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.

Figure 1

Enzyme therapy delivery strategies to restore or enhance immune system function.

Figure 2

Antibody-sialidase conjugates (T-Sia) that improve cancer immunotherapy by targeting the sialic acid axis of immune modulation. (A) Hypersialylated glycans on cancer cells bind to NK inhibitory receptors (Siglecs) and block interactions with NK-activating receptors (NKG2Ds). (B) Sialidase fused to trastuzumab (Tras) is localized to HER2+ cancer cells. Sialidase desialylates cancer cell surface glycans, which concurrently prevents Siglec binding and promotes NKG2D binding, thereby increasing tumor cell susceptibility to NK cell-mediated ADCC or “antibody dependent cell-mediated cytotoxicity”. (C) Cytotoxic activity of NK cells against different HER2-expressing cancer cells in the presence of either Tras or T-Sia in vitro. Reprinted with permission from ref . Copyright 2016 National Academy of Sciences.

Figure 3

Protective Antioxidant Carriers for Endothelial Targeting (PACkET). (A) Antioxidant enzymes are encapsulated within protective antioxidant carriers (PACs), while anti-PECAM monoclonal antibodies (Ab) are immobilized on the PAC surface. (B) Protection of endothelial cells exposed to H₂O₂ with catalase (CAT)-loaded Ab or IgG PACs. (C) Cytokine (MIP2 and TNF) expression levels in mice receiving superoxide dismutase (SOD)-loaded Ab or IgG PACs with and without LPS for 24 h. Reprinted with permission from ref . Copyright 2014 Elsevier.

Figure 4

Supraparticles that proteolytically degrade TNF-α. (A) Schematic representation of self-assembled porous hybrid supraparticles with immobilized pRgpA_CAT, a TNF-α-degrading enzyme. (B) Survival of L929 mouse fibroblasts treated with TNF-α (“Controls”), compared to TNF-α in the presence of soluble enzyme (black bars) or enzyme supraparticles (red bars). Reprinted with permission from ref . Copyright 2016 The Royal Society of Chemistry.