Fc Silenced

What are Fc Silenced Antibodies?

Fc silenced antibodies are a class of engineered antibodies that have been modified to reduce or eliminate the interaction between the antibody's Fc region and the immune system. This is achieved through various strategies, such as:

• Point mutations in the Fc region
• Glycoengineering of the Fc region
• Removal of the Fc region altogether

By reducing the Fc-mediated effector functions, Fc silenced antibodies can potentially minimize unwanted side effects and improve the therapeutic window of the antibody.

Advantages of Fc Silenced Antibodies

Fc silenced antibodies offer several advantages over traditional monoclonal antibodies:

• Reduced risk of antibody-dependent enhancement (ADE) of infection
• Minimized off-target effects due to reduced Fc-mediated effector functions
• Improved safety profile, particularly in the context of anti-viral antibodies
• Potential for higher dosing and more effective treatment

Applications of Fc Silenced Antibodies

Fc silenced antibodies have shown promise in various therapeutic areas, including:

• Infectious diseases: Fc silenced antibodies can be used to treat viral infections, such as HIV and dengue fever, without the risk of ADE.
• Oncology: By reducing Fc-mediated effector functions, Fc silenced antibodies can potentially enhance the anti-tumor activity of therapeutic antibodies.
• Autoimmune disorders: Fc silenced antibodies may be used to target specific autoantigens without triggering unwanted immune responses.

Examples:

1. Teplizumab (PRV-031)

• Indication: Type 1 diabetes
• Silencing mutation: Fc region modified with a single amino acid substitution (Ala/Ala genotype at position 158)

2. Evinacumab (REGN1500)

• Indication: Homozygous familial hypercholesterolemia
• Silencing mutation: Fc region modified with a triple amino acid substitution (L234A/L235A/P331S)

3. Inebilizumab (MEDI-551)

• Indication: Neuromyelitis optica spectrum disorder
• Silencing mutation: Fc region modified with a double amino acid substitution (L234A/L235A)

4. VIR-7831 (Sotrovimab)

• Indication: COVID-19
• Silencing mutation: Fc region modified with a double amino acid substitution (LS mutation)

8. SA237 (Anifrolumab)

• Indication: Systemic lupus erythematosus
• Silencing mutation: Fc region modified with a triple amino acid substitution (L234A/L235A/P331S)

9. ARGX-113 (Efgartigimod)

• Indication: Myasthenia gravis, primary immune thrombocytopenia
• Silencing mutation: Fc region modified with ABDEG mutations (L234A/L235A/P329G/N297A)

Fc silenced antibodies represent an exciting development in the field of antibody engineering. By minimizing the interaction between the antibody's Fc region and the immune system, these engineered antibodies offer the potential for improved safety and efficacy in a variety of therapeutic applications. As research continues, it is likely that we will see an increasing number of Fc silenced antibodies entering clinical development and ultimately reaching patients in need.