Glycan conjugates and methods of use thereof

Patent metadata

Field	Value
Publication number	US-10342858-B2
Application number	US-201514832993-A
Country	US
Kind code	B2
Filing date	Aug 21, 2015
Priority date	Jan 24, 2015
Publication date	Jul 9, 2019
Grant date	Jul 9, 2019

Abstract

The present disclosure is directed to vaccines, antibodies, and/or immunogenic conjugate compositions targeting the SSEA3/SSEA4/GloboH associated epitopes (natural and modified) which elicit antibodies and/or binding fragment production useful for modulating the globo-series glycosphingolipid synthesis. The present disclosure relates to methods and compositions which can modulate the globo-series glycosphingolipid synthesis. Particularly, the present disclosure is directed to glycoenzyme inhibitor compound and compositions and methods of use thereof that can modulate the synthesis of globo-series glycosphingolipid SSEA3/SSEA4/GloboH in the biosynthetic pathway; particularly, the glycoenzyme inhibitors target the alpha-4GalT; beta-4GalNAcT-I; or beta-3GalT-V enzymes in the globo-series synthetic pathway. Moreover, the present disclosure is also directed to the method of using the compositions described herein for the treatment or detection of hyperproliferative diseases and/or conditions.

First claim

We claim:

1. An immunogenic composition comprising:
(a) a glycan conjugate including a carrier and one or more glycans, and optionally
(b) an adjuvant;
wherein each of the one or more glycans is conjugated with the carrier through a linker,
and the glycan conjugate has the structure depicted in formula (III):

wherein:
X 1 is selected from —OR, wherein R is selected from a hydroxyl protecting group, optionally substituted C 1-10 alkyl, optionally substituted aryl, optionally substituted acyl, and optionally substituted imidoyl; or
X 1 is selected from —SR, wherein R is selected from a thiol protecting group, optionally substituted C 1-10 alkyl, optionally substituted aryl, optionally substituted acyl, and optionally substituted imidoyl;
each instance of R 1 , R 2 , R 3 , R 4 , and R 5 is independently selected from hydrogen, halogen, optionally substituted alkyl, optionally substituted alkenyl, optionally substituted alkynyl, optionally substituted heterocyclyl, optionally substituted aryl, —N 3 , —NO 2 , —N(R B ) 2 , —N(R A )C(O)R A , —OR A , —OC(O)R A , —SR A , —C(O)N(R B ) 2 , —CN, —C(O)R A , —C(O)OR A , —S(O)R A , —SO 2 R A , —SO 2 N(R B ) 2 , and —NHSO 2 R B ;
R 6 is selected from hydrogen, halogen, optionally substituted alkyl, optionally substituted alkenyl, optionally substituted alkynyl, optionally substituted aryl, —N 3 , —NO 2 , —N(R B ) 2 , —N(R A )C(O)R A , —OR A , —OC(O)R A , —SR A , —C(O)N(R B ) 2 , —CN, —C(O)R A , —C(O)OR A , —S(O)R A , —SO 2 R A , —SO 2 N(R B ) 2 , and —NHSO 2 R B ;
L is —OH;
each instance of R A is independently selected from hydrogen, optionally substituted alkyl, optionally substituted alkenyl, optionally substituted alkynyl, optionally substituted heterocyclyl, and optionally substituted aryl;
wherein, when R 6 is —OR A ,R A is not substituted heterocycle;
each instance of R B is independently selected from hydrogen, optionally substituted alkyl, optionally substituted alkenyl, optionally substituted alkynyl, optionally substituted heterocyclyl, and optionally substituted aryl; and
provided the glycan conjugate is not one of the formula (III-a):

2. An immunogenic composition comprising:
(a) a glycan conjugate including a carrier and one or more glycans, and optionally
(b) an adjuvant;
wherein each of the one or more glycans is conjugated with the carrier through a linker,
and the glycan conjugate has the structure depicted in formula (III):

wherein:
X 1 is selected from —OR, wherein R is selected from a hydroxyl protecting group, optionally substituted C 1-10 alkyl, optionally substituted aryl, optionally substituted acyl, and optionally substituted imidoyl; or
X 1 is selected from —SR, wherein R is selected from a thiol protecting group, optionally substituted C 1-10 alkyl, optionally substituted aryl, optionally substituted acyl, and optionally substituted imidoyl;
each instance of R 1 , R 2 , R 3 , R 4 , and R 5 is independently selected from hydrogen, halogen, optionally substituted alkyl, optionally substituted alkenyl, optionally substituted alkynyl, optionally substituted heterocyclyl, optionally substituted aryl, —N 3 , —NO 2 , —N(R B ) 2 , —N(R A )C(O)R A , —OR A , —OC(O)R A , —SR A , —C(O)N(R B ) 2 , —CN, —C(O)R A , —C(O)OR A , —S(O)R A , —SO 2 R A , —SO 2 N(R B ) 2 , and —NHSO 2 R B ;
R 6 is selected from hydrogen, halogen, optionally substituted alkyl, optionally substituted alkenyl, optionally substituted alkynyl, optionally substituted aryl, —N 3 , —NO 2 , —N(R B ) 2 , —N(R A )C(O)R A , —OR A , —OC(O)R A , —SR A , —C(O)N(R B ) 2 , —CN, —C(O)R A , —C(O)OR A , —S(O)R A , —SO 2 R A , —SO 2 N(R B ) 2 , and —NHSO 2 R B ;
L is selected from hydrogen, halogen, optionally substituted alkyl, optionally substituted alkenyl, optionally substituted alkynyl, optionally substituted aryl, —N 3 , —NO 2 , —N(R B ) 2 , —N(R A )C(O)R A , —OR A , —OC(O)R A , —SR A , —C(O)N(R B ) 2 , —CN, —C(O)R A , —C(O)OR A , —S(O)R A , —SO 2 R A , —SO 2 N(R B ) 2 , —NHSO 2 R B , and substituted heterocyclyl;
each instance of R A is independently selected from hydrogen, optionally substituted alkyl, optionally substituted alkenyl, optionally substituted alkynyl, optionally substituted heterocyclyl, and optionally substituted aryl;
each instance of R B is independently selected from hydrogen, optionally substituted alkyl, optionally substituted alkenyl, optionally substituted alkynyl, optionally substituted heterocyclyl, and optionally substituted aryl;
wherein at least one instance of R 1 , R 2 , R 3 , R 4 , R 5 and R 6 is selected from —N 3 or —F.

3. An immunogenic composition comprising:
(a) a glycan conjugate including a carrier and one or more glycans, and optionally
(b) an adjuvant;
wherein each of the one or more glycans is conjugated with the carrier through a linker,
and the glycan conjugate has the structure depicted in formula (IV):

wherein:
X 1 is selected from —OR, wherein R is selected from a hydroxyl protecting group, optionally substituted C 1-10 alkyl, optionally substituted aryl, optionally substituted acyl, and optionally substituted imidoyl; or
X 1 is selected from —SR, wherein R is selected from a thiol protecting group, optionally substituted C 1-10 alkyl, optionally substituted aryl, optionally substituted acyl, and optionally substituted imidoyl;
each instance of R 1 , R 2 , R 3 , R 8 , R 9 , R 10 , and R 11 is independently selected from hydrogen, halogen, optionally substituted alkyl, optionally substituted alkenyl, optionally substituted alkynyl, optionally substituted heterocyclyl, optionally substituted aryl, —N 3 , —NO 2 , —N(R B ) 2 , —N(R A )C(O)R A , —OR A , —OC(O)R A , —SR A , —C(O)N(R B ) 2 , —CN, —C(O)R A , —C(O)OR A , —S(O)R A , —SO 2 R A , —SO 2 N(R B ) 2 , and —NHSO 2 R B ;
R N -is selected from —N 3 , —NO 2 , —N(R B ) 2 , —N(R A )C(O)R A , —OR A , —OC(O)R A , —SR A , —C(O)N(R B ) 2 , —CN, —C(O)R A , —C(O)OR A , —S(O)R A , —SO 2 R A , —SO 2 N(R B ) 2 , and —NHSO 2 R B ;
each instance of R A is independently selected from hydrogen, optionally substituted alkyl, optionally substituted alkenyl, optionally substituted alkynyl, optionally substituted heterocyclyl, and optionally substituted aryl; and
each instance of R B is independently selected from hydrogen, optionally substituted alkyl, optionally substituted alkenyl, optionally substituted alkynyl, optionally substituted heterocyclyl, and optionally substituted aryl; and
provided the glycan conjugate is not formula (III-b):

 and
wherein at least one instance of R 1 , R 2 , R 3 , R 8 , R 9 , R 10 , R 11 and R N is selected from —N 3 or —F.

4. The immunogenic composition of claim 3 wherein the glycan conjugate has the following structure:

wherein:
R 10 is selected from hydrogen, halogen, optionally substituted alkyl, optionally substituted alkenyl, optionally substituted alkynyl, optionally substituted heterocyclyl, optionally substituted aryl, —N 3 , —NO 2 , —N(R B ) 2 , —N(R A )C(O)R A , —OR A , —OC(O)R A , —SR A , —C(O)N(R B ) 2 , —CN, —C(O)R A , —C(O)OR A , —S(O)R A , —SO 2 R A , —SO 2 N(R B ) 2 , and —NHSO 2 R B ; wherein R 12 is H, OH, or halogen;
R N is selected from —N 3 , —NO 2 , —N(R

Assignees

• Academia Sinica

Inventors

• Wong Chi-Huey
• Wu Chung-Yi

Classifications

• C07K16/44

  against material not provided for elsewhere {, e.g. haptens, metals, DNA, RNA, amino acids} · CPC title

• C07H15/26 Primary

  Acyclic or carbocyclic radicals, substituted by hetero rings · CPC title

• C07H5/06

  Aminosugars · CPC title

• C07H5/04

  to nitrogen · CPC title

• C07H5/02

  to halogen · CPC title