HLA class II antigen-associated invariant chain (CD74)

The HLA class II antigen-associated invariant chain, commonly known as CD74, is a type II transmembrane protein that primarily functions as a molecular chaperone for MHC class II molecules [1]. It regulates the assembly and intracellular trafficking of MHC class II complexes from the endoplasmic reticulum to the endolysosomal system, where a proteolytic fragment known as CLIP (class II-associated invariant chain peptide) occupies the peptide-binding groove to prevent premature loading of self-peptides [1,2]. Beyond its role in the immune system's antigen presentation pathway, CD74 serves as the primary high-affinity receptor for Macrophage Migration Inhibitory Factor (MIF) [3]. Upon MIF binding, CD74 forms a signaling complex with CD44, triggering the activation of the ERK1/2 and NF-kappaB pathways, which promote cell proliferation and anti-apoptotic signals [3,4]. In clinical medicine, CD74 is a significant therapeutic target due to its high and rapid internalization rate and its overexpression in various hematological malignancies and solid tumors, including multiple myeloma and B-cell lymphomas [5]. Therapeutic strategies focus on Antibody-Drug Conjugates (ADCs) like STRO-001, which exploit the fast endocytic recycling of CD74 to deliver cytotoxic agents directly into malignant cells [6]. Additionally, the CD74-MIF signaling axis is implicated in the pathogenesis of chronic inflammatory and autoimmune diseases, making it a target for inhibitory antibodies and small molecule antagonists [3,7]. While CD74 is expressed on normal B-cells and certain antigen-presenting cells, its differential expression levels in cancer provide a therapeutic window for targeted oncology treatments [5,6]. Sources: [1] UniProt (P04233) [2] Roche, P. A., & Furuta, K. (2015). Nature Reviews Immunology [3] Leng, L., et al. (2003). Journal of Experimental Medicine [4] Starlets, D., et al. (2006). Blood [5] Burton, J. D., et al. (2004). Clinical Cancer Research [6] Suthe, S. R., et al. (2018). Blood/ASH Annual Meeting [7] Farr, L., et al. (2020). Expert Opinion on Therapeutic Targets

Other names

CD74Invariant chainIiHLA-DR antigens-associated invariant chainp33p35p41p43DHLAG

Antibody-drug conjugates (ADCs) target CD74-expressing cells for rapid internalization and lysosomal delivery of cytotoxic payloads; Monoclonal antibodies or small molecules block the interaction between CD74 and its ligand MIF to inhibit pro-survival and inflammatory signaling pathways.