Details of the Drug Therapeutic Target (DTT)

General Information of Drug Therapeutic Target (DTT) (ID: TTIJP3Q)

• DTT Name: TNF related activation protein (CD40LG)
• Synonyms: Tumor necrosis factor ligand superfamily member 5; TRAP; TNFSF5; TNF-related activation protein; T-cell antigen Gp39; T cell antigen Gp39; CD40L; CD40-L; CD40 ligand; CD154 antigen; CD154
• Gene Name: CD40LG
• DTT Type: Clinical trial target; [1]
• BioChemical Class: Cytokine: tumor necrosis factor
• UniProt ID: CD40L_HUMAN
• TTD ID: T14755
• Sequence:
  MIETYNQTSPRSAATGLPISMKIFMYLLTVFLITQMIGSALFAVYLHRRLDKIEDERNLH
  EDFVFMKTIQRCNTGERSLSLLNCEEIKSQFEGFVKDIMLNKEETKKENSFEMQKGDQNP
  QIAAHVISEASSKTTSVLQWAEKGYYTMSNNLVTLENGKQLTVKRQGLYYIYAQVTFCSN
  REASSQAPFIASLCLKSPGRFERILLRAANTHSSAKPCGQQSIHLGGVFELQPGASVFVN
  VTDPSQVSHGTGFTSFGLLKL
• Function: Costimulates T-cell proliferation and cytokine production. Its cross-linking on T-cells generates a costimulatory signal which enhances the production of IL4 and IL10 in conjunction with the TCR/CD3 ligation and CD28 costimulation. Induces the activation of NF-kappa-B and kinases MAPK8 and PAK2 in T-cells. Induces tyrosine phosphorylation of isoform 3 of CD28. Mediates B-cell proliferation in the absence of co-stimulus as well as IgE production in the presence of IL4. Involved in immunoglobulin class switching. Cytokine that binds to CD40/TNFRSF5.
• KEGG Pathway:
  Cytokine-cytokine receptor interaction (hsa04060)
  NF-kappa B signaling pathway (hsa04064)
  Cell adhesion molecules (CAMs) (hsa04514)
  T cell receptor signaling pathway (hsa04660)
  Intestinal immune network for IgA production (hsa04672)
  Malaria (hsa05144)
  Toxoplasmosis (hsa05145)
  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

12 Clinical Trial Drug(s) Targeting This DTT

Drug Name	Drug ID	Indication	ICD 11	Highest Status	REF
BI 655064	DMF86P2	Lupus	4A40	Phase 2	[2]
Dapirolizumab pegol	DMIYFWA	Systemic lupus erythematosus	4A40.0	Phase 2	[3]
IL-2/CD40L-expressing leukemia vaccine	DMIHQ5G	Chronic lymphocytic leukaemia	2A82.0	Phase 2	[1]
ISF35	DMBZK3P	Chronic lymphocytic leukaemia	2A82.0	Phase 2	[4]
Lucatumumab	DMY2L7V	Lymphoma	2A80-2A86	Phase 2	[5]
PG-102	DMF5YEN	Autoimmune diabetes	5A10	Phase 2	[6]
ABBV-428	DMPD0KL	Solid tumour/cancer	2A00-2F9Z	Phase 1	[7]
BPX-101	DM51MSD	Prostate cancer	2C82.0	Phase 1	[8]
CDP-7657	DMN8I5Q	Systemic lupus erythematosus	4A40.0	Phase 1	[9]
Chi Lob 7/4	DMSOB5D	B-cell lymphoma	2A86	Phase 1	[10]
MEDI4920	DME7BMT	Rheumatoid arthritis	FA20	Phase 1	[11]
UltraCD40L	DMHG7DZ	Systemic lupus erythematosus	4A40.0	Phase 1	[12]

3 Discontinued Drug(s) Targeting This DTT

Drug Name	Drug ID	Indication	ICD 11	Highest Status	REF
IDEC-131	DMAU79Q	Thrombocytopenia	3B64	Discontinued in Phase 1	[13]
Antova	DMXKZDU	Thrombocytopenia	3B64	Terminated	[14]
Dacetuzumab	DMP3X6Q	Diffuse large B-cell lymphoma	2A81	Terminated	[15]

1 Investigative Drug(s) Targeting This DTT

Drug Name	Drug ID	Indication	ICD 11	Highest Status	REF
TriMixDC	DML3OYH	Melanoma	2C30	Investigative	[16]

Molecular Expression Atlas (MEA) of This DTT

Disease Name	ICD 11	Studied Tissue	p-value	Fold-Change	Z-score
Prostate cancer	2C82	Prostate	1.81E-06	-0.89	-1.99
Rheumatoid arthritis	FA20	Synovial tissue	8.34E-01	3.17E-03	7.24E-03
Sjogren's syndrome	4A43.2	Salivary gland tissue	8.02E-01	-0.13	-0.7
Thrombocytopenia	3B64	Whole blood	3.90E-01	0.04	0.05
Melanoma	2C82	Skin	3.31E-01	0.32	0.64

References

• [1] Immunotherapy of high-risk acute leukemia with a recipient (autologous) vaccine expressing transgenic human CD40L and IL-2 after chemotherapy and a... Blood. 2006 Feb 15;107(4):1332-41.
• [2] FRI0167 Patient-Reported Outcomes (PROS) During Treatment with Mavrilimumab, A Fully Human Monoclonal Antibody Targeting GMCSFR-Alpha, In the Phase IIB Earth Explorer 1 Study
• [3] Clinical pipeline report, company report or official report of the Pharmaceutical Research and Manufacturers of America (PhRMA)
• [4] Intratumoral injection of Ad-ISF35 (Chimeric CD154) breaks tolerance and induces lymphoma tumor regression. Hum Gene Ther. 2015 Jan;26(1):14-25.
• [5] Phase I study of the anti-CD40 humanized monoclonal antibody lucatumumab (HCD122) in relapsed chronic lymphocytic leukemia.Leuk Lymphoma.2012 Nov;53(11):2136-42.
• [6] Induction of an altered CD40 signaling complex by an antagonistic human monoclonal antibody to CD40.J Immunol.2015 May 1;194(9):4319-27.
• [7] Clinical pipeline report, company report or official report of the Pharmaceutical Research and Manufacturers of America (PhRMA)
• [8] Activation of antigen-exposed iMC-DCs at the ight place and ight time promotes potent anti-tumor immunity. Oncoimmunology. 2012 May 1; 1(3): 362-363.
• [9] CDP7657, an anti-CD40L antibody lacking an Fc domain, inhibits CD40L-dependent immune responses without thrombotic complications: an in vivo study. Arthritis Res Ther. 2015 Sep 3;17:234.
• [10] Agonistic CD40 antibodies and cancer therapy
• [11] ClinicalTrials.gov (NCT02151110) A Phase 1, Randomized, Blinded, Placebo-controlled, Single-ascending Dose Study to Evaluate the Safety and Tolerability of MEDI4920 in Healthy Adults. U.S. National Institutes of Health.
• [12] CD40L-Tri, a novel formulation of recombinant human CD40L that effectively activates B cells. Cancer Immunol Immunother. 2013 February; 62(2): 347-357.
• [13] Phase I clinical trial of a monoclonal antibody against CD40-ligand (IDEC-131) in patients with systemic lupus erythematosus. J Rheumatol. 2001 Jan;28(1):95-101.
• [14] CD40 and Autoimmunity: The Dark Side of a Great Activator
• [15] A phase I study of dacetuzumab (SGN-40, a humanized anti-CD40 monoclonal antibody) in patients with chronic lymphocytic leukemia.Leuk Lymphoma.2010 Feb;51(2):228-35.
• [16] Characterization of CD8+ T-cell responses in the peripheral blood and skin injection sites of melanoma patients treated with mRNA electroporated autologous dendritic cells (TriMixDC-MEL). Biomed Res Int. 2013;2013:976383.