Immunosuppression modulating compounds

Patent metadata

Field	Value
Publication number	US-9783578-B2
Application number	US-201414563568-A
Country	US
Kind code	B2
Filing date	Dec 8, 2014
Priority date	Jun 25, 2010
Publication date	Oct 10, 2017
Grant date	Oct 10, 2017

Abstract

The present invention provides immunosuppression compounds to inhibit the programmed cell death 1 (PD1) signalling pathway. The present invention further provides peptide based compositions for treatment of cancer or treatment of infections via immunopotentiation caused by inhibition of immunosuppressive signaling induced by PD-1, PD-L1, or PD-L2 and therapies using them, immunopotentiative substrates included as the active ingredient. Further, the invention provides an application of the compositions containing the peptide moieties for preventive and/or therapeutic agents for cancer, cancer metastasis, immunodeficiency, an infectious disease or the like and an application of peptide moieties as a testing or diagnostic agent or a research agent for such a disease.

First claim

What is claimed is:

1. A compound of formula (I)

or pharmaceutically acceptable salt thereof; wherein;
A is an amino acid sequence of from three amino acids to the full length of a peptide sequence of mammalian PD1 ectodomain fragments selected from FG loop, BC loop, C strand, or C′ strand to C′-C″ loop;
B is an amino acid sequence of from three amino acids to the full length of a peptide sequence of mammalian PD1 ectodomain fragments selected from BC loop, FG loop, C C′ loop to C′ strand, D strand, C′ strand to C′-C″ loop, or is absent;
with the proviso that if A is the amino acid sequence SNTSESF (SEQ ID NO: 4) and X is lysine then B cannot be the amino acid sequence SNTSESF SEQ ID NO: 4);
Z is the amino acid sequence FRVTQLAPKAQIKE (SEQ ID NO: 84);
D is up to two peptide sequences arranged in any order each being of from three amino acids up to the full length of a mammalian PD1 ectodomain fragment selected from BC loop, FG loop, or is absent;
E is up to four peptide sequences arranged in any order each being of from three amino acids up to the full length of a mammalian PD1 ectodomain fragment selected from D strand, FG loop, G strand, or is absent;
X and X′ are independently selected from lysine, ornithine, diaminopropionic acid, diaminobutyric acid or olefinic amino acid of formula

which is optionally linked with an additional lysine; or
X and X′ combine together forming a ring with olefinic amino acid which is optionally linked with an additional lysine; or
X′ is absent;
‘m’ is an integer selected from 1 to 6, both inclusive;
R 2 and R 3 are independently selected from group consisting of C 2 -C 20 acyl, absent or R a -L′;
R a is maleimido propionic acid;
L′ is —CO(CH 2 —CH 2 —O—) n NH; and
‘n’ is an integer selected from 2 to 10, both inclusive;

R 4 and R 5 are independently NH 2 , or one or both of R 4 or R 5 are absent, with the proviso to the compound of Formula (I), that in a compound of Formula (I) as above defined:
a) up to 5 but not more than 25% of the amino acids may be substituted with other natural or unnatural amino acids;
b) not more than 30% of the amino acids may be omitted;
c) in each said peptide sequence up to 2 amino acids may be added individually at any position;
d) up to 5 but not more than 25% of the peptide bonds may instead be replaced by reduced amide bond (—CH 2 NH—);
e) up to 100% of the amino acids may be D-amino acids;
f) up to 100% of the amino acids may be in reverse order.

2. The compound according to claim 1 , wherein said mammalian PD1 ectodomain fragments are from human, murine, dog, horse or rat PD1.

3. The compound according to claim 1 , wherein;
A is an amino acid sequence of from three amino acids to the full length of a peptide sequence of human or murine PD1 ectodomain fragments selected from FG loop, BC loop, C strand, or C′ strand to C′-C″ loop as in table below;

hPD-1
mPD-1

BC Loop
SNTSESF
SNWSEDL

(SEQ ID NO: 4)
(SEQ ID NO: 27)

C Strand
VLNWYRM
MLNWNRL

(SEQ ID NO: 5)
(SEQ ID NO: 28)

C′ strand to 
FPED
FCNG

C′-C″ loop
(SEQ ID NO: 21)
(SEQ ID NO: 37)

FG loop
LAPKA
LHPKA

(SEQ ID NO: 15)
(SEQ ID NO: 35)

B is an amino acid sequence of from three amino acids to the full length of a peptide sequence of human or murine PD1 ectodomain fragments selected from BC loop, FG loop, C C′ loop to C′ strand, D strand, C′ strand to C′-C″ loop as in table below, or is absent;

hPD-1
mPD-1

BC Loop
SNTSESF
SNWSEDL

(SEQ ID NO: 4)
(SEQ ID NO: 27)

C′ strand to 
FPED
FCNG

C′-C″ loop
(SEQ ID NO: 21)
(SEQ ID NO: 37)

C C′ loop to 
SPSNQTDKLAAFP
SPSNQTEKQAAFC

C′ strand
(SEQ ID NO: 23)
(SEQ ID NO: 39)

D Strand
FRVTQ
FQIIQ

(SEQ ID NO: 11)
(SEQ ID NO: 33)

FG loop
LAPKA
LHPKA

(SEQ ID NO: 15)
(SEQ ID NO: 35)

with the proviso that is A is the amino acid sequence SNTSESF (SEQ ID NO: 4) and X is lysine then B cannot be amino acid sequence SNTSESF (SEQ ID NO: 4);
Z is the amino acid sequence FRVTQLAPKAQIKE (SEQ ID NO: 84);
D is up to two peptide sequences arranged in any order each being of from three amino acids up to the full length of a human or murine PD1 ectodomain fragment selected from BC loop, FG loop, as in table below or is absent;

hPD-1
mPD-1

BC Loop
SNTSESF
SNWSEDL

(SEQ ID NO: 4)

Assignees

• Sasikumar Pottayil Govindan Nair
• Ramachandra Muralidhara
• Vadlamani Suresh Kumar
• Vemula Koteswara Rao
• Satyam Leena Khare
• Subbarao Krishnaprasad
• Shrimali K Rajeev
• Kandepu Sreenivas
• Aurigene Discovery Tech Ltd

Inventors

• Sasikumar Pottayil Govindan Nair
• Ramachandra Muralidhara
• Vadlamani Suresh Kumar
• Vemula Koteswara Rao
• Satyam Leena Khare
• Subbarao Krishnaprasad
• Shrimali K Rajeev
• Kandepu Sreenivas

Classifications

• A61K38/00

  Medicinal preparations containing peptides (peptides containing beta-lactam rings A61K31/00; cyclic dipeptides not having in their molecule any other peptide link than those which form their ring, e.g. piperazine-2,5-diones, A61K31/00; ergot alkaloids of the cyclic peptide type A61K31/48; containing macromolecular compounds having statistically distributed amino acid units A61K31/74; medicinal preparations containing antigens or antibodies A61K39/00; medicinal preparations characterised by the non-active ingredients, e.g. peptides as drug carriers, A61K47/00) · CPC title

• C07K7/08

  having 12 to 20 amino acids (gastrins C07K14/595; somatostatins C07K14/655; melanotropins C07K14/68) · CPC title

• C07K14/705 Primary

  Receptors; Cell surface antigens; Cell surface determinants {(tumour specific antigens C07K14/4748)} · CPC title

• C07K7/06

  having 5 to 11 amino acids · CPC title

• C07K9/00

  Peptides having up to 20 amino acids, containing saccharide radicals and having a fully defined sequence; Derivatives thereof · CPC title