Details of the Drug Therapeutic Target (DTT)

General Information of Drug Therapeutic Target (DTT) (ID: TT1RWL7)

• DTT Name: Hepatitis A virus cellular receptor 2 (TIM3)
• Synonyms: TIMD3; TIMD-3; TIM3; TIM-3; T-cell membrane protein 3; T-cell immunoglobulin mucin receptor 3; T-cell immunoglobulin and mucin domain-containing protein 3; HAVcr-2; HAVCR2; CD366
• Gene Name: Hepatitis A virus HAVCR2
• DTT Type: Clinical trial target; [1]
• BioChemical Class: Immunoglobulin
• UniProt ID: HAVR2_HUMAN
• TTD ID: T76233
• Sequence:
  MFSHLPFDCVLLLLLLLLTRSSEVEYRAEVGQNAYLPCFYTPAAPGNLVPVCWGKGACPV
  FECGNVVLRTDERDVNYWTSRYWLNGDFRKGDVSLTIENVTLADSGIYCCRIQIPGIMND
  EKFNLKLVIKPAKVTPAPTRQRDFTAAFPRMLTTRGHGPAETQTLGSLPDINLTQISTLA
  NELRDSRLANDLRDSGATIRIGIYIGAGICAGLALALIFGALIFKWYSHSKEKIQNLSLI
  SLANLPPSGLANAVAEGIRSEENIYTIEENVYEVEEPNEYYCYVSSRQQPSQPLGCRFAM
  P
• Function: Generally accepted to have an inhibiting function. Reports on stimulating functions suggest that the activity may be influenced by the cellular context and/or the respective ligand. Regulates macrophage activation. Inhibits T-helper type 1 lymphocyte (Th1)-mediated auto- and alloimmune responses and promotes immunological tolerance. In CD8+ cells attenuates TCR-induced signaling, specifically by blocking NF-kappaB and NFAT promoter activities resulting in the loss of IL-2 secretion. The function may implicate its association with LCK proposed to impair phosphorylation of TCR subunits, and/or LGALS9-dependent recruitment of PTPRC to the immunological synapse. In contrast, shown to activate TCR-induced signaling in T-cells probably implicating ZAP70, LCP2, LCK and FYN. Expressed on Treg cells can inhibit Th17 cell responses. Receptor for LGALS9. Binding to LGALS9 is believed to result in suppression of T-cell responses; the resulting apoptosis of antigen-specific cells may implicate HAVCR2 phosphorylation and disruption of its association with BAG6. Binding to LGALS9 is proposed to be involved in innate immune response to intracellular pathogens. Expressed on Th1 cells interacts with LGALS9 expressed on Mycobacterium tuberculosis-infected macrophages to stimulate antibactericidal activity including IL-1 beta secretion and to restrict intracellular bacterial growth. However, the function as receptor for LGALS9 has been challenged. Also reported to enhance CD8+ T-cell responses to an acute infection such as by Listeria monocytogenes. Receptor for phosphatidylserine (PtSer); PtSer-binding is calcium-dependent. May recognize PtSer on apoptotic cells leading to their phagocytosis. Mediates the engulfment of apoptotic cells by dendritic cells. Expressed on T-cells, promotes conjugation but not engulfment of apoptotic cells. Expressed on dendritic cells (DCs) positively regulates innate immune response and in synergy with Toll-like receptors promotes secretion of TNF-alpha. In tumor-imfiltrating DCs suppresses nucleic acid-mediated innate immune repsonse by interaction with HMGB1 and interfering with nucleic acid-sensing and trafficking of nucleid acids to endosomes. Expressed on natural killer (NK) cells acts as a coreceptor to enhance IFN-gamma production in response to LGALS9. In contrast, shown to suppress NK cell-mediated cytotoxicity. Negatively regulates NK cell function in LPS-induced endotoxic shock. Cell surface receptor implicated in modulating innate and adaptive immune responses.
• Reactome Pathway: Interleukin-2 family signaling (R-HSA-451927)

Molecular Interaction Atlas (MIA) of This DTT

10 Clinical Trial Drug(s) Targeting This DTT

Drug Name	Drug ID	Indication	ICD 11	Highest Status	REF
MBG453	DMBPY9Z	Myelodysplastic syndrome	2A37	Phase 3	[1]
AZD7789	DMOIHWI	Hodgkin lymphoma	2B30	Phase 2	[2]
GSK4069889	DMV6SNU	Non-small-cell lung cancer	2C25	Phase 2	[3]
RO7121661	DM8A120	Esophageal squamous cell carcinoma	2E60.1	Phase 2	[4]
TB006	DMKN524	Alzheimer disease	8A20	Phase 2	[5]
BGB-A425	DMI42Q0	Non-small-cell lung cancer	2C25	Phase 1/2	[6]
INCAGN2390	DM5SO1T	Solid tumour/cancer	2A00-2F9Z	Phase 1	[7]
LY3321367	DMD51GC	Solid tumour/cancer	2A00-2F9Z	Phase 1	[1]
LY3415244	DM5QO1A	Solid tumour/cancer	2A00-2F9Z	Phase 1	[8]
Sym023	DMV3L62	Lymphoma	2A80-2A86	Phase 1	[9]

References

• [1] Clinical pipeline report, company report or official report of the Pharmaceutical Research and Manufacturers of America (PhRMA)
• [2] Clinical pipeline report, company report or official report of AstraZeneca
• [3] Clinical pipeline report, company report or official report of GlaxoSmithKline.
• [4] Bispecific antibodies: a mechanistic review of the pipeline. Nat Rev Drug Discov. 2019 Aug;18(8):585-608.
• [5] Clinical pipeline report, company report or official report of TrueBinding
• [6] Clinical pipeline report, company report or official report of BeiGene.
• [7] Clinical pipeline report, company report or official report of Agenus.
• [8] Safety and Immunogenicity of LY3415244, a Bispecific Antibody Against TIM-3 and PD-L1, in Patients With Advanced Solid Tumors. Clin Cancer Res. 2021 May 15;27(10):2773-2781.
• [9] Clinical pipeline report, company report or official report of Symphogen.