Details of the Drug Therapeutic Target (DTT)

General Information of Drug Therapeutic Target (DTT) (ID: TTI2S1D)

• DTT Name: Cytotoxic T-lymphocyte protein 4 (CTLA-4)
• Synonyms: Cytotoxic T-lymphocyte-associated antigen 4; CTLA-4; CD152
• Gene Name: CTLA4
• DTT Type: Successful target; [1]
• BioChemical Class: Immunoglobulin
• UniProt ID: CTLA4_HUMAN
• TTD ID: T15000
• Sequence:
  MACLGFQRHKAQLNLATRTWPCTLLFFLLFIPVFCKAMHVAQPAVVLASSRGIASFVCEY
  ASPGKATEVRVTVLRQADSQVTEVCAATYMMGNELTFLDDSICTGTSSGNQVNLTIQGLR
  AMDTGLYICKVELMYPPPYYLGIGNGTQIYVIDPEPCPDSDFLLWILAAVSSGLFFYSFL
  LTAVSLSKMLKKRSPLTTGVYVKMPPTEPECEKQFQPYFIPIN
• Function: Inhibitory receptor acting as a major negative regulator of T-cell responses. The affinity of CTLA4 for its natural B7 family ligands, CD80 and CD86, is considerably stronger than the affinity of their cognate stimulatory coreceptor CD28.
• KEGG Pathway:
  Cell adhesion molecules (CAMs) (hsa04514)
  T cell receptor signaling pathway (hsa04660)
  Autoimmune thyroid disease (hsa05320)
  Rheumatoid arthritis (hsa05323)
• Reactome Pathway: CTLA4 inhibitory signaling (R-HSA-389513)

Molecular Interaction Atlas (MIA) of This DTT

2 Approved Drug(s) Targeting This DTT

Drug Name	Drug ID	Indication	ICD 11	Highest Status	REF
Ipilimumab	DMJTIYK	Melanoma	2C30	Approved	[1]
Tremelimumab	DMOQ9H1	Hepatocellular carcinoma	2C12.02	Approved	[2]

21 Clinical Trial Drug(s) Targeting This DTT

Drug Name	Drug ID	Indication	ICD 11	Highest Status	REF
AK04	DMU7K86	Actinic keratosis	EK90.0	Phase 3	[3]
KN046	DMSDBPG	Non-small-cell lung cancer	2C25.Y	Phase 3	[4]
AK104	DMXJ8Z4	Cervical cancer	2C77.0	Phase 2	[5]
Lorigerlimab	DM2E8Z5	Prostate cancer	2C82.0	Phase 2	[6]
Vudalimab	DMSEEI0	Prostate cancer	2C82.0	Phase 2	[7]
AGEN1884	DMAP5B4	Cervical cancer	2C77.0	Phase 1/2	[8]
BMS-986288	DMM10J4	Solid tumour/cancer	2A00-2F9Z	Phase 1/2	[9]
MK-1308	DM25QKC	Solid tumour/cancer	2A00-2F9Z	Phase 1/2	[10]
Zalifrelimab	DMNNYAE	Cervical cancer	2C77.0	Phase 1/2	[11]
A337	DMXWFP2	Aggressive cancer	2A00-2F9Z	Phase 1	[12]
ADG116	DMEXT97	Solid tumour/cancer	2A00-2F9Z	Phase 1	[13]
AGEN1181	DMV6JFK	Solid tumour/cancer	2A00-2F9Z	Phase 1	[14]
ALPN-202	DMTD4EF	Solid tumour/cancer	2A00-2F9Z	Phase 1	[15]
BMS-986249	DMHTEZ8	Solid tumour/cancer	2A00-2F9Z	Phase 1	[9]
MEDI5752	DMJ1E24	Non-small-cell lung cancer	2C25	Phase 1	[16]
MGD019	DM2BYWI	Solid tumour/cancer	2A00-2F9Z	Phase 1	[17]
ONC-392	DM8B40M	Non-small-cell lung cancer	2C25.Y	Phase 1	[18]
SI-B003	DMJW5R0	Solid tumour/cancer	2A00-2F9Z	Phase 1	[19]
XmAb20717	DMJIH83	Advanced malignancy	2A00-2F9Z	Phase 1	[20]
XmAb22841	DMQB3HD	Solid tumour/cancer	2A00-2F9Z	Phase 1	[21]
YH001	DMHQNVR	Aggressive cancer	2A00-2F9Z	Phase 1	[22]

7 Investigative Drug(s) Targeting This DTT

Drug Name	Drug ID	Indication	ICD 11	Highest Status	REF
Alpha-D-Mannose	DMF5DLW	Discovery agent	N.A.	Investigative	[23]
Concatameric CTLA4Ig	DMC5RKY	Discovery agent	N.A.	Investigative	[2]
CTLA-4-XTEN	DMKEIAS	Rheumatoid arthritis	FA20	Investigative	[2]
Del 60 tetramer	DMGZ2H5	Solid tumour/cancer	2A00-2F9Z	Investigative	[24]
Fucose	DMAHMSV	N. A.	N. A.	Investigative	[23]
GX-C4	DM8GFJP	Autoimmune diabetes	5A10	Investigative	[2]
YH006	DMRECC2	Aggressive cancer	2A00-2F9Z	Investigative	[25]

Molecular Expression Atlas (MEA) of This DTT

Disease Name	ICD 11	Studied Tissue	p-value	Fold-Change	Z-score
Prostate cancer	2C82	Prostate	2.73E-01	0.02	0.05
Rheumatoid arthritis	FA20	Synovial tissue	4.05E-03	-0.21	-1.52

References

• [1] Mullard A: 2010 FDA drug approvals. Nat Rev Drug Discov. 2011 Feb;10(2):82-5.
• [2] 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: 2743).
• [3] A multicenter, open-label phase Ib/II study of cadonilimab (anti PD-1 and CTLA-4 bispecific antibody) monotherapy in previously treated advanced non-small-cell lung cancer (AK104-202 study). Lung Cancer. 2023 Oct;184:107355.
• [4] Clinical pipeline report, company report or official report of Alphamab Oncology.
• [5] Clinical pipeline report, company report or official report of Akeso Biopharma.
• [6] Clinical pipeline report, company report or official report of MacroGenics
• [7] Clinical pipeline report, company report or official report of Xencor
• [8] Clinical pipeline report, company report or official report of the Pharmaceutical Research and Manufacturers of America (PhRMA)
• [9] Clinical pipeline report, company report or official report of CytomX Therapeutics.
• [10] Safety and efficacy of quavonlimab, a novel anti-CTLA-4 antibody (MK-1308), in combination with pembrolizumab in first-line advanced non-small-cell lung cancer. Ann Oncol. 2021 Mar;32(3):395-403.
• [11] Dual PD-1 and CTLA-4 Checkpoint Blockade Using Balstilimab and Zalifrelimab Combination as Second-Line Treatment for Advanced Cervical Cancer: An Open-Label Phase II Study. J Clin Oncol. 2022 Mar 1;40(7):762-771.
• [12] Clinical pipeline report, company report or official report of Klus Pharma
• [13] Clinical pipeline report, company report or official report of Adagene.
• [14] Clinical pipeline report, company report or official report of Agenus.
• [15] Clinical pipeline report, company report or official report of Alpine Immune Sciences.
• [16] Bispecific Antibodies to PD-1 and CTLA4: Doubling Down on T Cells to Decouple Efficacy from Toxicity. Cancer Discov. 2021 May;11(5):1008-1010.
• [17] Development and Preliminary Clinical Activity of PD-1-Guided CTLA-4 Blocking Bispecific DART Molecule. Cell Rep Med. 2020 Dec 22;1(9):100163.
• [18] Clinical pipeline report, company report or official report of OncoImmune.
• [19] Clinical pipeline report, company report or official report of SystImmune.
• [20] Clinical pipeline report, company report or official report of Xencor.
• [21] Clinical pipeline report, company report or official report of Xencor.
• [22] Clinical pipeline report, company report or official report of Biocytogen
• [23] How many drug targets are there Nat Rev Drug Discov. 2006 Dec;5(12):993-6.
• [24] Therapeutic applications of aptamers. Expert Opin Investig Drugs. 2008 Jan;17(1):43-60.
• [25] Clinical pipeline report, company report or official report of Biocytogen