NUCLEIC ACID ENCODING AN ANTI-VEGF ENTITY AND A NEGATIVE COMPLEMENT REGULATOR AND USES THEREOF FOR THE TREATMENT OF AGE-RELATED MACULAR DEGENERATION
The present invention relates to a product comprising (i) an anti-VEGF entity; and (ii) a negative complement regulator, or nucleotide sequences encoding therefor, as a combined preparation for simultaneous, separate or sequential use in therapy. In particular, the anti-VEGF entity is an anti-VEGF antibody, preferably aflibercept and the negative complement regulator is Complement Factor I (CFI) or Complement Factor H Like Protein 1 (FHL1). The main uses are for the treatment of eye diseases, in particular age-related macular degeneration (AMD).
1 . A polynucleotide comprising nucleotide sequences encoding (i) an anti-VEGF entity and (ii) a negative complement regulator.
2 . The polynucleotide of claim 1 , wherein the anti-VEGF entity is selected from an Ig fusion protein, an antibody, a polypeptide, a peptide, a non-antibody scaffold, an antisense oligonucleotide, siRNA, shRNA, CRISPR-guide strand and an aptamer.
3 . The polynucleotide of claim 2 , wherein the anti-VEGF entity is selected from aflibercept, ranibizumab, bevacizumab, brolucizumab and pegaptanib.
4 . The polynucleotide of claim 3 , wherein the anti-VEGF entity is aflibercept.
5 . The polynucleotide of claim 1 , wherein the negative complement regulator is selected from Complement Factor I (CFI), Complement Factor H Like Protein 1 (FHL1), Complement Factor H (CFH), Complement receptor type 1 (CR1), Membrane Cofactor Protein (MCP), Complement decay-accelerating factor (DAF), MAC-inhibitory protein (MAC-IP), C1-inhibitor, anaphylatoxins inhibitor, C4b binding protein (C4BP), clusterin, vitronectin, and variants and fragments thereof.
6 . The polynucleotide of claim 5 , wherein the negative complement regulator is selected from CFI and FHL1 and variants and fragments thereof.
7 . The polynucleotide of claim 4 , wherein the nucleotide sequence encoding aflibercept has at least 75% sequence identity to SEQ ID NO: 11.
8 . The polynucleotide am of claim 6 , wherein the nucleotide sequence encoding CFI has at least 75% sequence identity to SEQ ID NO: 35 or 36 or the nucleotide sequence encoding FHL-1 has at least 75% sequence identity to SEQ ID NO: 41.
9 . The polynucleotide of claim 3 , wherein the polynucleotide comprises the nucleotide sequence of any one of SEQ ID NO: 45 to 54, or a nucleotide sequence that has at least 75% sequence identity thereto.
10 . The polynucleotide of claim 1 , wherein the polynucleotide is less than or equal to 4.7 kb.
11 . A vector comprising the polynucleotide of claim 1 .
12 . The vector of claim 11 , wherein the vector is an adeno-associated viral (AAV) vector.
13 . A pharmaceutical composition comprising the polynucleotide of claim 1 in combination with a pharmaceutically acceptable carrier, diluent or excipient.
14 . (canceled)
15 . A method of treating or preventing a complement-mediated disorder of the eye, comprising administering the polynucleotide of claim 1 to a subject in need thereof.
16 . The method of claim 15 , wherein the complement-mediated disorder of the eye is wet AMD or dry AMD.
17 . The method of claim 15 , wherein i) the complement-mediated disorder of the eye is wet AMD and the administration prevents and/or treats onset of dry AMD in the subject, or ii) the complement-mediated disorder of the eye is dry AMD and the administration prevents and/or treats onset of wet AMD in the subject, or iii) the complement-mediated disorder of the eye is AMD and the administration prevents and/or treats dry AMD and wet AMD simultaneously.
18 . The method of claim 17 , wherein the subject has wet AMD and the administration prevents and/or treats onset of dry AMD in the subject.
19 . The method of claim 15 , wherein:
(i) the formation of geographic atrophy is prevented or reduced, and/or the amount of geographic atrophy is reduced or wherein the progression of geographic atrophy is slowed;
(ii) there is at least a 10% reduction in the increase in geographic atrophy area over the 12 months following administration to a treated eye of the subject, relative to an untreated eye over the same period; or
(iii) administration of the polynucleotide
increases the level of C3b-inactivating and iC3b-degradation activity in the subject, or in an eye of the subject.
20 . The method of claim 15 , wherein i) neovascularization is prevented or reduced, ii) vascular leakage is prevented or reduced and/or iii) retina edema is prevented or reduced.
21 . The method of claim 15 , wherein the polynucleotide is administered intraocularly.
22 . A method of treating and/or preventing wet AMD and/or dry AMD in a subject in need thereof, comprising administering to the subject (i) an anti-VEGF entity; and (ii) a negative complement regulator, or nucleotide sequences encoding therefor simultaneously, separately, or sequentially.
23 . The method of claim 22 , wherein the subject has wet AMD and the administration prevents and/or treats onset of dry AMD in the subject.
24 . The method of claim 22 , wherein the anti-VEGF entity is selected from an Ig fusion protein, an antibody, a polypeptide, a peptide, a non-antibody scaffold, an antisense oligonucleotide, siRNA, shRNA, CRISPR-guide strand and an aptamer, preferably wherein the anti-VEGF entity is selected from aflibercept, ranibizumab, bevacizumab, brolucizumab and pegaptanib.
25 . The method of claim 22 , wherein the negative complement regulator is selected from Complement Factor I (CFI), Complement Factor H Like Protein 1 (FHL1), Complement Factor H (CFH), Complement receptor type 1 (CR1), Membrane Cofactor Protein (MCP), Complement decay-accelerating factor (DAF), MAC-inhibitory protein (MAC-IP), C1-inhibitor, anaphylatoxins inhibitor, C4b binding protein (C4BP), clusterin, vitronectin and variants and fragments thereof.
26 . A product comprising (i) an anti-VEGF entity; and (ii) Factor I, or nucleotide sequences encoding therefor, as a combined preparation.
27 . A method of treating or preventing a complement-mediated ocular disorder comprising administering the product of claim 26 to a subject in need thereof, wherein the anti-VEGF entity and Factor I, or nucleotide sequences encoding therefor are administered simultaneously, separately, or sequentially.
28 . The method of claim 22 , wherein:
(i) the formation of geographic atrophy is prevented or reduced, and/or the amount of geographic atrophy is reduced or wherein the progression of geographic atrophy is slowed;
(ii) there is at least a 10% reduction in the increase in geographic atrophy area over the 12 months following administration to a treated eye of the subject, relative to an untreated eye over the same period; or
(iii) administration of the isolated polynucleotide, vector or pharmaceutical composition increases the level of C3b-inactivating and iC3b-degradation activity in the subject, or in an eye, of the subject.
29 . The method of claim 22 , wherein i) neovascularization is prevented or reduced, ii) vascular leakage is prevented or reduced and/or iii) retina edema is prevented or reduced.