Abstract
Duchenne muscular dystrophy is characterized by structural degeneration of muscle, which is exacerbated by localized functional ischemia due to loss of nitric oxide synthase-induced vasodilation. Treatment strategies aimed at increasing vascular perfusion have been proposed. Toward this end, we have developed monoclonal antibodies (mAbs) that bind to the vascular endothelial growth factor (VEGF) receptor VEGFR-1 (Flt-1) and its soluble splice variant isoform (sFlt-1) leading to increased levels of free VEGF and proangiogenic signaling. The lead chimeric mAb, 21B3, had high affinity and specificity for both human and mouse sFlt-1 and inhibited VEGF binding to sFlt-1 in a competitive manner. Proof-of-concept studies in the mdx mouse model of Duchenne muscular dystrophy showed that intravenous administration of 21B3 led to elevated VEGF levels, increased vascularization and blood flow to muscles, and decreased fibrosis after 6–12 weeks of treatment. Greater muscle strength was also observed after 4 weeks of treatment. A humanized form of the mAb, 27H6, was engineered and demonstrated a comparable pharmacologic effect. Overall, administration of anti-Flt-1 mAbs in mdx mice inhibited the VEGF:Flt-1 interaction, promoted angiogenesis, and improved muscle function. These studies suggest a potential therapeutic benefit of Flt-1 inhibition for patients with Duchenne muscular dystrophy.
Highlights
Duchenne muscular dystrophy (DMD) is an X-linked genetic disorder, primarily affecting males, that is characterized by progressive muscle degeneration and weakness.[1]
Antigen-binding fragments (Fabs) of interest were engineered as chimeric llama-human immunoglobulin Gs (IgGs) composed of llama variable heavy (VH)-chain/variable light (VL)-chain and human constant regions.[25]
Competition enzyme-linked immunosorbent assay (ELISA) experiments over a range of 169 pg/mL to 10 mg/mL 21B3 further revealed that the 21B3 interaction prevented the binding of vascular endothelial growth factor (VEGF) to sFlt-1 in a dose-dependent manner, with comparable half-maximal inhibitory concentration (IC50) values of 5.6 ng/mL (1.24 Â 10À10 M) and 7.4 ng/mL (1.64 Â 10À10 M) for the mouse and human orthologs, respectively (Figures 1C and 1D)
Summary
Duchenne muscular dystrophy (DMD) is an X-linked genetic disorder, primarily affecting males, that is characterized by progressive muscle degeneration and weakness.[1]. DMD results from mutations in the DMD gene,[1] which codes for dystrophin, a membrane-associated structural protein that functions within the dystrophin-associated protein complex to stabilize sarcolemma and maintain normal interactions with the local microvasculature.[2] The mutations lead to dysfunctional myofibers and subsequent muscle damage, followed by reduced ambulation and as the diaphragm muscle degenerates, loss of ventilation. The dystrophin-associated protein complex includes neuronal nitric oxide synthase, a key enzyme in the production of the vasodilation signaling molecule, nitric oxide.[3] Lack of nitric oxide results in decreased blood flow in the microvasculature, subsequent functional ischemia, and eventual myofiber necrosis and fibrosis.[4] It has been hypothesized that increased muscle perfusion, for example, through the use of vasoactive agents or by an increase in vascular density, could improve muscle function.[5,6,7]
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