Target Information

Target General Information

Target ID

T45758 (Former ID: TTDC00188)

Target Name

CD40L receptor (CD40)

Synonyms

Tumor necrosis factor receptor superfamily member 5; TNFRSF5; CDw40; Bp50; B-cell surfaceantigen CD40; B-cell surface antigen CD40

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Gene Name

CD40

Target Type

Clinical trial target

[1]

Disease

[+] 15 Target-related Diseases

Diabetes mellitus [ICD-11: 5A10]

Lupus erythematosus [ICD-11: 4A40]

Motor neuron disease [ICD-11: 8B60]

Multiple sclerosis [ICD-11: 8A40]

Myasthenia gravis [ICD-11: 8C6Y]

Rheumatoid arthritis [ICD-11: FA20]

Sjogren syndrome [ICD-11: 4A43]

Thyrotoxicosis [ICD-11: 5A02]

Transplant rejection [ICD-11: NE84]

Brain cancer [ICD-11: 2A00]

Crohn disease [ICD-11: DD70]

Melanoma [ICD-11: 2C30]

Ovarian cancer [ICD-11: 2C73]

Solid tumour/cancer [ICD-11: 2A00-2F9Z]

Thrombocytopenia [ICD-11: 3B64]

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.

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BioChemical Class

Cytokine receptor

UniProt ID

TNR5_HUMAN

Sequence

MVRLPLQCVLWGCLLTAVHPEPPTACREKQYLINSQCCSLCQPGQKLVSDCTEFTETECL
PCGESEFLDTWNRETHCHQHKYCDPNLGLRVQQKGTSETDTICTCEEGWHCTSEACESCV
LHRSCSPGFGVKQIATGVSDTICEPCPVGFFSNVSSAFEKCHPWTSCETKDLVVQQAGTN
KTDVVCGPQDRLRALVVIPIIFGILFAILLVLVFIKKVAKKPTNKAPHPKQEPQEINFPD
DLPGSNTAAPVQETLHGCQPVTQEDGKESRISVQERQ

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3D Structure

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AlphaFold

HIT2.0 ID

T11R4S

Drugs and Modes of Action

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Clinical Trial Drug(s)

[+] 17 Clinical Trial Drugs

APX005M

Drug Info

Phase 2

Melanoma

[2]

ASKP-1240

Drug Info

Phase 2

Transplant rejection

[3]

AT-1501

Drug Info

Phase 2

Amyotrophic lateral sclerosis

[4]

BI 655064

Drug Info

Phase 2

Lupus

[5]

CFZ533

Drug Info

Phase 2

Rheumatoid arthritis

[6]

Dazodalibep

Drug Info

Phase 2

Kidney transplant rejection

[7]

Frexalimab

Drug Info

Phase 2

Multiple sclerosis

[8]

Iscalimab

Drug Info

Phase 2

Type-1 diabetes

[9]

KPL-404

Drug Info

Phase 2

Rheumatoid arthritis

[10]

ABBV-323

Drug Info

Phase 1

Crohn disease

[5]

CDX-1140

Drug Info

Phase 1

Solid tumour/cancer

[11]

CP-870,893

Drug Info

Phase 1

Solid tumour/cancer

[12]

GEN1042

Drug Info

Phase 1

Solid tumour/cancer

[13]

NG-350A

Drug Info

Phase 1

Solid tumour/cancer

[14]

RG6189

Drug Info

Phase 1

Solid tumour/cancer

[15]

SL-172154

Drug Info

Phase 1

Ovarian cancer

[16]

YH003

Drug Info

Phase 1

Aggressive cancer

[17]

Discontinued Drug(s)

[+] 1 Discontinued Drugs

HuCD40L

Drug Info

Terminated

Solid tumour/cancer

[18], [19]

Mode of Action

[+] 4 Modes of Action

Agonist

[+] 7 Agonist drugs

APX005M

Drug Info

[11], [20]

CDX-1140

Drug Info

[25]

CP-870,893

Drug Info

[26]

GEN1042

Drug Info

[27]

NG-350A

Drug Info

[28]

RG6189

Drug Info

[15]

Human CD40 agonist ligand

Drug Info

[1]

Inhibitor

[+] 7 Inhibitor drugs

AT-1501

Drug Info

[4]

BI 655064

Drug Info

[5]

CFZ533

Drug Info

[5], [21]

Dazodalibep

Drug Info

[22]

Iscalimab

Drug Info

[23]

KPL-404

Drug Info

[24]

SL-172154

Drug Info

[29]

Antagonist

[+] 3 Antagonist drugs

Frexalimab

Drug Info

[8]

ABBV-323

Drug Info

[5]

Anti-CD40-XTEN

Drug Info

[1]

Binder

[+] 3 Binder drugs

HuCD40L

Drug Info

[31]

RhuCD40L

Drug Info

[32]

CD154

Drug Info

[33]

Cell-based Target Expression Variations

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Cell-based Target Expression Variations

Cell-based Target Expression Variations Info

Different Human System Profiles of Target	Top
Human Similarity Proteins of target is determined by comparing the sequence similarity of all human proteins with the target based on BLAST. The similarity proteins for a target are defined as the proteins with E-value < 0.005 and outside the protein families of the target. A target that has fewer human similarity proteins outside its family is commonly regarded to possess a greater capacity to avoid undesired interactions and thus increase the possibility of finding successful drugs (Brief Bioinform, 21: 649-662, 2020). Human Tissue Distribution of target is determined from a proteomics study that quantified more than 12,000 genes across 32 normal human tissues. Tissue Specificity (TS) score was used to define the enrichment of target across tissues. The distribution of targets among different tissues or organs need to be taken into consideration when assessing the target druggability, as it is generally accepted that the wider the target distribution, the greater the concern over potential adverse effects (Nat Rev Drug Discov, 20: 64-81, 2021). Human Pathway Affiliation of target is determined by the life-essential pathways provided on KEGG database. The target-affiliated pathways were defined based on the following two criteria (a) the pathways of the studied target should be life-essential for both healthy individuals and patients, and (b) the studied target should occupy an upstream position in the pathways and therefore had the ability to regulate biological function. Targets involved in a fewer pathways have greater likelihood to be successfully developed, while those associated with more human pathways increase the chance of undesirable interferences with other human processes (Pharmacol Rev, 58: 259-279, 2006). Biological Network Descriptors of target is determined based on a human protein-protein interactions (PPI) network consisting of 9,309 proteins and 52,713 PPIs, which were with a high confidence score of ≥ 0.95 collected from STRING database. The network properties of targets based on protein-protein interactions (PPIs) have been widely adopted for the assessment of target’s druggability. Proteins with high node degree tend to have a high impact on network function through multiple interactions, while proteins with high betweenness centrality are regarded to be central for communication in interaction networks and regulate the flow of signaling information (Front Pharmacol, 9, 1245, 2018; Curr Opin Struct Biol. 44:134-142, 2017). Human Similarity Proteins Human Tissue Distribution Human Pathway Affiliation Biological Network Descriptors

Different Human System Profiles of Target

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Human Similarity Proteins of target is determined by comparing the sequence similarity of all human proteins with the target based on BLAST. The similarity proteins for a target are defined as the proteins with E-value < 0.005 and outside the protein families of the target.

A target that has fewer human similarity proteins outside its family is commonly regarded to possess a greater capacity to avoid undesired interactions and thus increase the possibility of finding successful drugs (Brief Bioinform, 21: 649-662, 2020).

Human Tissue Distribution of target is determined from a proteomics study that quantified more than 12,000 genes across 32 normal human tissues. Tissue Specificity (TS) score was used to define the enrichment of target across tissues.

The distribution of targets among different tissues or organs need to be taken into consideration when assessing the target druggability, as it is generally accepted that the wider the target distribution, the greater the concern over potential adverse effects (Nat Rev Drug Discov, 20: 64-81, 2021).

Human Pathway Affiliation of target is determined by the life-essential pathways provided on KEGG database. The target-affiliated pathways were defined based on the following two criteria (a) the pathways of the studied target should be life-essential for both healthy individuals and patients, and (b) the studied target should occupy an upstream position in the pathways and therefore had the ability to regulate biological function.

Targets involved in a fewer pathways have greater likelihood to be successfully developed, while those associated with more human pathways increase the chance of undesirable interferences with other human processes (Pharmacol Rev, 58: 259-279, 2006).

Biological Network Descriptors of target is determined based on a human protein-protein interactions (PPI) network consisting of 9,309 proteins and 52,713 PPIs, which were with a high confidence score of ≥ 0.95 collected from STRING database.

The network properties of targets based on protein-protein interactions (PPIs) have been widely adopted for the assessment of target’s druggability. Proteins with high node degree tend to have a high impact on network function through multiple interactions, while proteins with high betweenness centrality are regarded to be central for communication in interaction networks and regulate the flow of signaling information (Front Pharmacol, 9, 1245, 2018; Curr Opin Struct Biol. 44:134-142, 2017).

Human Similarity Proteins

Human Tissue Distribution

Human Pathway Affiliation

Biological Network Descriptors

Protein Name	Pfam ID	Percentage of Identity (%)	E value
Activation-inducible TNFR family receptor (TNFRSF18)		27.966 (33/118)	5.00E-03


Note: If a protein has TS (tissue specficity) scores at least in one tissue >= 2.5, this protein is called tissue-enriched (including tissue-enriched-but-not-specific and tissue-specific). In the plots, the vertical lines are at thresholds 2.5 and 4.

KEGG Pathway	Pathway ID	Affiliated Target
Cytokine-cytokine receptor interaction	hsa04060	Affiliated Target
Class: Environmental Information Processing => Signaling molecules and interaction	Pathway Hierarchy
NF-kappa B signaling pathway	hsa04064	Affiliated Target
Class: Environmental Information Processing => Signal transduction	Pathway Hierarchy
Cell adhesion molecules	hsa04514	Affiliated Target
Class: Environmental Information Processing => Signaling molecules and interaction	Pathway Hierarchy
Toll-like receptor signaling pathway	hsa04620	Affiliated Target
Class: Organismal Systems => Immune system	Pathway Hierarchy
Intestinal immune network for IgA production	hsa04672	Affiliated Target
Class: Organismal Systems => Immune system	Pathway Hierarchy

Degree	29	Degree centrality	3.12E-03	Betweenness centrality	3.24E-03
Closeness centrality	2.46E-01	Radiality	1.43E+01	Clustering coefficient	1.53E-01
Neighborhood connectivity	3.57E+01	Topological coefficient	6.27E-02	Eccentricity	11
Download	Click to Download the Full PPI Network of This Target

Chemical Structure based Activity Landscape of Target

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Target Regulators

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Target-regulating microRNAs

Target-regulating microRNAs Info

Target-regulating Transcription Factors

Target-regulating Transcription Factors Info

Target-interacting Proteins

Target-interacting Proteins Info

Target Profiles in Patients

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Target Expression
Profile (TEP)

Target Expression Profile Info

Target Affiliated Biological Pathways		Top
KEGG Pathway	[+] 16 KEGG Pathways	+
1	Cytokine-cytokine receptor interaction
2	NF-kappa B signaling pathway
3	Cell adhesion molecules (CAMs)
4	Toll-like receptor signaling pathway
5	Intestinal immune network for IgA production
6	Malaria
7	Toxoplasmosis
8	HTLV-I infection
9	Epstein-Barr virus infection
10	Transcriptional misregulation in cancer
11	Asthma
12	Autoimmune thyroid disease
13	Systemic lupus erythematosus
14	Allograft rejection
15	Primary immunodeficiency
16	Viral myocarditis
PID Pathway	[+] 1 PID Pathways	+
1	CD40/CD40L signaling
WikiPathways	[+] 7 WikiPathways	+
1	Toll-like receptor signaling pathway
2	Inflammatory Response Pathway
3	NLR Proteins
4	Vitamin D Receptor Pathway
5	Human Complement System
6	Allograft Rejection
7	Regulation of toll-like receptor signaling pathway

Target-Related Models and Studies

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Target Validation

Target Validation Info

References

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REF 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).

REF 2

ClinicalTrials.gov (NCT04337931) A Study to Evaluate APX005M in Subjects With Unresectable or Metastatic Melanoma. U.S. National Institutes of Health.

REF 3

ClinicalTrials.gov (NCT01585233) A Multiple Dose Escalation Study of ASKP1240 in Subjects With Moderate to Severe Plaque Psoriasis. U.S. National Institutes of Health.

REF 4

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.

REF 5

Clinical pipeline report, company report or official report of the Pharmaceutical Research and Manufacturers of America (PhRMA)

REF 6

ClinicalTrials.gov (NCT02291029) Safety, Pharmacokinetics and Preliminary Efficacy Study of CFZ533 in Patients With Primary Sj ren's Syndrome. U.S. National Institutes of Health.

REF 7

ClinicalTrials.gov (NCT04046549) A Phase 2a Single-arm, Prospective, Open-label Pilot Study to Evaluate the Safety and Efficacy of Dual Costimulation Blockade With VIB4920 and Belatacept for Prophylaxis of Allograft Rejection in Adults Receiving a Kidney Transplant. U.S.National Institutes of Health.

REF 8

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.

REF 9

ClinicalTrials.gov (NCT04129528) Investigator- and Subject-blinded, Randomized, Placebo-controlled Study to Evaluate Safety, Tolerability, Pharmacokinetics and Efficacy Trial of CFZ533 in Pediatric and Young Adult Subjects With New Onset Type 1 Diabetes (T1DM). U.S.National Institutes of Health.

REF 10

ClinicalTrials.gov (NCT05198310) A Phase 2, Multicenter, Randomized, Double-blind, Placebo Controlled Study to Assess the Safety, Pharmacokinetics, and Efficacy of KPL-404 in Subjects With Moderate to Severe Active Rheumatoid Arthritis With Inadequate Response or Intolerance to at Least One Biologic Disease-modifying Anti-rheumatic Drug or a Janus Kinase Inhibitor. U.S.National Institutes of Health.

REF 11

Clinical pipeline report, company report or official report of the Pharmaceutical Research and Manufacturers of America (PhRMA)

REF 12

ClinicalTrials.gov (NCT01103635) Tremelimumab and CP-870,893 in Patients With Metastatic Melanoma. U.S. National Institutes of Health.

REF 13

ClinicalTrials.gov (NCT04083599) GEN1042 Safety Trial in Subjects With Malignant Solid Tumors. U.S. National Institutes of Health.

REF 14

ClinicalTrials.gov (NCT03852511) First in Human Study of NG-350A (an Oncolytic Adenoviral Vector Which Expresses an Anti-CD40 Antibody) (FORTITUDE). U.S. National Institutes of Health.

REF 15

Clinical pipeline report, company report or official report of Roche

REF 16

ClinicalTrials.gov (NCT04406623) Phase 1 Study of SL-172154 (SIRPalpha-Fc-CD40L) in Subjects With Ovarian Cancer. U.S. National Institutes of Health.

REF 17

ClinicalTrials.gov (NCT05017623) A Multicenter, Open-label, Phase 1 Dose Escalation Study to Evaluate the Safety, Tolerability, and Pharmacokinetics of YH003 in Subjects With Advanced Solid Tumors. U.S.National Institutes of Health.

REF 18

REF 19

Trusted, scientifically sound profiles of drug programs, clinical trials, safety reports, and company deals, written by scientists. Springer. 2015. Adis Insight (drug id 800008196)

REF 20

Clinical pipeline report, company report or official report of the Pharmaceutical Research and Manufacturers of America (PhRMA)

REF 21

Clinical pipeline report, company report or official report of the Pharmaceutical Research and Manufacturers of America (PhRMA)

REF 22

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.

REF 23

Developments in immunosuppression. Curr Opin Organ Transplant. 2021 Feb 1;26(1):91-96.

REF 24

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.

REF 25

Development of CDX-1140, an agonist CD40 antibody for cancer immunotherapy. Cancer Immunol Immunother. 2019 Feb;68(2):233-245.

REF 26

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.

REF 27

Clinical pipeline report, company report or official report of Genmab.

REF 28

Clinical pipeline report, company report or official report of PsiOxus Therapeutics.

REF 29

Clinical pipeline report, company report or official report of Shattuck Labs.

REF 30

Clinical pipeline report, company report or official report of Biocytogen

REF 31

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.

REF 32

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.

REF 33

Growth-inhibitory effects of CD40 ligand (CD154) and its endogenous expression in human breast cancer. Clin Cancer Res. 2001 Mar;7(3):691-703.

REF 34

Clinical pipeline report, company report or official report of Biocytogen

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