CD47

Target id: 2943

Nomenclature: CD47

Gene and Protein Information
Species	TM	AA	Chromosomal Location	Gene Symbol	Gene Name	Reference
Human	5	323	3q13.12	CD47	CD47 molecule
Mouse	5	303	16 B5	Cd47	CD47 antigen (Rh-related antigen, integrin-associated signal transducer)
Rat	5	303	11q21	Cd47	Cd47 molecule
Gene and Protein Information Comments
There are four alternatively spliced isoforms of human CD47 that differ only in the length of their cytoplasmic tail [9]. Although the functional significance of the alternate splice variants is poorly understood., evidence of the highly conserved nature of the isoforms between mouse and man, suggests an important role for the cytoplasmic domains in CD47 function. Isoform 2 is the most widely expressed form that is found in all circulating and immune cells.

Previous and Unofficial Names
CD47 antigen \| CD47 antigen (Rh-related antigen, integrin-associated signal transducer) \| CD47 antigen (Rh-related antigen \| integrin associated protein IAP \| integrin-associated signal transducer \| MER6

Previous and Unofficial Names

Database Links
Alphafold	Q08722 (Hs), Q61735 (Mm), P97829 (Rn)
CATH/Gene3D	2.60.40.10
ChEMBL Target	CHEMBL3714583 (Hs)
Ensembl Gene	ENSG00000196776 (Hs), ENSMUSG00000055447 (Mm), ENSRNOG00000001964 (Rn)
Entrez Gene	961 (Hs), 16423 (Mm), 29364 (Rn)
Human Protein Atlas	ENSG00000196776 (Hs)
KEGG Gene	hsa:961 (Hs), mmu:16423 (Mm), rno:29364 (Rn)
OMIM	601028 (Hs)
Pharos	Q08722 (Hs)
RefSeq Nucleotide	NM_198793 (Hs), NM_010581 (Mm), NM_019195 (Rn)
RefSeq Protein	NP_942088 (Hs), NP_034711 (Mm), NP_062068 (Rn)
UniProtKB	Q08722 (Hs), Q61735 (Mm), P97829 (Rn)
Wikipedia	CD47 (Hs)

Immunopharmacology Comments

CD47 belongs to the immunoglobulin superfamily and is reported to bind membrane integrins and the ligands thrombospondin-1 (TSP-1) and signal-regulatory protein alpha (SIRPα). It is a ubiquitously expressed membrane protein that is a 'marker of self', and which is involved in self tolerance. Binding to SIRPα produces an anti-phagocytic signal. CD47 expression is hijacked by cancer cells to evade immune surveillance and macrophage-mediated removal. Anti-CD47 monoclonal antibodies are being investigated as novel immuno-oncology agents [7]. Efficacy of this strategy has been demonstrated in malignant pediatric brain tumours, in vitro and in vivo in patient-derived orthotopic xenograft models [5]. A novel engineered dual-targeting bispecific antibody format, called κλ bodies [4] that selectively block the CD47-SIRPα interaction and simultaneously bind a tumour specific antigen (e.g. CD19 or mesothelin) and mediate immune activation via the Fc portion of the antibody have been shown to effectively kill cancer cells in vitro and in vivo, whilst sparing normal cells [3]. This approach is postulated to be applicable to targeting of other ubiquitously expressed therapeutic proteins. Intratumoural delivery of an anti-CD47 nanobody using engineered, non-pathogenic Escherichia coli has produced local and systemic anti-tumour effects in mouse syngeneic tumour models [2].
Several pharma companies have anti-CD47 therapeutics under early clinical evaluation (tabulated below)

Name	Company	Comment
Hu5F9-G4	Forty Seven	Phase 1/2 evaluations in combination with cetuximab or rituximab (NCT02953782, NCT02953509)
CC-90002/INBRX-103	Celgene/Inhibrx	Phase I in AML was terminated in October 2018 (NCT02641002)
ALX148	ALX Oncology (previously Alexo)	Phase 1 in combination with pembrolizumab, trastuzumab or rituximab (NCT03013218)
SRF231	Surface Oncology	Phase 1 monotherapy trial began in March 2018 (NCT03512340)

Trillium Therapeutics have two anti-SIRPα fusion proteins in Phase 1 (TTI-621 and TTI-622), and other companies have additional CD47/SIRPα-disrupting agents in preclinical testing (e.g. TG-1801 (NI-1701), NI-1801, OSE-172, AO-176, IBI188 and DSP107).

Immuno Process Associations

Immuno Process:

Inflammation

GO Annotations:

Associated to 5 GO processes

GO:0050729	positive regulation of inflammatory response	IBA
GO:0050766	positive regulation of phagocytosis	IBA
GO:0071346	cellular response to type II interferon	ISS
GO:1905450	negative regulation of Fc-gamma receptor signaling pathway involved in phagocytosis	ISS
GO:2000439	positive regulation of monocyte extravasation	ISS

Immuno Process:

T cell (activation)

GO Annotations:

Associated to 1 GO processes

GO:0050870

positive regulation of T cell activation

IDA

Immuno Process:

Immune regulation

GO Annotations:

Associated to 4 GO processes

GO:0050729	positive regulation of inflammatory response	IBA
GO:0050870	positive regulation of T cell activation	IDA
GO:1905450	negative regulation of Fc-gamma receptor signaling pathway involved in phagocytosis	ISS
GO:2000439	positive regulation of monocyte extravasation	ISS

Immuno Process:

Chemotaxis & migration

GO Annotations:

Associated to 2 GO processes

GO:0050870	positive regulation of T cell activation	IDA
GO:2000439	positive regulation of monocyte extravasation	ISS

Immuno Process:

Cellular signalling

GO Annotations:

Associated to 2 GO processes

GO:0050870	positive regulation of T cell activation	IDA
GO:1905450	negative regulation of Fc-gamma receptor signaling pathway involved in phagocytosis	ISS

Immuno Process:

Cytokine production & signalling

GO Annotations:

Associated to 8 GO processes

GO:0032649	regulation of type II interferon production	IMP
GO:0032653	regulation of interleukin-10 production	IMP
GO:0032655	regulation of interleukin-12 production	IMP
GO:0032675	regulation of interleukin-6 production	IMP
GO:0032680	regulation of tumor necrosis factor production	IMP
GO:0071346	cellular response to type II interferon	ISS
GO:0071347	cellular response to interleukin-1	ISS
GO:0071349	cellular response to interleukin-12	IMP

General Comments
CD47 is a ubiquitously expressed membrane protein that is a 'marker of self'. It is a ligand of SIRPα. The CD47/SIRPα anti-phagocytic axis is important for self-tolerance. CD47 binds thrombospondin-1 (TSP-1), an interaction with a role in the regulation of angiogenesis and inflammation, and in cellular functions including cell migration, adhesion, proliferation and apoptosis. CD47 also binds several membrane integrins [1] (e.g. αvβ3) which is likely involved in modulation of cellular adhesion, spreading and migration. CD47 is an immuno-oncology drug target [10].

General Comments

CD47 is a ubiquitously expressed membrane protein that is a 'marker of self'. It is a ligand of SIRPα. The CD47/SIRPα anti-phagocytic axis is important for self-tolerance. CD47 binds thrombospondin-1 (TSP-1), an interaction with a role in the regulation of angiogenesis and inflammation, and in cellular functions including cell migration, adhesion, proliferation and apoptosis. CD47 also binds several membrane integrins [1] (e.g. αvβ3) which is likely involved in modulation of cellular adhesion, spreading and migration. CD47 is an immuno-oncology drug target [10].

References

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1. Brown EJ, Frazier WA. (2001) Integrin-associated protein (CD47) and its ligands. Trends Cell Biol, 11 (3): 130-5. [PMID:11306274]

2. Chowdhury S, Castro S, Coker C, Hinchliffe TE, Arpaia N, Danino T. (2019) Programmable bacteria induce durable tumor regression and systemic antitumor immunity. Nat Med, 25 (7): 1057-1063. [PMID:31270504]

3. Dheilly E, Moine V, Broyer L, Salgado-Pires S, Johnson Z, Papaioannou A, Cons L, Calloud S, Majocchi S, Nelson R et al.. (2017) Selective Blockade of the Ubiquitous Checkpoint Receptor CD47 Is Enabled by Dual-Targeting Bispecific Antibodies. Mol Ther, 25 (2): 523-533. [PMID:28153099]

4. Fischer N, Elson G, Magistrelli G, Dheilly E, Fouque N, Laurendon A, Gueneau F, Ravn U, Depoisier JF, Moine V et al.. (2015) Exploiting light chains for the scalable generation and platform purification of native human bispecific IgG. Nat Commun, 6: 6113. [PMID:25672245]

5. Gholamin S, Mitra SS, Feroze AH, Liu J, Kahn SA, Zhang M, Esparza R, Richard C, Ramaswamy V, Remke M et al.. (2017) Disrupting the CD47-SIRPα anti-phagocytic axis by a humanized anti-CD47 antibody is an efficacious treatment for malignant pediatric brain tumors. Sci Transl Med, 9 (381). [PMID:28298418]

6. Kauder SE, Kuo TC, Harrabi O, Chen A, Sangalang E, Doyle L, Rocha SS, Bollini S, Han B, Sim J et al.. (2018) ALX148 blocks CD47 and enhances innate and adaptive antitumor immunity with a favorable safety profile. PLoS One, 13 (8): e0201832. [PMID:30133535]

7. Liu J, Wang L, Zhao F, Tseng S, Narayanan C, Shura L, Willingham S, Howard M, Prohaska S, Volkmer J et al.. (2015) Pre-Clinical Development of a Humanized Anti-CD47 Antibody with Anti-Cancer Therapeutic Potential. PLoS ONE, 10 (9): e0137345. [PMID:26390038]

8. Petrova PS, Viller NN, Wong M, Pang X, Lin GH, Dodge K, Chai V, Chen H, Lee V, House V et al.. (2017) TTI-621 (SIRPαFc): A CD47-Blocking Innate Immune Checkpoint Inhibitor with Broad Antitumor Activity and Minimal Erythrocyte Binding. Clin Cancer Res, 23 (4): 1068-1079. [PMID:27856600]

9. Reinhold MI, Lindberg FP, Plas D, Reynolds S, Peters MG, Brown EJ. (1995) In vivo expression of alternatively spliced forms of integrin-associated protein (CD47). J Cell Sci, 108 ( Pt 11): 3419-25. [PMID:8586654]

10. Sick E, Jeanne A, Schneider C, Dedieu S, Takeda K, Martiny L. (2012) CD47 update: a multifaceted actor in the tumour microenvironment of potential therapeutic interest. Br J Pharmacol, 167 (7): 1415-30. [PMID:22774848]

How to cite this page

CD molecules: CD47. Last modified on 27/06/2022. Accessed on 10/06/2023. IUPHAR/BPS Guide to PHARMACOLOGY, https://www.guidetomalariapharmacology.org/GRAC/ObjectDisplayForward?objectId=2943.

CD47

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References

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