Details of the Drug Therapeutic Target (DTT)

General Information of Drug Therapeutic Target (DTT) (ID: TTYA75N)

• DTT Name: MHC class II antigen DR (HLA-DR)
• Synonyms: HLA class II histocompatibility antigen
• Gene Name: HLA-DRA
• DTT Type: Clinical trial target; [1]
• BioChemical Class: MHC class II
• UniProt ID: DRA_HUMAN ; 2B1F_HUMAN ; DRB3_HUMAN ; DRB4_HUMAN ; DRB5_HUMAN
• TTD ID: T49146
• Sequence:
  MAISGVPVLGFFIIAVLMSAQESWAIKEEHVIIQAEFYLNPDQSGEFMFDFDGDEIFHVD
  MAKKETVWRLEEFGRFASFEAQGALANIAVDKANLEIMTKRSNYTPITNVPPEVTVLTNS
  PVELREPNVLICFIDKFTPPVVNVTWLRNGKPVTTGVSETVFLPREDHLFRKFHYLPFLP
  STEDVYDCRVEHWGLDEPLLKHWEFDAPSPLPETTENVVCALGLTVGLVGIIIGTIFIIK
  GVRKSNAAERRGPL
• Function: Binds peptides derived from antigens that access the endocytic route of antigen presenting cells (APC) and presents them on the cell surface for recognition by the CD4 T-cells. The peptide binding cleft accommodates peptides of 10-30 residues. The peptides presented by MHC class II molecules are generated mostly by degradation of proteins that access the endocytic route, where they are processed by lysosomal proteases and other hydrolases. Exogenous antigens that have been endocytosed by the APC are thus readily available for presentation via MHC II molecules, and for this reason this antigen presentation pathway is usually referred to as exogenous. As membrane proteins on their way to degradation in lysosomes as part of their normal turn-over are also contained in the endosomal/lysosomal compartments, exogenous antigens must compete with those derived from endogenous components. Autophagy is also a source of endogenous peptides, autophagosomes constitutively fuse with MHC class II loading compartments. In addition to APCs, other cells of the gastrointestinal tract, such as epithelial cells, express MHC class II molecules and CD74 and act as APCs, which is an unusual trait of the GI tract. To produce a MHC class II molecule that presents an antigen, three MHC class II molecules (heterodimers of an alpha and a beta chain) associate with a CD74 trimer in the ER to form a heterononamer. Soon after the entry of thiscomplex into the endosomal/lysosomal system where antigen processing occurs, CD74 undergoes a sequential degradation by various proteases, including CTSS and CTSL, leaving a small fragment termed CLIP (class-II-associated invariant chain peptide). The removal of CLIP is facilitated by HLA-DM via direct binding to the alpha-beta-CLIP complex so that CLIP is released. HLA-DM stabilizes MHC class IImolecules until primary high affinity antigenic peptides are bound. The MHC II molecule bound to a peptide is then transported to the cell membrane surface. In B-cells, the interaction between HLA-DMand MHC class II molecules is regulated by HLA-DO. Primary dendritic cells (DCs) also to express HLA-DO. Lysosomal microenvironment has been implicated in the regulation of antigen loading into MHC II molecules, increased acidification produces increased proteolysis and efficient peptide loading.
• KEGG Pathway:
  Phagosome (hsa04145)
  Cell adhesion molecules (CAMs) (hsa04514)
  Antigen processing and presentation (hsa04612)
  Hematopoietic cell lineage (hsa04640)
  Intestinal immune network for IgA production (hsa04672)
  Type I diabetes mellitus (hsa04940)
  Leishmaniasis (hsa05140)
  Toxoplasmosis (hsa05145)
  Staphylococcus aureus infection (hsa05150)
  Tuberculosis (hsa05152)
  Influenza A (hsa05164)
  HTLV-I infection (hsa05166)
  Herpes simplex infection (hsa05168)
  Epstein-Barr virus infection (hsa05169)
  Asthma (hsa05310)
  Autoimmune thyroid disease (hsa05320)
  Inflammatory bowel disease (IBD) (hsa05321)
  Systemic lupus erythematosus (hsa05322)
  Rheumatoid arthritis (hsa05323)
  Allograft rejection (hsa05330)
  Graft-versus-host disease (hsa05332)
  Viral myocarditis (hsa05416)
• Reactome Pathway:
  Translocation of ZAP-70 to Immunological synapse (R-HSA-202430)
  Generation of second messenger molecules (R-HSA-202433)
  MHC class II antigen presentation (R-HSA-2132295)
  PD-1 signaling (R-HSA-389948)
  Interferon gamma signaling (R-HSA-877300)
  Phosphorylation of CD3 and TCR zeta chains (R-HSA-202427)

Molecular Interaction Atlas (MIA) of This DTT

3 Clinical Trial Drug(s) Targeting This DTT

Drug Name	Drug ID	Indication	ICD 11	Highest Status	REF
Apolizumab	DMKVP7E	Solid tumour/cancer	2A00-2F9Z	Phase 2	[2]
AEA-35p	DMQRKXP	Influenza virus infection	1E30-1E32	Phase 1	[3]
IMMU-114	DMTFUM4	Haematological malignancy	2B33.Y	Phase 1	[1]

References

• [1] The humanized anti-HLA-DR moAb, IMMU-114, depletes APCs and reduces alloreactive T cells: implications for preventing GVHD. Bone Marrow Transplant. 2012 Jul;47(7):967-80.
• [2] A humanized HLA-DR antibody (hu1D10, apolizumab) in combination with granulocyte colony-stimulating factor (filgrastim) for the treatment of non-Hodgkin's lymphoma: a pilot study.
• [3] WO patent application no. 2013,1850,32, Nanotherapeutics for drug targeting.