Exploiting protease activation for therapy

Abstract

Proteases have crucial roles in homeostasis and disease; and protease inhibitors and recombinant proteases in enzyme replacement therapy have become key therapeutic applications of protease biology across several indications. This review briefly summarises therapeutic approaches based on protease activation and focuses on how recent insights into the spatial and temporal control of the proteolytic activation of growth factors and interleukins are leading to unique strategies for the discovery of new medicines. In particular, two emerging areas are covered: the first is based on antibody therapies that target the process of proteolytic activation of the pro-form of proteins rather than their mature form; the second covers a potentially new class of biopharmaceuticals using engineered, proteolytically activable and initially inactive pro-forms of antibodies or effector proteins to increase specificity and improve the therapeutic window.

Keywords: Activatable therapeutics; Antibody engineering; Cytokine; Protease; Proteolytic activation; Therapeutic antibodies; Zymogen.

Figure 1

(a) Principle of protease-driven protein maturation and activation. Proteins such as transforming growth factor (TGF)β, myostatin, complement C3 and C5 or interleukin (IL)-1b or IL-18 are expressed in a predominantly inactive form with a pro-domain shielding the active, mature domain. The protein remains in an inactive state until proteolytic cleavage, leading to dissociation of the masking domain and release of the active protein. (b) Targeting of the activating protease will keep the target protein in its latent inactive form. (c) Targeting of the pro-domain inhibits the proteolytic cleavage and therefore activation of the target protein, enabling effective neutralisation by inhibiting the activation of the inactive form.

Figure 2

Schematic depiction of a pro-antibody cleaved in the area of pathology via a disease-selective protease. Pro-antibodies are recombinant antibody pro-drugs engineered to remain inactive until they are activated, at the site of pathology, by removing a masking domain by disease or organ-specific proteases.