Methods of increasing delivery of active agents to brain comprising administering receptor associated protein (RAP) fragments conjugated to active agents

• US 7,560,431 B2
• Filed: 08/12/2005
• Issued: 07/14/2009
• Est. Priority Date: 06/20/2003
• Status: Expired due to Fees

• Current Assignee: Horizon Orphan, LLC (Amgen Inc.)
• Original Assignee: Biomarin Pharmaceutical Incorporated (Amgen Inc.)
• Inventors: Zankel, Todd, Gabathuler, Reinhard, Starr, Christopher M.
• Primary Examiner(s): Kolker; Daniel E.
• Application Number:
  US11/202,566
• Publication Number:
  US 20060029609A1
• Time in Patent Office: 1,432 Days
• Field of Search: None
• US Class Current: 514/1.1
• 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

This invention provides compounds of conjugates of therapeutic or active agents with RAP or a RAP polypeptide, their pharmaceutical compositions and methods for using the such compounds and compositions in the diagnosis, prophylaxis, or treatment of diseases and conditions, including particularly diseases of the central nervous system or lysosomal storage diseases.

Claims

1. A method of delivering a therapeutic or diagnostic/investigational agent across the blood brain baffler (BBB) into the central nervous system in a subject in need thereof, said method comprising:

administering to said subject a chimeric RAP fusion protein comprising said therapeutic or diagnostic/investigational agent, wherein the RAP portion of the chimeric RAP fusion protein consists of an amino acid sequence at least 80% identical to amino acids 221-323 of SEQ ID NO;

1.

2. The method of claim 1 wherein the agent is a therapeutic agent.

3. The method of claim 2 wherein the therapeutic agent is selected from the group consisting of neurotransmitters, glial-derived neurotrophic factor (GDNF), 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, PDGFs, caspase inhibitors, antibodies, antimicrobial agents and lymphokines.

4. The method of claim 1, wherein the subject is suffering from a neurological or psychological condition or disease.

5. The method of claim 4, wherein the subject is suffering from Alzheimer'"'"'s disease (AD), Parkinson'"'"'s disease (PD), multiple sclerosis (MS), or amyotrophic lateral sclerosis (ALS), schizophrenia, epilepsy, a neurological infection, or a neurological inflammatory condition.

6. The method of claim 4, wherein the subject is suffering from a brain tumor or tumor metastases in the brain and the chimeric RAP fusion protein further comprises a chemotherapeutic agent.

7. The method of claim 6 wherein the chemotherapeutic agent is adriamycin, cisplatin, 5-fluorouracil, camtothecin, or paclitaxel.

8. The method of claim 1 wherein the agent is a diagnostic/investigational agent and comprises a detectable label.

9. The method of claim 1 wherein the agent is conjugated to the RAP amino acid sequence via covalent bonding.

10. The method of claim 1 wherein the agent is conjugated to the RAP amino acid sequence via a peptide linker.

11. The method of claim 1 wherein said fragment is missing the endoplasmic reticulum retention signal at residues 320-323 of SEQ ID NO:

1.

12. A method of delivering a therapeutic or diagnostic/investigational agent across the blood brain barrier (BBB) into the central nervous system in a subject in need thereof, said method comprising:

administering to said subject a chimeric RAP fusion protein comprising said therapeutic or diagnostic/investigational agent, wherein the RAP portion of the chimeric RAP fusion protein consists of a RAP fragment of 50 to 103 consecutive amino acids within residues 221-323 of SEQ ID NO;

1.