IgG Recycling

FcRn Recycling

-circulation of antibodies in blood is extended by FcRn

-all 4 IgG subclasses bind Neonatal Fc receptor (FcRn) at pH <6.5

-unbound proteins degrade in lysosome

FcRn Recycling Steps

1.IgGs enter into endosomes via fluid phase endocytosis

2. Endosomes are acidified by ATPase H+ pump

3. In endosome FcRn binds IgGs at pH 5-6.5

4.FcRn bound IgGs are protected from lysosomal degradation

5.Bound IgGs are recycled to the plasma membrane

6.IgGs are released back into circulation (pH 7.4)

What is the end result of FcRn Recycling

creates a reservoir in blood endothelium (extends half-life in circulation)

FcRn

• at pH 6-6.5

• Interactions depend on CH2/CH3 amino acid and carbohydrates

• Fc glycans are important for structural integrity and conformation

IgG Glycosylation and mAb therapeutics

-Process dependent complexities: Produced in living host:

-Mammalian cell secertion

-Composition of IgG carbohydrates is a function of the host cell line

-Enzymatic glycostatin (OST)

-site specific —→ Asn 297 on CH2 domain → N-Glycans

-Complex branched carbohydrates

Biosimilars

-Generally made from living sources

-Require a specialized process to produce

-Nearly identical to original biologics

-Faster development process

-Usually less expensive than original biologics

Generics

-Generally made from chemicals

-Have a simpler process to copy

-Copy of brand-name drugs

-Faster development process

-Usually less expensive than brand-name drugs