Megalin-based delivery of therapeutic compounds to the brain and other tissues
View Patent ↗The present invention is directed to a methods and compositions for receptor mediated drug delivery, particularly across the blood-brain barrier.
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).