TIM3 (CD366)

Target id: 2940

Nomenclature: TIM3 (CD366)

Family: Other immune checkpoint proteins, CD molecules

Gene and Protein Information
Species	TM	AA	Chromosomal Location	Gene Symbol	Gene Name	Reference
Human	1	301	5q33.3	HAVCR2	hepatitis A virus cellular receptor 2	5
Mouse	1	281	11 B1.1	Havcr2	hepatitis A virus cellular receptor 2
Rat	1	282	10q21	Havcr2	hepatitis A virus cellular receptor 2

Previous and Unofficial Names
T-cell immunoglobulin mucin family member 3 \| TIM-3 \| TIMD-3

Database Links
Alphafold	Q8TDQ0 (Hs), Q8VIM0 (Mm), P0C0K5 (Rn)
CATH/Gene3D	2.60.40.10
ChEMBL Target	CHEMBL4630879 (Hs)
Ensembl Gene	ENSG00000135077 (Hs), ENSMUSG00000020399 (Mm), ENSRNOG00000031443 (Rn)
Entrez Gene	84868 (Hs), 171285 (Mm), 363578 (Rn)
Human Protein Atlas	ENSG00000135077 (Hs)
KEGG Gene	hsa:84868 (Hs), mmu:171285 (Mm), rno:363578 (Rn)
OMIM	606652 (Hs)
Pharos	Q8TDQ0 (Hs)
RefSeq Nucleotide	NM_032782 (Hs), NM_134250 (Mm), NM_001100762 (Rn)
RefSeq Protein	NP_116171 (Hs), NP_599011 (Mm), NP_001094232 (Rn)
UniProtKB	Q8TDQ0 (Hs), Q8VIM0 (Mm), P0C0K5 (Rn)
Wikipedia	HAVCR2 (Hs)

Natural/Endogenous Ligands
galectin 9 {Sp: Human}

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Antibodies

Key to terms and symbols

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Antibody		Sp.	Action	Value	Parameter	Reference
sabatolimab		Hs	Binding	9.8	pK_d	7
⤷	pK_d 9.8 (K_d 1.67x10^-10 M) [7] Description: Binding affinity for recombinant hTIM3 by BiaCore analysis
sabatolimab		Monkey	Binding	9.1	pK_d	7
⤷	pK_d 9.1 (K_d 7.24x10^-10 M) [7] Description: Binding affinity for recombinant cyno TIM3 by BiaCore analysis
sabatolimab		Hs	Inhibition	8.3	pIC₅₀	7
⤷	pIC₅₀ 8.3 (IC₅₀ 4.74x10^-9 M) [7] Description: Inhibition of galectin-9 binding to hTIM3 using a MesoScale discovery platform with plate-bound TIM3 and Sulfo-Tagged galectin-9 as substrate

Immunopharmacology Comments
TIM3 is an immunoglobulin type protein expressed exclusively on the surface of differentiated Th1 cells [5]. It is a co-inhibitory receptor immune checkpoint protein that regulates macrophage activation, and inhibits Th1-mediated auto- and alloimmune responses, and promotes immunological tolerance. TIM3 is an immuno-oncology drug target [1,6], and may provide an additional strategy for cancers that develop adaptive resistance to current PD-1/PD-L1 axis immune checkpoint inhibitor therapies [3]. LY3321367 and MBG453 are anti-TIM3 monoclonals in early stage clinical trial: LY3321367 in Phase 1 trial NCT03099109 with LY3300054 (a novel anti-PD-L1 checkpoint inhibitor), and MBG453 ± spartalizumab (PDR001, anti-PD-1) vs. both advanced solid tumours (NCT02608268, Phase 1/2) and hematological malignancies (NCT03066648, Phase 1). Symphogen have the anti-TIM3 mAb Sym023 in their immuno-oncology pipeline (see Phase 1 trial NCT03489343). Tesaro's anti-TIM3 mAb TSR-022 is also in Phase 1 development (NCT02817633).

Immunopharmacology Comments

TIM3 is an immunoglobulin type protein expressed exclusively on the surface of differentiated Th1 cells [5]. It is a co-inhibitory receptor immune checkpoint protein that regulates macrophage activation, and inhibits Th1-mediated auto- and alloimmune responses, and promotes immunological tolerance. TIM3 is an immuno-oncology drug target [1,6], and may provide an additional strategy for cancers that develop adaptive resistance to current PD-1/PD-L1 axis immune checkpoint inhibitor therapies [3]. LY3321367 and MBG453 are anti-TIM3 monoclonals in early stage clinical trial: LY3321367 in Phase 1 trial NCT03099109 with LY3300054 (a novel anti-PD-L1 checkpoint inhibitor), and MBG453 ± spartalizumab (PDR001, anti-PD-1) vs. both advanced solid tumours (NCT02608268, Phase 1/2) and hematological malignancies (NCT03066648, Phase 1). Symphogen have the anti-TIM3 mAb Sym023 in their immuno-oncology pipeline (see Phase 1 trial NCT03489343). Tesaro's anti-TIM3 mAb TSR-022 is also in Phase 1 development (NCT02817633).

Cell Type Associations

Immuno Cell Type:	T cells
Cell Ontology Term:	T-helper 1 cell (CL:0000545)
Comment:	TIM3 is a selective marker of differentiated Th1 cells. Upregulation of TIM3 expression is reported as a biomarker associated with adaptive resistance to PD-1 blockade.
References:	3

Immuno Cell Type:	Natural killer cells
Comment:	TIM3 is expressed by mature NK cells, including human decidual NK cells. Its expression is upregulated on NK cells from patients with melanoma and lung adenocarcinoma. Elevated expression impairs NK cell effector functions.
References:	2,4,8

Immuno Cell Type:	Innate lymphoid cells
Cell Ontology Term:	group 3 innate lymphoid cell (CL:0001071)
Comment:	TIM3 expression has been reported on human ILC3s.
References:	4

Immuno Process Associations

Immuno Process:

Inflammation

GO Annotations:

Associated to 11 GO processes

GO:0030886	negative regulation of myeloid dendritic cell activation	IMP
GO:2001189	negative regulation of T cell activation via T cell receptor contact with antigen bound to MHC molecule on antigen presenting cell	IDA
	click arrow to show/hide IEA associations
GO:0002281	macrophage activation involved in immune response	IEA
GO:0002859	negative regulation of natural killer cell mediated cytotoxicity directed against tumor cell target	IEA
GO:0006954	inflammatory response	IEA
GO:0034138	toll-like receptor 3 signaling pathway	IEA
GO:0034154	toll-like receptor 7 signaling pathway	IEA
GO:0034162	toll-like receptor 9 signaling pathway	IEA
GO:0043032	positive regulation of macrophage activation	IEA
GO:0045087	innate immune response	IEA
GO:0045089	positive regulation of innate immune response	IEA

Immuno Process:

T cell (activation)

GO Annotations:

Associated to 6 GO processes

GO:2001189	negative regulation of T cell activation via T cell receptor contact with antigen bound to MHC molecule on antigen presenting cell	IDA
	click arrow to show/hide IEA associations
GO:0002250	adaptive immune response	IEA
GO:0002652	regulation of tolerance induction dependent upon immune response	IEA
GO:0002826	negative regulation of T-helper 1 type immune response	IEA
GO:0042102	positive regulation of T cell proliferation	IEA
GO:0042130	negative regulation of T cell proliferation	IEA

Immuno Process:

Immune regulation

GO Annotations:

Associated to 14 GO processes

GO:0030886	negative regulation of myeloid dendritic cell activation	IMP
GO:2001189	negative regulation of T cell activation via T cell receptor contact with antigen bound to MHC molecule on antigen presenting cell	IDA
	click arrow to show/hide IEA associations
GO:0002652	regulation of tolerance induction dependent upon immune response	IEA
GO:0002826	negative regulation of T-helper 1 type immune response	IEA
GO:0002859	negative regulation of natural killer cell mediated cytotoxicity directed against tumor cell target	IEA
GO:0032815	negative regulation of natural killer cell activation	IEA
GO:0034138	toll-like receptor 3 signaling pathway	IEA
GO:0034154	toll-like receptor 7 signaling pathway	IEA
GO:0034162	toll-like receptor 9 signaling pathway	IEA
GO:0042102	positive regulation of T cell proliferation	IEA
GO:0042130	negative regulation of T cell proliferation	IEA
GO:0043032	positive regulation of macrophage activation	IEA
GO:0045089	positive regulation of innate immune response	IEA
GO:2000521	negative regulation of immunological synapse formation	IEA

Immuno Process:

Immune system development

GO Annotations:

Associated to 2 GO processes

GO:0002519	natural killer cell tolerance induction	IMP
	click arrow to show/hide IEA associations
GO:0002652	regulation of tolerance induction dependent upon immune response	IEA

Immuno Process:

Cytokine production & signalling

GO Annotations:

Associated to 15 GO processes

GO:0032687	negative regulation of interferon-alpha production	IDA
GO:0032689	negative regulation of type II interferon production	IDA
GO:0032703	negative regulation of interleukin-2 production	IDA
GO:0032712	negative regulation of interleukin-3 production	IDA
GO:0032720	negative regulation of tumor necrosis factor production	IMP
GO:0032753	positive regulation of interleukin-4 production	IMP
GO:0032760	positive regulation of tumor necrosis factor production	IMP
GO:0071656	negative regulation of granulocyte colony-stimulating factor production	IDA
	click arrow to show/hide IEA associations
GO:0032715	negative regulation of interleukin-6 production	IEA
GO:0032722	positive regulation of chemokine production	IEA
GO:0032729	positive regulation of type II interferon production	IEA
GO:0032732	positive regulation of interleukin-1 production	IEA
GO:0034138	toll-like receptor 3 signaling pathway	IEA
GO:0034154	toll-like receptor 7 signaling pathway	IEA
GO:0034162	toll-like receptor 9 signaling pathway	IEA

Immuno Process:

Chemotaxis & migration

GO Annotations:

Associated to 4 GO processes

GO:2001189	negative regulation of T cell activation via T cell receptor contact with antigen bound to MHC molecule on antigen presenting cell	IDA
	click arrow to show/hide IEA associations
GO:0032722	positive regulation of chemokine production	IEA
GO:0042102	positive regulation of T cell proliferation	IEA
GO:0042130	negative regulation of T cell proliferation	IEA

Immuno Process:

Cellular signalling

GO Annotations:

Associated to 11 GO processes

GO:0030886	negative regulation of myeloid dendritic cell activation	IMP
GO:2001189	negative regulation of T cell activation via T cell receptor contact with antigen bound to MHC molecule on antigen presenting cell	IDA
	click arrow to show/hide IEA associations
GO:0002281	macrophage activation involved in immune response	IEA
GO:0032815	negative regulation of natural killer cell activation	IEA
GO:0034138	toll-like receptor 3 signaling pathway	IEA
GO:0034154	toll-like receptor 7 signaling pathway	IEA
GO:0034162	toll-like receptor 9 signaling pathway	IEA
GO:0042102	positive regulation of T cell proliferation	IEA
GO:0042130	negative regulation of T cell proliferation	IEA
GO:0043032	positive regulation of macrophage activation	IEA
GO:2000521	negative regulation of immunological synapse formation	IEA

Immuno Process:

B cell (activation)

GO Annotations:

Associated to 3 GO processes, IEA only

	click arrow to show/hide IEA associations
GO:0002250	adaptive immune response	IEA
GO:0002652	regulation of tolerance induction dependent upon immune response	IEA
GO:0002826	negative regulation of T-helper 1 type immune response	IEA

General Comments
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. The C-type lectin galectin-9 is a TIM3 ligand [1].

References

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1. Anderson AC. (2014) Tim-3: an emerging target in the cancer immunotherapy landscape. Cancer Immunol Res, 2 (5): 393-8. [PMID:24795351]

2. da Silva IP, Gallois A, Jimenez-Baranda S, Khan S, Anderson AC, Kuchroo VK, Osman I, Bhardwaj N. (2014) Reversal of NK-cell exhaustion in advanced melanoma by Tim-3 blockade. Cancer Immunol Res, 2 (5): 410-22. [PMID:24795354]

3. Koyama S, Akbay EA, Li YY, Herter-Sprie GS, Buczkowski KA, Richards WG, Gandhi L, Redig AJ, Rodig SJ, Asahina H et al.. (2016) Adaptive resistance to therapeutic PD-1 blockade is associated with upregulation of alternative immune checkpoints. Nat Commun, 7: 10501. [PMID:26883990]

4. Mariotti FR, Quatrini L, Munari E, Vacca P, Moretta L. (2019) Innate Lymphoid Cells: Expression of PD-1 and Other Checkpoints in Normal and Pathological Conditions. Front Immunol, 10: 910. [PMID:31105707]

5. Monney L, Sabatos CA, Gaglia JL, Ryu A, Waldner H, Chernova T, Manning S, Greenfield EA, Coyle AJ, Sobel RA et al.. (2002) Th1-specific cell surface protein Tim-3 regulates macrophage activation and severity of an autoimmune disease. Nature, 415 (6871): 536-41. [PMID:11823861]

6. Romero D. (2016) Immunotherapy: PD-1 says goodbye, TIM-3 says hello. Nat Rev Clin Oncol, 13 (4): 202-3. [PMID:26977783]

7. Schwartz S, Patel N, Longmire T, Jayaraman P, Jiang X, Lu H, Baker L, Velez J, Ramesh R, Wavreille AS et al.. (2022) Characterization of sabatolimab, a novel immunotherapy with immuno-myeloid activity directed against TIM-3 receptor. Immunother Adv, 2 (1): ltac019. [PMID:36196369]

8. Xu L, Huang Y, Tan L, Yu W, Chen D, Lu C, He J, Wu G, Liu X, Zhang Y. (2015) Increased Tim-3 expression in peripheral NK cells predicts a poorer prognosis and Tim-3 blockade improves NK cell-mediated cytotoxicity in human lung adenocarcinoma. Int Immunopharmacol, 29 (2): 635-641. [PMID:26428847]

How to cite this page

Other immune checkpoint proteins: TIM3 (CD366). Last modified on 09/02/2023. Accessed on 26/09/2023. IUPHAR/BPS Guide to PHARMACOLOGY, https://www.guidetomalariapharmacology.org/GRAC/ObjectDisplayForward?objectId=2940.

TIM3 (CD366)

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References

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