Modified glycolipids and methods of making and using the same

Patent metadata

Field	Value
Publication number	US-2016346384-A1
Application number	US-201615173226-A
Country	US
Kind code	A1
Filing date	Jun 3, 2016
Priority date	Feb 8, 2013
Publication date	Dec 1, 2016
Grant date	—

Abstract

The invention is directed to compositions and methods related to proteins that are physically associated with ceramide-like glycolipids for use as activators of NKT cells. The compositions and methods of the present invention are useful for the prevention and treatment of diseases.

First claim

That which is claimed:

1 . A modified ceramide-like glycolipid comprising a photoreactive group, wherein said photoreactive group has been covalently bound to the N-acyl lipophilic moiety of a ceramide-like glycolipid.

2 . The modified ceramide-like glycolipid of claim 1 , wherein said photoreactive group is covalently bound to the terminus of an acyl chain of said ceramide-like glycolipid.

3 . The modified ceramide-like glycolipid of claim 2 , wherein said acyl chain is a linear acyl chain comprising at least 11 atoms, excluding hydrogens.

4 . The modified ceramide-like glycolipid of claim 3 , wherein said acyl chain is selected from the group consisting of:

wherein Y if present is —O—, —CH 2 —, —S—, —OCH 2 —, —SCH 2 —, —CH 2 CH 2 —; or a bond; and PRG is the photoreactive group.

5 . The modified ceramide-like glycolipid of claim 1 , wherein said photoreactive group is a benzophenone group.

6 . The modified ceramide-like glycolipid of claim 1 , wherein said ceramide-like glycolipid comprises a glycosylceramide or an analog thereof.

7 . The modified ceramide-like glycolipid of claim 6 , wherein said glycosylceramide or analog thereof comprises Formula I:

wherein R1 is a linear or branched C 1 -C 27 alkane or C 2 -C 27 alkene; or R1 is —C(OH)—R3 wherein R3 is a linear or branched C 1 -C 26 alkane or C 2 -C 26 alkene; or R1 is a C 6 -C 27 alkane or alkene wherein (i) the C 6 -C 27 alkane or alkene is substituted with a C 5 -C 15 cycloalkane, C 5 -C 15 cycloalkene, heterocycle, or aromatic ring or (ii) the C 6 -C 27 alkane or alkene includes, within the C 6 -C 27 alkyl or alkenyl chain, a C 5 -C 15 cycloalkane, C 5 -C 15 cycloalkene, heterocycle, or aromatic ring;
R2 is one of the following (a)-(e):
(a) —CH 2 (CH 2 ) x CH 3 ,
(b) —CH(OH)(CH 2 ) x CH 3 ,
(c) —CH(OH)(CH 2 ) x CH(CH 3 ) 2 ,
(d) —CH═CH(CH 2 ) x CH 3 ,
(e) —CH(OH)(CH 2 ) x CH(CH 3 )CH 2 CH 3 ,
wherein X is an integer ranging from 4-17;
R4 is an α-linked or a β-linked monosaccharide, or when R1 is a linear or branched C 1 -C 27 alkane, R4 is:

and
A is O or —CH 2 .

8 . The modified ceramide-like glycolipid of claim 7 , wherein R1 is —(CH 2 ) 22 CH 3 or —(CH 2 ) 24 CH 3 .

9 . The modified ceramide-like glycolipid of claim 7 , wherein R2 is —CH(OH)—(CH 2 ) 13 CH 3 .

10 . The modified ceramide-like glycolipid of claim 7 , wherein R4 is galactosyl, mannosyl, fucosyl or glucosyl.

11 . The modified ceramide-like glycolipid of claim 1 , wherein said ceramide-like glycolipid comprises an α-galactosylceramide or an analog thereof.

12 . The modified ceramide-like glycolipid of claim 11 , wherein said α-galactosylceramide or analog thereof comprises Formula II:

wherein
R1 is a linear or branched C 1 -C 27 alkane or C 2 -C 27 alkene; or R1 is —C(OH)—R3 wherein R3 is linear or branched C 1 -C 26 alkane or C 2 -C 26 alkene; and
R2 is one of the following (a)-(e):
(a) —CH 2 (CH 2 ) x CH 3 ,
(b) —CH(OH)(CH 2 ) x CH 3 ,
(c) —CH(OH)(CH 2 ) x CH(CH 3 ) 2 ,
(d) —CH═CH(CH 2 ) x CH 3 ,
(e) —CH(OH)(CH 2 )—CH(CH 3 )CH 2 CH 3 ,
wherein X is an integer ranging from 4-17.

13 . The modified ceramide-like glycolipid of claim 12 , wherein R2 is —CH(OH)—(CH 2 ) 13 CH 3 .

14 . The modified ceramide-like glycolipid of claim 12 , wherein R1 is selected from the group consisting of (CH 2 ) 9 CH═CH—CH 2 —CH═CH(CH 2 ) 4 CH 3 , (CH 2 ) 8 CH═CH—CH 2 —CH═CH(CH 2 ) 4 CH 3 , (CH 2 ) 7 CH═CH—CH 2 —CH═CH(CH 2 ) 4 CH 3 , (CH 2 ) 3 CH═CH—CH 2 —CH═CH—CH 2 —CH═CH—CH 2 —CH═CH—(CH 2 ) 4 CH 3 , (CH 2 ) 3 CH═CH—CH 2 —CH═CH—CH 2 —CH═CH—CH 2 —CH═CH—CH 2 —CH═CH—CH 2 CH 3 , (CH 2 ) 7 CH═CH—CH 2 —CH═CH═(CH 2 ) 4 CH 3 , (CH 2 ) 7 CH═CH—CH═CH(CH 2 ) 5 CH 3 , (CH 2 ) 8 CH═CH—CH═CH(CH 2 ) 4 CH 3 , (CH 2 ) 9 CH═CH—CH═CH(CH 2 ) 5 CH 3 , (CH 2 ) 6 CH═CH—CH═CH—CH═CH(CH 2 ) 4 CH 3 , (CH 2 ) 6 CH═CH—CH═CH—CH═CH(CH 2 ) 4 CH 3 and (CH 2 ) 7 CH═CH—CH═CH—CH═CH(CH 2 ) 3 CH 3 .

15 . The modified ceramide-like glycolipid of claim 14 , wherein the double bonds are cis or trans.

16 . The modified ceramide-like glycolipid of claim 11 , wherein said α-galactosylceramide or analog thereof comprises Formula III:

wherein R is —C(O)R1, wherein R1 is a linear or branched C 1 -C 27 alkane or C 2 -C 27 alkene; or R1 is —C(OH)—R3 wherein R3 is a linear or branched C 1 -C 26 alkane or C 2 -C 26 alkene; or R1 is a C 6 -C 27 alkane or alkene wherein (i) the C 6 -C 27 alkane or alkene is substituted with a C 5 -C 15 cycloalkane, C 5 -C 15 cycloalkene, heterocycle, or aromatic ring or (ii) the C 6 -C 27 alkane or alkene includes, within the C 6 -C 27 alkyl or alkenyl chain, a C 5 -C 15 cycloalkane, C 5 -C 15 cycloalkene, heterocycle, or aromatic ring; or R1 is an optionally substituted aromatic ring, or an aralkyl, and
R2 is one of the following (a)-(e):
(a) —CH 2 (CH 2 ) x CH 3 ,
(b) —CH(OH)(CH 2 ) x CH 3 ,
(c) —CH(OH)(CH 2 ) x CH(CH 3 ) 2 ,
(d) —CH═CH(CH 2 ) x CH 3 ,
(e) —CH(OH)(CH 2 ) x CH(CH 3 )CH 2 CH 3 ,
wherein X is an integer ranging from 4-17.

17 . The modified ceramide-like glycolipid of claim 16 , wherein R1 is substituted with oxo; hydroxy; halogen; phenyl; —OC(O)R6; —OR6; —C(O)R6; or N(R6) 2 ,
wherein each R6 is independently a C 1 -C 6 substituted alkyl, or a substituted aromatic ring optionally substituted with halogen; hydroxy; —OC(O)R7; —OR7; —C(O)R7 or N(R7) 2 , and
wherein each R7 is a substituted C 1 -C 6 alkyl.

18 . The modified ceramide-like glycolipid of claim 16 , wherein R1 is selected from the group consisting of

where ( ) represent the point of attachment of R1 to the compound of Formula III.

19 . The modified ceramide-like glycolipid of claim 11 , wherein said α-galactosylceramide or analog thereof is selected from the group consisting of: (2S,3S,4R)-1-O-(α-D-galactopyranosyl)-N-hexacosanoyl-2-amino-1,3,4-octadecanetriol (KRN7000), (2S,3 S)-1-O-(α-D-galactopyranosyl)-N-hexacosanoyl-2-amino-1,3-octadecanediol), and (2S,3S,4R)-1-CH 2 —(α-galactopyranosyl)-N-hexacosanoyl-2-amino-1,3,4-octadecanetriol (α-C-GalCer).

20 . The modified ceramide-like glycolipid of claim 1 , wherein said modified glycolipid has a structure selected from the group consisting of:
a)

b)

c)

d)

Assignees

• Vaccinex Inc
• Albert Einstein College Medicine Inc

Inventors

• Porcelli Steven A
• Zauderer Maurice

Classifications

• C07K2317/622

  Single chain antibody (scFv) · CPC title

• A61K2039/572

  cytotoxic response · CPC title

• C07K2319/30

  Non-immunoglobulin-derived peptide or protein having an immunoglobulin constant or Fc region, or a fragment thereof, attached thereto · CPC title

• A61K2039/55572

  Lipopolysaccharides; Lipid A; Monophosphoryl lipid A · CPC title

• C07K16/30

  from tumour cells · CPC title