FUSION PROTEINS: APPLICATIONS AND CHALLENGES - Fusion Protein Technologies for Biopharmaceuticals: Applications and Challenges - page 2

FUSION PROTEINS: APPLICATIONS AND CHALLENGES

S TEFAN R. S CHMIDT

Rentschler Biotechnologie GmbH, Laupheim, Germany

1.1 History
1.2 Definitions and categories
1.3 Patenting
1.4 Design and engineering
1.5 Manufacturing
1.6 Regulatory challenges
1.7 Competition and market
1.8 Conclusion and future perspective
References

Chemical processes were developed to obtain the fully human
variant from the pig isoform [2]. Finally, the first recombinant
human insulin was manufactured by Eli Lilly & Co in
partnership with Genentech, approved in 1982 by the FDA
and marketed under the name Humulin 1 [3]. This was also
the first therapeutic recombinant protein for human use.
Since that time, the number of recombinant products and
approved biopharmaceuticals has increased considerably.
Initially, recombinant copies of proteins were made that
replaced the natural protein, which until then was harvested
from animal or human sources. With the exception of factor
VIII against hemophilia, all these proteins such as human
growth hormone (hGH) or follicle stimulating hormone
(FSH) belonged to the class of hormones. They were
soon accompanied by a growing number of first generation
therapeutics that could only be obtained recombinantly such
as erythropoietin (EPO), interferon (IFN) or tissue plasmin-
ogen activator (tPA), just to name a few. After this first
enthusiasm and the success with reproducing natural pro-
teins by recombinant DNA technology, researchers started to
consider the de novo design of therapeutic proteins that do
not occur in nature. There is one specific class that can be
seen as intermediate link between natural and designed
proteins, monoclonal antibodies (mABs).
Antibodies, being a major part of the organism's immune
defense, are large proteins that exist in all higher animals. In
1975, a method was developed to generate murine cell lines
producing antibody molecules of a single specificity, the so-
called monoclonal antibodies (mABs) [4]. The first thera-
peutic monoclonal antibody, orthoclone OKT3, was of
murine origin and approved in 1986. From then, this concept
was further refined with the help of modern recombinant
DNA technology to obtain the first fully human antibody
against tumor necrosis factor- a (TNF- a ), marketed under

1.1 HISTORY

Proteins as drugs have a long history. In the beginning,
natural proteins were extracted from animal, human sources,
or in some rare cases even from plants. Large-scale proc-
essing of human plasma became a primary source for the
isolation of many proteins [1]. For instance, blood factors
became available as a therapy against the different forms of
hemophilia or the lack of functional ( a -1 antitrypsin. The
major serum component, albumin, has now been used for
more than 50 years as a treatment for shock, trauma, or
burns. Immune globulins isolated from human sources are
also used successfully in various immunodeficiency dis-
eases. However, despite the great success of plasma prod-
ucts, contaminations with the HIV or hepatitis virus in the
1970-1980s triggered more intensified efforts to prepare
virus-free recombinant therapeutic proteins.
Since its identification in the 1920s until the 1980s, insulin
from animals was the only treatment for diabetes patients.
Particularly, the porcine insulin was widely used since there is
only a single amino acid variation from the human form.