VAR2CSA-drug conjugates

Patent metadata

Field	Value
Publication number	US-10675355-B2
Application number	US-201415108258-A
Country	US
Kind code	B2
Filing date	Dec 29, 2014
Priority date	Dec 27, 2013
Publication date	Jun 9, 2020
Grant date	Jun 9, 2020

Abstract

VAR2CSA-drug conjugates having biological activity are disclosed. Methods associated with preparation and use of such conjugates, as well as pharmaceutical compositions comprising such conjugates, are also disclosed.

First claim

What is claimed is:

1. A compound of Formula I:
T-L-P   I

wherein:
T is a targeting moiety comprising a VAR2CSA polypeptide, and
L-P is L 1 -P 1 or L 2 -P 2 ;

wherein:
L 1 is a linker, or L 1 is absent;
P 1 is a monovalent radical of a compound of Formula XV:

wherein:
R 26 is selected from the group consisting of optionally substituted alkyl, optionally substituted alkylamino, optionally substituted cycloalkyl, optionally substituted aryl, optionally substituted heterocyclyl, optionally substituted heteroaryl, —COR 27 , —CSR 27 , —OR 27 , and —NHR 27 , wherein each R 27 is, independently, alkyl optionally substituted with halogen, —OH or —SH;
R 29 is selected from the group consisting of optionally substituted alkyl, optionally substituted alkylamino, optionally substituted cycloalkyl, optionally substituted aryl, optionally substituted heterocyclyl and optionally substituted heteroaryl;
R 30 is selected from the group consisting of H and C 1-6 alkyl;
R 31 is selected from the group consisting of H and C 1-6 alkyl;
R 32 and R 38 are each independently selected from the group consisting of H, C 1-6 alkyl and —SH, with the proviso that R 32 and R 38 cannot both be H;
R 33 , R 34 , R 35 and R 36 are each independently H or C 1-6 alkyl, wherein at least one of R 33 and R 34 is H; or R 34 and R 35 form a double bond, R 33 is H, and R 36 is H or C 1-6 alkyl; and
R 37 is selected from the group consisting of H and C 1-6 alkyl; and

wherein:
L 2 is a linker;
P 2 is a cytotoxic compound; and
L 2 -P 2 has the following structure (III):

wherein:
R is selected from the group consisting of optionally substituted alkyl, optionally substituted alkylamino, optionally substituted cycloalkyl, optionally substituted aryl, optionally substituted heterocyclyl, optionally substituted heteroaryl, —COR 27 , —CSR 27 , —OR 27 , and —NHR 27 , wherein each R 27 is, independently, optionally substituted alkyl, optionally substituted alkylamino, optionally substituted cycloalkyl, optionally substituted aryl, optionally substituted heterocyclyl and optionally substituted heteroaryl, or R is absent;
P 3 is the remaining portion of compound P 2 ; and
L 3 is the remaining portion of linker L 2 or is absent.

2. The compound of claim 1 , wherein said VAR2CSA polypeptide comprises a sequential amino acid sequence of
a. ID1; and
b. DBL2Xb.

3. The compound of claim 1 , wherein said VAR2CSA polypeptide binds chondroitin sulfate A (CSA) on proteoglycans (CSPG) with an affinity as measured by a K D lower than 100 nM.

4. The compound of claim 1 , wherein said VAR2CSA polypeptide comprises an amino acid sequence having at least 70% sequence identity with an amino acid sequence selected from: amino acids 1-577 of SEQ ID NO: 1; amino acids 1-592 of SEQ ID NO:3; amino acids 1-579 of SEQ ID NO:4; amino acids 1-576 of SEQ ID NO:5; amino acids 1-586 of SEQ ID NO: 10; amino acids 1-579 of SEQ ID NO: 11; amino acids 1-565 of SEQ ID NO:29; amino acids 1-584 of SEQ ID NO:34; amino acids 1-569 of SEQ ID NO:36; amino acids 1-575 of SEQ ID NO:37; amino acids 1-592 of SEQ ID NO:38; amino acids 1-603 of SEQ ID NO:41; amino acids 1-588 of SEQ ID NO:43; amino acids 1-565 of SEQ ID NO:44; amino acids 1-589 of SEQ ID NO:45; amino acids 1-573 of SEQ ID NO:48; amino acids 1-583 of SEQ ID NO:53; amino acids 1-569 of SEQ ID NO:54; amino acids 578-640 of SEQ ID NO:1; amino acids 593-656 of SEQ ID NO:3; amino acids 580-643 of SEQ ID NO:4; amino acids 577-640 of SEQ ID NO:5; amino acids 587-650 of SEQ ID NO: 10; amino acids 580-643 of SEQ ID NO: 11; amino acids 566-628 of SEQ ID NO:29; amino acids 585-647 of SEQ ID NO:34; amino acids 570-632 of SEQ ID NO:36; amino acids 576-639 of SEQ ID NO:37; amino acids 593-655 of SEQ ID NO:38; amino acids 604-667 of SEQ ID NO:41; amino acids 589-652 of SEQ ID NO:43; amino acids 566-628 of SEQ ID NO:44; amino acids 590-653 of SEQ ID NO:45; amino acids 574-637 of SEQ ID NO:48; amino acids 584-646 of SEQ ID NO:53; amino acids 570-632 of SEQ ID NO:54; SEQ ID NO:2; SEQ ID NO:6; SEQ ID NO:7; SEQ ID NO:8; SEQ ID NO:9; SEQ ID NO:12; SEQ ID NO:13; SEQ ID NO:14; SEQ ID NO:15; SEQ ID NO:16; SEQ ID NO:17; SEQ ID NO:18; SEQ ID NO:19; SEQ ID NO:20; SEQ ID NO:21; SEQ ID NO:22; SEQ ID NO:23; SEQ ID NO:24; SEQ ID NO:25; SEQ ID NO:26; SEQ ID NO:27; SEQ ID NO:28; SEQ ID NO:30; SEQ ID NO:31; SEQ ID NO:32; SEQ ID NO:33; SEQ ID NO:35; SEQ ID NO:39; SEQ ID NO:40; SEQ ID NO:42; SEQ ID NO:46; SEQ ID NO:47; SEQ ID NO:49; SEQ ID NO:50; SEQ ID NO:51; SEQ ID NO:52; SEQ ID NO: 1; SEQ ID NO:3; SEQ ID NO:4; SEQ ID NO:5; SEQ ID NO: 10; SEQ ID NO:11; SEQ ID NO:29; SEQ ID NO:34; SEQ ID NO:36; SEQ ID NO:37; SEQ ID NO:38; SEQ ID NO:41; SEQ ID NO:43; SEQ ID NO:44; SEQ ID NO:45; SEQ ID NO:48; SEQ ID NO:53; and SEQ ID NO:54.

5. The compound of claim 1 , wherein said VAR2CSA polypeptide comprises an amino acid sequence having at least 70% sequence identity with an amino acid sequence selected from: amino acids 1-577 of SEQ ID NO: 1; amino acids 1-592 of SEQ ID NO:3; amino acids 1-579 of SEQ ID NO:4; amino acids 1-576 of SEQ ID NO:5; amino acids 1-586 of SEQ ID NO: 10; amino acids 1-579 of SEQ ID NO: 11; amino acids 1-565 of SEQ ID NO:29; amino acids 1-584 of SEQ ID NO:34; amino acids 1-569 of SEQ ID NO:36; amino acids 1-575 of SEQ ID NO:37; amino acids 1-592 of SEQ ID NO:38; amino acids 1-603 of SEQ ID NO:41; amino acids 1-588 of SEQ ID NO:43; amino acids 1-565 of SEQ ID NO:44; amino acids 1-589 of SEQ ID NO:45; amino acids 1-573 of SEQ ID NO:48; amino acids 1-583 of SEQ ID NO:53; amino acids 1-569 of SEQ ID NO:54; SEQ ID NO: 1; SEQ ID NO:3; SEQ ID NO:4; SEQ ID NO:5; SEQ ID NO:10; SEQ ID NO:11; SEQ ID NO:29; SEQ ID NO:34; SEQ ID NO:36; SEQ ID NO:37; SEQ ID NO:38; SEQ ID NO:41; SEQ ID NO:43; SEQ ID NO:44; SEQ ID NO:45; SEQ ID NO:48; SEQ ID NO:53; and SEQ ID NO:54.

6. The compound of claim 1 , wherein said VAR2CSA polypeptide consists of an amino acid sequence having a length of less than 700 amino acids.

7. The compound of claim 1 , wherein said VAR2CSA polypeptide is a recombinant protein.

8. The compound of claim 1 , wherein L-P is L 2 -P 2 .

9. The compound of claim 8 , wherein:
P 2 is a compound of Formula V:

L 2 -T has the following structure (VI):

wherein
P 4 is the remaining portion of compound P 2 ;
the —NH— group bonded to R in Formula V forms a peptide bond (JPB) with AA 1 in formula VI, wherein said JPB is enzymatically cleavable;
R is selected from the group consisting of optionally substituted alkyl, optionally substituted alkylamino, optionally substituted cycloalkyl, optionally substituted aryl, optionally substituted heterocyclyl, optionally substituted heteroaryl, —COR 27 , —CSR 27 , —OR 27 , and —NHR 27 , wherein each R 27 is, independently, optionally substituted alkyl, optionally substituted alkylamino, optionally substituted cycloalkyl, optionally substituted aryl, optionally substituted heterocyclyl or optionally substituted heteroaryl;
each AA is independently an amino acid;
n is an integer from 0 to 25;
L 4 is the remaining portion of linker L 2 or is absent;
T is said targeting moiety, and

Assignees

• Zymeworks Inc
• Var2 Pharmaceuticals Aps

Inventors

• Rich James R
• Babcook John
• El-Salanti Ali
• Daugaard Mads
• Dahlback Madeleine
• Hedberg Bradley J
• Winters Geoffrey C
• Mandel Alexander L
• Bourque Elyse Marie Josée
• Hsieh Tom Han Hsiao

Classifications

• A61K47/64 Primary

  Drug-peptide, drug-protein or drug-polyamino acid conjugates, i.e. the modifying agent being a peptide, protein or polyamino acid which is covalently bonded or complexed to a therapeutically active agent (peptidic linkers A61K47/65) · CPC title

• C07K14/445

  Plasmodium · CPC title

• A61K38/05

  Dipeptides · CPC title

• A61K47/54

  the modifying agent being an organic compound · CPC title

• Y02A50/30

  Against vector-borne diseases, e.g. mosquito-borne, fly-borne, tick-borne or waterborne diseases whose impact is exacerbated by climate change · CPC title