BIODEGRADABLE MICROPARTICLES FOR SUSTAINED DELIVERY OF ANTI-ANGIOGENIC PEPTIDE
The present invention provides microparticle compositions comprising anti-angiogenic peptides, as well as methods of treatment, including for macular degeneration.
1 . A microparticle comprising poly(lactide-co-glycolide) (PLGA) having a having lactic acid (LA) to glycolic acid (GA) ratio (L/G) of more than 1:1, the microparticle further comprising an anti-angiogenic peptide derived from the α5 fibril of type IV collagen.
2 . The microparticle of claim 1 , wherein the PLGA is at least 60:40 L/G.
3 . The microparticle of claim 2 , wherein the PLGA is 65:35 L/G.
4 . The microparticle of claim 2 , wherein the PLGA is 75:25 L/G.
5 . The microparticle of claim 2 , wherein the PLGA is 85:15 L/G.
6 . The microparticle of any one of claims 1 to 5 , wherein the anti-angiogenic peptide has the amino acid sequence LRRFSTXPXXXXNINNVXNF (SEQ ID NO:1), where X is a standard amino acid or a non-genetically-encoded amino acid.
7 . The microparticle of any one of claims 1 to 5 , wherein the anti-angiogenic peptide has the amino acid sequence LRRFSTXPXXXXDINDVXNF (SEQ ID NO:2), where X is a standard amino acid or non-genetically-encoded amino acid.
8 . The microparticle of claim 6 or 7 , wherein the anti-angiogenic peptide is LRRFSTAPFAFIDINDVINF (SEQ ID NO:3) or LRRFSTAPFAFININNVINF (SEQ ID NO:4).
9 . The microparticle of any one of claims 1 to 5 , wherein the anti-angiogenic peptide is any one of:
(SEQ ID NO: 5)
LRRFSTAPFAFIDINDVINW,
(SEQ ID NO: 6)
FTNINNVTN,
(SEQ ID NO: 7)
FTDINDVTN,
(SEQ ID NO: 8)
(4-ClPhe)(Abu)NINNV(Abu)NF,
(SEQ ID NO: 9)
A(Abu)NINNV(Abu)NF,
(SEQ ID NO: 10)
F(Abu)NINNV(Abu)N,
(SEQ ID NO: 11)
F(AllyGly)NINNV(AllyGly)NF,
(SEQ ID NO: 12)
FANINNVANF,
(SEQ ID NO: 13)
FIDINDVINF,
(SEQ ID NO: 14)
FIDINDVINW,
(SEQ ID NO: 15)
FININNVINF,
(SEQ ID NO: 16)
FSNINNVSNF,
(SEQ ID NO: 17)
FVNINNVVNF,
(SEQ ID NO: 18)
(dL)RR(dL)RRFSTAPFAFIDINDVINF,
(SEQ ID NO: 19)
(dL)RRFSTAPFAFIDINDVIN(dF),
(SEQ ID NO: 20)
LRRFSTAPF(dA)FIDINDVINF,
(SEQ ID NO: 21)
LRRFSTAPFAFIDINDVIN(dF),
(SEQ ID NO: 22)
LRRFSTAPFdAFIDINDVINF,
(SEQ ID NO: 23)
LRRFSTMPAMF(Abu)NINNV(Abu)NF,
(SEQ ID NO: 24)
LRRFSTMPF(dA)FININNVINF,
(SEQ ID NO: 25)
LRRFSTMPF(Nle)F(Abu)NINNV(Abu)NF,
(SEQ ID NO: 26)
LRRFSTMPFAF(Abu)NINNV(Abu)NF,
(SEQ ID NO: 27)
LRRFSTMPFAFININNVINF,
(SEQ ID NO: 28)
LRRFSTMPFdAFININNVINF,
(SEQ ID NO: 29)
LRRFSTMPFM(4-ClPhe)(Abu)NINNV(Abu)NF,
(SEQ ID NO: 30)
LRRFSTMPFMA(Abu)NINNV(Abu)NF,
(SEQ ID NO: 31)
LRRFSTMPFMF(Abu)NINNV(Abu)NF,
(SEQ ID NO: 32)
LRRFSTMPFMF(AllyGly)NINNV(AllyGly)NF,
(SEQ ID NO: 33)
LRRFSTMPFMFANINNVANF,
(SEQ ID NO: 34)
LRRFSTMPFMFGNINNVGNF,
(SEQ ID NO: 35)
LRRFSTMPFMFININN,
(SEQ ID NO: 36)
LRRFSTMPFMFININNVINF,
(SEQ ID NO: 37)
LRRFSTMPFMFSNINNVSNF,
(SEQ ID NO: 38)
LRRFSTMPFMFTNINN,
(SEQ ID NO: 39)
LRRFSTMPFMFTNINNVTNF,
or
(SEQ ID NO: 40)
LRRFSTMPFMFVNINNVVNF.
10 . The microparticle of any one of claims 1 to 9 , wherein the microparticle is approximately spherical.
11 . The microparticle of any one of claims 1 to 9 , wherein the microparticle is non-spherical, e.g., is ellipsoidal.
12 . The microparticle of any one of claims 1 to 11 , further comprising PLGA-PEG copolymers.
13 . The microparticle of claim 12 , comprising from about 10% to about 95% PLGA-PEG copolymers (by mass of polymer).
14 . The microparticle of any one of claims 1 to 13 , wherein the microparticle comprises from about 0.1% to about 20% peptide by weight of the microparticle.
15 . A pharmaceutical composition comprising the microparticle of any one of claims 1 to 14 , and a pharmaceutically acceptable carrier or excipient.
16 . The pharmaceutical composition of claim 15 , further comprising excess free peptide, optionally being a peptide selected from SEQ ID NO:1 or SEQ ID NO:2, where X is a standard amino acid or non-genetically-encoded amino acid.
17 . The pharmaceutical composition of claim 15 , further comprising excess free peptide selected from SEQ ID NO:3 to SEQ ID NO: 40.
18 . The pharmaceutical composition of claim 17 , wherein the composition comprises from about 20% to about 95% free peptide (in moles).
19 . The pharmaceutical composition of claim 17 or claim 18 , wherein the anti-angiogenic peptide comprised by the microparticle is the same peptide as the free peptide.
20 . The pharmaceutical composition of claim 17 or claim 18 , wherein the anti-angiogenic peptide comprised by the microparticle is a different peptide from the free peptide.
21 . A method for treating one or more of macular degeneration, macular edema, retinal vein occlusion, and diabetic retinopathy, comprising: administering the pharmaceutical composition of any one of claims 15 to 20 by intravitreal administration to a subject in need.
22 . The method of claim 21 , wherein the subject has an age-related macular degeneration (AMD).
23 . The method of claim 22 , wherein the AMD is wet AMD.
24 . The method of claim 21 , wherein the subject has diabetic macular edema.
25 . The method of claim 21 , wherein the subject has retinal vein occlusion or diabetic retinopathy.
26 . The method of any one of claims 21 to 25 , wherein the pharmaceutical composition is administered no more than once per month.
27 . The method of claim 26 , wherein the pharmaceutical composition is administered no more than once every two months.
28 . The method of claim 27 , wherein the pharmaceutical composition is administered no more than once every three months.
29 . The method of claim 28 , wherein the pharmaceutical composition is administered no more than once every four months.
30 . The method of claim 28 , wherein the pharmaceutical composition is administered no more than once every five or six months.
31 . The method of any one of claims 21 to 30 , wherein the subject's condition is refractory or only partially responsive to a VEGF blockade therapy.
32 . The method of claim 31 , wherein the pharmaceutical composition is administered instead of a VEGF blockade therapy.
33 . The method of claim 31 , wherein the pharmaceutical composition is administered to a patient undergoing a VEGF blockade therapy.