Details of the Drug Therapeutic Target (DTT)

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

• DTT Name: Complement C5 (CO5)
• Synonyms: C3 and PZP-like alpha-2-macroglobulin domain-containing protein 4
• Gene Name: C5
• DTT Type: Successful target; [1]
• BioChemical Class: Complement system
• UniProt ID: CO5_HUMAN
• TTD ID: T60708
• Sequence:
  MGLLGILCFLIFLGKTWGQEQTYVISAPKIFRVGASENIVIQVYGYTEAFDATISIKSYP
  DKKFSYSSGHVHLSSENKFQNSAILTIQPKQLPGGQNPVSYVYLEVVSKHFSKSKRMPIT
  YDNGFLFIHTDKPVYTPDQSVKVRVYSLNDDLKPAKRETVLTFIDPEGSEVDMVEEIDHI
  GIISFPDFKIPSNPRYGMWTIKAKYKEDFSTTGTAYFEVKEYVLPHFSVSIEPEYNFIGY
  KNFKNFEITIKARYFYNKVVTEADVYITFGIREDLKDDQKEMMQTAMQNTMLINGIAQVT
  FDSETAVKELSYYSLEDLNNKYLYIAVTVIESTGGFSEEAEIPGIKYVLSPYKLNLVATP
  LFLKPGIPYPIKVQVKDSLDQLVGGVPVTLNAQTIDVNQETSDLDPSKSVTRVDDGVASF
  VLNLPSGVTVLEFNVKTDAPDLPEENQAREGYRAIAYSSLSQSYLYIDWTDNHKALLVGE
  HLNIIVTPKSPYIDKITHYNYLILSKGKIIHFGTREKFSDASYQSINIPVTQNMVPSSRL
  LVYYIVTGEQTAELVSDSVWLNIEEKCGNQLQVHLSPDADAYSPGQTVSLNMATGMDSWV
  ALAAVDSAVYGVQRGAKKPLERVFQFLEKSDLGCGAGGGLNNANVFHLAGLTFLTNANAD
  DSQENDEPCKEILRPRRTLQKKIEEIAAKYKHSVVKKCCYDGACVNNDETCEQRAARISL
  GPRCIKAFTECCVVASQLRANISHKDMQLGRLHMKTLLPVSKPEIRSYFPESWLWEVHLV
  PRRKQLQFALPDSLTTWEIQGVGISNTGICVADTVKAKVFKDVFLEMNIPYSVVRGEQIQ
  LKGTVYNYRTSGMQFCVKMSAVEGICTSESPVIDHQGTKSSKCVRQKVEGSSSHLVTFTV
  LPLEIGLHNINFSLETWFGKEILVKTLRVVPEGVKRESYSGVTLDPRGIYGTISRRKEFP
  YRIPLDLVPKTEIKRILSVKGLLVGEILSAVLSQEGINILTHLPKGSAEAELMSVVPVFY
  VFHYLETGNHWNIFHSDPLIEKQKLKKKLKEGMLSIMSYRNADYSYSVWKGGSASTWLTA
  FALRVLGQVNKYVEQNQNSICNSLLWLVENYQLDNGSFKENSQYQPIKLQGTLPVEAREN
  SLYLTAFTVIGIRKAFDICPLVKIDTALIKADNFLLENTLPAQSTFTLAISAYALSLGDK
  THPQFRSIVSALKREALVKGNPPIYRFWKDNLQHKDSSVPNTGTARMVETTAYALLTSLN
  LKDINYVNPVIKWLSEEQRYGGGFYSTQDTINAIEGLTEYSLLVKQLRLSMDIDVSYKHK
  GALHNYKMTDKNFLGRPVEVLLNDDLIVSTGFGSGLATVHVTTVVHKTSTSEEVCSFYLK
  IDTQDIEASHYRGYGNSDYKRIVACASYKPSREESSSGSSHAVMDISLPTGISANEEDLK
  ALVEGVDQLFTDYQIKDGHVILQLNSIPSSDFLCVRFRIFELFEVGFLSPATFTVYEYHR
  PDKQCTMFYSTSNIKIQKVCEGAACKCVEADCGQMQEELDLTISAETRKQTACKPEIAYA
  YKVSITSITVENVFVKYKATLLDIYKTGEAVAEKDSEITFIKKVTCTNAELVKGRQYLIM
  GKEALQIKYNFSFRYIYPLDSLTWIEYWPRDTTCSSCQAFLANLDEFAEDIFLNGC
• Function: Activation of C5 by a C5 convertase initiates the spontaneous assembly of the late complement components, C5-C9, into the membrane attack complex. C5b has a transient binding site for C6. The C5b-C6 complex is the foundation upon which the lytic complex is assembled. Derived from proteolytic degradation of complement C5, C5 anaphylatoxin is a mediator of local inflammatory process. Binding to the receptor C5AR1 induces a variety of responses including intracellular calcium release, contraction of smooth muscle, increased vascular permeability, and histamine release from mast cells and basophilic leukocytes (PubMed:8182049). C5a is also a potent chemokine which stimulates the locomotion of polymorphonuclear leukocytes and directs their migration toward sites of inflammation.
• KEGG Pathway:
  Complement and coagulation cascades (hsa04610)
  Prion diseases (hsa05020)
  Pertussis (hsa05133)
  Staphylococcus aureus infection (hsa05150)
  Herpes simplex infection (hsa05168)
  Systemic lupus erythematosus (hsa05322)
• Reactome Pathway:
  Peptide ligand-binding receptors (R-HSA-375276)
  G alpha (i) signalling events (R-HSA-418594)
  Regulation of Complement cascade (R-HSA-977606)
  Activation of C3 and C5 (R-HSA-174577)

Molecular Interaction Atlas (MIA) of This DTT

4 Approved Drug(s) Targeting This DTT

Drug Name	Drug ID	Indication	ICD 11	Highest Status	REF
Avacincaptad pegol	DM1Z3Z2	Geographic atrophy	9B75	Approved	[2]
Pozelimab	DMTE8DC	Large B Cell Lymphoma		Approved	[3]
Ravulizumab	DMSWNJF	Paroxysmal nocturnal haemoglobinuria	3A21.0	Approved	[1]
Zilucoplan	DM9Z4N5	Generalized myasthenia gravis	8C60	Approved	[4]

13 Clinical Trial Drug(s) Targeting This DTT

Drug Name	Drug ID	Indication	ICD 11	Highest Status	REF
ABP959	DMDXE4I	Paroxysmal nocturnal haemoglobinuria	3A21.0	Phase 3	[5]
ALXN1720	DMOB3CI	Generalized myasthenia gravis	8C60	Phase 3	[6]
Coversin	DMMEAOL	Paroxysmal nocturnal haemoglobinuria	3A21.0	Phase 3	[7]
Nomacopan	DML6E6G	Bullous pemphigoid	EB41.0	Phase 3	[8]
SB12	DMME6GJ	Paroxysmal nocturnal haemoglobinuria	3A21.0	Phase 3	[9]
SKY59	DMWOF1E	Haemolytic uraemic syndrome	3A21.2	Phase 3	[10]
Zimura	DM09TVB	Macular degeneration	9B78.3	Phase 3	[11]
LFG-316	DMCT1RQ	Macular degeneration	9B78.3	Phase 2	[13]
NNC-0151-0000-0000	DMU3KOH	Rheumatoid arthritis	FA20	Phase 2	[14]
Tesidolumab	DMR4YEG	Age-related macular degeneration	9B75.0	Phase 2	[15]
ARC-1905	DMY0DPM	Macular degeneration	9B78.3	Phase 1	[16]
MEDI7814	DM8BXDI	Chronic obstructive pulmonary disease	CA22	Phase 1	[17]
REV-576	DMLHIMO	Autoimmune diabetes	5A10	Phase 1	[18]

1 Drugs in Phase 2 Trial Targeting This DTT

Drug Name	Drug ID	Indication	ICD 11	Highest Status	REF
IFX-1	DMPLQ1V	Coronavirus Disease 2019 (COVID-19)	1D6Y	Phase 2/3 Trial	[12]

3 Discontinued Drug(s) Targeting This DTT

Drug Name	Drug ID	Indication	ICD 11	Highest Status	REF
Pexelizumab	DM4IM0G	Cardiovascular disease	BA00-BE2Z	Discontinued in Phase 3	[19]
MP-435	DMMKHGN	Rheumatoid arthritis	FA20	Discontinued in Phase 2	[20]
CGS-32359	DM1VZ2I	Inflammation	1A00-CA43.1	Terminated	[22]

1 Preclinical Drug(s) Targeting This DTT

Drug Name	Drug ID	Indication	ICD 11	Highest Status	REF
SAND-5	DM7E324	Glomerulonephritis	5D00.Y	Preclinical	[21]

Molecular Expression Atlas (MEA) of This DTT

Disease Name	ICD 11	Studied Tissue	p-value	Fold-Change	Z-score
Chronic obstructive pulmonary disease	CA23	Lung tissue	8.42E-01	-0.02	-0.03
Chronic obstructive pulmonary disease	CA23	Small airway epithelium	8.64E-03	-0.15	-0.43
Rheumatoid arthritis	FA20	Synovial tissue	7.69E-01	-0.12	-0.23

References

• [1] 2018 FDA drug approvals.Nat Rev Drug Discov. 2019 Feb;18(2):85-89.
• [2] FDA Approved Drug Products from FDA Official Website. 2023. Application Number: 217225
• [3] Inhibition of complement pathway activation with Pozelimab, a fully human antibody to complement component C5. PLoS One. 2020 May 8;15(5):e0231892.
• [4] Clinical pipeline report, company report or official report of the Pharmaceutical Research and Manufacturers of America (PhRMA)
• [5] A randomized, double-blind, single-dose, three-arm, parallel group study to determine pharmacokinetic similarity of ABP 959 and eculizumab (Soliris ?) in healthy male subjects. Eur J Haematol. 2020 Jul;105(1):66-74.
• [6] Trusted, scientifically sound profiles of drug programs, clinical trials, safety reports, and company deals, written by scientists. Springer. 2023. Adis Insight
• [7] Use of the complement inhibitor Coversin to treat HSCT-associated TMA. Blood Adv. 2017 Jul 3;1(16):1254-1258.
• [8] Evaluation of Nomacopan for Treatment of Bullous Pemphigoid: A Phase 2a Nonrandomized Controlled Trial. JAMA Dermatol. 2022 Jun 1;158(6):641-649.
• [9] Clinical promise of next-generation complement therapeutics. Nat Rev Drug Discov. 2019 Sep;18(9):707-729.
• [10] The complement C5 inhibitor crovalimab in paroxysmal nocturnal hemoglobinuria. Blood. 2020 Mar 19;135(12):912-920.
• [11] C5 Inhibitor Avacincaptad Pegol for Geographic Atrophy Due to Age-Related Macular Degeneration: A Randomized Pivotal Phase 2/3 Trial. Ophthalmology. 2021 Apr;128(4):576-586.
• [12] Clinical pipeline report, company report or official report of the Pharmaceutical Research and Manufacturers of America (PhRMA)
• [13] Advances in the management of macular degeneration. F1000Prime Rep. 2014; 6: 29.
• [14] Complement-targeted therapeutics. Nat Biotechnol. 2007 Nov;25(11):1265-75.
• [15] Intravenous immunoglobulin significantly reduces exposure of concomitantly administered anti-C5 monoclonal antibody tesidolumab. Am J Transplant. 2020 Sep;20(9):2581-2588.
• [16] ClinicalTrials.gov (NCT00950638) A Study of ARC1905 (Anti-C5 Aptamer) in Subjects With Dry Age-related Macular Degeneration. U.S. National Institutes of Health.
• [17] Interpreting expression profiles of cancers by genome-wide survey of breadth of expression in normal tissues. Genomics 2005 Aug;86(2):127-41.
• [18] Complement C5-inhibitor rEV576 (coversin) ameliorates in-vivo effects of antiphospholipid antibodies. Lupus. 2014 Oct;23(12):1324-6.
• [19] Pexelizumab reduces death and myocardial infarction in higher risk cardiac surgical patients. Ann Thorac Surg. 2006 Aug;82(2):486-92.
• [20] Trusted, scientifically sound profiles of drug programs, clinical trials, safety reports, and company deals, written by scientists. Springer. 2015. Adis Insight (drug id 800027730)
• [21] Progress and Trends in Complement Therapeutics. Adv Exp Med Biol. 2013; 734: 1-22.
• [22] Anticomplement therapy. Biologics. 2008 December; 2(4): 671-685.