VEGFR-1/Flt-1 inhibition increases angiogenesis and improves muscle function in a mouse model of Duchenne muscular dystrophy

Jennifer Bosco; Zhiwei Zhou; Sofie Gabriëls; Mayank Verma; Nan Liu; Brian K Miller; Sheng Gu; Dianna M Lundberg; Yan Huang; Eilish Brown; Serene Josiah; Muthuraman Meiyappan; Matthew J Traylor; Nancy Chen; Atsushi Asakura; Natalie De Jonge; Christophe Blanchetot; Hans de Haard; Heather S Duffy; Dennis Keefe

doi:10.1016/j.omtm.2021.03.013

VEGFR-1/Flt-1 inhibition increases angiogenesis and improves muscle function in a mouse model of Duchenne muscular dystrophy

Mol Ther Methods Clin Dev. 2021 Mar 23:21:369-381. doi: 10.1016/j.omtm.2021.03.013. eCollection 2021 Jun 11.

Authors

Jennifer Bosco¹, Zhiwei Zhou¹, Sofie Gabriëls², Mayank Verma³, Nan Liu¹, Brian K Miller¹, Sheng Gu¹, Dianna M Lundberg¹, Yan Huang¹, Eilish Brown¹, Serene Josiah¹, Muthuraman Meiyappan¹, Matthew J Traylor¹, Nancy Chen¹, Atsushi Asakura³, Natalie De Jonge², Christophe Blanchetot², Hans de Haard², Heather S Duffy¹, Dennis Keefe¹

Affiliations

¹ Shire Human Genetic Therapies, a Takeda company, Lexington, MA, USA.
² argenx BVBA, Zwijnaarde, Belgium.
³ Stem Cell Institute, Paul and Sheila Wellstone Muscular Dystrophy Center, Department of Neurology, University of Minnesota Medical School, Minneapolis, MN, USA.

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.

Keywords: Duchenne muscular dystrophy; angiogenesis; fibrosis; monoclonal antibody; vascular endothelial growth factor.