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EP-3411066-B1 - PARATHYROID HORMONE ANTI-RANKL ANTIBODY FUSION COMPOUNDS

EP3411066B1EP 3411066 B1EP3411066 B1EP 3411066B1EP-3411066-B1

Inventors

  • KORYTKO, ANDREW
  • MA, Yanfei L.
  • DATTA-MANNAN, Amita
  • OBUNGU, VICTOR H.

Dates

Publication Date
20260513
Application Date
20170125

Claims (13)

  1. A compound comprising a first polypeptide and a second polypeptide, wherein a.) said first polypeptide comprises a parathyroid hormone (PTH) peptide and a mAb IgG heavy chain (HC), the PTH peptide having an amino acid sequence given by SEQ ID NO: 13, and the HC having a heavy chain variable region (HCVR) having an amino acid sequence given by SEQ ID NO: 5; and b.) said second polypeptide comprises a mAb light chain (LC) comprising a light chain variable region (LCVR) having an amino acid sequence given by SEQ ID NO: 6, wherein the PTH peptide is linked to the HC via a polypeptide linker (L1), L1 being covalently attached to the N-terminus of HC and the C-terminus of the PTH peptide.
  2. The compound of claim 1, wherein L1 has an amino acid sequence given by SEQ ID NO: 14.
  3. The compound of claim 1 or 2, wherein the first polypeptide has an amino acid sequence given by SEQ ID NO: 1 and the second polypeptide has an amino acid sequence given by SEQ ID NO: 2.
  4. The compound of any of claims 1 to 3 comprising two first polypeptides and two second polypeptides.
  5. A DNA molecule comprising a polynucleotide sequence encoding a polypeptide chain having the amino acid sequence of SEQ ID NO: 1 and comprising a polynucleotide sequence encoding a polypeptide chain having the amino acid sequence of SEQ ID NO: 2.
  6. An isolated mammalian cell comprising (i) a DNA molecule comprising a polynucleotide sequence encoding a polypeptide chain having the amino acid sequence of SEQ ID NO: 1, and (ii) a DNA molecule comprising a polynucleotide sequence encoding a polypeptide chain having the amino acid sequence of SEQ ID NO: 2, which cell is capable of expressing a polypeptide chain having the amino acid sequence of SEQ ID NO: 1 and a polypeptide chain having the amino acid sequence of SEQ ID NO: 2.
  7. An isolated mammalian cell comprising the DNA molecule of claim 5, which cell is capable of expressing a polypeptide chain having the amino acid sequence of SEQ ID NO: 1 and a polypeptide chain having the amino acid sequence of SEQ ID NO: 2.
  8. The mammalian cell of claim 6 or 7, wherein the mammalian cell is a Chinese Hamster Ovary cell.
  9. A process for producing a compound comprising a first polypeptide whose amino acid sequence is given by SEQ ID NO: 1 and a second polypeptide whose amino acid sequence is given by SEQ ID NO: 2, comprising cultivating the mammalian cell of claim 6 or claim 7 under conditions such that the compound is expressed, and recovering the expressed compound.
  10. A compound produced by the process of claim 9.
  11. A compound of any of claims 1 to 4 and 10 for use in therapy.
  12. A compound of any of claims 1 to 4 and 10 for use in the treatment of at least one of osteoporosis, osteopenia, osteogenesis imperfecta, transplant-associated bone loss, autoimmune-induced bone loss, disuse-induced bone loss, degenerative lumbar spondylolisthesis, or degenerative disk disease.
  13. A pharmaceutical composition comprising a compound of any of claims 1 to 4 and 10 and one or more pharmaceutically acceptable carriers, diluents, or excipients.

Description

The present invention is in the field of medicine. More particularly, the present invention relates to fusion compounds, and pharmaceutical compositions thereof, which include an agonist of human parathyroid hormone receptors and an antibody directed against human receptor activator of nuclear factor kappa-B ligand (RANKL) and which are as defined in the appended claims. The fusion compounds of the present invention are expected to be useful in the treatment of bone disorders, and more particularly in the treatment of low bone mass disorders, including osteopenia, osteogenesis imperfecta, transplant-associated bone loss, autoimmune-induced bone loss, and/or disuse-induced bone loss, and/or in bone healing of disorders such as degenerative lumbar spondylolisthesis or degenerative disk disease as well as bone healing in spinal fusion and fracture patients. Bone disorders affect millions of individuals, often causing painful and debilitating symptoms. Osteoporosis, a common metabolic bone disorder, is characterized by progressive loss of bone mass resulting, at least in part, from excessive osteoclastic bone resorption relative to osteoblastic bone formation. The loss of bone mass associated with osteoporosis puts bones at a greater risk of fracture. Long-term consequences of osteoporosis-associated loss of bone mass can result in severe physical consequences including bone fractures, chronic pain, disability, and/or immobility, as well as rendering the skeleton unable to provide adequate structural support for the body. Osteoporosis-related fractures constitute a major health concern and economic burden for health care systems. According to the National Osteoporosis Foundation, 9.9 million Americans have osteoporosis and an additional 43.1 million suffer from low bone density. Annually, over two million bone fractures and more than four-hundred thousand hospital admissions are attributed to osteoporosis. The U.S. Surgeon General estimates osteoporosis-related bone fractures result in direct care expenditure of between twelve and eighteen billion dollars annually. Thus, there remains a need for alternative therapies which could lead to better outcomes for patients. Preferably such alternative therapy will comprise an agent which both increases bone formation and reduces bone resorption. Additionally, such alternative therapy will preferably be capable of demonstrating efficacy in treatment of low bone mass disorders such as osteopenia, osteogenesis imperfecta, transplant-associated bone loss, autoimmune-induced bone loss, and/or disuse-induced bone loss and/or in bone healing of disorders such as degenerative lumbar spondylolisthesis or degenerative disk disease. The fusion compounds of the present invention provide an alternative therapy which is expected to meet at least one of the above needs. RANKL is a member of the TNF-superfamily of proteins and plays an important role in bone remodeling. RANKL is expressed by osteoblasts and binds its cognate receptor RANK on the surface of osteoclasts and osteoclast precursor cells. Binding of RANKL to RANK induces the formation, activation, and survival of mature osteoclasts and the stimulation of intracellular signaling cascades leading to increased bone resorption. Neutralizing antibodies to RANKL are known in the art. For example, U.S. Patent No. 6,740,522 discloses anti-RANKL antibodies including Denosumab, marketed under the name Prolia®, which is the only approved anti-RANKL therapeutic antibody (approved for the treatment of osteoporosis in postmenopausal women and men at high risk for fracture). Parathyroid hormone (PTH) is an eighty-four amino acid peptide which plays a central role in bone remodeling. PTH binding to the PTH receptor 1 directly induces bone formation through activation of cyclic AMP and canonical wnt-signaling pathways. Therapeutic PTH peptides are known in the art. For example, International Patent Publication No. WO/2000/010596 discloses teriparatide (rhPTH(1-34)), a therapeutic PTH peptide marketed as Forteo®. Forteo® is a thirty-four amino acid N-terminal fragment of PTH that has been shown to increase bone formation activity in osteoporotic patients and is the only bone anabolic agent approved in the United States to treat osteoporosis. Although neutralizing antibodies to RANKL and therapeutic PTH peptides are known, there exists no combined therapy for inhibiting the activity of RANKL and promoting the bone anabolic properties of PTH. Thus, there remains a need for an alternative therapy that combines the bone anabolic properties of PTH with the anti-bone resorptive properties of anti-RANKL for patients having low bone mass disorders such as osteopenia, osteogenesis imperfecta, transplant-associated bone loss, autoimmune-induced bone loss, and/or disuse-induced bone loss and/or to aide in bone healing of disorders such as degenerative lumbar spondylolisthesis or degenerative disk disease as well as bone healing for spinal fusion and fr