Treatment of osteogenesis imperfecta

Patent metadata

Field	Value
Publication number	US-2023144192-A1
Application number	US-202218051468-A
Country	US
Kind code	A1
Filing date	Oct 31, 2022
Priority date	Nov 1, 2021
Publication date	May 11, 2023
Grant date	—

Abstract

The present disclosure provides methods for treating and improving b1osteogenesis imperfecta (OI) in a subject by administering to the subject a therapeutically effective amount of an agent that binds and neutralizes transforming growth factor beta (TGF-β).

First claim

1 . A method for treating osteogenesis imperfecta (OI) in a human subject in need thereof, comprising administering to the subject a therapeutically effective amount of an anti-TGF-β antibody,
wherein the antibody comprises heavy chain complementarity-determining regions (CDRs) 1-3 comprising SEQ ID NOs:4-6, respectively, light chain CDR1-3 comprising SEQ ID NOs:7-9, respectively, wherein the antibody comprises a human IgG4 constant region having a proline at position 228 (Eu numbering), and
wherein the therapeutic effective amount is
1 to 8 mg/kg, optionally 2, 2.5, or 5 mg/kg, administered bi-annually, or 0.1 to 1 mg/kg, optionally 0.35, 0.4, or 0.5 mg/kg, administered every 3 months (Q3M).

2 . The method of claim 1 , wherein the antibody comprises a heavy chain variable domain comprising SEQ ID NO:10 and a light chain variable domain comprising SEQ ID NO:11.

3 . The method of claim 1 , wherein the antibody comprises a human IgG4 constant region and/or a human κ light chain constant region.

4 . The method of claim 3 , wherein the antibody comprises a heavy chain comprising SEQ ID NO:3 and a light chain comprising SEQ ID NO:2.

5 . The method of claim 1 , wherein the antibody comprises a bone-targeting moiety, optionally wherein the bone-targeting moiety is a poly-arginine peptide.

6 . The method of claim 5 , wherein the antibody comprises one or more poly-arginine peptides.

7 . The method of claim 6 , wherein the antibody is fused to a poly-arginine peptide at the N-terminus, or the C-terminus, or both termini, of the heavy chain, and/or at the C-terminus of the light chain, of the antibody.

8 . The method of claim 5 , wherein the poly-arginine peptide is D10 (SEQ ID NO:14).

9 . The method of claim 1 , wherein the OI is moderate-to-severe OI or type IV OI.

10 . The method of claim 1 , wherein the OI is type I, II, or III OI.

11 . The method of claim 1 , wherein the human subject is an adult patient (≥18 years of age), or a pediatric patient (<18 years of age).

12 . The method of claim 1 , wherein the human subject has a mutation in a COL1A1 or COL1A2 gene, optionally wherein the mutation is a glycine substitution mutation in the COL1A1 or COL1A2 gene or a valine deletion in the COL1A2 gene.

13 . The method of claim 1 , wherein the administration improves a bone parameter selected from the group consisting of bone mineral density (BMD), bone volume density (BV/TV), total bone surface (BS), bone surface density (BS/BV), trabecular number (Tb.N), trabecular thickness (Tb.Th), trabecular spacing (Tb.Sp), and total volume (Dens TV).

14 . The method of claim 1 , wherein the administration decreases bone turnover and/or osteocyte density, optionally wherein the decreased bone turnover is indicated by a decrease in serum CTX or an increase in serum osteocalcin (OCN).

15 . The method of claim 1 , wherein the antibody is administered at 2 mg/kg bi-annually or at 0.4 mg/kg Q3M, optionally wherein the administration leads to an increase of BMD in the subject by about 5%.

16 . The method of claim 1 , wherein the antibody is administered at 5 mg/kg bi-annually or at 0.5 mg/kg Q3M, optionally wherein the administration leads to an increase of BV in the subject by about 5%.

17 . The method of claim 1 , wherein the antibody is administered at 2.5 mg/kg bi-annually or at 0.35 mg/kg Q3M, optionally wherein the administration leads to a decrease of the TGF-β level in the subject to the homeostatic value.

18 . The method of claim 1 , wherein the antibody is administered by intravenous infusion.

19 . The method of claim 1 , further comprising administering to the subject a bisphosphonate, parathyroid hormone, calcitonin, teriparatide, or an anti-sclerostin agent.

20 . The method of claim 19 , wherein the bisphosphonate is selected from alendronate, pamidronate, zoledronate, and risedronate.

21 . An article of manufacture or kit, comprising an anti-TGF-β antibody for use in treating osteogenesis imperfecta in the method of claim 1 .

Assignees

• Genzyme Corp

Inventors

• Mavroudis Panteleimon D
• Pillai Nikhil
• Wang Qingping

Classifications

• A61K2300/00

  Mixtures or combinations of active ingredients, wherein at least one active ingredient is fully defined in groups A61K31/00 - A61K41/00 · CPC title

• A61K2039/505

  comprising antibodies · CPC title

• A61K2039/545

  characterised by the dose, timing or administration schedule · CPC title

• C07K2317/21

  from primates, e.g. man · CPC title

• A61P19/08

  for bone diseases, e.g. rachitism, Paget's disease · CPC title