IP Library › Granted Patent US 12,186,430
Granted Patent B2
US 12,186,430 · App. 17/224,068 · Granted Jan 7, 2025

Lyophilized mesenchymal stem cell derived secretome and uses thereof

Inventor: Spencer Alford (Newark, CA)
Assignee: COMBANGIO, INC.
A61K9/19A61K9/0048A61K9/1611A61K9/1623A61K9/1652A61K35/28A61P27/02C12N5/0662G01N33/502G01N33/5058
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Quick Facts
Patent No.
US 12,186,430
App. No.
17/224,068
Granted
Jan 7, 2025
Kind
B2
Abstract

The present application provides methods and processes for making and using a lyophilized mesenchymal stem cell secretome, as well as methods for treating ocular conditions and/disorders with the reconstituted lyophilized mesenchymal stem cell secretome described herein.

Claims (31)

1. A mesenchymal stem cell (MSC) secretome composition for lyophilization and/or after being lyophilized comprising:

i. less than about 250 μM IDO (Indoleamine-2,3-dioxygenase) enzyme activity;

ii. at least one trophic factors/cytokines selected from the group consisting of HGF, FGF-7, TIMP-1, TIMP-2, PAI-1 (Serpin E1), VEGF-A, and b-NGF;

iii. at least one additional factor selected from the group consisting of sFLT-1, PEDF (Serpin F1), Serpin A1, IGFBP-2, IGFBP-3, SDF-1, TSG-14, Kallikrein 3, MCP-1, bFGF, Angiogenin, MCP-2, Angio-2, IL-6, IL-17, G-CSF, M-CSF, GM-CSF, IL-8, TNF-beta, PDGF, SOD1, SOD2, SOD3, and/or HO-1; and/or

iv. At least one additional factor selected from the group consisting of DPPIV (dipeptidyl peptidase-4), uPA, Angiopoietin-1, Angiopoietin-2, Amphiregulin, Endostatin, Endothelin-1, Thrombospondin-2, and/or Thrombospondin-1;

wherein the MSC secretome composition for lyophilization and/or after being lyophilized further comprises a tonicity modifying agent;

wherein the composition further comprises an adhesive agent selected from the group consisting of hypromellose, Poloxamer 407, Poloxamer 188, Poloxomer 237, Poloxomer 338, Hypromellose, (HPMC), polycarbophil, polyvinylpyrrolidone (PVP), PVA (polyvinyl alcohol), polyimide, sodium hyaluronate, gellan gum, poly (lactic acid-co-glycolic acid) (PLGA), polysiloxane, polyimide, carboxymethylcellulose (CMC), or hydroxypropyl methylcellulose (HPMC), hydroxy methyl cellulose, hydroxy ethyl cellulose, sodium carboxy methyl cellulose, fibrin glue, polyethyelene glycol, and GelCORE; and

wherein the MSC secretome is a bone marrow-derived MSC secretome; and

wherein the lyophilized MSC secretome composition when reconstituted induces corneal wound healing, and wherein the corneal wound healing induced in about 48 hours is at a level of at least about 50% or about 75% of the level of corneal wound healing induced by a freshly thawed MSC secretome composition that has not been lyophilized.

2. A stable mesenchymal stem cell (MSC) secretome lyophilized formulation comprising:

i. 1-20 μg, or 2 μg-8 μg, of the MSC secretome composition according to claim 1 per mL;

ii. 2 mg-3 mg monobasic sodium phosphate per mL;

iii. 11 mg-12 mg dibasic sodium phosphate per mL;

iv. 11.5 mg-13 mg mannitol per mL;

v. 23 mg-24 mg trehalose dihydrate;

vi. 0.5 mg-2 mg hypromellose per mL; and

wherein the pH is about 4.7 to about 7.5.

3. The MSC secretome composition for lyophilization and/or after being lyophilized according to claim 1 , wherein the MSC secretome further comprises 1 ng/ml-400 ng/mL, 1 ng/mL-300 ng/mL, 1 ng/ml-200 ng/ml, 1 ng/ml-100 ng/ml, 1 ng/ml-50 ng/mL, 1 ng/ml-10 ng/ml, or 1 ng/mL-8 ng/ml of at least one factor selected from the group consisting of Serpin E1, Serpin A1, TIMP-1, Thrombospondin-1, Pentraxin-3 (TSG-14), Platelet Factor 4, and Serpin F1.

4. The MSC secretome composition for lyophilization and/or after being lyophilized according to claim 1 , wherein the MSC secretome further comprises 400 pg/mL-3000 pg/mL of at least one factor selected from the group consisting of Angiopoietin-1, Angiopoietin-2, Amphiregulin, Endostatin, Endothelin-1, Thrombospondin-2, Thrombospondin-1, Angiogenin, DPPIV, IGFBP-3, and/or uPA.

5. The MSC secretome composition for lyophilization and/or after being lyophilized according to claim 1 , wherein the MSC secretome further comprises at least one factor selected from the group consisting of Apolipoprotein A1, Complement Factor D, C-reactive protein, Cystatin C, DKK-1, Emmprin, Osteopontin, vitamin D BP, MIF, RANTES, uPAR, IL-17a, GDF-15, and/or IFNγ.

6. The MSC secretome composition for lyophilization and/or after being lyophilized according to claim 1 , wherein the MSC secretome further comprises 0 pg/mL-200 pg/mL or 1 pg/mL-400 pg/mL of VEGF.

7. The MSC secretome composition for lyophilization and/or after being lyophilized according to claim 1 , wherein the level of VEGF is 5-10 fold lower than the level of Serpin E1.

8. The MSC secretome composition for lyophilization and/or after being lyophilized according to claim 1 , wherein the MSC secretome does not comprise and/or comprises very low levels of bFGF, PLGF, and PDGF, less than 1000 pg/mL.

9. The MSC secretome composition for lyophilization and/or after being lyophilized according to claim 1 , wherein the MSC secretome composition for lyophilization and/or after being lyophilized has a pH of about 4.7 to about 7.5.

10. The MSC secretome composition for lyophilization and/or after being lyophilized according to claim 1 , wherein the MSC secretome is formulated in a buffer system selected from the group consisting of di/mono sodium phosphate, sodium citrate/citric acid, boric acid/sodium citrate, boric acid/sodium tetraborate, and citric acid/disodium phosphate.

11. The MSC secretome composition for lyophilization and/or after being lyophilized according to claim 1 , wherein the tonicity modifying agent is selected from the group consisting of NaCl, KCl, mannitol, dextrose, sucrose, sorbitol, and glycerin.

12. The MSC secretome composition for lyophilization and/or after being lyophilized according to claim 1 , wherein the MSC secretome further comprises mono/di-sodium phosphate, mannitol, and trehalose, wherein the composition has a pH of about pH 7.4.

13. The MSC secretome composition for lyophilization and/or after being lyophilized according to claim 1 , wherein the MSC secretome further comprises divalent cations.

14. The MSC secretome composition for lyophilization and/or after being lyophilized of claim 13 , wherein the divalent cations are selected from the group consisting of Mg2+, Ca2+, and Zn2+.

15. The MSC secretome composition for lyophilization and/or after being lyophilized according to claim 1 , wherein the MSC secretome further comprises di-sodium phosphate/citric acid, mannitol, and trehalose, wherein the composition has a pH of about pH 6.4.

16. The MSC secretome composition for lyophilization and/or after being lyophilized according to claim 1 , wherein the bone marrow-derived MSC secretome comprises: HGF; Pentraxin-3 (TSG-14); VEGF; TIMP-1; Serpin E1; and <5 ng/ml IL-8.

Assignments (4)
FIRST AMENDMENT TO IP SECURITY AGREEMENT Recorded Dec 22, 2022
From: KALA PHARMACEUTICALS, INC.
To: OXFORD FINANCE LLC
Reel/Frame 062205/0883 →
FIRST AMENDMENT TO IP SECURITY AGREEMENT Recorded Dec 22, 2022
From: COMBANGIO, INC.
To: OXFORD FINANCE LLC
Reel/Frame 062209/0615 →
SECURITY INTEREST Recorded Nov 16, 2021
From: COMBANGIO, INC.
To: OXFORD FINANCE LLC
Reel/Frame 058122/0256 →
ASSIGNMENT OF ASSIGNOR'S INTEREST Recorded Aug 25, 2021
From: ALFORD, SPENCER
To: COMBANGIO, INC.
Reel/Frame 057284/0189 →
Continuity (2)
Provisional Application 63006680 · Apr 7, 2020
Related Publication 20210369617A1 · Dec 2, 2021
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