SIGNAL CONVERTER PROTEINS - Fusion Protein Technologies for Biopharmaceuticals: Applications and Challenges - page 437

IIIA NOVEL CONCEPTS, NOVEL SCAFFOLDS
30

SIGNAL CONVERTER PROTEINS

M ARK L. T YKOCINSKI

Department of Pathology, Anatomy and Cell Biology, Jefferson Medical College,
Thomas Jefferson University, Philadelphia, PA, USA

30.1 Introduction
30.2 Historical roots of signal conversion: artificial veto cell
engineering and protein painting
30.3 Trans signal converter proteins
30.4 Expanding trans signal conversion options: redirecting
signals
30.5 From trans to cis signal conversion: driving auto-signaling
30.6 Mechanistic dividends of chimerization
30.7 Targeting multiple diseases with individual signal converters
30.8 Structural constraints in SCP design
30.9 Coding SCP functional repertoires
30.10 Expanding the catalog of inhibitory SCP
30.11 Immune activating SCP
30.12 Experimental tools for screening SCP candidates
30.13 SCP frontiers: mining the surface protein interactome,
rewiring cellular networks
References

their signal modulation within complex and dynamic cellular
networks. Pinning diverse and inherently multifunctional
SCP onto multicellular frameworks generates richness in
matrices of cellular interaction and therapeutic outputs.
Over the past decade, the signal converter story has
steadily evolved, with interesting twists and turns along
the way. The catalog of SCP types has expanded, with the
original straightforward paradigm—conversion of contact-
dependent signaling between two interacting cells—giving
way to more intricate paradigms. Redirection of signaling is
one such newer paradigm, and it itself has spawned its own
variants. Converted signals can be redirected not only to
third-party cells, but also to receptors on the very same cell in
an auto-signaling, loop-back mode. Remarkably, the same
SCP can sometimes redirect signals in more than one direc-
tion, manifesting both intercellular- and auto-signaling
capacities. Moreover, the array of cell types and diseases
that can be targeted by SCP has continuously expanded. Early
studies geared toward immune inhibition for autoimmune and
inflammatory diseases set the stage for newer SCP designed
for other purposes. These include immune activation in the
context of immunization, and even entirely different non-
immunological ends, for example, cancer cell eradication.
This chapter details some of the evolving signal converter
paradigms and their associated SCP categories, putting them
within an historical context and mapping a future landscape
with ever expanding SCP possibilities.

30.1 INTRODUCTION

Fusion proteins that feature an ability to convert cell surface
signals constitute a new protein therapeutic frontier. Such
signal converter proteins, or SCP, modulate signals that are
exchanged between cell surface proteins. A diverse set of
multifunction signal converters have emerged in recent years,
showcasing a spectrum of signal-converting functionalities.
Uncannily, each new SCP seems to surprise, whether by its
unexpectedly high efficacy, multiplicity of cellular targets,
or mechanisms of action not anticipated from the known
activities of the chimeric protein's component parts. The
functional tapestry for signal converters is enriched by the
very nature of their in vivo operative settings, since they effect

30.2 HISTORICAL ROOTS OF SIGNAL
CONVERSION: ARTIFICIAL VETO CELL
ENGINEERING AND PROTEIN PAINTING

The experimental path that led to SCP has its deeper roots in
a seminal discovery made a number of years ago in the field