BAFF (BLys) & APRIL: Emerging Targets For Autoimmune Disease & Cancer Therapeutics
LeadDiscovery
January 1, 2006 SKU: LD1328781
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BAFF & APRIL: Emerging Targets for autoimmune & Cancer Therapeutics offers a detailed look at BAFF and APRIL focusing on:
- 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
In short, if your company is looking to enter the emerging field of BAFF this report will provide all the key information necessary to help you fast track this process.
Some of our key conclusions are:
- 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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- 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
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