Fibronectin-based scaffold domain proteins that bind myostatin: a patent evaluation of WO2014043344

Abstract

Muscular dystrophies (MD) are commonly characterized by progressive loss of muscle mass and function. It is hypothesized that therapeutic blockade of the TGF-β ligand myostatin, a negative regulator of muscle mass, will stimulate muscle growth and restore muscle function. Although many anti-myostatin targets are currently being pursued in the clinical setting, the efficacies of the tested molecules have shown mixed results. The patent WO2014043344 describes a novel approach for myostatin inhibition using a modified fibronectin type III domain that could potentially be used to treat MD and other muscle-related pathologies.

Development and Differentiation in Monobodies Based on the Fibronectin Type 3 Domain

“…This polymer is produced as a mixture of molecular weights with high polydispersity, is not amenable to further chemical functionalization and is known to produce formaldehyde upon degradation. Alternatively, a straightforward application of fibronectin-like modular design is to increase circulating half-life and thus improve pharmacokinetic properties via fusion with non-monobody domains [75].…”

“…After classical antibody inhibitors had failed to show an effect on muscle growth in Duchenne Muscular Dystrophy (DMD) [86], an Adnectin monobody targeting myostatin was fused with an IgG1-Fc domain to produce a clinical inhibitor [87]. Interestingly, PEGylation was again found to be an inferior method of half-life extension following discovery work identifying Fc fusion as a superior tag [75]. This anti-myostatin fusion was shown to increase skeletal growth in pre-clinical models of DMD [88] and healthy humans [89] and is now in an ongoing phase 2 investigation for treatment of DMD [90].…”

“…This is exacerbated in bispecific antibodies, where only one of many possible interdomain pairings will yield a viable multivalent molecule [22] with the best reported results including an 85% correct bispecific pairing [99]. In stark contrast, mimicking the modular physiological state where multiple fused FN3 domains act independently can result in monobody chains with multi-valency or multi-specificity [75]. This mix-and-match approach of combining monobody domains mimics the natural assembly of FN3 domains within fibronectin as a beads-on-a-chain pattern ( Figure 3A), with each FN3 domain interacting with a unique partner in the extracellular matrix [25].…”

Development and Differentiation in Monobodies Based on the Fibronectin Type 3 Domain

“…This polymer is produced as a mixture of molecular weights with high polydispersity, is not amenable to further chemical functionalization and is known to produce formaldehyde upon degradation. Alternatively, a straightforward application of fibronectin-like modular design is to increase circulating half-life and thus improve pharmacokinetic properties via fusion with nonmonobody domains [74].…”

Discovery and Characterization of a Novel CD4-Binding Adnectin with Potent Anti-HIV Activity

“…The versatility of Adnectins and their potential as therapeutics against a wide variety of therapeutic targets, including vascular endothelial growth factor receptor 2 (VEGFR2) (30)(31)(32)(33)(34), epidermal growth factor receptor (35)(36)(37), insulin-like growth factor 1 receptor (34,37), interleukin-23 (35,38), proprotein convertase subtilisin/kexin type 9 (39), and myostatin (40), have been previously demonstrated. Here, we report the application of the mRNA display selection technology to the discovery and optimization of CD4-binding Adnectins with potent, broad-spectrum anti-HIV-1 activity.…”