A single dose of anti-NGF antibody exerts a long-lasting analgesic effect on pain during motion in a rat model of OA. This finding could be associated with the analgesic efficacies that anti-NGF antibodies have exhibited in clinical studies. It appears unlikely that analgesia is secondary to inhibition of joint edema and lesion.

Nerve growth factor (NGF) has emerged as a key driver of pain perception in several chronic pain conditions, including osteoarthritis (OA), and plays an important role in the generation and survival of neurons. Although anti-NGF antibodies improve pain control and physical function in patients with clinical chronic pain conditions, anti-NGF IgGs are associated with safety concerns such as effects on fetal and postnatal development and the risk of rapidly progressive osteoarthritis. To overcome these drawbacks, we generated a novel anti-NGF PEGylated Fab’ antibody. The anti-NGF PEGylated Fab’ showed specific binding to and biological inhibitory activity against NGF, and analgesic effects in adjuvant-induced arthritis model mice in a similar manner to an anti-NGF IgG. In collagen-induced arthritis model mice, the anti-NGF PEGylated Fab’ showed higher accumulation in inflamed foot pads than the anti-NGF IgG. In pregnant rats and non-human primates, the anti-NGF PEGylated Fab’ was undetectable in fetuses, while the anti-NGF IgG was detected and caused abnormal postnatal development. The PEGylated Fab’ and IgG also differed in their ability to form immune complexes in vitro. Additionally, while both PEGylated Fab’ and IgG showed analgesic effects in sodium monoiodoacetate-induced arthritic model rats, their effects on edema were surprisingly quite different. While the anti-NGF IgG promoted edema over time, the anti-NGF PEGylated Fab’ did not. The anti-NGF PEGylated Fab’ (ASP6294) may thus be a potential therapeutic candidate with lower risk of adverse effects for various diseases in which NGF is involved such as OA and chronic back pain.

Activation of the tyrosine kinase with Ig and epidermal growth factor homology domain 2 (Tie2) receptor by angiopoietin-1 (Ang1) is critical for vascular stabilization: it promotes survival signal transduction via auto-phosphorylation and reduces vascular permeability by strengthening tight junctions between endothelial cells. Thus, Tie2/Ang1 signaling is a promising therapeutic target for vascular diseases. However, in vivo use of existing Tie2 signaling modulators, such as recombinant Ang1, is restricted by limitations in manufacturability and stability. Here, we present a novel engineered tetra-valent agonistic antibody, ASP4021, which can specifically and fully activate the Tie2 receptor in an equivalent manner to Ang1. ASP4021 induced Tie2 self-phosphorylation and inhibited apoptosis in a human primary endothelial cell line. Additionally, single administration of ASP4021 significantly suppressed mustard-oil-induced vascular permeability in rats. ASP4021 may thus be a potential therapeutic candidate for diseases associated with vascular weakness such as diabetic retinopathy, diabetic macular edema and critical limb ischemia.

Activation of the tyrosine kinase with Ig and epidermal growth factor homology domain 2 (Tie2) receptor by angiopoietin-1 (Ang1) is critical for vascular stabilization: it promotes survival signal transduction via auto-phosphorylation and reduces vascular permeability by strengthening tight junctions between endothelial cells. Thus, Tie2/Ang1 signaling is a promising therapeutic target for vascular diseases. However, in vivo use of existing Tie2 signaling modulators, such as recombinant Ang1, is restricted by limitations in manufacturability and stability. Here, we present a novel engineered tetra-valent agonistic antibody, ASP4021, which can specifically and fully activate the Tie2 receptor in an equivalent manner to Ang1. ASP4021 induced Tie2 self-phosphorylation and inhibited apoptosis in a human primary endothelial cell line. Additionally, single administration of ASP4021 significantly suppressed mustard-oil-induced vascular permeability in rats. ASP4021 may thus be a potential therapeutic candidate for diseases associated with vascular weakness such as diabetic retinopathy, diabetic macular edema and critical limb ischemia.