Protein-polymer drug conjugates

Patent metadata

Field	Value
Publication number	US-2024082417-A1
Application number	US-202217812498-A
Country	US
Kind code	A1
Filing date	Jul 14, 2022
Priority date	Jul 14, 2022
Publication date	Mar 14, 2024
Grant date	—

Abstract

A polymeric scaffold useful for conjugating with a protein based recognition-molecule (PBRM) to form a PBRM-polymer-drug conjugate is described herein. The scaffold includes one or more terminal maleimido groups. Also disclosed is a PBRM-polymer-drug conjugate prepared from the scaffold. Compositions comprising the conjugates, methods of their preparation, and methods of treating various disorders with the conjugates or their compositions are also described.

First claim

What is claimed is:

1 . A therapeutic drug and targeting conjugate useful in anti-neoplastic therapies comprising:
(a) a ligand (LG) which comprises an immunoglobulin or functional fragment thereof which targets human oncofetal protein 5T4, the ligand having bound thereto m 5 of polymeric scaffolds of (b), wherein m 5 is one to about ten; (b) a polymeric scaffold comprising poly(1-hydroxymethylethylene hydroxymethyl-formal) (PHF) which has a molecular weight ranging from about 2 kDa to about 40 kDa, wherein the polymeric scaffold comprises randomly arranged monomeric units m, m 1 , m 2 , m 3a and m 3b , defined as follows:
(i) m 3a :

wherein m 3a is absent or 1 to about 17 monomeric m 3a units are present in the polymer scaffold, and in each unit, X a and X b are independently selected from (A) one is H and the other is a maleimido blocking moiety, or (B) X a and X b , together with the carbon atoms to which they are attached form a carbon-carbon double bond;
(ii) m 3b ,

 wherein the sulfide bond forms the point of attachment to the ligand, and wherein 1 to about 8 monomer m 3b units are present in the polymeric scaffold, provided that the sum of m 3a and m 3b is 1 to 18, and wherein the sulfur atom is part of the ligand,
(iii) m:

 wherein 1 to about 300 monomer m units are present in the polymeric scaffold;
(iv) m 1 :

 wherein 1 to about 140 monomeric m 1 units are present in the polymer scaffold;
(v): m 2 :

 wherein 1 to about 40 monomeric m 2 units are present in the polymer scaffold;

wherein in each of the monomeric units m, m 1 , m 2 , m 3a , and m 3b , X is CH 2 , O or NH,
the sum of m, m 1 , m 2 , m 3a , and m 3b ranges from about 15 to about 300, and wherein
each occurrence of D independently is a therapeutic agent having a molecular weight of ≤5 kDa, and the

 between D and the carbonyl group denotes direct or indirect attachment of D to the carbonyl group.

2 . The therapeutic drug and targeting conjugate of claim 1 , wherein the ligand has a molecular weight of greater than about 40 kD and the PHF has a molecular weight ranging from about 2 kDa to about 40 kDa.

3 . The therapeutic drug and targeting conjugate of claim 1 , wherein the ligand comprises an immunoglobulin or a functional fragment thereof.

4 . The therapeutic drug and targeting conjugate of claim 3 , wherein the immunoglobulin or functional fragment thereof is selected from the group consisting of a monoclonal antibody, a chimeric antibody, a humanized antibody, a human antibody, an immunoadhesin, a F(Ab) 2 , a minibody, Fab′, a single-domain antibody, a nanobody, a single chain Fv, a tandem/bis-scFv, a F(ab) 3 , a scFv-Fc (or scFvFc), a dsFv, a diabody, a triabody, and a tetrabody.

5 . The therapeutic drug and targeting conjugate of claim 4 , wherein the immunoglobulin or a functional fragment thereof is an anti-5T4 scFvFc and has the amino acid sequence of SEQ ID NO: 7.

6 . The therapeutic drug and targeting conjugate of claim 1 , wherein m 5 is 2 to 8.

7 . The therapeutic drug and targeting conjugate of claim 6 , wherein m 5 is 2 to 4.

8 . The therapeutic drug and targeting conjugate of claim 7 , D is independently selected from the group consisting of (a) an auristatin and its analogs; (b) a calicheamicin and its derivatives; (c) duocarmycin and its analogs; (d) SN38, and (e) pyrrolobenzodiazepine and its analogs.

9 . The therapeutic drug and targeting conjugate of claim 8 , wherein the auristatin or analog thereof is selected from the group consisting of auristatin, dolastatin, monomethylauristatin E (MMAE), monomethylauristatin F (MMAF), auristatin F phenylenediamine (AFP) and auristatin F hydroxypropyl amide (AF HPA).

10 . The therapeutic drug and targeting conjugate of claim 8 , wherein the duocarmycin or analogs thereof is selected from the group consisting of duocarmycin A, duocarmycin B1, duocarmycin B2, duocarmycin C1, duocarmycin C2, duocarmycin D, duocarmycin SA, CC-1065, adozelesin, bizelesin, and carzelesin.

11 . The therapeutic drug and targeting conjugate of claim 1 , wherein X is NH.

12 . The therapeutic drug and targeting conjugate of claim 1 , wherein the PHF has a molecular weight ranging from about 2 kDa to about 20 kDa; the sum of m, m 1 , m 2 , m 3a and m 3b is about 15 to about 150; m 1 is 1 to about 70; m 2 is 1 to about 20; m 3a is 0 to about 9; m 3b is 1 to about 8 and m 5 is 2 to about 8, and wherein the sum of m 3a and m 3b is 1 to 10.

13 . The therapeutic drug and targeting conjugate of claim 1 , wherein the PHF has a molecular weight ranging from about 3 kDa to about 15 kDa; the sum of m, m 1 , m 2 , m 3a and m 3b is about 20 to about 110; m 1 is 2 to about 50; m 2 is 2 to about 15 m 3a is 0 to about 7; m 3b is 1 to about 8 and m 5 is 2 to about 4, and wherein the sum of m 3a and m 3b is 1 to 8.

14 . The therapeutic drug and targeting conjugate of claim 1 , wherein the PHF has a molecular weight ranging from about 5 kDa to about 10 kDa; the sum of m, m 1 , m 2 , m 3a and m 3b is about 40 to about 75; m 1 is about 5 to about 35; m 2 is about 3 to about 10; m 3a is 0 to about 4; m 3b is 1 to about 5 and m 5 is 2 to about 4, and wherein the sum of m 3a and m 3b is 1 to 5.

15 . The therapeutic drug and targeting conjugate of claim 1 , wherein m 5 is 2 to 4.

16 . The therapeutic drug and targeting conjugate of claim 1 , having Formula (B):

wherein:
the PHF has a molecular weight ranging from about 5 kDa to about 10 kDa;
the sulfur atom is part of the ligand;
m is 1 to 75;
m 1 is about 5 to about 35;
m 2 is about 3 to about 10;
m 3a is 0 to about 4;
m 3b is 1 to about 5;
the sum of m, m 1 , m 2 , m 3a , and m 3b is about 40 to about 75; and
m 5 is 2 to about 4.

17 . The therapeutic drug and targeting conjugate of claim 1 , wherein the sum of m 1 and m 2 is about 8 to about 45.

18 . The therapeutic drug and targeting conjugate of claim 1 , wherein the PHF has a molecular weight ranging from about 2 kDa to about 20 kDa; m 2 is 1 to about 20; the sum of m 3a and m 3b is 1 to about 10; m 1 is an integer from 1 to about 70 and the sum of m, m 1 , m 2 and m 3a and m 3b is about 15 to about 150.

19 . The therapeutic drug and targeting conjugate of claim 1 , wherein the PHF has a molecular weight ranging from about 3 kDa to about 15 kDa; m 2 is an integer from 2 to about 15; the sum of m 3a and m 3b is 1 to about 8; m 1 is an integer from 2 to about 50 and the sum of m, m 1 , m 2 and m 3a and m 3b is about 20 to about 110.

20 . The therapeutic drug and targeting conjugate of claim 1 , wh

Assignees

• Asana Biosciences Llc

Inventors

• Smith Roger A
• Damle Nitin K
• Yurkovetskiy Aleksandr V
• Yin Mao
• Lowinger Timothy B
• Thomas Joshua D
• Stevenson Cheri A
• Gurijala Venu R

Classifications

• A61K47/68037

  the drug being a camptothecin [CPT] or derivatives · CPC title

• A61K47/68031

  the drug being an auristatin · CPC title

• A61K47/6803

  Drugs conjugated to an antibody or immunoglobulin, e.g. cisplatin-antibody conjugates · CPC title

• A61K47/6851 Primary

  the antibody targeting a determinant of a tumour cell · CPC title

• A61K47/6883

  Polymer-drug antibody conjugates, e.g. mitomycin-dextran-Ab; DNA-polylysine-antibody complex or conjugate used for therapy · CPC title