Soluble monomeric IgG1 Fc.

Area of Science:

• Biopharmaceutical Development
• Protein Engineering
• Immunology

Background:

• Antibody fragments are promising biopharmaceuticals due to their small size.
• These fragments have short half-lives because they cannot bind the neonatal Fc receptor (FcRn).
• Current therapeutic strategies involve Fc fusion proteins or engineered Fc domains, typically dimeric.

Purpose of the Study:

• To engineer small, soluble monomeric Fc fragments (mFcs) that retain FcRn binding.
• To investigate if FcRn binding requires Fc dimerization.
• To explore the potential of mFcs for developing novel therapeutics.

Main Methods:

• Structure-based rational protein design was employed to create three human soluble monomeric IgG1 Fc variants (mFcs).
• Multiple screening strategies were utilized to identify functional mFcs.
• Binding affinity of mFcs to human FcRn was assessed and compared to dimeric Fc.

Main Results:

• Three highly soluble human monomeric Fc (mFc) variants were successfully generated.
• These mFcs demonstrated retained binding to human FcRn, comparable to dimeric Fc.
• Experimental evidence confirmed that FcRn binding does not necessitate Fc dimerization.

Conclusions:

• Efficient binding to human FcRn can be achieved with monomeric Fc fragments.
• The newly developed mFcs are suitable for creating Fc fusion proteins.
• mFcs offer potential for novel, small-sized therapeutic antibodies with prolonged half-lives.