Recombinant factor viii-fc for treating hemophilia and low bone mineral density

A bone mineral density, FVIII technology, applied in the direction of factor VII, coagulation/fibrinolytic factors, drug combination, etc., can solve the problem of unclear mechanism of BMD reduction in hemophiliac patients

Pending Publication Date: 2022-02-01
比奥维拉迪维治疗股份有限公司
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  • Summary
  • Abstract
  • Description
  • Claims
  • Application Information

AI Technical Summary

Problems solved by technology

Despite this link, the mechanism of BMD reduction in hemophiliacs is currently unknown

Method used

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  • Recombinant factor viii-fc for treating hemophilia and low bone mineral density
  • Recombinant factor viii-fc for treating hemophilia and low bone mineral density
  • Recombinant factor viii-fc for treating hemophilia and low bone mineral density

Examples

Experimental program
Comparison scheme
Effect test

Embodiment 1

[0212] Example 1: Recombinant factor VIII Fc fusion protein (rFVIIIFc) negatively regulates inflammatory osteoclast formation in vitro

[0213] The decreased bone mineral density observed in patients with severe hemophilia A (HemA) suggests that the absence of FVIII activity and the associated bleeding episodes have profound effects on bone homeostasis.

[0214] Without being bound by any scientific theory, it is hypothesized that the proinflammatory environment in these patients may lead to monocyte / macrophage-derived osteoclast formation and subsequent exacerbated bone erosion, similar to that seen in arthritis-associated osteoporosis. incidents reported under the circumstances. The effect of rFVIII versus rFVIIIFc treatment on monocyte-derived osteoclast formation was investigated to determine whether rFVIIIFc inhibits pro-inflammatory osteoclast formation by upregulating the antioxidant NRF2 pathway.

[0215] To test this hypothesis, human monocytes were isolated from per...

Embodiment 2

[0224] Example 2: rFVIIIFc inhibits the bone resorption activity of osteoclasts in vitro

[0225] Since rFVIIIFc is able to inhibit osteoclast formation, we next examined the effect of rFVIIIFc on the bone resorption activity of osteoclasts. CD14 + Monocytes were treated on day 0 with vehicle, IgGl alone, rFVIII or rFVIIIFc alone and cultured for 3 days in the presence of M-CSF and RANKL. On day 3, monocytes were replated on bovine cortical bone slices and co-cultured in the presence of M-CSF and RANKL for 7–10 days. After a co-culture period of 7-10 days, monocyte-derived cells were removed and bone sections were examined by toluidine blue staining (Figure 6). Bone slices co-cultured with monocytes treated with vehicle (Fig. 7A), IgG1 (Fig. 7B) or rFVIII (Fig. 7C) showed clear bone resorption (Fig. 7A, Fig. 7B, Fig. 7C; circled areas), indicating that Osteoclasts derived from this treatment pool are still actively breaking down bone. Bone slices co-cultured with rFVIIIFc-...

Embodiment 3

[0228] Example 3: Effect of rFVIIIFc on gene expression and function in osteoclastogenesis

[0229] Next, we investigated whether the reduced osteoclast activity and morphology by rFVIIIFc corresponded to a reduction in osteoclast-associated genes. CD14 + Monocytes were treated on day 0 with vehicle, IgGl alone, rFVIII or rFVIIIFc alone and cultured for 7 days in the presence of M-CSF and RANKL. Cells were then harvested, RNA was extracted, and gene expression levels were quantified by quantitative real-time PCR (Figure 8). Osteoclasts were then measured in vehicle-treated (Figure 9, black bars), IgG1-treated (Figure 9, dark gray bars), rFVIII-treated (Figure 9, light gray bars) and rFVIIIFc-treated (Figure 9, white bars) cells Cell-associated genes and normalized to the expression levels of the vehicle-treated group. Markers of osteoclast differentiation (Fig. 9, RANK, NFATC1) and bone resorption activity (Fig. 9, CATK, TRAP, MMP9) were analyzed. No significant changes we...

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Abstract

Disclosed herein are methods of treating subjects with hemophilia and low bone mineral density (BMD) with a chimeric protein comprising a coagulation factor and a Fc domain. In certain embodiments, the chimeric protein is rFVIIIFc. In certain embodiments, a subject to be treated has hemophilia A.

Description

[0001] Cross References to Related Applications [0002] This application claims the benefit of priority to U.S. Provisional Application No. 62 / 863,831, filed June 19, 2019, and U.S. Provisional Application No. 62 / 968,785, filed January 31, 2020, both of which are incorporated by reference in their entirety Incorporated into this article. [0003] sequence listing [0004] This application contains a Sequence Listing that has been filed electronically in ASCII format and is hereby incorporated by reference in its entirety. Said ASCII copy, created on June 16, 2020, is named 706564_SA9-503PC_ST25.txt and is 46,080 bytes in size. Background technique [0005] Hemophilia is a group of bleeding disorders caused by defects in genes encoding blood clotting factors and affects 1-2 in 10,000 male infants. Graw et al., Nat. Rev. Genet. 6(6):488-501 (2005). Hemophilia A is characterized by the absence of functional endogenous coagulation factor VIII (FVIII). Patients with severe he...

Claims

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Application Information

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Patent Type & Authority Applications(China)
IPC IPC(8): A61K38/37A61K47/68A61P7/04A61P19/10C07K19/00
CPCA61K38/37A61K47/6811A61P7/04A61P19/10C07K14/755C07K2319/30A61Q19/10A61P19/08
Inventor S·段K·基斯-托特G·M·拉贾尼J·萨拉斯
Owner 比奥维拉迪维治疗股份有限公司
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