FUSION PROTEINS WITH A TARGETING FUNCTION - Fusion Protein Technologies for Biopharmaceuticals: Applications and Challenges - page 370

IIC TARGETING: FUSION PROTEINS ADDRESSING SPECIFIC
CELLS, ORGANS, AND TISSUES
25

FUSION PROTEINS WITH A TARGETING FUNCTION

S TEFAN R. S CHMIDT

Rentschler Biotechnologie GmbH, Laupheim, Germany

25.1 Introduction
25.2 Targeting organs
25.3 Intracellular delivery
25.4 Oral delivery
25.5 Conclusions and future perspectives
References

[5]. Other molecules that can be found on cell membranes
are receptors, channels, or adhesion proteins. Recognition
motifs for cellular receptors include protein sequences or
oligosaccharide patterns. In the case of the extracellular
matrix, glycoproteins and collagen fibrils build a network to
which the receptors such as integrins can bind. Both recep-
tors and matrix molecules play a role in human disease and
represent targets for intervention [6].
Components of therapeutic fusion proteins addressing
surface molecules can be the natural ligands, peptide
domains, antibodies, or other designer molecules based on
novel scaffolds [7]. Targeted drug delivery is a highly
relevant strategy, particularly for large therapeutic molecules
such as proteins to separate them from regions in the body
where they are quickly degraded or because systemic distri-
bution might never reach a sufficiently efficacious dose.

25.1 INTRODUCTION

This part deals with the many approaches to selectively
target specific organs, cells, or even intracellular localiza-
tions with fusion proteins.
This requires a high specificity to epitopes that are unique
for the respective targets. Over the last decades, systematic
investigations identified a long list of cell-specific surface
antigens. This is of primary interest for targeted therapies
against cancer, where it is critical to only address malignant
cells while sparing normal cells. Cancer cells frequently
overexpress growth factor receptors or specific tumor-asso-
ciated antigens [1]. In some cases, even intracellular proteins
such as heat shock proteins appear aberrantly on the surface
of cancer cells, and can be reached by antibodies [2].
Intracellular targets sometimes become accessible because
of an increase of abnormally permeable and degenerating
cells in necrotic regions of tumors. These epitopes are highly
selective cancer targets since they are not accessible in
normal tissues [3]. However, targeted therapy is nowadays
also focusing on the processes that lead to malignant trans-
formation, proliferation, survival, and angiogenesis [4].
In addition, intracellular mislocalization of proteins
can cause disease and generate targets for therapeutics

25.2 TARGETING ORGANS

Targeting to certain organs is quite useful from a pharma-
cological perspective. The desirable accumulation of drugs
in specific tissues on one hand increases the local concen-
tration while on the other hand reduces systemic exposure
that could be harmful. The challenge is to find highly
specific surface molecules and simultaneously to identify
ways to overcome organ boundaries.

25.2.1 Brain

Targeting the brain is more complicated than reaching any
other organ, since the brain is separated from normal blood
flow by the blood-brain barrier (BBB). This barrier is formed
by brain capillary endothelial cells. These cells are fused
together by tight junctions, making them impermeable [8].