Details of the Drug Therapeutic Target (DTT)

General Information of Drug Therapeutic Target (DTT) (ID: TTN6Y9A)

• DTT Name: CD40L receptor (CD40)
• Synonyms: Tumor necrosis factor receptor superfamily member 5; TNFRSF5; CDw40; Bp50; B-cell surfaceantigen CD40; B-cell surface antigen CD40
• Gene Name: CD40
• DTT Type: Clinical trial target; [1]
• BioChemical Class: Cytokine receptor
• UniProt ID: TNR5_HUMAN
• TTD ID: T45758
• Sequence:
  MVRLPLQCVLWGCLLTAVHPEPPTACREKQYLINSQCCSLCQPGQKLVSDCTEFTETECL
  PCGESEFLDTWNRETHCHQHKYCDPNLGLRVQQKGTSETDTICTCEEGWHCTSEACESCV
  LHRSCSPGFGVKQIATGVSDTICEPCPVGFFSNVSSAFEKCHPWTSCETKDLVVQQAGTN
  KTDVVCGPQDRLRALVVIPIIFGILFAILLVLVFIKKVAKKPTNKAPHPKQEPQEINFPD
  DLPGSNTAAPVQETLHGCQPVTQEDGKESRISVQERQ
• Function: Transduces TRAF6- and MAP3K8-mediated signals that activate ERK in macrophages and B cells, leading to induction of immunoglobulin secretion. Receptor for TNFSF5/CD40LG.
• KEGG Pathway:
  Cytokine-cytokine receptor interaction (hsa04060)
  NF-kappa B signaling pathway (hsa04064)
  Cell adhesion molecules (CAMs) (hsa04514)
  Toll-like receptor signaling pathway (hsa04620)
  Intestinal immune network for IgA production (hsa04672)
  Malaria (hsa05144)
  Toxoplasmosis (hsa05145)
  HTLV-I infection (hsa05166)
  Epstein-Barr virus infection (hsa05169)
  Transcriptional misregulation in cancer (hsa05202)
  Asthma (hsa05310)
  Autoimmune thyroid disease (hsa05320)
  Systemic lupus erythematosus (hsa05322)
  Allograft rejection (hsa05330)
  Primary immunodeficiency (hsa05340)
  Viral myocarditis (hsa05416)
• Reactome Pathway:
  TNFR2 non-canonical NF-kB pathway (R-HSA-5668541)
  TNF receptor superfamily (TNFSF) members mediating non-canonical NF-kB pathway (R-HSA-5676594)
  Immunoregulatory interactions between a Lymphoid and a non-Lymphoid cell (R-HSA-198933)

Molecular Interaction Atlas (MIA) of This DTT

17 Clinical Trial Drug(s) Targeting This DTT

Drug Name	Drug ID	Indication	ICD 11	Highest Status	REF
APX005M	DMX2P5G	Melanoma	2C30	Phase 2	[2]
ASKP-1240	DM1CLKO	Transplant rejection	NE84	Phase 2	[1]
AT-1501	DMQIA5K	Amyotrophic lateral sclerosis	8B60.0	Phase 2	[3]
BI 655064	DMF86P2	Lupus	4A40	Phase 2	[4]
CFZ533	DM1TWIE	Graves disease	5A02.0	Phase 2	[4]
Dazodalibep	DM7YII9	Kidney transplant rejection	NE84	Phase 2	[5]
Frexalimab	DMMJTYP	Multiple sclerosis	8A40	Phase 2	[6]
Iscalimab	DMW4CR8	Type-1 diabetes	5A10	Phase 2	[7]
KPL-404	DMQJODL	Rheumatoid arthritis	FA20	Phase 2	[8]
ABBV-323	DM49O6Y	Crohn disease	DD70	Phase 1	[4]
CDX-1140	DMUGN0J	Melanoma	2C30	Phase 1	[9]
CP-870,893	DM32TFO	Solid tumour/cancer	2A00-2F9Z	Phase 1	[10]
GEN1042	DMNP6T3	Solid tumour/cancer	2A00-2F9Z	Phase 1	[11]
NG-350A	DMQK5ET	Solid tumour/cancer	2A00-2F9Z	Phase 1	[12]
RG6189	DMYFGN4	Solid tumour/cancer	2A00-2F9Z	Phase 1	[13]
SL-172154	DMN3D72	Ovarian cancer	2C73	Phase 1	[14]
YH003	DM84TF8	Aggressive cancer	2A00-2F9Z	Phase 1	[15]

2 Discontinued Drug(s) Targeting This DTT

Drug Name	Drug ID	Indication	ICD 11	Highest Status	REF
HuCD40L	DMTGCA6	Solid tumour/cancer	2A00-2F9Z	Terminated	[16]
RhuCD40L	DMW4UTB	N. A.	N. A.	Terminated	[17]

5 Investigative Drug(s) Targeting This DTT

Drug Name	Drug ID	Indication	ICD 11	Highest Status	REF
Anti-CD40-XTEN	DMGZM6V	Rheumatoid arthritis	FA20	Investigative	[1]
CD154	DM9BMDO	Discovery agent	N.A.	Investigative	[18]
Human CD40 agonist ligand	DM8FLVH	Discovery agent	N.A.	Investigative	[1]
PG-120	DMWP0BX	Autoimmune diabetes	5A10	Investigative	[1]
YH008	DMTIP9S	Aggressive cancer	2A00-2F9Z	Investigative	[19]

Molecular Expression Atlas (MEA) of This DTT

Disease Name	ICD 11	Studied Tissue	p-value	Fold-Change	Z-score
Rheumatoid arthritis	FA20	Synovial tissue	1.43E-06	0.96	4.15
Thrombocytopenia	3B64	Whole blood	4.61E-01	0.56	0.5

References

• [1] 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: 1874).
• [2] Clinical pipeline report, company report or official report of the Pharmaceutical Research and Manufacturers of America (PhRMA)
• [3] ClinicalTrials.gov (NCT04322149) A Phase 2a Open-Label, Multi-Center Study to Evaluate the Safety and Tolerability of Multiple Doses of AT-1501 in Adults With ALS. U.S.National Institutes of Health.
• [4] Clinical pipeline report, company report or official report of the Pharmaceutical Research and Manufacturers of America (PhRMA)
• [5] The enhanced immunopharmacology of VIB4920, a novel Tn3 fusion protein and CD40L antagonist, and assessment of its safety profile in cynomolgus monkeys. Br J Pharmacol. 2020 Mar;177(5):1061-1076.
• [6] ClinicalTrials.gov (NCT04879628) A Phase 2, Double-blind, Randomized, Placebo-controlled Study Assessing Efficacy and Safety of SAR441344, a CD40L-antagonist Monoclonal Antibody, in Participants With Relapsing Multiple Sclerosis. U.S.National Institutes of Health.
• [7] Developments in immunosuppression. Curr Opin Organ Transplant. 2021 Feb 1;26(1):91-96.
• [8] Anti-CD40 antibody KPL-404 inhibits T cell-mediated activation of B cells from healthy donors and autoimmune patients. Arthritis Res Ther. 2021 Jan 6;23(1):5.
• [9] Development of CDX-1140, an agonist CD40 antibody for cancer immunotherapy. Cancer Immunol Immunother. 2019 Feb;68(2):233-245.
• [10] Clinical activity and immune modulation in cancer patients treated with CP-870,893, a novel CD40 agonist monoclonal antibody. J Clin Oncol. 2007 Mar 1;25(7):876-83.
• [11] Clinical pipeline report, company report or official report of Genmab.
• [12] Clinical pipeline report, company report or official report of PsiOxus Therapeutics.
• [13] Clinical pipeline report, company report or official report of Roche
• [14] Clinical pipeline report, company report or official report of Shattuck Labs.
• [15] Clinical pipeline report, company report or official report of Biocytogen
• [16] Recombinant human CD40 ligand inhibits simian immunodeficiency virus replication: a role for interleukin- 16. J Med Primatol. 1999 Aug-Oct;28(4-5):190-4.
• [17] Recombinant CD40 ligand therapy has significant antitumor effects on CD40-positive ovarian tumor xenografts grown in SCID mice and demonstrates an augmented effect with cisplatin. Cancer Res. 2001 Oct 15;61(20):7556-62.
• [18] Growth-inhibitory effects of CD40 ligand (CD154) and its endogenous expression in human breast cancer. Clin Cancer Res. 2001 Mar;7(3):691-703.
• [19] Clinical pipeline report, company report or official report of Biocytogen