SIRPA (CD172a)

Target id: 2942

Nomenclature: SIRPA (CD172a)

Family: CD molecules, Signal regulatory proteins

Gene and Protein Information
Species	TM	AA	Chromosomal Location	Gene Symbol	Gene Name	Reference
Human	1	504	20p13	SIRPA	signal regulatory protein alpha
Mouse	1	513	2 63.19 cM	Sirpa	signal-regulatory protein alpha
Rat	1	509	3q36	Sirpa	signal-regulatory protein alpha
Gene and Protein Information Comments
Details are provided for the shorter protein isoform (isoform 1) encoded by the human gene. Isofom 2 is the longer protein at 508 amino acids (see NP_001317657). For the mouse, we show isoform 3 peptide details.

Database Links
Alphafold	P78324 (Hs), P97797 (Mm), P97710 (Rn)
CATH/Gene3D	2.60.40.10
Ensembl Gene	ENSG00000198053 (Hs), ENSMUSG00000037902 (Mm), ENSRNOG00000004763 (Rn)
Entrez Gene	140885 (Hs), 19261 (Mm), 25528 (Rn)
Human Protein Atlas	ENSG00000198053 (Hs)
KEGG Gene	hsa:140885 (Hs), mmu:19261 (Mm), rno:25528 (Rn)
OMIM	602461 (Hs)
Pharos	P78324 (Hs)
RefSeq Nucleotide	NM_001040022 (Hs), NM_001291020 (Mm), NM_013016 (Rn)
RefSeq Protein	NP_001035111 (Hs), NP_001277949 (Mm), NP_037148 (Rn)
UniProtKB	P78324 (Hs), P97797 (Mm), P97710 (Rn)
Wikipedia	SIRPA (Hs)

Other Binding Ligands

Key to terms and symbols

Click column headers to sort

Ligand											Sp.	Action	Value	Parameter	Reference
thrombospondin 1 {Sp: Human}											Hs	Binding	-	-
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Immunopharmacology Comments
SIRPα is an important inhibitory immune response regulator. In interaction with CD47, SIRPα controls an inhibitory innate immune checkpoint that provides an anti-phagocytic (do not eat) signal. SIRPα is predominantly expressed by macrophages. Laboratory work has established that SIRPα is expressed by a subset of intestinal dendritic cells (integrin CD103⁺ DCs) that are critical for maintaining intestinal (mucosal) immune system homeostasis. This subset of CD103⁺SIRPα⁺ DCs selectively activates Th17 cells and type 3 innate lymphoid cells (ILC3) [3,8]. Studies by Hansen et al. (2018) have shown that CD103⁺SIRPα⁺ DCs can be transformed in to pro-inflammatory cells via a process involving FcαRI co-stimulation-induced glycolytic reprogramming. This work shows how IgA-immune complexes in the human intestine can convert a tolerogenic milieu to a pro-inflammatory one, following exposure to environmental agents [2]. In the cancer setting, SIRPα expressed on immune cells binds to CD47 on tumour cells, which down-regulates myeloid lineage cells, including DCs, tumour-associated macrophages (TAMs) and myeloid-derived suppressor cells. The SIRPα/CD47 anti-phagocytic signal is exploited by some cancers to avoid immune destruction. Pharmacological agents which block this anti-phagocytic axis are being investigated as potential immuno-oncology therapeutics which would act to promote immunosurveillance and increase phagocytosis of cancer cells by TAMs [5,7]. The anti-SIPRα monoclonal antibody (mAb) BI765063 (formerly OSE-172) is in early stage development (OSE IMMUNOTherapeutics), and proof of concept has been demonstrated in in vivo models. Preclinical testing suggests that the therapeutic effect of BI765063 is observed in both monotherapy or when combined with other checkpoint inhibitors, or with immune system stimulators. Anti-CD47 antibodies are also in early stage development, as reported by Gholamin et al. (2017) [1]. Trillium Therapeutics are developing SIRPα-Fc fusion proteins (e.g. ontorpacept/TTI-621 [6]) to disrupt SIRPα/CD47 signalling as an alternative to anti-SIRPα or anti-CD47 mAbs. A strategy that involves derivatizing a kinase inhibitor with a cholesterol anchor (in this case creating an analogue of the CSF1R inhibitor sotuletinib) and assembling it in a supramolecular structure with a macrophage-targeting anti-SIRPα mAb has been reported to enhance phagocytosis and removal of melanoma cells by TAMs in vitro and in vivo [4].

Immunopharmacology Comments

SIRPα is an important inhibitory immune response regulator. In interaction with CD47, SIRPα controls an inhibitory innate immune checkpoint that provides an anti-phagocytic (do not eat) signal. SIRPα is predominantly expressed by macrophages. Laboratory work has established that SIRPα is expressed by a subset of intestinal dendritic cells (integrin CD103⁺ DCs) that are critical for maintaining intestinal (mucosal) immune system homeostasis. This subset of CD103⁺SIRPα⁺ DCs selectively activates Th17 cells and type 3 innate lymphoid cells (ILC3) [3,8]. Studies by Hansen et al. (2018) have shown that CD103⁺SIRPα⁺ DCs can be transformed in to pro-inflammatory cells via a process involving FcαRI co-stimulation-induced glycolytic reprogramming. This work shows how IgA-immune complexes in the human intestine can convert a tolerogenic milieu to a pro-inflammatory one, following exposure to environmental agents [2].

In the cancer setting, SIRPα expressed on immune cells binds to CD47 on tumour cells, which down-regulates myeloid lineage cells, including DCs, tumour-associated macrophages (TAMs) and myeloid-derived suppressor cells. The SIRPα/CD47 anti-phagocytic signal is exploited by some cancers to avoid immune destruction. Pharmacological agents which block this anti-phagocytic axis are being investigated as potential immuno-oncology therapeutics which would act to promote immunosurveillance and increase phagocytosis of cancer cells by TAMs [5,7]. The anti-SIPRα monoclonal antibody (mAb) BI765063 (formerly OSE-172) is in early stage development (OSE IMMUNOTherapeutics), and proof of concept has been demonstrated in in vivo models. Preclinical testing suggests that the therapeutic effect of BI765063 is observed in both monotherapy or when combined with other checkpoint inhibitors, or with immune system stimulators. Anti-CD47 antibodies are also in early stage development, as reported by Gholamin et al. (2017) [1]. Trillium Therapeutics are developing SIRPα-Fc fusion proteins (e.g. ontorpacept/TTI-621 [6]) to disrupt SIRPα/CD47 signalling as an alternative to anti-SIRPα or anti-CD47 mAbs.
A strategy that involves derivatizing a kinase inhibitor with a cholesterol anchor (in this case creating an analogue of the CSF1R inhibitor sotuletinib) and assembling it in a supramolecular structure with a macrophage-targeting anti-SIRPα mAb has been reported to enhance phagocytosis and removal of melanoma cells by TAMs in vitro and in vivo [4].

Immuno Process Associations

Immuno Process:

Inflammation

Immuno Process:

Chemotaxis & migration

Immuno Process:

Cellular signalling

Immuno Process:

Cytokine production & signalling

Immuno Process:

Immune regulation

Immuno Process:

T cell (activation)

Immuno Process:

Antigen presentation

Immuno Process:

Immune system development

General Comments
The SIPRα protein binding interaction with CD47 produces an antiphagocytic signal, that is often termed a 'don't eat me' signal. This protein contains an immunoglobulin (Ig)-like domain that resembles the antibody variable domain, that has been coined the 'V-set domain'. The genes for all human V-set domain containing proteins are listed in HGNC gene group 590.

References

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1. 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]

2. Hansen IS, Krabbendam L, Bernink JH, Loayza-Puch F, Hoepel W, van Burgsteden JA, Kuijper EC, Buskens CJ, Bemelman WA, Zaat SAJ et al.. (2018) FcαRI co-stimulation converts human intestinal CD103⁺dendritic cells into pro-inflammatory cells through glycolytic reprogramming. Nat Commun, 9 (1): 863. [PMID:29491406]

3. Joeris T, Müller-Luda K, Agace WW, Mowat AM. (2017) Diversity and functions of intestinal mononuclear phagocytes. Mucosal Immunol, 10 (4): 845-864. [PMID:28378807]

4. Kulkarni A, Chandrasekar V, Natarajan SK, Ramesh A, Pandey P, Nirgud J, Bhatnagar H, Ashok D, Ajay AK, Sengupta S. (2018) A designer self-assembled supramolecule amplifies macrophage immune responses against aggressive cancer. Nat Biomed Eng, 2 (8): 589-599. [PMID:30956894]

5. Oronsky B, Carter C, Reid T, Brinkhaus F, Knox SJ. (2020) Just eat it: A review of CD47 and SIRP-α antagonism. Semin Oncol, 47 (2-3): 117-124. [PMID:32517874]

6. 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]

7. Russ A, Hua AB, Montfort WR, Rahman B, Riaz IB, Khalid MU, Carew JS, Nawrocki ST, Persky D, Anwer F. (2018) Blocking "don't eat me" signal of CD47-SIRPα in hematological malignancies, an in-depth review. Blood Rev, 32 (6): 480-489. [PMID:29709247]

8. Watchmaker PB, Lahl K, Lee M, Baumjohann D, Morton J, Kim SJ, Zeng R, Dent A, Ansel KM, Diamond B et al.. (2014) Comparative transcriptional and functional profiling defines conserved programs of intestinal DC differentiation in humans and mice. Nat Immunol, 15 (1): 98-108. [PMID:24292363]

How to cite this page

CD molecules: SIRPA (CD172a). Last modified on 04/12/2023. Accessed on 11/12/2024. IUPHAR/BPS Guide to PHARMACOLOGY, https://www.guidetomalariapharmacology.org/GRAC/ObjectDisplayForward?objectId=2942.

SIRPA (CD172a)

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References

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