Details of the Drug Therapeutic Target (DTT)

General Information of Drug Therapeutic Target (DTT) (ID: TTT1V78)

• DTT Name: Interleukin-6 (IL6)
• Synonyms: Interferon beta-2; IL-6; IFNB2; IFN-beta-2; Hybridoma growth factor; CTL differentiation factor; CDF; BSF-2; B-cell stimulatory factor 2
• Gene Name: IL6
• DTT Type: Successful target; [1]
• BioChemical Class: Cytokine: interleukin
• UniProt ID: IL6_HUMAN
• TTD ID: T32578
• Sequence:
  MNSFSTSAFGPVAFSLGLLLVLPAAFPAPVPPGEDSKDVAAPHRQPLTSSERIDKQIRYI
  LDGISALRKETCNKSNMCESSKEALAENNLNLPKMAEKDGCFQSGFNEETCLVKIITGLL
  EFEVYLEYLQNRFESSEEQARAVQMSTKVLIQFLQKKAKNLDAITTPDPTTNASLLTKLQ
  AQNQWLQDMTTHLILRSFKEFLQSSLRALRQM
• Function: It is a potent inducer of the acute phase response. Plays an essential role in the final differentiation of B-cells into Ig-secreting cells Involved in lymphocyte and monocyte differentiation. Acts on B-cells, T-cells, hepatocytes, hematopoietic progenitor cells and cells of the CNS. Required for the generation of T(H)17 cells. Also acts as a myokine. It is discharged into the bloodstream after muscle contraction and acts to increase the breakdown of fats and to improve insulin resistance. It induces myeloma and plasmacytoma growth and induces nerve cells differentiation. Cytokine with a wide variety of biological functions.
• KEGG Pathway:
  Cytokine-cytokine receptor interaction (hsa04060)
  HIF-1 signaling pathway (hsa04066)
  FoxO signaling pathway (hsa04068)
  PI3K-Akt signaling pathway (hsa04151)
  Toll-like receptor signaling pathway (hsa04620)
  NOD-like receptor signaling pathway (hsa04621)
  Cytosolic DNA-sensing pathway (hsa04623)
  Jak-STAT signaling pathway (hsa04630)
  Hematopoietic cell lineage (hsa04640)
  TNF signaling pathway (hsa04668)
  Intestinal immune network for IgA production (hsa04672)
  Non-alcoholic fatty liver disease (NAFLD) (hsa04932)
  Prion diseases (hsa05020)
  Salmonella infection (hsa05132)
  Pertussis (hsa05133)
  Legionellosis (hsa05134)
  Chagas disease (American trypanosomiasis) (hsa05142)
  African trypanosomiasis (hsa05143)
  Malaria (hsa05144)
  Amoebiasis (hsa05146)
  Tuberculosis (hsa05152)
  Hepatitis B (hsa05161)
  Measles (hsa05162)
  Influenza A (hsa05164)
  HTLV-I infection (hsa05166)
  Herpes simplex infection (hsa05168)
  Pathways in cancer (hsa05200)
  Transcriptional misregulation in cancer (hsa05202)
  Inflammatory bowel disease (IBD) (hsa05321)
  Rheumatoid arthritis (hsa05323)
  Graft-versus-host disease (hsa05332)
  Hypertrophic cardiomyopathy (HCM) (hsa05410)
• Reactome Pathway:
  MAPK3 (ERK1) activation (R-HSA-110056)
  MAPK1 (ERK2) activation (R-HSA-112411)
  Senescence-Associated Secretory Phenotype (SASP) (R-HSA-2559582)
  Interleukin-6 signaling (R-HSA-1059683)

Molecular Interaction Atlas (MIA) of This DTT

1 Approved Drug(s) Targeting This DTT

Drug Name	Drug ID	Indication	ICD 11	Highest Status	REF
Siltuximab	DMGEATB	Anemia	3A00-3A9Z	Approved	[1]

13 Clinical Trial Drug(s) Targeting This DTT

Drug Name	Drug ID	Indication	ICD 11	Highest Status	REF
Olokizumab	DM4Z9QI	Rheumatoid arthritis	FA20	Phase 3	[2]
RG6179	DMO1VP9	uveitic macular edema	9B78	Phase 3	[3]
Sirukumab	DMK8AQP	Cutaneous lupus erythematosus	EB5Z	Phase 3	[4]
Ziltivekimab	DME841B	Heart failure	BD10-BD13	Phase 3	[5]
ALD-518	DMPWSBL	Psoriatic arthritis	FA21	Phase 2	[6]
CDP-6038	DM3YB2C	Rheumatoid arthritis	FA20	Phase 2	[6]
PF-04236921	DM826SW	Crohn disease	DD70	Phase 2	[4]
YSIL6	DM0K8U7	Crohn disease	DD70	Phase 2	[7]
C326	DMR0S8U	Crohn disease	DD70	Phase 1	[8]
Gerilimzumab	DMA9UX2	Rheumatoid arthritis	FA20	Phase 1	[4]
MEDI5117	DM3IJQ5	Rheumatoid arthritis	FA20	Phase 1	[9]
OP-R003	DMH6SNO	Haematological malignancy	2B33.Y	Phase 1	[10]
SAR444419	DMQICTG	Inflammation	1A00-CA43.1	Phase 1	[11]

1 Drugs in Phase 2 Trial Targeting This DTT

Drug Name	Drug ID	Indication	ICD 11	Highest Status	REF
Clazakizumab	DM6ZOUV	Coronavirus Disease 2019 (COVID-19)	1D6Y	Phase 2 Trial	[4]

Molecular Expression Atlas (MEA) of This DTT

Disease Name	ICD 11	Studied Tissue	p-value	Fold-Change	Z-score
Rheumatoid arthritis	FA20	Synovial tissue	1.49E-03	2.13	1.87
Shwachman-Diamond syndrome	3B64	Bone marrow	8.08E-01	-0.77	-1.15

References

• [1] 2014 FDA drug approvals. Nat Rev Drug Discov. 2015 Feb;14(2):77-81.
• [2] Efficacy and safety of olokizumab in patients with rheumatoid arthritis with an inadequate response to TNF inhibitor therapy: outcomes of a randomised Phase IIb study. Ann Rheum Dis. 2014 September; 73(9): 1607-1615.
• [3] Clinical pipeline report, company report or official report of Roche
• [4] Clinical pipeline report, company report or official report of the Pharmaceutical Research and Manufacturers of America (PhRMA)
• [5] IL-6 inhibition with ziltivekimab in patients at high atherosclerotic risk (RESCUE): a double-blind, randomised, placebo-controlled, phase 2 trial. Lancet. 2021 May 29;397(10289):2060-2069.
• [6] Interpreting expression profiles of cancers by genome-wide survey of breadth of expression in normal tissues. Genomics 2005 Aug;86(2):127-41.
• [7] Trusted, scientifically sound profiles of drug programs, clinical trials, safety reports, and company deals, written by scientists. Springer. 2015. Adis Insight (drug id 800020380)
• [8] The molecular basis of hepcidin-resistant hereditary hemochromatosis. Blood. 2009 Jul 9;114(2):437-43.
• [9] Whole-molecule antibody engineering: generation of a high-affinity anti-IL-6 antibody with extended pharmacokinetics. J Mol Biol. 2011 Aug 26;411(4):791-807.
• [10] A high-affinity fully human anti-IL-6 mAb (OP-R003-1, 1339) for the treatment of Multiple Myeloma
• [11] Clinical pipeline report, company report or official report of Sanofi