Megalin-based delivery of therapeutic compounds to the brain and other tissues

• US 8,609,103 B2
• Filed: 11/08/2010
• Issued: 12/17/2013
• Est. Priority Date: 06/20/2003
• Status: Expired due to Fees

• Current Assignee: Horizon Orphan, LLC (Amgen Inc.)
• Original Assignee: Raptor Pharmaceuticals Inc. (Amgen Inc.)
• Inventors: Zankel, Todd C., Starr, Christopher M.
• Primary Examiner(s): Emch, Gregory S
• Application Number:
  US12/941,619
• Publication Number:
  US 20110142763A1
• Time in Patent Office: 1,135 Days
• Field of Search: None
• US Class Current: 424/178.1
• CPC Class Codes: A61K 38/00 Medicinal preparations containing peptides peptides containing beta-lactam rings A61K31/00; cyclic dipeptides not having in their molecule any other peptide link than those which form their ring, e.g. piperazine-2,5-diones, A61K31/00; ergot alkaloids of the cyclic peptide type A61K31/48; containing macromolecular compounds having statistically distributed amino acid units A61K31/74; medicinal preparations containing antigens or antibodies A61K39/00; medicinal preparations characterised by the non-active ingredients, e.g. peptides as drug carriers, A61K47/00
• CPC Class Codes: A61K 47/64 Drug-peptide, drug-protein or drug-polyamino acid conjugates, i.e. the modifying agent being a peptide, protein or polyamino acid which is covalently bonded or complexed to a therapeutically active agent peptidic linkers A61K47/65
• CPC Class Codes: A61P 25/00 Drugs for disorders of the nervous system
• CPC Class Codes: A61P 25/02 for peripheral neuropathies
• CPC Class Codes: A61P 25/16 Anti-Parkinson drugs
• CPC Class Codes: A61P 25/18 Antipsychotics, i.e. neuroleptics; Drugs for mania or schizophrenia
• CPC Class Codes: A61P 25/28 for treating neurodegenerative disorders of the central nervous system, e.g. nootropic agents, cognition enhancers, drugs for treating Alzheimer's disease or other forms of dementia
• CPC Class Codes: A61P 35/00 Antineoplastic agents
• CPC Class Codes: A61P 9/10 for treating ischaemic or atherosclerotic diseases, e.g. antianginal drugs, coronary vasodilators, drugs for myocardial infarction, retinopathy, cerebrovascula insufficiency, renal arteriosclerosis
• CPC Class Codes: C07K 14/705 Receptors; Cell surface antigens; Cell surface determinants tumour specific antigens C07K14/4748
• CPC Class Codes: C07K 2319/00 Fusion polypeptide
• CPC Class Codes: C07K 2319/22 containing a Strep-tag
• CPC Class Codes: C07K 2319/23 containing a GST-tag

Abstract

The present invention is directed to a methods and compositions for receptor mediated drug delivery, particularly across the blood-brain barrier.

Claims

1. A conjugate comprising a receptor associated protein (RAP) polypeptide and a therapeutic or diagnostic/investigational agent which is an antibody, wherein the RAP polypeptide consists of an amino acid sequence at least 80% identical to amino acids 221-323 of RAP (SEQ ID NO:

1) that retains megalin-binding activity.

2. The conjugate of claim 1, wherein the antibody is a therapeutic antibody directed toward a constituent of the CNS.

3. The conjugate of claim 1, wherein the antibody is a monoclonal antibody which binds a marker of a CNS disorder.

4. The conjugate of claim 1, wherein the antibody is further conjugated to a therapeutic agent.

5. The conjugate of claim 1, wherein the antibody is a diagnostic/investigational agent and comprises a detectable label.

6. The conjugate of claim 1, wherein the antibody is conjugated to the RAP amino acid sequence via covalent bonding.

7. The conjugate of claim 1, wherein the antibody is conjugated to the RAP amino acid sequence via a peptide linker.

8. The conjugate of claim 1, wherein the RAP polypeptide is further missing the endoplasmic reticulum retention signal at residues 320-323 of SEQ ID NO:

1.

9. The conjugate of claim 1, wherein the conjugate is a fusion protein of RAP and a therapeutic agent.

10. The conjugate of claim 1, wherein the RAP polypeptide is at least 85% identical to amino acids 221-323 of RAP (SEQ ID NO:

1).

11. The conjugate of claim 1, wherein the RAP polypeptide is at least 90% identical to amino acids 221-323 of RAP (SEQ ID NO:

1).

12. A sterile composition comprising the conjugate of claim 1 and a pharmaceutically acceptable carrier.

13. The conjugate of claim 1, wherein the conjugate is useful to treat a CNS condition or disorder.

14. The conjugate of claim 13, wherein the CNS disorder is selected from the group consisting of Alzheimer'"'"'s Disease, Parkinson'"'"'s Disease, Multiple Sclerosis, Amylotrophic Lateral Sclerosis, ischemia-related disease and stroke, spinal muscular atrophy, cerebellar degeneration, perivenous encephalitis, schizophrenia, epilepsy and a central nervous system cancer.

15. The conjugate of claim 13 wherein the antibody is further conjugated to a neurotrophic factor.

16. The conjugate of claim 15, wherein the a neurotrophic factor is selected from the group consisting of Glial-Derived Neurotrophic Factor, Nerve Growth Factor, Brain-Derived Neurotrophic Factor, Neurotrophin-3, Neurotrophin-4/5, aFGF, bFGF, CNTF, Leukemia Inhibitory Factor, Cardiotrophin-1, TGFβ

, BMPs, GDFs, Neurturin, Artemin, Persephin, EGF, TGFα

, Neuregulins, IGF-1, IGF-2, ADNF and PDGF.

17. The conjugate of claim 15 wherein the neurotrophic factor is brain-derived neurotrophic factor (BDNF).