Journal Article

An APRIL to remember: novel TNF ligands as therapeutic targets

Gross, Jane A., Novak, Anne J., Dillon, Stacey R., Ansell, Stephen M.

2006

Overview

Key Points TNF family members have a multitude of crucial roles in the immune response, and numerous companies have invested millions of dollars to develop therapeutic drugs that target many of these molecules, including TNF, CD40-L, RANK-L, TRAIL and CD30-L. Two novel TNF family members were discovered several years ago through expressed sequence tag (EST) database searches: APRIL (a proliferation-inducing ligand) and BLyS (B-lymphocyte stimulator), which is also well known as BAFF (B-cell activating factor of the TNF family). It was subsequently shown that both ligands bind to two TNF-R family members, TACI (transmembrane activator and CAML interactor and BCMA (B-cell maturation antigen), and that BLyS also specifically binds to another TNF-R family member, BAFF-R. After a long search for a third TNF-R-like receptor that specifically binds APRIL but not BLyS, two groups recently demonstrated that APRIL also binds to heparan sulfate proteoglycans (HSPG). Although the biological functions of BLyS have been more readily discerned than those of APRIL, especially from studies of transgenic and knockout mice, many recently published experiments have provided more clues about the normal and pathogenic functions of APRIL. APRIL is produced by many of the same cell types that express BLyS, including monocytes, dendritic cells, macrophages and T cells, but is also produced (unlike BLyS) by various carcinomas. Importantly, APRIL is also aberrantly expressed by malignant B cells (normal B cells do not express BLyS or APRIL), and by various cells within the B-cell tumour micro-environment, including 'nurse-like' cells derived from B-chronic lymphocytic leukaemia patients and osteoclasts and stromal cells in the bone marrow from multiple myeloma patients. Becuase these malignant B cells also express at least one of the three BLyS/APRIL receptors (TACI, BCMA and/or BAFF-R), and inhibition of BLyS or APRIL enhances the apoptosis of these tumour cells, many groups have proposed the existence of an autocrine and/or paracrine survival loop mediated by BLyS and APRIL. Some of the normal functions of APRIL are thought to be: co-stimulating antigen-activated B cells; increasing B-cell antigen presentation function via BCMA; enabling isotype switching in B cells; and augmenting plasma cell survival, and possibly affecting plasma cell trafficking. In addition, APRIL may co-stimulate pre-activated T cells, although the data supporting this function are still rather contentious. APRIL and BLyS levels are elevated in the sera of patients suffering from a variety of autoimmune diseases, including systemic lupus erythematosus, rheumatoid arthritis, Sjögren's syndrome and multiple sclerosis. Additionally, it has recently been discovered that certain mutations in TACI in common variable immunodeficiency (CVID) and IgA deficiency (IgAD) patients lead to impaired APRIL binding and consequent inhibition of isotype switching. Based on these and other findings linking APRIL and BLyS to autoimmune disease, immunodeficiency and various cancers, seven biotechnology companies have invested in the development of at least four therapeutic molecules, including a neutralizing anti-BLyS monoclonal antibody and two soluble receptors (BAFF-R and TACI), that target BLyS alone, or BLyS and APRIL together. Two of the newest members of the tumour-necrosis factor family, BLyS and APRIL, are crucial in B-cell development and survival, and are implicated in autoimmune diseases and cancer. Dillon and colleagues review APRIL biology, and compare potential therapeutics that target APRIL and/or BLyS. Since their discovery in 1998, the two TNF family members APRIL and BLyS/BAFF have received increasing attention. In addition to regulating normal B-cell development and immune responses, these molecules might be crucial in a diverse set of diseases, including autoimmunity and cancer. Although more has been published about the general biology of BLyS/BAFF than that of APRIL, many recent articles have described novel APRIL biology. Here we focus on APRIL, exploring its normal and pathological functions, and comparing the therapeutic molecules currently under development that target BLyS/BAFF alone, or APRIL and BLyS/BAFF together.

• Publisher: Nature Publishing Group UK,Nature Publishing Group
• Subject: Animals / Autoimmune Diseases - drug therapy / Autoimmune Diseases - metabolism / B-Cell Activating Factor / Biomedical and Life Sciences / Biomedicine / Biotechnology / Cancer Research / Drug Design / Humans / Ligands / Medicinal Chemistry / Membrane Proteins - biosynthesis / Membrane Proteins - metabolism / Membrane Proteins - physiology / Membrane Proteins - therapeutic use / Molecular Medicine / Neoplasms - drug therapy / Neoplasms - metabolism / Pharmacology/Toxicology / Receptors, Tumor Necrosis Factor - metabolism / Recombinant Proteins - pharmacology / review-article / Tumor Necrosis Factor Ligand Superfamily Member 13 / Tumor Necrosis Factor-alpha - biosynthesis / Tumor Necrosis Factor-alpha - metabolism / Tumor Necrosis Factor-alpha - physiology / Tumor Necrosis Factor-alpha - therapeutic use