COMPOUNDS AND METHODS FOR ACTIVATING TIE2 SIGNALING
The present invention in various aspects and embodiments, involves methods for treating Tie2-related vascular permeability by administering one or more collagen IV-derived biomimetic peptides and involves compositions for treating Tie2-related vascular permeability comprising one or more collagen IV-derived biomimetic peptides. Such peptides can promote the Tie2 agonist activities of Angiopoietin 2 (Ang2), thereby stabilizing vasculature and/or lymphatic vessels.
1 . A method for preventing or treating a condition involving Tie-2-related vascular or lymphatic permeability in a patient, comprising: administering collagen IV-derived biomimetic peptide to said patient in an amount effective to reduce Tie-2-dependent vascular or lymphatic permeability.
2 . The method of claim 1 , wherein the condition is diabetic macular edema, retinal vein occlusion, wet age-related macular degeneration (wet AMD), background diabetic retinopathy, cancer, influenza, hemorrhagic fever, or cerebral malaria.
3 . The method of claim 1 , wherein the condition is tumor growth or metastasis.
4 . The method of claim 1 , wherein the condition is an inflammatory condition involving lymphatic dysfunction.
5 . The method of claim 1 , wherein the condition is vascular permeability prior to chemotherapy for cancer.
6 . The method of claim 5 , wherein the peptide is administered in an amount effective to normalize tumor vasculature, followed by administration of chemotherapy.
7 . The method of claim 1 , wherein the condition is lung cancer, which is optionally NSCLC or SCLC, liver cancer, triple-negative breast cancer, or glioblastoma.
8 . The method of claim 1 , wherein the condition is sepsis.
9 . The method of claim 1 , wherein the condition is capillary leak syndrome.
10 . The method of claim 1 , wherein the condition is an inflammatory condition of the lung, which is optionally acute respiratory distress syndrome, chronic asthma, or chronic obstructive pulmonary disorder (COPD).
11 . The method of claim 1 , wherein the condition is angioedema.
12 . The method of claim 1 , wherein the condition is vascular leak syndrome.
13 . The method of claim 2 , wherein a composition comprising the peptide of SEQ ID NOs: 1-4 is administered to a patient having diabetic macular edema, retinal vein occlusion, wet age-related macular degeneration (wet AMD), or background diabetic retinopathy, by intravitreal injection at a dose of from about 100 μg to about 1000 μg of the peptide, and with a frequency of injection of no more than monthly.
14 . The method of claim 13 , wherein the frequency of injection is no more than about every other month.
15 . The method of claim 13 , wherein the frequency of injection is no more than about every three months.
16 . The method of claim 13 , wherein the peptide is administered after unsuccessful VEGF blockade or inhibitor therapy.
17 . The method of any one of claims 1 to 16 , wherein the condition is refractory or only partially-responsive to VEGF blockade or inhibitor therapy.
18 . The method of claim 17 , wherein the peptide is administered after unsuccessful VEGF blockade or inhibitor therapy.
19 . The method of claim 18 , wherein the peptide is administered as an alternative to VEGF blockade or inhibitor therapy.
20 . The method of claim 19 , wherein the peptide is administered in combination with VEGF blockade therapy.
21 . The method of any one of claims 1 to 20 , wherein the peptide comprises the amino acid sequence of any one of SEQ ID NOs: 1-4.
22 . The method of any one of claims 1 to 21 , wherein the peptide is derived from the α5 fibril of collagen IV, or a biomimetic thereof.
23 . The method of claim 22 , wherein the peptide is:
(SEQ ID NO: 5)
LRRFSTMPFMF(Abu)NINNV(Abu)NF,
(SEQ ID NO: 6)
LRRFSTMPAMF(Abu)NINNV(Abu)NF,
(SEQ ID NO: 7)
LRRFSTMPFAF(Abu)NINNV(Abu)NF,
(SEQ ID NO: 8)
LRRFSTMPFMA(Abu)NINNV(Abu)NF,
(SEQ ID NO: 9)
LRRFSTMPF(Nle)F(Abu)NINNV(Abu)NF,
(SEQ ID NO: 10)
LRRFSTMPFM(4-ClPhe)(Abu)NINNV(Abu)NF,
(SEQ ID NO: 11)
LRRFSTMPFMFSNINNVSNF,
(SEQ ID NO: 12)
LRRFSTMPFMFANINNVANF,
(SEQ ID NO: 13)
LRRFSTMPFMFININNVINF,
(SEQ ID NO: 14)
LRRFSTMPFMFTNINNVTNF,
(SEQ ID NO: 15)
LRRFSTMPFMF(AllyGly)NINNV(AllyGly)NF ,
(SEQ ID NO: 16)
LRRFSTMPFMFVNINNVVNF,
(SEQ ID NO: 17)
LRRFSTMPFdAFININNVINF,
(SEQ ID NO: 18)
LRRFSTMPFAFININNVINF,
(SEQ ID NO: 19)
LRRFSTAPFAFININNVINF,
(SEQ ID NO: 20)
LRRFSTAPFdAFIDINDVINF,
(SEQ ID NO: 21)
LRRFSTAPFAFIDINDVINW,
(SEQ ID NO: 22)
dLRRdLRRFSTAPFAFIDINDVINF,
(SEQ ID NO: 23)
LRRFSTAPFAFIDINDVINdF,
or
(SEQ ID NO: 24)
dLRRFSTAPFAFIDINDVINdF.
24 . The method of claim 22 , wherein the peptide is:
(SEQ ID NO: 25)
F(Abu)NINNV(Abu)N,
(SEQ ID NO: 26)
FTNINNVTN,
(SEQ ID NO: 27)
FININNVINF,
(SEQ ID NO: 28)
FSNINNVSNF,
(SEQ ID NO: 29)
FANINNVANF,
(SEQ ID NO: 30)
F(AllyGly)NINNV(AllyGly)NF,
(SEQ ID NO: 31)
FVNINNVVNF,
(SEQ ID NO: 32)
FIDINDVINF,
(SEQ ID NO: 33)
FIDINDVINW,
(SEQ ID NO: 34)
FTDINDVTN,
(SEQ ID NO: 35)
A(Abu)NINNV(Abu)NF,
or
(SEQ ID NO: 36)
(4-ClPhe)(Abu)NINNV(Abu)NF.
25 . The method of any one of claims 1 to 24 , wherein the peptide is conjugated to, or loaded into, nanoparticles or microparticles.
26 . The method of claim 25 , wherein the nanoparticles or microparticles comprise PLGA-PEG.
27 . A peptide or particle formulation thereof, the peptide having the amino acid sequence of any one of SEQ ID NOs: 1-36, and which is optionally a peptide having a sequence selected from SEQ ID NOs: 5 to 36.
28 . The peptide or particle formulation of claim 27 , wherein the formulation comprises from 100 μg to about 1000 μg of peptide agent.
29 . The formulation of claim 28 , wherein the formulation does not involve encapsulation into particles.
30 . The peptide or particle formulation of claim 27 , wherein the formulation comprises from about 1 mg to about 10 mg per dose.
31 . The peptide or particle formulation of claim 30 , wherein the formulation involves encapsulation into microparticles, optionally with free peptide.