DEVELOPMENT OF LATENT CYTOKINE FUSION PROTEINS - Fusion Protein Technologies for Biopharmaceuticals: Applications and Challenges - page 231

FIGURE 16.1 Latent cytokines. The latency-associated peptide (LAP) from TGF- b forms a shell
around the therapeutic cytokine, rendering it biologically inactive. A cleavage site specific for matrix
metalloproteinase (MMP) is engineered in between the LAP and the cytokine, enabling the release of
the cytokine at the sites of disease. Source: Reprinted from Reference [8]. Copyright (2004), with
permission from Elsevier.

cancer cells, pulmonary fibrosis, and neuroinflammation [15].
The role of MMPs in many of these conditions is concerned
with tissue destruction caused by elevated levels of these
enzymes. It has long been noted that the pathologies of
autoimmune diseases and cancer share many similar facets
[16], namely, aberrant cell proliferation, ECM remodelling,
and alteration of the cell microenvironment. It is now abun-
dantly clear that MMP activity contributes significantly to the
progression of these diseases by remodeling the ECM and
altering the microenvironment. There are now many reports
implicating a number of different MMPs in cancer (MMPs-2,
-7, and -11) and in RA (MMPs-1, -2, -3, -9, and -13).
MMPs are likely to play a pathological role in any
condition where tissue destruction forms part of

pathology, for example, periodontal disease, brain injury
[17], and neuroinflammatory diseases [18]. In addition to
their effects on tissue destruction, MMPs have also been
implicated in fibrosis, most notably in atherosclerosis, which
is associated with alterations in the arterial ECM [19]. There
are a number of reports detailing the role of a range of MMPs
in many of the processes that occur in atherosclerosis [20].
Therefore, there are many pathological conditions where
the concentration of one, or more, MMP(s) is elevated at the
site of disease. The latent cytokine technology takes advan-
tage of this increase in local MMP concentration to provide a
targeted release of therapeutic cytokine only at these sites. In
addition, the release of the cytokine at the site of disease will
also be dependent on the degree of MMP activity, thereby the

FIGURE 16.2 Illustration of the use of the latent cytokine technology to treat rheumatoid arthritis.
The latent cytokine remains biologically inactive until cleaved by MMP at the inflamed joint.