Delivery of antibodies to the central nervous system
The invention relates to improvements in the field of drug delivery. More particularly, the invention relates to polypeptide derived from aprotinin and from aprotinin analogs as well as conjugates and pharmaceutical compositions comprising these polypeptides. The present invention also relates to the use of these polypeptide for transporting an antibody or antibody fragment across the blood-brain barrier of an individual and in the treatment and diagnosis of neurological diseases.
1 . A biologically active polypeptide able to cross a cell layer mimicking a mammalian blood brain barrier in an in vitro assay, said polypeptide being selected from the group of;
a) an aprotinin fragment comprising the amino acid sequence defined in SEQ ID NO.:1,
b) an aprotinin fragment consisting of SEQ ID NO.:1,
c) a biologically active analogue of SEQ ID NO.:1,
d) a biologically active fragment of SEQ ID NO.:1, and;
e) a biologically active fragment of a SEQ ID NO.:1 analogue.
2 . The biologically active polypeptide of claim 1 , wherein the amino acid of position 10 of SEQ ID NO.:1 is a lysine.
3 . The biologically active polypeptide of claim 1 , wherein the amino acid of position 15 of SEQ ID NO.:1 is a lysine.
4 . The biologically active polypeptide of claim 2 , wherein the amino acid of position 15 of SEQ ID NO.:1 is a lysine.
5 . The biologically active polypeptide of claim 4 , wherein the amino acid of position 7 is a serine.
6 . The polypeptide of claim 1 , wherein said polypeptide is in multimeric form.
7 . The polypeptide of claim 6 , wherein said multimeric form is a dimer.
8 . The polypeptide of claim 1 , wherein said biologically active analogue of SEQ ID NO.:1 comprises an amino acid sequence selected from the group consisting of an amino acid sequence defined in SEQ ID NO.:107 to 112.
9 . The polypeptide of claim 1 , wherein said polypeptide is acetylated.
10 . The polypeptide of claim 1 , wherein said biologically active analogue is from 10 to 54 amino acids in length.
11 . The polypeptide of claim 1 , wherein said biologically active analogue is from 10 to 18 amino acids in length.
12 . A conjugate comprising;
a) a carrier selected from the group consisting of the polypeptides of claim 1 , and;
b) an agent selected from the group consisting of an antibody and an antibody fragment thereof.
13 . A method for transporting an antibody or an antibody fragment across a blood brain barrier of an individual, the method comprising administering the conjugate of claim 12 in a mammal in need thereof.
14 . The method of claim 13 , wherein the mammal has a neurological disease.
15 . The method as defined in claim 14 , wherein said neurological disease is selected from the group consisting of a brain tumor and a brain metastasis.
16 . A method for treating a patient having a neurological disease comprising administering the conjugate of claim 12 to said patient.
17 . A method for diagnosing a neurological disease in a patient in need thereof comprising administering the conjugate of claim 12 to said patient and wherein said conjugate comprises a label.
18 . A pharmaceutical composition comprising
a) the conjugate of claim 12 and;
b) a pharmaceutically acceptable carrier.
19 . The pharmaceutical composition of claim 18 , wherein said pharmaceutical composition is used for the treatment of a neurological disease.
20 . The pharmaceutical composition of claim 18 , wherein said pharmaceutical composition is used for the diagnosis of a neurological disease.
21 . A pharmaceutical composition comprising
a) the polypeptide of claim 6 and;
b) a pharmaceutically acceptable carrier.
22 . A pharmaceutical composition comprising
a) the polypeptide of claim 8 and;
b) a pharmaceutically acceptable carrier.
23 . A nucleotide sequence encoding the polypeptides of claim 8 .
24 . The nucleotide sequence of claim 23 , wherein said sequence is composed of a nucleotide selected from the group consisting of a ribonucleotide, a deoxyribonucleotide and nucleotide analogs thereof.