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Tolerogenic synthetic nanocarrier compositions with transplantable graft antigens and methods of use

a synthetic nanocarrier and antigen technology, applied in the direction of peptide/protein ingredients, liposome delivery, peptide/protein delivery, etc., can solve the problems of adverse immune responses of transplant recipients, use of broad-acting immunosuppressants, and the risk of severe side effects of broad-acting immunosuppressants, so as to reduce side effects

Inactive Publication Date: 2012-11-01
SELECTA BIOSCI
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  • Summary
  • Abstract
  • Description
  • Claims
  • Application Information

AI Technical Summary

Benefits of technology

[0009]In another embodiment, the composition is in an amount effective to reduce the generation of an undesired immune response to the APC presentable transplant antigens or cells on, in or by which the APC presentable transplant antigens are expressed. In one embodiment, the undesired immune response is CD8+ T cell proliferation and / or activity.
[0022]In yet another aspect, a method comprising administering to a subject a composition comprising (i) a first population of synthetic nanocarriers that are coupled to immunosuppressants, and (ii) a second population of synthetic nanocarriers that are coupled to APC presentable transplant antigens, wherein the composition is in an amount effective to reduce the generation of an undesired immune response against the APC presentable transplant antigens is provided. In still another aspect, a method comprising reducing the generation of an undesired immune response in a subject by administering a composition comprising (i) a first population of synthetic nanocarriers that are coupled to immunosuppressants, and (ii) a second population of synthetic nanocarriers that are coupled to APC presentable transplant antigens is provided. In still another aspect, a method comprising administering a composition to a subject according to a protocol that was previously shown to reduce the generation of an undesired immune response to APC presentable transplant antigens in one or more test subjects, where the composition comprises (i) a first population of synthetic nanocarriers that are coupled to immunosuppressants, and (ii) a second population of synthetic nanocarriers that are coupled to the APC presentable transplant antigens is provided.
[0027]In another embodiment, the composition reduces the generation of the undesired immune response to the APC presentable transplant antigens or cells on, in or by which the APC presentable transplant antigens are expressed.
[0044]In preferred embodiments of any of the compositions, dosage forms, methods, processes or uses, the synthetic nanocarrier compositions provided herein will allow for administration of lower doses of immunosuppressants than the current standard of care, thereby reducing side effects.

Problems solved by technology

Transplants can also result in adverse immune responses to the recipient of a transplant, such as in graft versus host disease.
Unfortunately, the use of broad-acting immunosuppressants are associated with a risk of severe side effects, such as tumors, infections, nephrotoxicity and metabolic disorders.

Method used

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  • Tolerogenic synthetic nanocarrier compositions with transplantable graft antigens and methods of use
  • Tolerogenic synthetic nanocarrier compositions with transplantable graft antigens and methods of use
  • Tolerogenic synthetic nanocarrier compositions with transplantable graft antigens and methods of use

Examples

Experimental program
Comparison scheme
Effect test

example 1

Immune Response of Synthetic Nanocarriers with Coupled Rapamycin with and without Ovalbumin Peptide (323-339)

Materials

[0219]Ovalbumin peptide 323-339, a 17 amino acid peptide known to be a T and B cell epitope of Ovalbumin protein, was purchased from Bachem Americas Inc. (3132 Kashiwa Street, Torrance Calif. 90505; Part #4065609). Rapamycin was purchased from TSZ CHEM (185 Wilson Street, Framingham, Mass. 01702; Product Catalogue #R1017). PLGA with a lactide:glycolide ratio of 3:1 and an inherent viscosity of 0.75 dL / g was purchased from SurModics Pharmaceuticals (756 Tom Martin Drive, Birmingham, Ala. 35211; Product Code 7525 DLG 7A). Polyvinyl alcohol (85-89% hydrolyzed) was purchased from EMD Chemicals (Product Number 1.41350.1001).

[0220]Solution 1: Ovalbumin peptide 323-339 @ 20 mg / mL in dilute hydrochloric acid aqueous solution. The solution was prepared by dissolving ovalbumin peptide in 0.13 M hydrochloric acid solution at room temperature.

[0221]Solution 2: Rapamycin @ 50 mg / ...

example 2

Mesoporous Silica Nanoparticles with Coupled Ibuprofen (Prophetic)

[0233]Mesoporous SiO2 nanoparticle cores are created through a sol-gel process. Hexadecyltrimethyl-ammonium bromide (CTAB) (0.5 g) is dissolved in deionized water (500 mL), and then 2 M aqueous NaOH solution (3.5 mL) is added to the CTAB solution. The solution is stirred for 30 min, and then Tetraethoxysilane (TEOS) (2.5 mL) is added to the solution. The resulting gel is stirred for 3 h at a temperature of 80° C. The white precipitate which forms is captured by filtration, followed by washing with deionized water and drying at room temperature. The remaining surfactant is then extracted from the particles by suspension in an ethanolic solution of HCl overnight. The particles are washed with ethanol, centrifuged, and redispersed under ultrasonication. This wash procedure is repeated two additional times.

[0234]The SiO2 nanoparticles are then functionalized with amino groups using (3-aminopropyl)-triethoxysilane (APTMS)....

example 3

Liposomes Containing Cyclosporine A (Prophetic)

[0237]The liposomes are formed using thin film hydration. 1,2-Dipalmitoyl-sn-glycero-3-phosphocholine (DPPC) (32 μmol), cholesterol (32 μmol), and cyclosporin A (6.4 μmol) are dissolved in pure chloroform (3 mL). This lipid solution is added to a 50 mL round-bottom flask, and the solvent is evaporated on a rotary evaporator at a temperature of 60° C. The flask is then flushed with nitrogen gas to remove remaining solvent. Phosphate buffered saline (2 mL) and five glass beads are added to the flask, and the lipid film is hydrated by shaking at 60° C. for 1 h to form a suspension. The suspension is transferred to a small pressure tube and sonicated at 60° C. for four cycles of 30 s pulses with a 30 s delay between each pulse. The suspension is then left undisturbed at room temperature for 2 h to allow for complete hydration. The liposomes are washed by centrifugation followed by resuspension in fresh phosphate buffered saline.

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Abstract

Disclosed are synthetic nanocarrier compositions, and related methods, comprising APC presentable transplant antigens and immunosuppressants that provide tolerogenic immune responses (e.g., a reduction in CD8+ T cell proliferation and / or activity) specific to the APC presentable transplant antigens.

Description

RELATED APPLICATIONS[0001]This application claims the benefit under 35 U.S.C. §119 of U.S. provisional application 61 / 480,946, filed Apr. 29, 2011, 61 / 513,514, filed Jul. 29, 2011, 61 / 531,147, filed Sep. 6, 2011, 61 / 531,153, filed Sep. 6, 2011, 61 / 531,164, filed Sep. 6, 2011, 61 / 531,168, filed Sep. 6, 2011, 61 / 531,175, filed Sep. 6, 2011, 61 / 531,180, filed Sep. 6, 2011, 61 / 531,194, filed Sep. 6, 2011, 61 / 531,204, filed Sep. 6, 2011, 61 / 531,209, filed Sep. 6, 2011, 61 / 531,215, filed Sep. 6, 2011, the entire contents of each of which are incorporated herein by reference.FIELD OF THE INVENTION[0002]This invention relates to synthetic nanocarrier compositions with antigen-presenting cell (APC) presentable transplant antigens and immunosuppressants, and related methods. The compositions and methods allow for efficient uptake by APCs to shift the immune response in favor of tolerogenic immune response development specific to the APC presentable transplant antigens. The compositions and me...

Claims

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Application Information

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Patent Type & Authority Applications(United States)
IPC IPC(8): A61K39/385A61K9/14A61P37/06A61K39/00B82Y5/00B82Y40/00
CPCA61K39/00C12N5/0637A61K39/0005A61K9/127A61K47/48861A61K47/48884A61K47/48915A61K9/51A61K2039/577A61K2039/6093B82Y5/00A61K2039/55511A61K39/36A61K2300/00A61K39/385A61K9/14A61K9/5115A61K9/5146A61K9/5153A61K31/192A61K38/13A61K38/1816A61K38/38A61K39/0008A61K39/001A61K39/35A61K47/50A61K47/52A61K47/544A61K47/593A61K47/643A61K47/69A61K47/6923A61K47/6929A61K47/6937G01N33/505G01N33/56972A61K2039/5154A61K2039/55555B82Y40/00G01N2333/7051G01N2333/70514G01N2333/70517A61K31/436A61K45/06A61K31/366A61P1/16A61P11/02A61P11/06A61P15/00A61P17/00A61P29/00A61P35/00A61P37/00A61P37/02A61P37/04A61P37/06A61P37/08A61P41/00A61P43/00A61P7/06Y02A50/30
Inventor FRASER, CHRISTOPHERKISHIMOTO, TAKASHI KEIMALDONADO, ROBERTO A.
Owner SELECTA BIOSCI
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