Systemically Administered, Target-Specific, Multi-Functional Therapeutic Recombinant Proteins in Regenerative Medicine

Abstract

Growth factors, chemokines and cytokines guide tissue regeneration after injuries. However, their applications as recombinant proteins are almost non-existent due to the difficulty of maintaining their bioactivity in the protease-rich milieu of injured tissues in humans. Safety concerns have ruled out their systemic administration. The vascular system provides a natural platform for circumvent the limitations of the local delivery of protein-based therapeutics. Tissue selectivity in drug accumulation can be obtained as organ-specific molecular signatures exist in the blood vessels in each tissue, essentially forming a postal code system (“vascular zip codes”) within the vasculature. These target-specific “vascular zip codes” can be exploited in regenerative medicine as the angiogenic blood vessels in the regenerating tissues have a unique molecular signature. The identification of vascular homing peptides capable of finding these unique “vascular zip codes” after their systemic administration provides an appealing opportunity for the target-specific delivery of therapeutics to tissue injuries. Therapeutic proteins can be “packaged” together with homing peptides by expressing them as multi-functional recombinant proteins. These multi-functional recombinant proteins provide an example how molecular engineering gives to a compound an ability to home to regenerating tissue and enhance its therapeutic potential. Regenerative medicine has been dominated by the locally applied therapeutic approaches despite these therapies are not moving to clinical medicine with success. There might be a time to change the paradigm towards systemically administered, target organ-specific therapeutic molecules in future drug discovery and development for regenerative medicine.

Generation of a multi‐functional, target organ‐specific, anti‐fibrotic molecule by molecular engineering of the extracellular matrix protein, decorin

“…One of the goals of modern pharmaceutical treatment is to be as target specific as possible; drugs should be highly active against the disease while having as few side effects in the healthy parts of the body as possible (Järvinen et al, ). This goal is usually obtained by developing drugs that act on molecules selectively expressed in the diseased organ.…”

“…Injured tissue provides an excellent target for ligand‐mediated delivery of systemically administered therapeutic agents (Järvinen et al, ). The first actual sign of tissue regeneration after the injury and subsequent inflammatory period is massive angiogenesis in the injured area.…”

“…The first actual sign of tissue regeneration after the injury and subsequent inflammatory period is massive angiogenesis in the injured area. The formation of angiogenic capillaries is induced by the hypoxia resulting from disrupted circulation in the damaged tissue (Barker et al, ; Järvinen et al, ). Hypoxia triggers the production of angiogenic growth factors, which induce angiogenesis in the injured tissue.…”

“…Expressing a short homing peptide as part of a larger recombinant fusion protein makes it possible to circumvent two major pharmacological disadvantages of peptides, short half‐life in the circulation and low binding affinity towards the target molecule (Järvinen et al, ). Thus, multiple therapeutic multi‐functional recombinant fusion proteins consisting of vascular targeting element and a therapeutic molecule have been described in the biomedical literature, and the most advanced ones have already moved to clinical trials (Phase III) in humans.…”

“…For example, they are shorter that the complementary determining regions inserted into therapeutic antibodies, which usually do not cause immune reaction and are considered safe as drugs. Furthermore, vascular homing peptides sometimes share sequence homology with parts of human and mammalian proteins, as is the case with CAR peptide, which is also likely to reduce immunogenicity (Järvinen et al, ).…”