Antibody Basics: Part 9 - Therapeutic targets - Autoimmune Diseases

Welcome to Biointron's Antibody Basics! In this episode, we’ll talk about therapeutics targeting autoimmune diseases.

Autoimmune Diseases: A Global Challenge

• Autoimmune diseases affect almost 5% of the global population

• Represent a diverse group of >80 conditions targeting various organs and tissues
  

• This dysregulated immune response leads to chronic inflammation and tissue damage, manifesting in a wide range of symptoms across various organs and systems

• Examples: rheumatoid arthritis, lupus, psoriasis, inflammatory bowel disease

Antibody Targets in Autoimmune Diseases

Cell Surface Receptors: These receptors on immune cells can be blocked by antibodies, preventing inflammatory signals.

• TNF-α receptors (TNFRs): TNF-α is a potent inflammatory cytokine implicated in various autoimmune diseases like rheumatoid arthritis, psoriasis, and inflammatory bowel disease. Antibody drugs like Etanercept and Adalimumab bind to TNFRs, preventing TNF-α from signaling and thereby reducing inflammation.

• IL-6 receptors (IL-6Rs): IL-6 is another key inflammatory cytokine involved in autoimmune processes. Tocilizumab is an example of an antibody drug that targets the IL-6 receptor, blocking both soluble and membrane-bound IL-6, offering a broader blockade of this inflammatory pathway in diseases like rheumatoid arthritis and systemic lupus erythematosus. 

Other Cytokines: These are signaling molecules that antibody drugs can neutralize, dampening inflammation.

• Interleukin-17 (IL-17): This cytokine plays a crucial role in psoriatic arthritis, promoting inflammation and skin cell proliferation. Secukinumab is an antibody drug that specifically neutralizes IL-17, leading to significant improvement in symptoms and skin lesions.

• B-Cell Activating Factor (BAFF): BAFF is a critical survival factor for B cells, the immune cells responsible for antibody production. In some autoimmune diseases like systemic lupus erythematosus, excessive B cell activity contributes to pathology. Belimumab is an antibody drug that targets BAFF, helping to regulate B cell activity.

Costimulatory Molecules:

• CTLA-4: This molecule acts as a "brake" on T cell activation. In autoimmune diseases, T cell overactivity can contribute to tissue damage. Ipilimumab is an antibody drug that blocks CTLA-4. This approach is being explored cautiously in autoimmune diseases where a more controlled T cell activation might be beneficial.

Specific Autoantigens:

• In some autoimmune diseases, the target is a specific protein or molecule unique to a particular tissue. For instance, Rituximab is an antibody drug that targets CD20, a protein on the surface of mature B cells. This B cell depletion strategy is used in some autoimmune diseases like rheumatoid arthritis and multiple sclerosis.

Complement System Proteins:

• The complement system is a group of proteins involved in the immune system's inflammatory response. In some autoimmune diseases, dysregulation of the complement system can contribute to tissue damage. Eculizumab is an antibody drug that targets a specific complement protein (C5), used to treat a rare autoimmune disease called paroxysmal nocturnal hemoglobinuria (PNH).

48 Antibody Drugs in Autoimmunity Approved

• Adalimumab (Humira): Approved in 2002, it targets TNF-alpha to treat rheumatoid arthritis.

• Infliximab (Remicade): Approved in 1998, it also targets TNF-alpha to treat Crohn’s disease.

• Belimumab (Benlysta): Approved in 2011, it targets BLyS to treat systemic lupus erythematosus.

• Rozanolixizumab (Rystiggo): The latest drug approved in 2023, it targets FcRn to treat generalized myasthenia gravis.
  

B cell depletion therapies

B cell depletion therapies (BCDTs) reduce autoimmune symptoms by decreasing the number of B cells, and thus the production of autoantibodies, which mistakenly attack healthy tissues. BCDTs target various molecules on the surface of B cells:

• CD20: This is the most common target. It is a protein present on mature B cells but not on stem cells or plasma cells.

• CD19: This protein is expressed throughout B cell development, making it a broader target compared to CD20.

• BAFF (B-cell activating factor): This is a molecule that helps B cells survive and mature.

BCDT in systemic lupus erythematosus (SLE) Treating SLE effectively has been difficult due to its heterogeneity, a challenge further highlighted in the bioinformatics era. SLE is characterized by class-switched antibodies to intracellular antigens, especially nuclear antigens. These antibodies can form immune complexes which cause tissue damage in multiple target organs. To improve therapeutic efficacy, Lee et al. suggests developing combination therapies or to target two cytokines with one drug.