DEVELOPMENT OF LATENT CYTOKINE FUSION PROTEINS - Fusion Protein Technologies for Biopharmaceuticals: Applications and Challenges - page 241

latent cytokines described by Adams et al. [7] in that LAP is
positioned at the C-terminus of the melittin. The LAP-
melittin fusion protein was constructed in this way out of
necessity, as fusing the melittin at its N-terminal removed all
lytic activity. In vitro studies have shown that melittin can be
released by cleavage with MMP-2, while in vivo studies have
shown that treatment with melittin-LAP can decrease tumor
volume in mice without significant systemic toxicity [105].
It is not clear at this time why this melittin-LAP fusion is
fully latent, as it has been clearly demonstrated by Adams
et al. [7] that construction of IFN- b with LAP located at the
C-terminus of the fusion protein is not latent.
These examples illustrate the fact that the latent cytokine
technology is by no means limited to cytokines as the
therapeutic molecule of choice. In fact, any therapeutic
molecule can theoretically be made latent and targeted to
the site of disease using this system. The latent cytokine
technology is proving to be an elegant, effective, and
versatile method of targeting therapeutic molecules to sites
of disease. There is certainly scope for using this technology
to make ever more specific treatments for disease by har-
nessing disease-specific changes that occur locally at the
sites of disease, including, but not limited to the up-regula-
tion of MMPs. Similarly, the range of therapeutic molecules
that can be produced in a latent form is not limited to
cytokines, but can also be used for other therapeutic pep-
tides. This versatility means that there are numerous poten-
tial applications for this technology.

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ACKNOWLEDGMENTS

Funding for this work was obtained from the MRC, EU,
Wellcome Trust, Arthritis Research UK, and the British
Heart Foundation.

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