BAFF (BLys) & APRIL: Emerging Targets for autoimmune disease & Cancer Therapeutics

• 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