Compositions and methods concerning immune tolerance

Patent metadata

Field	Value
Publication number	US-12383617-B2
Application number	US-201917250015-A
Country	US
Kind code	B2
Filing date	May 9, 2019
Priority date	May 9, 2018
Publication date	Aug 12, 2025
Grant date	Aug 12, 2025

Abstract

The present disclosure provides compositions comprising mannose-fused antigens to target mannose receptors. The compositions may be used to prevent immunity or reduce an immune response protein-based drugs that would otherwise elicit an immune response.

First claim

The invention claimed is:

1. A compound of Formula 1:
X—[Y(Z) p ] m —R 2    Formula 1

where:
X comprises an antigen, a tolerogenic portion thereof, or a mimetic thereof;
Y comprises a linker moiety;
Z comprises a moiety that specifically targets a mannose receptor;
p is an integer from 2 to 250;
m is an integer from 1 to 100;
R 2 is any of functional groups I-III:

where Ar is a substituted or unsubstituted aromatic group and one or more of:
R 3 is C 1-6 -alkyl; or
R 11 is C 1-6 -alkyl.

2. The compound of claim 1 , wherein the moiety that specifically targets a mannose receptor is selected from the group consisting of α-linked mannose, β-linked mannose, substituted mannose, mannose-6-phosphate, N-acetyl mannosamine, and mannan having β(1-4), α(1-6), α(1-2), and/or α(1-3) linkages.

3. The compound of claim 1 , wherein Y is a linker resulting from reaction of at least one of a N-hydroxysuccinamidyl linker, maleimide linker, PEG linker, vinylsulfone linker, pyridyl di-thiol-poly (ethylene glycol) linker, pyridyl di-thiol linker, n-nitrophenyl carbonate linker, NHS-ester linker, and nitrophenoxy poly (ethylene glycol) ester linker.

4. The compound of claim 3 , wherein Y is covalently bound to X.

5. The compound of claim 1 , wherein —[Y(Z) p ]— is represented by one of Formula Ya to Yr:

where
n is an integer from 1 to 100;
q is an integer from 1 to 44;
k is an integer from 1 to 12;
i is an integer from 0 to 20;
v is an integer from 1 to 4;
p is an integer from 2 to 250;
r is an integer from 0 to 250;
R 1 is —CH 2 —, —(CH 2 ) 2 —C(CH 3 )(CN)—, —(CH 2 ) 2 —C(CH 3 )(CH 3 )—, —(CH 2 ) 2 —CH(CH 3 )— or —CH(CH 3 )—;
W 1 and W 2 are as defined below:

R 9 is a direct bond, —(CH2)2-NH—C(O)— (an ethylaceetamido group or “EtAcN”) or —(CH2)2-(O—CH2-CH2)t-NH—C(O)— (a pegylated ethylacetamido group or “Et-PEGt-AcN”)
t is an integer from 1 to 5;
Z is mannose or a mannose receptor-targeting moiety; and
R 10 is an aliphatic group, an alcohol, an aliphatic amine-containing group, or an aliphatic alcohol.

6. The compound of claim 1 , wherein Y is an antibody, antibody fragment, peptide or other ligand that binds to X.

7. The compound of claim 1 , wherein X is an antigen against which a patient may develop or has developed an unwanted immune response.

8. The compound of claim 7 , wherein the antigen is a foreign transplant antigen, an alloantigen, an autoimmune antigen, a food antigen, an animal antigen, a plant antigen, an environmental antigen, a therapeutic antigen, a synthetic self-antigen, or a tolerogenic portion thereof.

9. The compound of claim 8 , wherein X is an asparaginase antigen or an ovalbumin antigen.

10. The compound of claim 1 , wherein the mannose receptor is mannose-6-phosphate receptor.

11. The compound of claim 1 , wherein Y and X are connected through a bond configured to cleave when the compound reaches a target area.

12. The compound of claim 1 , wherein Ar is selected from:

where each instance of R″, where present, is independently selected from an optionally substituted C 1-6 -alkyl, optionally substituted C 1-6 alkoxy, optionally substituted amino, OH, or halogen and wherein, X″ is a heteroatom.

13. The compound of claim 12 wherein X″ is N.

14. The compound of claim 1 , wherein R 11 is —CH 3 .

15. A composition comprising the compound of claim 1 .

16. A method of inducing immunological tolerance to an antigen target comprising administering to a subject a composition Formula 1:
X—[Y(Z) p ] m —R 2    Formula 1

where:
X comprises an antigen, a tolerogenic portion thereof, or a mimetic thereof;
Y comprises a linker moiety;
Z comprises a moiety that specifically targets a mannose receptor;
p is an integer from 2 to 250;
m is an integer from 1 to 100;

R 2 is any of functional groups I-III:

where Ar is a substituted or unsubstituted aromatic group and one or more of:
R 3 is C 1-6 -alkyl; or
R 11 is C 1-6 - alkyl.

17. The method of claim 16 , wherein the moiety that specifically targets a mannose receptor is selected from the group consisting of α-linked mannose, β-linked mannose, substituted mannose, mannose-6-phosphate, N-acetyl mannosamine, and mannan having β(1-4), α(1-6), α(1-2), and/or α(1-3) linkages.

Assignees

• Univ Chicago
• Anokion Sa

Inventors

• Hubbell Jeffrey A
• Wilson David Scott
• Brünggel Kym
• Lorentz Kristen Marie

Classifications

• A61K40/42

  Cancer antigens · CPC title

• A61K40/11

  T-cells, e.g. tumour infiltrating lymphocytes [TIL] or regulatory T [Treg] cells; Lymphokine-activated killer [LAK] cells · CPC title

• A61K2239/38

  characterised by the dose, timing or administration schedule · CPC title

• A61K39/001154 Primary

  Enzymes · CPC title

• C08G81/025

  containing polyether sequences · CPC title