Details of the Drug Therapeutic Target (DTT)

General Information of Drug Therapeutic Target (DTT) (ID: TTSHG0T)

• DTT Name: Toll-like receptor 9 (TLR9)
• Synonyms: UNQ5798/PRO19605; TLR-9; CD289
• Gene Name: TLR9
• DTT Type: Clinical trial target; [1]
• BioChemical Class: Toll-like receptor
• UniProt ID: TLR9_HUMAN
• TTD ID: T11451
• Sequence:
  MGFCRSALHPLSLLVQAIMLAMTLALGTLPAFLPCELQPHGLVNCNWLFLKSVPHFSMAA
  PRGNVTSLSLSSNRIHHLHDSDFAHLPSLRHLNLKWNCPPVGLSPMHFPCHMTIEPSTFL
  AVPTLEELNLSYNNIMTVPALPKSLISLSLSHTNILMLDSASLAGLHALRFLFMDGNCYY
  KNPCRQALEVAPGALLGLGNLTHLSLKYNNLTVVPRNLPSSLEYLLLSYNRIVKLAPEDL
  ANLTALRVLDVGGNCRRCDHAPNPCMECPRHFPQLHPDTFSHLSRLEGLVLKDSSLSWLN
  ASWFRGLGNLRVLDLSENFLYKCITKTKAFQGLTQLRKLNLSFNYQKRVSFAHLSLAPSF
  GSLVALKELDMHGIFFRSLDETTLRPLARLPMLQTLRLQMNFINQAQLGIFRAFPGLRYV
  DLSDNRISGASELTATMGEADGGEKVWLQPGDLAPAPVDTPSSEDFRPNCSTLNFTLDLS
  RNNLVTVQPEMFAQLSHLQCLRLSHNCISQAVNGSQFLPLTGLQVLDLSHNKLDLYHEHS
  FTELPRLEALDLSYNSQPFGMQGVGHNFSFVAHLRTLRHLSLAHNNIHSQVSQQLCSTSL
  RALDFSGNALGHMWAEGDLYLHFFQGLSGLIWLDLSQNRLHTLLPQTLRNLPKSLQVLRL
  RDNYLAFFKWWSLHFLPKLEVLDLAGNQLKALTNGSLPAGTRLRRLDVSCNSISFVAPGF
  FSKAKELRELNLSANALKTVDHSWFGPLASALQILDVSANPLHCACGAAFMDFLLEVQAA
  VPGLPSRVKCGSPGQLQGLSIFAQDLRLCLDEALSWDCFALSLLAVALGLGVPMLHHLCG
  WDLWYCFHLCLAWLPWRGRQSGRDEDALPYDAFVVFDKTQSAVADWVYNELRGQLEECRG
  RWALRLCLEERDWLPGKTLFENLWASVYGSRKTLFVLAHTDRVSGLLRASFLLAQQRLLE
  DRKDVVVLVILSPDGRRSRYVRLRQRLCRQSVLLWPHQPSGQRSFWAQLGMALTRDNHHF
  YNRNFCQGPTAE
• Function: Key component of innate and adaptive immunity. TLRs (Toll-like receptors) control host immune response against pathogens through recognition of molecular patterns specific to microorganisms. TLR9 is a nucleotide-sensing TLR which is activated by unmethylated cytidine-phosphate-guanosine (CpG) dinucleotides. Acts via MYD88 and TRAF6, leading to NF-kappa-B activation, cytokine secretion and the inflammatory response. Controls lymphocyte response to Helicobacter infection. Upon CpG stimulation, induces B-cell proliferation, activation, survival and antibody production.
• KEGG Pathway:
  Toll-like receptor signaling pathway (hsa04620)
  Chagas disease (American trypanosomiasis) (hsa05142)
  African trypanosomiasis (hsa05143)
  Malaria (hsa05144)
  Tuberculosis (hsa05152)
  Measles (hsa05162)
  Herpes simplex infection (hsa05168)
• Reactome Pathway:
  Trafficking and processing of endosomal TLR (R-HSA-1679131)
  TRAF6 mediated IRF7 activation in TLR7/8 or 9 signaling (R-HSA-975110)
  TRAF6 mediated induction of NFkB and MAP kinases upon TLR7/8 or 9 activation (R-HSA-975138)
  MyD88 dependent cascade initiated on endosome (R-HSA-975155)
  PI3K Cascade (R-HSA-109704)

Molecular Interaction Atlas (MIA) of This DTT

26 Clinical Trial Drug(s) Targeting This DTT

Drug Name	Drug ID	Indication	ICD 11	Highest Status	REF
Cadi-05	DMPTCYB	Prostate cancer	2C82.0	Phase 3	[2]
IMO-2125	DM735FA	Melanoma	2C30	Phase 3	[3]
MGN-1703	DMCJRL1	Colorectal cancer	2B91.Z	Phase 3	[4]
SD-101	DMAMTGI	Hepatitis C virus infection	1E51.1	Phase 3	[1]
Tilsotolimod	DMGYK2N	Melanoma	2C30	Phase 3	[5]
BL-7040	DMSBPJI	Inflammatory bowel disease	DD72	Phase 2	[6]
CpG-10101	DM6MUCX	Hepatitis C virus infection	1E51.1	Phase 2	[7]
CYT003	DM4LJH8	Asthma	CA23	Phase 2	[8]
IMO-2055	DM6IQ3V	Renal cell carcinoma	2C90	Phase 2	[3]
IMO-3100	DMM549D	Psoriasis vulgaris	EA90	Phase 2	[9]
JVRS-100	DMPMU38	leukaemia	2A60-2B33	Phase 2	[10]
Lefitolimod	DMS6E9J	Human immunodeficiency virus-1 infection	1C62	Phase 2	[11]
MIS-416	DM7K4YR	Autoimmune diabetes	5A10	Phase 2	[12]
Tolamba	DMORFZD	Allergic rhinitis	CA08.0	Phase 2	[13]
AST-008	DM7C68W	Solid tumour/cancer	2A00-2F9Z	Phase 1	[14]
AZD1419	DM6UOXF	Asthma	CA23	Phase 1	[15]
Cavrotolimod	DMO53AD	Solid tumour/cancer	2A00-2F9Z	Phase 1	[16]
CMP-001	DMGMI8P	Melanoma	2C30	Phase 1	[17]
CPG 52364	DMVDYTG	Systemic lupus erythematosus	4A40.0	Phase 1	[18]
DV-1179	DMDSVRP	Autoimmune disease	4A40-4A45	Phase 1	[19]
DV281	DMJ0Y86	Non-small-cell lung cancer	2C25.Y	Phase 1	[14]
GNKG-168	DMYWDT4	Chronic lymphocytic leukaemia	2A82.0	Phase 1	[20]
Litenimod	DMESZQU	Glioblastoma multiforme	2A00.0	Phase 1	[21]
MGN-1706	DMTS5VF	Solid tumour/cancer	2A00-2F9Z	Phase 1	[21]
N-8295	DM3PC0J	Influenza virus infection	1E30-1E32	Phase 1	[22]
SAR-21609	DMO8QY1	Asthma	CA23	Phase 1	[2]

4 Discontinued Drug(s) Targeting This DTT

Drug Name	Drug ID	Indication	ICD 11	Highest Status	REF
IR-103	DM7SA9J	Human immunodeficiency virus infection	1C62	Discontinued in Phase 3	[21]
Agatolimod	DM497SK	Lung cancer	2C25.0	Discontinued in Phase 2	[23]
IM0-8400	DMEF9JW	Diffuse large B-cell lymphoma	2A81	Discontinued in Phase 1/2	[24]
AVE0675	DM4UTXV	Asthma	CA23	Terminated	[25]

1 Preclinical Drug(s) Targeting This DTT

Drug Name	Drug ID	Indication	ICD 11	Highest Status	REF
IMO-2134	DMXN2ZQ	Allergy	4A80-4A85	Preclinical	[3]

3 Investigative Drug(s) Targeting This DTT

Drug Name	Drug ID	Indication	ICD 11	Highest Status	REF
COV08-0064	DM2LWNF	Parkinson disease	8A00.0	Investigative	[26]
DIMS-9054	DMJGKND	Infectious disease	1A00-CA43.1	Investigative	[21]
ODN-2088	DM692XV	Spinal cord injury	ND51.2	Investigative	[27]

Molecular Expression Atlas (MEA) of This DTT

Disease Name	ICD 11	Studied Tissue	p-value	Fold-Change	Z-score
Prostate cancer	2C82	Prostate	2.58E-01	-0.06	-0.17
Rectal cancer	2C82	Rectal colon tissue	4.48E-03	-0.52	-2.31
Asthma	CA23	Nasal and bronchial airway	5.79E-02	-0.14	-0.35
Lung cancer	2C82	Lung tissue	2.11E-03	0.09	0.29
Renal cancer	2C82	Kidney	4.82E-01	-0.03	-0.12
Acute myelocytic leukaemia	2C82	Bone marrow	2.64E-02	0.05	0.19
Glioma	2C82	Brainstem tissue	1.43E-01	-0.68	-2.71
Glioma	2C82	White matter	1.45E-06	-0.62	-2.53

References

• [1] Novel drugs targeting Toll-like receptors for antiviral therapy. Future Virol. 2014 September; 9(9): 811-829.
• [2] Trial Watch: Experimental Toll-like receptor agonists for cancer therapy. Oncoimmunology. 2012 August 1; 1(5): 699-716.
• [3] Clinical pipeline report, company report or official report of Idera Pharmaceuticals (2011).
• [4] Maintenance treatment with the immunomodulator MGN1703, a Toll-like receptor 9 (TLR9) agonist, in patients with metastatic colorectal carcinoma and disease control after chemotherapy: a randomised, double-blind, placebo-controlled trial. J Cancer Res Clin Oncol. 2014 Sep;140(9):1615-24.
• [5] Tilsotolimod with ipilimumab drives tumor responses in anti-PD-1 refractory melanoma. Cancer Discov. 2021 Mar 11;candisc.1546.2020.
• [6] Gut feeling: MicroRNA discriminators of the intestinal TLR9-cholinergic links. Int Immunopharmacol. 2015 Nov;29(1):8-14.
• [7] Safety, pharmacokinetics and immune effects in normal volunteers of CPG 10101 (ACTILON), an investigational synthetic toll-like receptor 9 agonist. Antivir Ther. 2007;12(5):741-51.
• [8] CYT003, a TLR9 agonist, in persistent allergic asthma - a randomized placebo-controlled Phase 2b study. Allergy. 2015 Sep;70(9):1160-8.
• [9] Company report (Iderapharma)
• [10] Cationic lipid/DNA complexes (JVRS-100) combined with influenza vaccine (Fluzone ) increases antibody response, cellular immunity, and antigenically drifted protection. Vaccine. 2009 June 12; 27(29):3811-3820.
• [11] Beneficial modulation of the tumor microenvironment and generation of anti-tumor responses by TLR9 agonist lefitolimod alone and in combination with checkpoint inhibitors. Oncoimmunology. 2019 Sep 20;8(12):e1659096.
• [12] DOI: 10.1371/journal.pone.0087712
• [13] Phase II study of a TLR-9 agonist (1018 ISS) with rituximab in patients with relapsed or refractory follicular lymphoma. Br J Haematol. 2009 August; 146(3): 282-291.
• [14] Clinical pipeline report, company report or official report of the Pharmaceutical Research and Manufacturers of America (PhRMA)
• [15] Clinical pipeline report, company report or official report of dynavax.
• [16] Clinical pipeline report, company report or official report of Exicure.
• [17] Clinical pipeline report, company report or official report of Checkmate Pharmaceuticals.
• [18] Coley Pharmaceutical Group Diversifies Pipeline with First-in-Class TLR Antagonist for the Treatment of Systemic Lupus Erythematosus. Lupus Foundation of America, Inc. 2007.
• [19] Company report (Dynavax)
• [20] National Cancer Institute Drug Dictionary (drug id 662816).
• [21] URL: http://www.guidetopharmacology.org Nucleic Acids Res. 2015 Oct 12. pii: gkv1037. The IUPHAR/BPS Guide to PHARMACOLOGY in 2016: towards curated quantitative interactions between 1300 protein targets and 6000 ligands. (Target id: 1759).
• [22] Trusted, scientifically sound profiles of drug programs, clinical trials, safety reports, and company deals, written by scientists. Springer. 2015. Adis Insight (drug id 800019871)
• [23] Pfizer. Product Development Pipeline. March 31 2009.
• [24] Clinical pipeline report, company report or official report of Idera Pharmaceuticals.
• [25] Pharma & Vaccines. Product Development Pipeline. April 29 2009.
• [26] The novel TLR9 antagonist COV08-0064 protects from ischemia/reperfusion injury in non-steatotic and steatotic mice livers. Biochem Pharmacol. 2016 Jul 15;112:90-101.
• [27] Toll-like receptor 9 antagonism modulates astrocyte function and preserves proximal axons following spinal cord injury. Brain Behav Immun. 2019 Aug;80:328-343.