Treatment of α-galactosidase A deficiency
View Patent ↗The invention provides methods of treating α-galactosidase A deficiency. Dosage forms, methods of administration, and methods of analyzing human α-galactosidase A are also included.
1. A method for selecting a human α-Gal A preparation having a desired pharmacokinetic parameter, the method comprising:
obtaining or providing a first test α-Gal A preparation; and
determining if the first test α-Gal A preparation has each of the characteristics (1)-(7):
(1) has at least about 75% neutral, mono- and di-sialylated glycans combined;
(2) has less than about 35% tri- and tetra-sialylated glycans combined;
(3) has greater than 50% complex glycans;
(4) has less than about 45% phosphorylated glycans;
(5) has greater than about 45% sialylated glycans;
(6) has a ratio of sialic acid to mannose-6-phosphate on a mole per mole basis greater than 1.5 to 1; and
(7) has a ratio of sialylated glycans to phosphorylated glycans greater than 1,
and selecting the first test α-Gal A preparation if it has each of the characteristics (1)-(7), wherein a human α-Gal A preparation having each of the characteristics (1 )-(7) is predicted to have the desired pharmacokinetic parameter, to thereby select a human α-Gal A preparation having the desired pharmacokinetic parameter.
2. The method of claim 1 , wherein the method further comprises the step of entering the result of the determination into a record.
3. The method of claim 1 , wherein the determination is performed by one or more methods chosen from the group consisting of: ion exchange chromatography, high performance anion exchange (HPAE) chromatography, high performance liquid chromatography (HPLC), and mass spectroscopy.
4. The method of claim 1 , wherein the first test α-Gal A preparation is harvested from a mammalian cell.
5. The method of claim 4 , wherein the mammalian cell is a human cell.
6. The method of claim 4 , wherein the mammalian cell is a non-human cell.
7. The method of claim 4 , wherein the mammalian cell is a CHO cell.
8. The method of claim 1 , wherein a carbohydrate signature of the test preparation has been modified before the determining step is performed.
9. The method of claim 7 , wherein the carbohydrate signature of the test preparation has been modified by treatment with an enzyme.
10. The method of claim 9 , wherein the enzyme is a glycosidase, glycosyl transferase, phosphoryl transferase, kinas or sialyl transferase.
11. The method of claim 8 , wherein the carbohydrate signature of the test preparation has been modified by treatment with a phosphatase inhibitor.
12. The method of claim 8 , wherein the carbohydrate signature of the test preparation has been modified by glyco-engineering.
13. The method of claim 8 , wherein the carbohydrate signature of the test preparation has been modified by treatment with an inhibitor of glycosylation.
14. The method of claim 1 , further comprising the step of comparing the first test α-Gal A preparation to a reference α-Gal A preparation.
15. The method of claim 14 , wherein the reference α-Gal A preparation is a human α-Gal A preparation made in human cells.
16. The method of claim 1 , further comprising the steps of:
obtaining or providing a second test α-Gal A preparation;
determining if the second preparation has each of the characteristics (1)-(7); and
entering the result of each determination into a record,
wherein the first and second preparations are first and second batches of a pharmaceutical α-Gal A preparation.
17. The method of claim 1 , further comprising the steps of:
analyzing a pharmacokinetic parameter or biological activity of the test α-Gal A preparation.
18. The method of claim 17 , wherein the pharmacokinetic parameter or biological activity is selected from the group consisting of: enzymatic activity, serum clearance and tissue uptake.
19. The method of claim 17 , wherein the pharmacokinetic parameter or biological activity is selected from the group consisting of: liver uptake, renal uptake and cardiovascular uptake.
20. The method of claim 17 , wherein the pharmacokinetic parameter or biological activity is tissue targeting to at least one of: liver endothelial cells, liver sinusoidal cells, capillary/vascular endothelial cells, renal glomerular epithelial cells (podocytes), glomerular mesangial cells, renal endothelial cells, pulmonary cells, renal cells, neural cells, or cardiac myocytes.
21. The method of claim 1 , further comprising the step of using the prediction to design an α-Gal A therapeutic preparation for a specific patient or a specific variant of Fabry disease.
22. The method of claim 1 , wherein the specific variant of Fabry disease is renal variant Fabry disease or cardiac variant Fabry disease.
23. The method of claim 1 , further comprising determining if the first test α-Gal A preparation has one or more of biological or pharmacokinetic characteristics (a) to (c):
(a) the preparation has serum clearance from human circulation of less than 4 mL/min/kg on the linear portion of the AUC vs. dose curve;
(b) the preparation is preferentially targeted to capillary/vascular endothelial cells, renal glomerular epithelial cells (podocytes) and glomerular mesangial cells, renal endothelial cells, cardiac myocytes, liver endothelial cells, liver sinusoidal cells, pulmonary cells, or neural cells; and
(c) the preparation is not taken up by liver hepatocytes.
24. The method of claim 1 , wherein the desired pharmacokinetic parameter comprises reducing the amount of the human α-Gal A preparation administered or reducing number of dose administrations of the human α-Gal A preparation used for α-Gal A replacement therapy.
25. The method of claim 1 , further comprising the steps of:
obtaining or providing a second test α-Gal A preparation; and
determining if the second preparation has each of the characteristics (1)-(7).
26. The method of claim 25 , wherein the first and second preparations are first and second batches of a pharmaceutical α-Gal A preparation.