Exploiting the Multiple Functions of FcRn for Therapy
E. Sally Ward,
Professor,
Texas A&M University Health Science Center
The central role of FcRn in regulating IgG persistence and transport
provides opportunities for targeting this receptor in multiple different
diagnostic and therapeutic situations. The engineering of IgGs with
higher affinity for FcRn can be used to produce antibodies with longer
in vivo half-lives, but only if the pH dependence of the IgG-FcRn
interaction is retained. Conversely, engineered IgGs with increased
affinity for FcRn at both acidic and near neutral pH act as potent
inhibitors of FcRn. Consequently, such antibodies (‘Abdegs’, for
antibodies that enhance IgG degradation) can lower the levels of
endogenous IgG. Recent studies in our laboratory have also resulted in
the generation of engineered Fc-fusions that selectively clear
antigen-specific antibodies (‘Seldegs’, for selective degradation).
Recent developments related to the modulation of IgG dynamics will be
presented. We have demonstrated that the loss of expression of FcRn in
tumor cells results in increased intracellular albumin accumulation and
tumor growth in mouse models. These observations have implications for
tumor immunotherapy and indicate a novel function for FcRn as a
metabolic regulator.
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