FUSION PROTEINS: APPLICATIONS AND CHALLENGES - Fusion Protein Technologies for Biopharmaceuticals: Applications and Challenges - page 15

A fusion protein specifi c com plicati on is the increased
potential of immunogeni city. For instanc e, im munotoxins
contain frequently nonhum an prot eins that elicit immune
responses and neutral izing antibodi es. Also the conjunct ion
site betwee n the two fusi on partners forms a novel epitope
even whe n com bining only huma n protei ns. In both cases, a
detailed stud y of the pote ntial risk has to be d one in form of
specializ ed assa ys. Chapte r 5 of this boo k explains the
current appro aches.
Typical challenges for bi-specific molecules are the diffi-
culty to have similar potency/affinity against both targets, the
lack of individual dosing or pharmacokinetic and the potential
of overlapping and cross-linked toxicity. Dosing and potency
can be addressed by combining two molecules with suitable
affinities or altering them accordingly. In the case of transfer-
rin fusions, the simultaneous or sequential binding of both
fusion partners to their respective cell surface receptors has a
huge impact on recycling, degradation, and biological activity
[166]. Toxicity issues can be predicted to some degree in
simulation models. A number of adverse side effects of
antibodies that are primarily dependent on the Fc part have
been described in the past [167]. It is important to take the
multiple functions of Fc domains into account when designing
Fc-fusion proteins. Surprisingly, the majority of Fc fusions
contain IgG1 that can trigger ADCC or CDC reactions.
Therefore, it is advisable to select the Fc part of IgG2 or 4
as fusion partner. A number of novel scaffolds also serve as
building blocks for fusion proteins. It is recommended to
adapt the preclinical safety testing to the individual molecules
and their mode of action [168].
Recently, som e fusion protein s failed in clini cal trials for
differ ent reasons. In the case of Zalbin TM , an interfero n-
a 2b-HSA fusion, the risk benefit ratio was not suffic iently
favorable, which let Novartis and Human Gen ome Scien ce
withdraw their biologi cs licens e applica tion (BLA) in 2010. 2
The glucagon- like peptide -1 (GL P-1)-Transferri n fusi on of
Pfizer and BioR exis was discont inued in Phase I becau se a
reversible increase in hear t rate was obser ved. 3 Surpr isingly
and witho ut disc losing speci fic reas ons, Am evive 1 (leuk o-
cyte functi on antigen -3 (LFA-3) linked to Fc of IgG1) that
was never approved for Eu ropean mar kets and was with-
drawn from the U.S. market by Astel las Ph arma in 2011. 4

the years thereafte r only a few were approved by the FDA to
reach patients, the majority being FC- fusion protei ns [169] .
The only exception within the eight market ed fusion pro-
teins in 2011 is an immu notoxin, Ontak 1 . Despite that fact
that Ontak does not capt ure a hu ge market, many othe r
immu notoxins are in the clini cal p ipeline, proba bly expand-
ing the numb er of approved fusion prot eins soon.
In contras t, a total of 25 mA Bs were acce pted by regula -
tory authori ties since 1998. Th is triple numb er of p roducts is
also reflecte d in sales. In 2010, the six so far approved fusion
protei ns collec ted $8.3 billion in revenues, whe reas mAB s
had sales of $40.8 billion globally. 5 This indicates that the
compet ition of antibodies is really strong, and only Enbrel
and Orencia have blockbuster status . On the example of
Enbrel, the strong com petition and evolution of antibodies in
the market seg ment of TNF- a bloc kers can be demonst rated
(Table 1.1).
However, the big opportuni ty for fusion prot eins can be
found in appl ications where they do not have to face the
fierce compet ition of antibodi es. Many arisi ng conce pts
focus on novel scaffolds that can replace antibodi es and
represe nt the binding moiety of fusion protei ns [13]. Fre-
quently, thes e small scaffold s can reach different targets than
antibodi es, but suffering from pharm acokinetic limit ations.
Most of them require plasma half-life extension strategies as
explained in Part IIa of this topic . But due to their small siz e
they are ideal candidates for generat ing bi-func tional mol-
ecules by com bining two of them.
With regard to bi-spec ific antibodi es, a subt opic of this
topic, this mark et is just emerging, with the tri-funct ional
Removab 1 as the first approved multispe cific antibody in
2009 [170]. The rising interest in this class of mol ecules is
also reflecte d in increased merger and acquisition (M&A )
activitie s such as Amgen buying Mic romet for $1.2 billion in
2012. 6
As descr ibed previously, the desig n of fusion proteins is
based on genetic engi neering; many of the conce pts are
patent protected and have been used to build com panies. In
times when large pharmac eutical corporatio ns are facing
expiring pate nts, these com panies became targets for acquis-
itions to bols ter emptying pipelines. In Table 1.2, the M & A
deals of the las t decade affecti ng com panies with fusion
protei n technol ogy or drugs in various developme nt sta ges
are collec ted.
Overall a fast growth for pr otein t he rapeut ics c an be
predicted [ 171]. The t op 30 biological s gathered gl obal
sales wort h more than $1 07 billi on i n 2010, with Enbrel
being the most successful drug. 7 Overall t he global phar-
maceutical market grew by 4.1%, but interest ingly s ales of

1.7 COMPE TITION AND MA RKET

Fusion proteins are relat ive recent entrants to the market of
therape utic prot eins, appeari ng first with Enbrel in 1998. In

2 http://www.hgsi.com/latest/human-genome-sciences-announces-
withdrawal-of-european-marketing-authorization-application-for-joulferon-
zalbin-for-the-treatment-of-chronic-hepati-7.html
3 http://clinicaltrials.gov/ct2/show/NCT00637338?term ¼ PF-
04603629&rank ¼ 1
4 http://www.amevive.com/Patient%20letter.pdf

5 Datamonitor: PharmaVitae: Monoclonal Antibodies: 2011 - Market Size
Update. October 2011.
6 http://www.amgen.com/media/media_pr_detail.jsp?releaseID ¼ 1653062
7 La Merie S.L., Travesia Balmins, 7, Bajos, 2a, 08870 Sitges, Spain: Top 30
Biologics 2010, 04 March 2011.