase deficiency	Blau syndrome
		Schnitzler syndrome	TAFRO syndrome
		Sweet syndrome	HHV-8 positive multicentric Castleman disease
		VEXAS syndrome	heterozygous mutations in the MEFV and NOD2 genes
Hematologic disease		autoimmune hemolytic anemia	hemophagocytic syndrome
		macrophage activation syndrome	acquired hemophilia A
		posttransfusion hyperhemolysis	pancytopenia with a STAT3 gain-of -function mutation
		post-operative myelomonocytic leukemoid reaction
Skin disease		alopecia areata	lupus erythematosus profundus
		pyoderma gangrenosum	mucous membrane pemphigoid
		NXP2-positive skin edema	adult H syndrome
		Mucha-Habermann disease	Parry Romberg disease
Pulmonary disease		anti-MDA5-positive dermatomyositis interstitial lung disease	organizing pneumonia with Sjögren’s syndrome
		sarcoidosis	pleuritis with SLE
Eye disease		noninfectious uveitis	uveitic macular edema
		scleritis	orbital myositis
Neurological disease		autoimmune encephalitis	myasthenia gravis
		myelopathy with Sjögren’s syndrome	febrile infection-related epilepsy syndrome
		anti-Caspr2 syndrome	status epilepticus,
		CLIPPERS syndrome
Allergic and eosinophilic disease		atopic dermatitis	asthma
		eosinophilic fasciitis
transplantation		Ab-mediated rejection in kidney transplant	pulmonary GVHD
		GVHD after stem cell transplantation
Cancer		Cancer-related cachexia	paraneoplastic inflammatory syndrome
		triple-negative breast cancer
Immune-related adverse event (irAE)		Myocarditis	cardiotoxicity
		hemophagocytic lymphohistiocytosis	esophageal stenosis
		cytokine release syndrome

Figure 2. Diseases for which IL-6–targeting therapy has been approved, efficacy has been confirmed in randomized clinical trials, or efficacy has been reported in the case series can be divided into four categories: chronic inflammatory disease, acute inflammatory disease, autoantibody-induced disease, and interstitial lung disease.

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