BIOCOMPATIBLE TOLEROGENIC NANOPARTICLES
The present invention relates to nanoparticles, methods and compositions which are suitable for the detection and/or follow-up and/or treatment of type 1 diabetes. In particular, it relates to biocompatible tolerogenic nanoparticles comprising at least: (i) a ligand which can bind to an aryl hydrocarbon receptor (AHR) transcription factor; an (ii) a diabetes autoantigen selected from: insulin, preproinsulin, proinsulin, or an immunologically active fragment thereof The inventors have shown that such biocompatible tolerogenic nanoparticles are efficient for the identification of type-1 diabetes. It has also been shown that they can accumulate into the pancreas, and induce temporary or lasting remission of disease in spontaneously diabetic NOD mice. Kits and compositions are further provided.
1 . A method for treating type-I diabetes in a subject in need thereof, comprising administering to the subject a biocompatible tolerogenic nanoparticle comprising at least:
(i) a ligand which can bind to an aryl hydrocarbon receptor (AHR) transcription factor; and
(ii) a diabetes autoantigen selected from: insulin, preproinsulin, proinsulin, or an immunologically active fragment thereof.
2 . A method for the in vivo diagnosis of type-I diabetes in a subject in need thereof comprising administering to the subject a biocompatible tolerogenic nanoparticle comprising at least:
(i) a ligand which can bind to an aryl hydrocarbon receptor (AHR) transcription factor; and
(ii) a diabetes autoantigen selected from: insulin, preproinsulin, proinsulin, or an immunologically active fragment thereof.
3 . A biocompatible tolerogenic nanoparticle comprising at least:
(i) a ligand which can bind to an aryl hydrocarbon receptor (AHR) transcription factor; and
(ii) a diabetes autoantigen selected from: insulin, preproinsulin, proinsulin, or an immunologically active fragment thereof;
wherein the said nanoparticle is a magnetic nanoparticle.
4 . A biocompatible tolerogenic nanoparticle comprising at least:
(i) a ligand which can bind to an aryl hydrocarbon receptor (AHR) transcription factor;
(ii) a diabetes autoantigen selected from: insulin, preproinsulin, proinsulin, or an immunologically active fragment thereof;
wherein the nanoparticle has an average size of less than about 50 nm.
5 . The biocompatible tolerogenic nanoparticle according to claim 3 ; wherein the said nanoparticle has an average size of less than about 50 nm.
6 . The biocompatible tolerogenic nanoparticle according to claim 3 ; wherein the diabetes autoantigen is in the form of a fusion protein characterised in that the fusion protein comprises:
an IgG binding moiety, and
as a cargo moiety, a polypeptide comprising a sequence selected from the group consisting of insulin, preproinsulin, proinsulin, and an immunologically active fragment thereof.
7 . The biocompatible tolerogenic nanoparticle according to claim 4 ; wherein the nanoparticle is a magnetic nanoparticle.
8 . The biocompatible tolerogenic nanoparticle according to claim 3 ; wherein the nanoparticle is an iron oxide nanoparticle.
9 . The biocompatible tolerogenic nanoparticle according to claim 3 ; wherein the ligand which can bind to an aryl hydrocarbon receptor (AHR) transcription factor is 2-(1′H-indole-3′-carbonyl)-thiazole-4-carboxylic acid methyl ester (ITE).
10 . The biocompatible tolerogenic nanoparticle according to claim 3 ; wherein the diabetes autoantigen is a polypeptide comprising a sequence selected from the group consisting of proinsulin and an immunologically active fragment thereof.
11 . The biocompatible tolerogenic nanoparticle according to claim 3 ; wherein the nanoparticle has an average size of less than about 20 nm.
12 . The biocompatible tolerogenic nanoparticle according to claim 3 ; wherein the nanoparticle is functionalized with phosphonate polyethylene glycol (PEG) molecules.
13 . The biocompatible tolerogenic nanoparticle according to claim 12 ; wherein the average density of PEG molecules at the surface of the nanoparticle is from 0.5 to 2 PEG per nm 2 .
14 . The biocompatible tolerogenic nanoparticle according to claim 3 ; wherein the nanoparticle is linked to a ligand which can bind to an AHR transcription factor with an average density of ligand at the surface of the nanoparticle from 0.5 to 4 ligands per nm 2 .
15 . A composition comprising a contrast agent, in combination with the biocompatible tolerogenic nanoparticle of claim 3 .
16 . A kit comprising:
a first container containing the biocompatible tolerogenic nanoparticle of claim 3 ; and
a second container containing a contrast agent.
17 . A method for preparing a contrast composition, comprising a step of bringing into contact a contrast agent with the biocompatible tolerogenic nanoparticle of claim 3 .
18 . A method for preparing a contrast composition, comprising a step of bringing into contact the biocompatible tolerogenic nanoparticle of claim 4 with (i) a ligand which can bind to an aryl hydrocarbon receptor (AHR) transcription factor, and (ii) a diabetes autoantigen selected from: insulin, preproinsulin, proinsulin, or an immunologically active fragment thereof.
19 . The biocompatible tolerogenic nanoparticle according to claim 14 , wherein the ligand is 2-(1′H-indole-3′-carbonyl)-thiazole-4-carboxylic acid methylester (ITE).