Methods of using VEGF-C biomarkers for age-related macular degeneration (AMD) diagnosis
The present application is directed to the use of a VEGF-C inhibitor, a VEGFR-2 inhibitor and/or a VEGFR-3 inhibitor as a prophylactic or therapeutic for the treatment of eye disorders such as a maculopathy and pathogenic ocular neovascularization. The application is also directed to the use of a VEGF-C measurement from a biological sample from a mammalian subject as a predictive marker, a selected marker, a responsive marker or a tracking marker for a disease or condition selected from the group consisting of a maculopathy and pathogenic ocular neovascularization.
1. A method of prophylaxis or treatment of a disease or condition selected from macular degeneration and pathogenic ocular neovascularization, the method comprising:
(a) measuring VEGF-C protein in a biological sample from a human subject to obtain a VEGF-C measurement,
(b) determining from the VEGF-C protein measurement that VEGF-C protein is elevated in the subject, and
(c) administering, to the eye of a subject identified as having elevated VEGF-C protein in the biological sample, a composition formulated for ophthalmic administration and comprising a VEGF-C inhibitor, said VEGF-C inhibitor comprising:
(i) a polypeptide comprising a VEGFR-3 fragment, said fragment having an amino terminus selected from positions 1-47 of SEQ ID NO: 4, and a carboxy terminus selected from positions 211-247 of SEQ ID NO: 4, or
(ii) a polypeptide comprising the sequence of amino acids defined by positions 47-314 of SEQ ID NO: 4, with the proviso that positions of the polypeptide corresponding to positions 104-106 of SEQ ID NO: 4 are not identical to N-X-S or N-X-T,
wherein said inhibitor binds human VEGF-C.
2. A method of monitoring and adjusting the dose of a prophylactic or therapeutic administered to a human subject for macular degeneration or for pathogenic ocular neovascularization, the method comprising:
(a) administering to a human subject diagnosed with, or identified as having elevated risk for, a macular degeneration or pathogenic ocular neovascularization, a composition formulated for ophthalmic administration and comprising a VEGF-C inhibitor, said VEGF-C inhibitor comprising a polypeptide comprising:
(i) a VEGFR-3 fragment, said fragment having an amino terminus selected from positions 1-47 of SEQ ID NO: 4, and a carboxy terminus selected from positions 211-247 of SEQ ID NO: 4, or
(ii) a polypeptide comprising the sequence of amino acids defined by positions 47-314 of SEQ ID NO: 4, with the proviso that positions of the polypeptide corresponding to positions 104-106 of SEQ ID NO: 4 are not identical to N-X-S or N-X-T,
wherein said inhibitor binds human VEGF-C;
(b) measuring VEGF-C protein in a biological sample from the subject, after the administering, to obtain a VEGF-C protein measurement;
(c) re-administering the composition to the subject:
(i) wherein the VEGF-C protein measurement from step (b) is elevated, and wherein the re-administering is performed with a greater dose and/or a more frequent dosing schedule to further reduce the VEGF-C in the subject; or
(ii) wherein the VEGF-C protein measurement from step (b) is normal or below normal compared to apparently healthy subjects, and wherein the re-administering is performed with a smaller dose and/or a less frequent dosing schedule.
3. The method according to claim 1 , wherein the disease or condition is macular degeneration.
4. The method according to claim 1 , wherein the VEGF-C inhibitor is selected from the group consisting of:
(a) a polypeptide comprising the extracellular domain fragment of VEGFR-3; and
b) a fragment of (a) that retains VEGF-C binding activity.
5. The method according to claim 4 , further comprising co-administering to the subject a composition that comprises an inhibitor selected from the group consisting of a VEGF-A inhibitor, a VEGFR-2 inhibitor, and an inhibitor of the VEGFR-2 signalling pathway.
6. The method according to claim 4 , wherein the biological sample comprises blood, serum, plasma, ocular tissue, ocular fluid, blood vessel tissue, or lymphatic vessel tissue.
7. The method according to claim 4 , wherein the determination of elevated VEGF-C protein is made compared to one or more of the following reference measurements:
(a) a VEGF-C protein or VEGF C mRNA measurement from the subject from a biological sample obtained at an earlier point in time; or
(b) a VEGF-C protein measurement from one or more apparently healthy control subjects.
8. The method according to claim 4 , further comprising measuring at least one additional maculopathy biomarker.
9. The method according to claim 4 , further comprising measuring at least one environmental or lifestyle factor selected from the group consisting of age, weight, and body mass index.
10. The method according to claim 1 , wherein the VEGF-C inhibitor further comprises an immunoglobulin constant region fragment (Fc) fused polypeptide comprising the VEGFR-3 fragment.
11. The method according to claim 1 , wherein the polypeptide comprises an amino acid sequence having a sequence of amino acids defined by positions 47-314 of SEQ ID NO: 4, with the proviso that positions of the polypeptide corresponding to positions 104-106 of SEQ ID NO: 4 are not identical to N-X-S or N-X-T, and wherein the polypeptide binds to human VEGF-C.
12. The method according to claim 1 , further comprising co-administering, to the eye of the subject identified as having the elevated VEGF-C protein, a composition that comprises an inhibitor selected from the group consisting of a VEGF-A inhibitor, a VEGFR-2 inhibitor, and an inhibitor of the VEGFR-2 signalling pathway.
13. The method according to claim 1 , wherein the biological sample comprises blood, serum, plasma, ocular tissue, ocular fluid, blood vessel tissue, or lymphatic vessel tissue.
14. The method according to claim 1 , wherein the administering to the eye comprises administering by intravitreal injection.
15. The method according to claim 2 , comprising repeating steps (b) and (c).
16. The method according to claim 2 , wherein the VEGF-C inhibitor further comprises an immunoglobulin constant region fragment (Fc) fused polypeptide comprising the VEGFR-3 fragment.
17. The method according to claim 2 , wherein the polypeptide comprises an amino acid sequence having a sequence of amino acids defined by positions 47-314 of SEQ ID NO: 4, with the proviso that positions of the polypeptide corresponding to positions 104-106 of SEQ ID NO: 4 are not identical to N-X-S or N-X-T, and wherein the polypeptide binds to human VEGF-C.
18. The method according to claim 2 , for monitoring and adjusting the dose of a prophylactic or therapeutic administration to a human subject for macular degeneration.
19. The method according to claim 2 , wherein the biological sample comprises blood, serum, plasma, ocular tissue, ocular fluid, blood vessel tissue, or lymphatic vessel tissue.
20. The method according to claim 2 , wherein the administering comprises intravitreal injection.
21. A method comprising obtaining an ocular tissue or fluid from a human subject,
measuring VEGF-C protein in the ocular tissue or fluid;
detecting an elevated VEGF-C protein measurement in the ocular tissue or fluid from the subject, compared to VEGF-C measurements from corresponding ocular tissue or fluid from apparently healthy control subjects; and
administering to the eye of the subject a composition formulated for ophthalmic administration and comprising a VEGF-C inhibitor, said VEGF-C inhibitor comprising:
(i) polypeptide comprising a VEGFR-3 fragment, said fragment having an amino terminus selected from positions 1-47 of SEQ ID NO: 4, and a carboxy terminus selected from positions 211-247 of SEQ ID NO: 4, or
(ii) a polypeptide comprising the sequence of amino acids defined by positions 47-314 of SEQ ID NO: 4, with the proviso that positions of the polypeptide corresponding to positions 104-106 of SEQ ID NO: 4 are not identical to N-X-S or N-X-T,
wherein said inhibitor binds human VEGF-C.
22. The method according to claim 21 , wherein the VEGF-C inhibitor further comprises an immunoglobulin constant region fragment (Fc) fused polypeptide comprising the VEGFR-3 fragment.
23. The method according to claim 21 , wherein the polypeptide comprises an amino acid sequence having a sequence of amino acids defined by positions 47-314 of SEQ ID NO: 4, with the proviso that positions of the polypeptide corresponding to positions 104-106 of SEQ ID NO: 4 are not identical to N-X-S or N-X-T, and wherein the polypeptide binds to human VEGF-C.
24. The method according to claim 21 , wherein the subject has macular degeneration.
25. The method according to claim 21 , further comprising co-administering, to the eye of the subject with the elevated VEGF-C protein measurement, a composition that comprises an inhibitor selected from the group consisting of a VEGF-A inhibitor, a VEGFR-2 inhibitor, and an inhibitor of the VEGFR-2 signalling pathway.
26. The method according to claim 21 , wherein the administering to the eye comprises administering by intravitreal injection.
27. A method comprising:
(a) measuring VEGF-C protein in a biological sample from a human subject to obtain a VEGF-C protein measurement;
(b) detecting elevated VEGF-C protein in the biological sample,
(c) determining that the subject has an increased risk of developing macular degeneration or pathogenic ocular neovascularization from the elevated measurement of VEGF-C protein in the biological sample;
(d) administering, to the eye of the subject determined to have the increased risk, a composition formulated for ophthalmic administration and comprising a VEGF-C inhibitor, said VEGF-C inhibitor comprising:
(i) a VEGFR-3 fragment, said fragment having an amino terminus selected from positions 1-47 of SEQ ID NO: 4, and a carboxy terminus selected from positions 211-247 of SEQ ID NO: 4, or
(ii) a polypeptide comprising the sequence of amino acids defined by positions 47-314 of SEQ ID NO: 4, with the proviso that positions of the polypeptide corresponding to positions 104-106 of SEQ ID NO: 4 are not identical to N-X-S or N-X-T,
wherein said inhibitor binds human VEGF-C.
28. The method according to claim 27 , wherein the VEGF-C inhibitor further comprises an immunoglobulin constant region fragment (Fc) fused polypeptide comprising the VEGFR-3 fragment.
29. The method according to claim 27 , wherein the polypeptide comprises an amino acid sequence having a sequence of amino acids defined by positions 47-314 of SEQ ID NO: 4, with the proviso that positions of the polypeptide corresponding to positions 104-106 of SEQ ID NO: 4 are not identical to N-X-S or N-X-T, and wherein the polypeptide binds to human VEGF-C.
30. The method according to claim 27 , further comprising co-administering, to the eye of the subject determined to have the increased risk, a composition that comprises an inhibitor selected from the group consisting of a VEGF-A inhibitor, a VEGFR-2 inhibitor, and an inhibitor of the VEGFR-2 signalling pathway.
31. The method according to claim 27 , wherein the biological sample comprises blood, serum, plasma, ocular tissue, ocular fluid, blood vessel tissue, or lymphatic vessel tissue.
32. The method according to claim 27 , wherein the detecting of elevated VEGF-C protein is made compared to one or more of the following reference measurements:
(a) a VEGF-C protein measurement from the subject from a biological sample obtained at an earlier point in time; or
(b) a VEGF-C protein measurement from one or more apparently healthy control subjects.
33. The method according to claim 27 , wherein the administering to the eye comprises administering by intravitreal injection.