Enzymes as Immunotherapeutics

Abstract

Enzymes are attractive as immunotherapeutics because they can catalyze shifts in the local availability of immunostimulatory and immunosuppressive signals. Clinical success of enzyme immunotherapeutics frequently hinges upon achieving sustained biocatalysis over relevant time scales. The time scale and location of biocatalysis are often dictated by the location of the substrate. For example, therapeutic enzymes that convert substrates distributed systemically are typically designed to have a long half-life in circulation, whereas enzymes that convert substrates localized to a specific tissue or cell population can be more effective when designed to accumulate at the target site. This Topical Review surveys approaches to improve enzyme immunotherapeutic efficacy via chemical modification, encapsulation, and immobilization that increases enzyme accumulation at target sites or extends enzyme half-life in circulation. Examples provided illustrate "replacement therapies" to restore deficient enzyme function, as well as "enhancement therapies" that augment native enzyme function via supraphysiologic doses. Existing FDA-approved enzyme immunotherapies are highlighted, followed by discussion of emerging experimental strategies such as those designed to enhance antitumor immunity or resolve inflammation.

Locally anchoring enzymes to tissues via extracellular glycan recognition

“…Various chemical modifications can extend enzyme half-life or increase accumulation within target tissues. For example, modifying enzymes with hydrophilic polymers (e.g., poly(ethylene glycol, PEG) or dextran) can extend half-life in circulation by increasing drug hydrodynamic radius to prevent renal clearance and by masking proteolytic degradation sites 10 , 11 , as seen for Pegadamase and Pegaspargase 12 . However, modification with hydrophilic polymers does not promote enzyme accumulation at target sites within solid tissues and therefore is largely limited to enzymes that are effective in systemic circulation.…”

Activatable Polymer Nanoenzymes for Photodynamic Immunometabolic Cancer Therapy

“…[ 14 ] In contrast to small‐molecule inhibitors, enzyme immunotherapeutics possess highly selective capabilities in catalyzing shifts in the local availability of immunostimulatory and immunosuppressive signals. [ 15 ] Additionally, enzyme treatment eliminates immunosuppressive metabolite irrespective of different pathways and alleviates concerns of mutation and the drug resistance, thus overpassing many limitations of small‐molecule inhibitors. [ 16 ] However, the clinical success of enzyme immunotherapeutics frequently hinges upon achieving sustained biocatalysis over relevant time scales at the designated site owing to rapid clearance enzyme degradation via proteases and insufficient accumulation at target tissues.…”

“…[ 16 ] However, the clinical success of enzyme immunotherapeutics frequently hinges upon achieving sustained biocatalysis over relevant time scales at the designated site owing to rapid clearance enzyme degradation via proteases and insufficient accumulation at target tissues. [ 17 ] Therefore, the integration of enzyme immunotherapeutics with activable nanoplatforms could be a promising strategy to address these issues.…”

Supramolecular Assembly of a Molecularly Engineered Protein and Polymer

“…This approachm ay enableo ptimisation of the size, shape and surfacec haracteristics of the co-assemblies by varyingt he structure and/ora mount of polymer to achieve desired pharmacokinetics, in vivo stabilitya gainst bio-degradation, suitable particle size for EPR effects, efficient cellular uptake and so on, whicha re relevant fort heir applicationsi n biomedicine. [12] To test these possibilities, we have studied the SSDU-conjugated protein (NDI-BSA) and its co-assembly with the SSDUfunctionalised temperature-responsive polymer NDI-PNIPAM ( Figure 1b). Herein, we reveal the ability of the SSDU to produce well-defined nanostructures by assembly/co-assembly of the molecularly engineered protein and polymer, althought he hydrophobic content is < 1wt% in these engineered macromolecules.…”

“…We envisaged this would endow new opportunities for 1) protein assemblies with tuneable nanostructures, depending on the nature of the hydrogen‐bonding group in the SSDU; and 2) supramolecular protein–polymer conjugation (similar to covalent polymer–protein conjugation), as long as both/multiple building blocks are conjugated with the same SSDU because the assembly is expected to be primarily driven by specific molecular interactions, depending on the encoded information in the SSDU. This approach may enable optimisation of the size, shape and surface characteristics of the co‐assemblies by varying the structure and/or amount of polymer to achieve desired pharmacokinetics, in vivo stability against bio‐degradation, suitable particle size for EPR effects, efficient cellular uptake and so on, which are relevant for their applications in biomedicine …”