STRAND EXCHANGE ENGINEERED DOMAIN (SEED): A NOVEL PLATFORM DESIGNED TO GENERATE MONO AND MULTISPECIFIC PROTEIN THERAPEUTICS - Fusion Protein Technologies for Biopharmaceuticals: Applications and Challenges - page 533

37

STRAND EXCHANGE ENGINEERED DOMAIN (SEED): A
NOVEL PLATFORM DESIGNED TO GENERATE MONO
AND MULTISPECIFIC PROTEIN THERAPEUTICS

A LEC W. G ROSS , 1 J ESSICA P. D AWSON , 1 M ARCO M UDA , 1, y C HRISTIE K ELTON , 1 S EAN D. M C K ENNA , 1 AND
B J ¨ RN H OCK 2
1 EMD Serono Research Institute, Billerica, MA, USA
2 Merck Serono, Protein Engineering and Antibody Technologies, Darmstadt, Germany

37.1 Introduction
37.2 Technical aspects
37.3 Potential therapeutic applications
37.4 Future perspectives
37.5 Conclusions
Acknowledgments
References

targets by trying to exploit protein engineering technologies
to improve antibody activity, for example, enhanced effector
functions [3], introduce immunoconjugates [4] or tailored PK
properties [5], or to achieve reduction of treatment costs.
Another strategy to enhance efficacy involves combin-
ing mABs with different modes of action (MOA): As an
example, different targets in connected pathways such as
EGFR and IGFR can be combined to produce synergistic
MOAs [6] or to suppress resistance mechanisms as des-
cribed for EGFR and cMET [7].
MAB combinations, although self-evident as a best in
class strategy, are challenging from a development and
marketing perspective: First, each single antibody as well
as the combination likely require regulatory testing and
approval from authorities such as FDA and EMEA leading
to delays and a significant increase in development costs.
Secondly, the interdependency of efficacy and pharmaco-
kinetics (PK) needs to be carefully studied. In addition,
combination of individual mABs leads to high costs. Based
on these challenges bispecific antibody (bsABs) technolo-
gies become an attractive alternative because they offer a
solution to combine synergistic MOAs in a single entity. In
addition, bsABs open newMOAs as demonstrated by Micro-
met's BiTE technology [8].
Although the bsAB concept provides a striking solution
for the combination of different MOA, production of those
molecules turned out to be very challenging. Shortly after
invention of the mAB technology [9], Milstein and Cuello
[10,11] described the Quadroma technology for

37.1 INTRODUCTION

Monoclonal antibodies (mABs) have achieved outstanding
commercial success as therapeutics in the last decade and of
the top 10 best selling drugs in 2009, four belonged to this
class [1]. On the other hand, the target space seems to be
limited. In oncology for example, nine marketed products
correspond to only six different targets (VEGF, EGFR, Her2,
CD20, CD33, and CD52). For autoimmune and inflamma-
tory diseases, four TNF- a -neutralizing mABs have been
marketed (Infliximab, Adalimumab, Golimumab, and Cer-
tolizumab PEGol) [2]. The number of mAB launches val-
idating new targets is limited to one or fewer per year
demonstrating that new therapeutic target discovery is an
elusive and costly business. Therefore, some next-generation
mAB therapeutics will likely build on existing well validated

the

y Present Address: Merrimack Pharmaceuticals, Cambridge, MA, USA.