Glycotargeting therapeutics

Patent metadata

Field	Value
Publication number	US-2016243248-A1
Application number	US-201514859292-A
Country	US
Kind code	A1
Filing date	Sep 19, 2015
Priority date	Feb 21, 2014
Publication date	Aug 25, 2016
Grant date	—

Abstract

Glycotargeting therapeutics are useful in the treatment of transplant rejection, autoimmune disease, food allergy, and immune response against a therapeutic agent.

First claim

We claim:

1 . A composition comprising a compound of Formula 1:

where:
m is an integer from about 1 to 100;
X comprises an antigen against which a patient develops an unwanted immune response, or a tolerogenic portion thereof; or
X comprises an antibody, antibody fragment or ligand that specifically binds a circulating protein or peptide or antibody, which circulating protein or peptide or antibody is causatively involved in transplant rejection, immune response against a therapeutic agent, autoimmune disease, hypersensitivity and/or allergy;
Y comprises a linker moiety; and
Z comprises a liver-targeting moiety.

2 . The composition of claim 1 where Z comprises galactose, galactosamine, N-acetylgalactosamine, glucose, glucosamine or N-acetylglucosamine.

3 . The composition of claim 2 comprising Z conjugated at its C1, C2 or C6 to Y.

4 . The composition of claim 1 where Y is selected from N-hydroxysuccinamidyl linkers, malaemide linkers, vinylsulfone linkers, pyridyl di-thiol-poly(ethylene glycol) linkers, pyridyl di-thiol linkers, n-nitrophenyl carbonate linkers, NHS-ester linkers, and nitrophenoxy poly(ethylene glycol)ester linkers.

5 . The composition of claim 1 where Y comprises:
an antibody, antibody fragment, peptide or other ligand that specifically binds X;
a disulfanyl ethyl ester;
a structure represented by one of Formulae Ya to Yp:

or has a portion represented by Formula Y′-CMP:

where:
the left bracket “(” indicates the bond between X and Y;
the right or bottom bracket and “)” indicates the bond between Y and Z;
n is an integer from about 1 to 100;
p is an integer from about 2 to 150;
q is an integer from about 1 to 44;
R 8 is —CH 2 — or —CH 2 —CH 2 —C(CH 3 )(CN)—;
R 9 is a direct bond or —CH 2 —CH 2 —NH—C(O)—; and
Y′ represents the remaining portion of Y.

6 . The composition of claim 5 where:
n is about 40 to 80;
p is about 10 to 100;
q is about 3 to 20;
R 8 is —CH 2 —CH 2 —C(CH 3 )(CN)—; and
when R 9 is —CH 2 —CH 2 —NH—C(O)—, Z is glucose or N-acetylglucosamine conjugated at its C1.

7 . The composition of claim 5 where Y comprises Formula Ya, Formula Yb, Formula Yh, Formula Yi, Formula Yk, Formula Ym or Formula Yn.

8 . The composition of claim 5 where Y comprises Formula Ya, Formula Yb, Formula Ym or Formula Yn.

9 . The composition of claim 6 where Y comprises Formula Ya, Formula Yb, Formula Ym or Formula Yn.

10 . The composition of claim 1 wherein X comprises:
a foreign transplant antigen against which transplant recipients develop an unwanted immune response;
a foreign food, animal, plant or environmental antigen against which patients develop an unwanted immune response;
a foreign therapeutic agent against which patients develop an unwanted immune response; or
a synthetic self-antigen against the endogenous version of which patients develop an unwanted immune response,
or a tolerogenic portion thereof.

11 . A method of treatment for an unwanted immune response against an antigen by administering to a mammal in need of such treatment an effective amount of a composition comprising a compound of Formula 1:

where:
m is an integer from about 1 to 100;
X comprises an antigen against which a patient develops an unwanted immune response, or a tolerogenic portion thereof; or
X comprises an antibody, antibody fragment or ligand that specifically binds a circulating protein or peptide or antibody, which circulating protein or peptide or antibody is causatively involved in transplant rejection, immune response against a therapeutic agent, autoimmune disease, hypersensitivity and/or allergy;
Y comprises a linker moiety; and
Z comprises a glucosylated liver-targeting moiety.

12 . The method of claim 11 where:
X comprises an antigen against which a patient develops an unwanted immune response, or a tolerogenic portion thereof; and
Y comprises:
an antibody, antibody fragment, peptide or other ligand that specifically binds X;
a disulfanyl ethyl ester;
a structure represented by one of Formulae Ya to Yp:

or has a portion represented by Formula Y′-CMP:

where:
the left bracket “(” indicates the bond between X and Y;
the right or bottom bracket and “)” indicates the bond between Y and Z;
n is an integer from about 1 to 100;
p is an integer from about 2 to 150;
q is an integer from about 1 to 44;
R 8 is —CH 2 — or —CH 2 —CH 2 —C(CH 3 )(CN)—;
R 9 is a direct bond or —CH 2 —CH 2 —NH—C(O)—; and
Y′ represents the remaining portion of Y.

13 . The method of claim 11 wherein X comprises the antibody, antibody fragment or ligand, and the composition is administered for clearance of a circulating protein or peptide or antibody that specifically binds to X, which circulating protein or peptide or antibody is causatively involved in transplant rejection, immune response against a therapeutic agent, autoimmune disease, hypersensitivity and/or allergy.

14 . The method of claim 11 wherein X comprises the antibody, antibody fragment or ligand, and the composition is administered in an amount effective to reduce a concentration of the antibodies that are causatively involved in transplant rejection, immune response against a therapeutic agent, autoimmune disease, hypersensitivity and/or allergy in blood of the patient by at least 50% w/w, as measured at a time between about 12 to about 48 hours after the administration.

15 . The method of claim 11 wherein the composition is administered for tolerization of the patient with respect to antigen moiety X.

16 . The method of claim 11 where X comprises:
a foreign transplant antigen against which transplant recipients develop an unwanted immune response;
a foreign food, animal, plant or environmental antigen against which patients develop an unwanted immune response;
a foreign therapeutic agent against which patients develop an unwanted immune response; or
a synthetic self-antigen against the endogenous version of which patients develop an unwanted immune response,

or a tolerogenic portion thereof.

Assignees

• Ecole Polytechnique Fed De Lausanne (Epfl)

Inventors

• Hubbell Jeffrey A
• Wilson David Scott

Classifications

• A61K47/549

  Sugars, nucleosides, nucleotides or nucleic acids · CPC title

• A61K39/001 Primary

  Preparations to induce tolerance to non-self, e.g. prior to transplantation · CPC title

• A61K2039/577

  tolerising response · CPC title

• A61K39/35

  Allergens · CPC title

• A61K39/0002

  Fungal antigens, e.g. Trichophyton, Aspergillus, Candida · CPC title