Compositions comprising receptor-associated protein (RAP) variants specific for CR-containing proteins and uses thereof

• US 9,879,064 B2
• Filed: 06/23/2015
• Issued: 01/30/2018
• Est. Priority Date: 09/16/2005
• Status: Expired due to Fees

• Current Assignee: Horizon Orphan, LLC (Amgen Inc.)
• Original Assignee: Horizon Orphan, LLC (Amgen Inc.)
• Inventors: Zankel, Todd C., Starr, Christopher M.
• Primary Examiner(s): BALLARD, KIMBERLY
• Application Number:
  US14/747,716
• Publication Number:
  US 20160024172A1
• Time in Patent Office: 952 Days
• 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 38/1709 from mammals
• 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 21/00 Drugs for disorders of the muscular or neuromuscular system
• CPC Class Codes: A61P 21/02 Muscle relaxants, e.g. for tetanus or cramps
• CPC Class Codes: A61P 25/00 Drugs for disorders of the nervous system
• CPC Class Codes: A61P 25/08 Antiepileptics; Anticonvulsants
• 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 25/22 Anxiolytics
• CPC Class Codes: A61P 25/24 Antidepressants
• 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 3/06 Antihyperlipidemics
• CPC Class Codes: A61P 31/04 Antibacterial agents
• CPC Class Codes: A61P 35/00 Antineoplastic agents
• CPC Class Codes: A61P 37/06 Immunosuppressants, e.g. drugs for graft rejection
• CPC Class Codes: A61P 5/00 Drugs for disorders of the endocrine system
• CPC Class Codes: A61P 9/00 Drugs for disorders of the cardiovascular system
• CPC Class Codes: C07K 14/47 from mammals
• CPC Class Codes: C07K 14/705 Receptors; Cell surface antigens; Cell surface determinants tumour specific antigens C07K14/4748

Abstract

The present invention relates generally to receptor-selective variants of the low-density lipoprotein receptor-associated protein (RAP) and compositions thereof, methods of generating such variants and methods of using such receptor-selective RAP variant compositions for therapeutic purposes.

Claims

1. An isolated polypeptide comprising an amino acid sequence variant of the alpha-2-macroglobulin/low density lipoprotein receptor-related protein-associated protein 1 (RAP), wherein said RAP variant binds selectively to a pair of complement-type repeats within a protein, with an affinity that is at least 3-fold greater than the affinity of wild-type RAP for the same pair of complement-type repeats, and wherein said RAP variant consists of an amino acid sequence that lacks amino acids 1-143 and 320-323 of a mature RAP set forth in SEQ ID NO:

121, has an amino acid sequence at least 95% identical to the corresponding portion of SEQ ID NO;

121, and contains at least one mutation within positions 205-250 of RAP set forth in SEQ ID NO;

121 or at least one mutation within positions 271-319 of RAP set forth in SEQ ID NO;

121.

2. The polypeptide of claim 1, wherein said CR-containing protein is selected from the group consisting of LDLR (P01130), LRP1 (P98157), LRP1B (Q9NZR2), LRP2 (P98164), LRP3 (075074), LRP4 (075096), LRP5 (075197), LRP6 (075581), LRP8 (Q14114), Sortilin (Q92673), LRP10 (Q7Z4F1), LRP11 (Q86VZ4), LRP12 (Q9Y561), FDC-D86 (CD320), VLDLR (P98155), TADG-15 (ST14, Q8WVC1), TMPS3 (P57727), TMPS4 (Q9NRS4), TMPS6 (Q8IU80), Q6ICC2, Q6PJ72, Q76B61, Q7RTY8, Q7Z7K9, Q86YD5, Q8NAN7, Q8NBJ0, Q8WW88, Q96NT6, Q9BYE1, Q9BYE2, Q9NPF0 and corin (Q8IZR7).

3. The polypeptide of claim 1 wherein the variant binds selectively to a protein selected from the group consisting of a matriptase protein, a VLDLR protein and an FDC-8D6 (CD320) protein.

4. The polypeptide according to claim 1, wherein said mutation is the replacement of an acidic amino acid with a basic amino acid.

5. The polypeptide according to claim 1, wherein said mutation is the replacement of a basic amino acid with an acidic amino acid.

6. The polypeptide according to claim 1, wherein said mutation is the replacement of an amino acid selected from the group consisting of A, C, D, E, G, I, K, L, M, N, P, Q, R, S, T, and V with an amino acid selected from the group consisting of F, Y, W, and H.

7. The polypeptide of claim 1, wherein said RAP variant comprises a mutation at two or more of the following positions set forth in SEQ ID NO:

121;

175, 205, 213, 217, 226, 230, 232, 239, 246, 249, 251, 256, 257, 261, 266, 267, 268, 270, 273, 287, 290, 294, 296, 297, 298, 305, 312, 313.

8. A polypeptide consisting of oligomeric combinations of polypeptides of claim 1 with multivalent binding properties defined by each polypeptide of the combination.

9. A compound comprising the polypeptide according to claim 1 conjugated to a diagnostic or therapeutic agent.

10. The compound of claim 9, wherein the polypeptide and diagnostic or therapeutic agent are linked through a linker.

11. The compound of claim 10, wherein said linker is a peptide linker.

12. A pharmaceutical composition comprising a compound of claim 9 in a pharmaceutically acceptable carrier, diluent or excipient.