Biomedical Engineering Reference
In-Depth Information
antibodies tocilizumab [198] or REGN88 (also called sar-
ilumab) [199], or other biologic therapeutics under devel-
opment [97,98,200]. Therefore, it remains an open question
whether CR5/18 will prove superior to other biological
therapies targeting IL-6.
remains open whether receptor-Fc or Traps might be pre-
ferred over other biologics in any specific clinical setting.
The main competition to these Fc fusion proteins is pre-
sented by monoclonal antibodies—which represent the
fastest growing class of protein-based therapeutics [199].
The ability of any given receptor-Fc or Trap to interact with
multiple ligands or to elicit additional responses (e.g.,
reverse signaling), or to selectively block its differentially
acting pool of target cytokine (e.g., the trans-signaling pool)
remains possible differentiating properties. Therefore,
although monoclonal antibodies provide a quicker and
perhaps more straightforward path to clinical development,
receptor-Fc fusion proteins, and Traps present relevant
alternatives. Sometimes, these advantages may be as simple
as higher affinity leading to less frequent dosing, but there is
still not enough clinical data to allow us to pinpoint all the
clinically important differences, advantageous, or otherwise,
of each receptor-Fc or Trap in comparison to other drugs that
have been developed against the same target. One exception
is offered by the receptor-Fc therapeutic, etanercept, which
has been widely used in the clinic for a long time. The
differences between etanercept and antibody-based TNF-
a
blockers have been reviewed extensively elsewhere
[23,55,191,212]. These reviews as well as overall clinical
practice demonstrate that some patients respond better to
one type of TNF blocker than another, and this may reflect
subtle differences in the mechanism of action of these drugs
[213]. The fact that etanercept remains one of the best-
selling biologics even in the face of increased competition
by antibody-based therapeutics provides credence to the
idea that Fc fusions remain a useful and lasting therapeutic
modality for a large number of patients.
9.6.3 Immunogenicity
A third concern that has been raised with receptor-Fc fusions
and Traps is the possibility of immunogenicity, particularly,
raising autoantibodies that cross-react with their correspond-
ing native ectodomains. The potential for immunogenicity is
not limited to these Fc fusions—it has been observed for
many protein-based therapeutics [201,202]—and it appears
that receptor-Fc fusions and Traps may be less immunogenic
than their antibody counterparts [203-205]. There are only
few reports of anti-receptor-Fc or anti-Trap antibodies. In
one case, for Fc-OPG, the formation of neutralizing anti-
bodies in one patient was listed as one of the reasons for
halting further development of this therapeutic
[115,157,206]. One well-documented case of antibody for-
mation to a receptor-Fc was observed in clinical trials with
TNFR55-IgG1 (lenercept). The antibodies that formed
against lenercept were not neutralizing, but they resulted
in rapid clearance of the drug that in turn led to suspension of
further clinical development [207-209]. Antibodies induced
against other Fc fusion proteins have also been nonneutral-
izing, and their clinical significance remains unclear. For
example, anti-etanercept nonneutralizing antibodies have
been observed in some clinical settings involving chronic
use of this TNF blocker, but the immune response does not
appear to decrease the efficacy of the drug, as these anti-
bodies do not dramatically accelerate drug clearance
[203,204,210,211]. Similarly, anti-rilonacept nonneutraliz-
ing antibodies have been detected in CAPS patients, who
have been chronically dosed with rilonacept, but the titers
are very low and do not appear to impact pharmacokinetics
and efficacy, or have other detrimental effects on the health
of the patients [63]. Overall, immunogenicity has not been a
greater concern for Fc fusions than other protein-based
therapeutics, and therefore it will probably not be the
main limiting factor for their clinical application.
ACKNOWLEDGMENT
We would like to acknowledge Stephen Jaspers, Scott
Mellis, Nicholas Papadopoulos Evangelos Pefanis, John
S. Rudge, and Christopher Schoenherr for critical reading
of this manuscript.
REFERENCES
9.7 CONCLUSION
1. Huang C. (2009) Receptor-Fc fusion therapeutics, traps, and
MIMETIBODY technology. Curr. Opin. Biotechnol. 20,
692-699.
2. Andersen JT, Pehrson R, Tolmachev V, Daba MB, Abrahmsen
L, Ekblad C. (2011) Extending half-life by indirect targeting
of the neonatal Fc receptor (FcRn) using a minimal albumin
binding domain. J. Biol. Chem. 286, 5234-5241.
3. Gill DS, Damle NK. (2006) Biopharmaceutical drug discov-
ery using novel protein scaffolds. Curr. Opin. Biotechnol. 17,
653-658.
This review has summarized how receptor-Fc fusions and
Traps, as well as other biologics such as antibodies raised
against the same target can all be successfully used in
research and in the clinic. The concerns that have been
raised for the use of receptor-Fc fusions or Traps as ther-
apeutics have largely not materialized, and in those cases
where adverse events have been noted in the clinic, this has
happened early on in the development process. The question
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