Deriving Immune Modulating Drugs from Viruses-A New Class of Biologics

Abstract

Viruses are widely used as a platform for the production of therapeutics. Vaccines containing live, dead and components of viruses, gene therapy vectors and oncolytic viruses are key examples of clinically-approved therapeutic uses for viruses. Despite this, the use of virus-derived proteins as natural sources for immune modulators remains in the early stages of development. Viruses have evolved complex, highly effective approaches for immune evasion. Originally developed for protection against host immune responses, viral immune-modulating proteins are extraordinarily potent, often functioning at picomolar concentrations. These complex viral intracellular parasites have "performed the R&D", developing highly effective immune evasive strategies over millions of years. These proteins provide a new and natural source for immune-modulating therapeutics, similar in many ways to penicillin being developed from mold or streptokinase from bacteria. Virus-derived serine proteinase inhibitors (serpins), chemokine modulating proteins, complement control, inflammasome inhibition, growth factors (e.g., viral vascular endothelial growth factor) and cytokine mimics (e.g., viral interleukin 10) and/or inhibitors (e.g., tumor necrosis factor) have now been identified that target central immunological response pathways. We review here current development of virus-derived immune-modulating biologics with efficacy demonstrated in pre-clinical or clinical studies, focusing on pox and herpesviruses-derived immune-modulating therapeutics.

Keywords: biologic; chemokine; chemokine binding protein; cytokine; growth factor; immune modulation; interleukin; protein; serpin; therapeutic; virus.

Figure 1

A general overview of therapeutic uses of viruses, including direct use as immunogens for vaccines, gene therapy vectors for delivery of therapeutic protein-coding sequences, tools for destroying cancer cells in oncolytic virotherapy and as sources for novel therapeutic proteins.

Figure 2

Comparison of different classes of immune modulators produced by large DNA viruses. Herpesviruses, which replicate in the nucleus, and poxviruses, which replicate in a peri-nuclear factory, both produce chemokine mimics and inhibitors, cytokine and cytokine receptor mimics and inhibitors and growth factor mimics. A major distinguishing feature of poxviruses is the production of both intracellular and extracellular serine protease inhibitors (serpins).

Figure 3

General overview of serpin function. The two major functional components of a serpin structure are the reactive center loop (RCL; magenta) and the A β-sheet (yellow). The RCL presents a protease cleavage site as a substrate to serine (and cysteine in cross-class serpins) proteases (cyan). When the target protease acts upon the RCL substrate a transient Michaelis complex forms (left), wherein the serpin and the protease are temporarily covalently bound to each other. When this Michaelis complex forms, the RCL performs a dramatic rearrangement and inserts as the third of five strands in the A β-sheet (right). The deformed and neutralized protease and serpin are permanently linked in a suicide complex, which then gets degraded. Structures are modeled on RSCB entries 1K9O (left) [36] and 1EZX (right) [35].

Figure 4

An overview of chemokine function and role. (A) Chemokines exhibit highly conserved overall structure with classification by the arrangement of their N-terminal cysteine residues. (B) Chemokines bind G protein-coupled receptors (GPCR)-type receptors on chemotactic cells such as mononuclear cells via their N-terminus, and are anchored to tissue matrices and endothelial layers by glycosaminoglycans in the glycocalyx. Viral chemokine signaling modulators are indicated in red boxes with an approximate location of interference indicated. (C) Gradients formed by the anchoring of chemokines to the glycocalyx direct circulating immune cells to infiltrate into the site of injury or infection.

Figure 5

Summary overview of diseases and conditions tested for therapeutic efficacy of virus-derived proteins in preclinical models discussed in this review.