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  • Review Article
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An APRIL to remember: novel TNF ligands as therapeutic targets

Nature Reviews Drug Discovery volume 5, pages 235–246 (2006)Cite this article

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.

Abstract

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.

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Figure 1: Pairing of APRIL and BLyS with their receptors.
Figure 2: APRIL, like BLyS, co-stimulates B-cell proliferation induced by anti-IgM+IL-4.
Figure 3: APRIL and BLyS mediate survival of malignant B cells.
Figure 4: APRIL exhibits diverse biological functions on normal and malignant cells.

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Acknowledgements

Many thanks to M. Moore, B. Fox, M. Kelley, C. Ostrander, and P. Shea for the design, expression, characterization, and purification of ZZ APRIL, to B. Harder and J. Ellsworth for providing the data shown in Fig. 2, and to K. Lewis, S. Rene and S. McMillan for performing the Biacore analyses with ZZ APRIL and BLyS described in Table 2. Thanks also to Z. Zhang, and to S. Peano and R. Ponce for sharing unpublished results. We also thank G. Vieira for artwork, and G. McKnight, M. Bernard, A. Ching, and D. Louden for assistance with literature research. Finally, we are grateful to our colleagues at Serono and ZGEN for providing helpful comments on the manuscript.

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Authors and Affiliations

  1. Department of Autoimmunity and Inflammation, ZymoGenetics, Inc., 1201 Eastlake Avenue East, Seattle, 98102, Washington, USA

    Stacey R. Dillon & Jane A. Gross

  2. Division of Hematology and Internal Medicine, Mayo Clinic College of Medicine, Mayo Clinic, Rochester, 55905, Minnesota, USA

    Stephen M. Ansell & Anne J. Novak

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  1. Stacey R. Dillon
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Correspondence to Stacey R. Dillon.

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Competing interests

S.D. and J.G. are employees of ZymoGenetics, Inc. and have stock options in the company. A.N. and S.A. receive some research funding from ZymoGenetics as part of a research agreement.

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DATABASES

OMIM

B-CCL

Multiple myeloma

Multiple sclerosis

NHL

Reiter's syndrome

Rheumatoid arthritis

Sjögren's syndrome

SLE

FURTHER INFORMATION

Amgen (AMG 623 description)

Cluster of Differentiation nomenclature

HGS press release describing results from Phase 2 clinical trial with LymphoStat-B in SLE

HGS press release describing results from Phase 2 clinical trial with LymphoStat-B in rheumatoid arthritis

Human Genome Organization nomenclature

ZGEN press release describing results from Phase 1b clinical trial with TACI-Ig in RA

Glossary

Expressed sequence tag

(EST). A partial, short (200–500 base pairs) sequence from either end of a cDNA clone (that is, from a gene that has been expressed in some tissue or at some stage of development) that can be mapped, by a combination of genetic mapping procedures, to a unique locus in the genome and which serves to identify that gene locus. A database of ESTs can be helpful for picking protein-coding sequences out of a long stretch of DNA, or for providing a larger context for very short sequences.

Heparan sulphate proteoglycans

(HSPGs). Ubiquitous macromolecules associated with the cell surface and extracellular matrix of a wide range of cells of vertebrate and invertebrate tissues, which are essential cofactors in cell–matrix adhesion processes, in cell–cell recognition systems, and in receptor–growth factor interactions.

Surface plasmon resonance (Biacore)

A biophysical technique used to measure the binding interactions and kinetics of very small amounts of a target protein. A ligand is immobilized on a special chip, a solution of the target molecule flows across the chip and the progress of binding is then measured by optical instruments.

Chronic lymphocytic leukaemia

(CLL). A common leukaemia characterized by a neoplastic proliferation of well-differentiated and mature lymphocytes (usually B cells) that is manifested by the progressive accumulation of these cells in the blood, bone marrow and lymphatic tissues.

Germinal centre

A discrete area within the lymph node and spleen containing rapidly dividing B cells that respond to antigen, along with the antigen-specific helper T cells that helped activate them. Germinal centre B cells can undergo somatic hypermutation and isotype switching, and give rise to both effector and memory B cells bearing high-affinity antibodies.

Class switch recombination

(CSR; also known as isotype switch). The shift of a B cell or its progeny from the secretion of antibody of one isotype or class of antibody with the same V regions but a different heavy-chain constant region and, therefore, of a different isotype.

Immune complex

An antigen bound to antibody; levels of immune complexes are elevated in many autoimmune disorders.

Non-Hodgkin's lymphoma

(NHL). A group of more than 29 types of lymphomas characterized by cancerous growth of B or T cells, excluding those characterized by Hodgkin's disease, and which are classified by cell type and rate of growth (aggressive or indolent).

Nurse-like cell

(NLC). Cells that derive from a subset of blood CD14+ mononuclear cells from patients with CLL, which differentiate in vitro in the presence of CLL (but not normal) B cells, and can protect CLL B cells from apoptosis.

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Dillon, S., Gross, J., Ansell, S. et al. An APRIL to remember: novel TNF ligands as therapeutic targets. Nat Rev Drug Discov 5, 235–246 (2006). https://doi.org/10.1038/nrd1982

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