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.

Recombinant Myxoma Virus-Derived Immune Modulator M-T7 Accelerates Cutaneous Wound Healing and Improves Tissue Remodeling

“…In the case of Myxoma virus, an estimated 10 million years of evolution have gone into developing expert modulators of the host immune response [ 16 ]. Thus, the suite of immune modulating proteins in Myxoma virus are a valuable, highly optimized “medicine cabinet” for targeting immune-driven pathologies, and for harnessing immune function to enhance tissue repair [ 12 ]. Further work will investigate the potential for combining these proteins in cocktails, towards further enhancing therapeutic responses in wound healing and other models.…”

“…Our group and others have investigated the application of immune modulators from viruses as an approach toward deriving novel protein therapeutics [ 12 ]. The co-evolution of viruses with their natural hosts invokes an adaptation arms race, whereby a successful strategy for the virus relies on immune evasion, often targeting key pathways that drive immune activation [ 13 ].…”

“…Large DNA viruses, such as poxviruses and herpesviruses, are adept at evading the innate immune system via a suite of virulence factors [ 14 , 15 ]. Translationally, these factors constitute a rich toolbox for developing immune modulators for treating disease [ 12 ].…”

Attenuation of acute and chronic inflammation using compounds derived from plants

“…These have been identified and purified and may have utility in subduing inflammatory events in a novel manner. 23 Extracts of aged Allium sativum have been found to reduce production of inflammatory cytokines and histamine. While such extracts are complex and of uncertain composition, the active constituents have been characterized and are well-defined.…”

Neuroprotective Effect of Subdural Infusion of Serp-1 in Spinal Cord Trauma

“…In another experiment, Serp-1 delivered in the chitosan hydrogel in the acute lesion created by the dorsal spinal column crush also resulted in anti-inflammatory effect associated with reduction of the size of the lesion and improvement in clinical scores [ 9 ]. Serp-1 binds and inhibits tissue- and urokinase-type plasminogen activators, plasmin in the thrombolytic cascade, and thrombin and Factor X in the coagulation/thrombotic cascade [ 10 ]. This serpin protein biologic has been shown to reduce vasculitis in vascular injury and in organ transplant models [ 11 ].…”