MONOMERIC Fc-FUSION PROTEINS - Fusion Protein Technologies for Biopharmaceuticals: Applications and Challenges - page 105

FIGURE 7.1 Schematic diagram for erythropoietin Fc (EpoFc) dimer and monomer. The dimer is
composed of two molecules of Epo joined to dimeric Fc and the monomer has a single molecule
of Epo joined to dimeric Fc. Source: Reproduced from Reference [32] with permission from Adis
( # Springer International Publishing AG (2006) All rights reserved).

therapeutic protein and its receptor. Thus, a molecule was
created that was comprised of a single molecule of Epo coupled
to dimeric Fc, and was described as the EpoFc monomer.
Pulmonary uptake of the EpoFc monomer was compared
to the EpoFc dimer after a single dose in cynomolgus
monkeys [12]. The systemic exposure of the EpoFc mono-
mer, measured by peak concentration (C max ) and area under
the curve (AUC), was markedly increased compared to the
EpoFc dimer (Figure 7.2). There was a 4- to 5-fold increase
in C max and a 6- to 10-fold increase in the AUC. Further-
more, the half-life was improved to 25 h compared to 16 h,
for the monomer and dimer, respectively, and bioavailability
of the EpoFc monomer was also improved to

compared to 5-10% for the dimer. Because of the superior
PK parameters of the monomeric EpoFc, this configuration
was applied to other therapeutic proteins.

7.3 TYPICAL APPLICATIONS

Several Fc-fusion proteins have been generated which are
monomeric with respect to the effector moiety, and in each
case improvements relative to the dimeric Fc-fusion proteins
have been observed in various characteristics of the molecule
including bioactivity and PK parameters [32]. Several exam-
ples of monomer Fc-fusion proteins are described below.

30%

>

FIGURE 7.2 Pulmonary delivery of EpoFc monomer and dimer in nonhuman primates. Equivalent
doses (20mg/kg) of EpoFc dimer or EpoFc monomer were aerosolized with an Aeroneb Pro 1
nebulizer and delivered directly into the lungs of intubated cynomolgus monkeys using shallow
breathing maneuvers. Serum concentrations of the dimer and monomer were measured with an Epo-
specific ELISA. The number of animals per group were n ¼ 2 for EpoFc dimer and n ¼ 4 for EpoFc
monomer. Source: This research was originally published in Reference [12].