BAFF (BLys) & APRIL: Emerging Targets For Autoimmune Disease & Cancer Therapeutics

Published by: LeadDiscovery

Published: Jan. 1, 2006

Table of Contents

An introduction to B-cell immunology

Basic immunology

B-cell development in secondary lymphatic organs

Figure: Organization of Lymphatic Organs

Figure: Maturation of B-cells

Regulation of B-cell function by TNF family members

Table: The TNF superfamilly and their phylogenetic relationship

An overview of TNF ligands with B-cell modulatory activity

CD70

APRIL (TALL2)

BAFF (BLyS; TNFSF13B; TALL1; THANK

Figure: BAFF/APRIL receptors and signaling pathways

Receptors for BAFF/APRIL

BCMA (B-Cell Maturation factor)

TACI (transmembrane activator and CAML interactor)

BAFF-R

Figure: Expression profile of BAFF receptors through B-cell maturation

Table: Selectivity of BAFF receptors

The TRAF proteins

Response to BAFF receptor activation

The BAFF family and B-cell maturation

Figure: B-cell maturation

Stimulation of antibody production and Ig switching

T-independent responses

B-cell survival/Apoptosis

T-cell modulation

Autoimmune disease

An introduction to autoimmune disease

Figure: Prevalence of 20 most prevalent autoimmune diseases

A pathological role for BAFF and APRIL in autoimmune disease

Systemic lupus erythematosus (SLE)

Prevalence, etiology and treatment of SLE

Table: Symtomology of SLE

Involvement of BAFF/APRIL in etiology of SLE

Figure: anti-dsDNA levels in BAFF transgenic mice

Rheumatoid Arthritis

Prevalence, etiology and treatment of rheumatoid arthritis

Involvement of BAFF/APRIL in etiology of rheumatoid arthritis

Figure: Rheumatoid factor levels in BAFF transgenic mice

Figure: BAFF levels in patients with SLE or rheumatoid arthritis

Sjögren’s disease

Prevalence, etiology and treatment of Sjögren's syndrome

Figure: Etiology of Sjögren's syndrome

Involvement of BAFF/APRIL in etiology of Sjögren's syndrome

Figure: BAFF levels in patients with Sjögren's syndrome

Multiple Sclerosis

Prevalence, etiology and treatment of multiple sclerosis

Figure: Treatment of multiple sclerosis over the course of disease progression

Involvement of BAFF/APRIL in etiology of multiple sclerosis

Figure: BAFF levels in patients with multiple sclerosis

A pathophysiological role for BAFF and APRIL in hematological cancers

Prevalence, etiology and treatment of multiple myeloma

Prevalence, etiology and treatment of on-Hodgkin's Lymphomas (NHL)

Figure: Increasing incidence of NHL

Indolent NHL

Aggressive NHL

Involvement of BAFF/APRIL in etiology of multiple myeloma and NHL

Figure: Relationship of BAFF levels to aggressiveness of NHL

Figure: Survival effect of BAFF on NHL cells

Figure: Levels of BAFF and APRIL in Myeloma

Figure: Increased cell death of Myeloma cells in response to TAC-Ig alone and in combination with current therapies

Prevalence, etiology and treatment of Chronic lymphocytic leukemia (CLL)

Involvement of BAFF/APRIL in etiology of CLL

Figure: APRIL levels in CLL

Blocking BAFF/APRIL

Risks and benefits

Strategies for Blockade

Candidate BAFF blockers

TACI-Ig (Zymogenetics)

Clinical data and developmental activity of TACI-Ig

LymphoStat-B (Human Genome Sciences)

Clinical data and developmental activity of LymphoStat-B

Rheumatoid Arthritis

SLE

LymphoRad131 (Human Genome Sciences)

Clinical data and developmental activity of LymphoRad131

Market potential and competition

Figure: Rituxan sales figures

Summary & Strategic Recommendations

Abstract

• A detailed but easy to understand backgrounder on B-cell immunology designed to bring all drug development personnel up to speed in this area
• Proof of concept for developing blockers of BAFF and/or APRIL. CD70, a homologue of these proteins, and it’s receptor CD27 are also evaluated briefly.
• Identification of target indications for BAFF and/or APRIL blockers
• Prevalence, current treatments and etiology of target indications
• Clinical data for BAFF blockers in advanced development
• Strategies for improving the efficacy of currently developed BAFF blockers

• There is particularly good evidence to support a role of BAFF in the etiology of rheumatoid arthritis although based on cross-study comparison the efficacy of the lead therapeutic in this class, LymphoStat-B, appears to be inferior to Rituxan. LymphoStat-B blocks just BAFF however APRIL is also elevated in the synovial fluid of rheumatoid arthritis patients. We conclude that dual blockade of APRIL as well as BAFF may be required for optimal therapeutic activity. Data from ZymoGenetic’ study of TACI-Ig may shed some light on this issue.
• Immunosuppressive adverse effects of BAFF/APRIL blockers should be less than those resulting from Rituxan
• Blocking BAFF and/or APRIL may be a useful adjuvant to TNF blockers, increasing efficacy while possibly reducing the heightened risk of lymphoma associated with this major therapeutic class.
• There is good evidence to suggest that BAFF contributes to the etiology of systemic lupus erythematosus however optimal selectivity of therapeutic agents aimed at BAFF remains to be established.
• Of all the autoimmune conditions investigated, the serum levels of BAFF are highest in Sjögren's syndrome. One particularly attractive advantage of blocking BAFF and/or APRIL is that this approach may prevent the development of lymphomas, a co-morbidity associated with a subgroup of patients.
• Other autoimmune diseases that have yet to fall under the spotlight of BAFF/APRIL should be evaluated as target indications. In particular multiple sclerosis and inflammatory bowel disease may represent potential indications.
• Strong evidence supports the blockade of BAFF/APRIL as a treatment of multiple myeloma and non-Hodgkin’s lymphoma. Elevated levels of these molecules may limit the efficacy of existing therapeutic agents, while their blockade is likely to act in an additive or possible synergistic fashion with steroids or IL-6 therapeutics.

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