# US 9,872,918 B2 · Hydroxyl-polymer-drug-protein conjugates

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- Number: US 9,872,918 B2
- Document ID: US9872918B2
- Status: Granted
- Kind: B2
- Application number: 14/651,640
- Filed: 2013-12-12
- Published: 2015-10-29
- Granted: 2018-01-23
- Earliest claimed: 2012-12-12
- Assignees: Mersana Therapeutics, Inc.
- Applicants: Mersana Therapeutics, Inc.
- Inventors: Aleksandr V. Yurkovetskiy
- Web page: https://patentgrep.com/patent/US9872918B2

## CPC

- A61K 47/64: 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)
- A61K 31/4412: having oxo groups directly attached to the heterocyclic ring
- A61K 31/475: having an indole ring, e.g. yohimbine, reserpine, strychnine, vinblastine (vincamine A61K31/4375)
- A61K 31/5377: not condensed and containing further heterocyclic rings, e.g. timolol
- A61K 38/05: Dipeptides
- A61K 38/08: Peptides having 5 to 11 amino acids {(A61K38/043 - A61K38/046 take precedence)}
- A61K 47/56: the modifying agent being an organic macromolecular compound, e.g. an oligomeric, polymeric or dendrimeric molecule
- A61K 47/60: the organic macromolecular compound being a polyoxyalkylene oligomer, polymer or dendrimer, e.g. PEG, PPG, PEO or polyglycerol
- A61K 47/6849: {the antibody targeting a receptor, a cell surface antigen or a cell surface determinant}
- A61K 47/6851: {the antibody targeting a determinant of a tumour cell}
- A61K 47/6855: {the tumour determinant being from breast cancer cell}
- C07K 16/2887: {against CD20}
- C07K 16/32: against translation products of oncogenes
- A61K: PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES (devices or methods specially adapted for bringing pharmaceutical products into particular physical or administering forms A61J3/00; chemical aspects of, or use of materials for deodorisation of air, for disinfection or sterilisation, or for bandages, dressings, absorbent pads or surgical articles A61L; soap compositions C11D)
- C07K: PEPTIDES (peptides in foodstuffs A23; obtaining protein compositions for foodstuffs, working-up proteins for foodstuffs A23J; preparations for medicinal purposes A61K; peptides containing beta-lactam rings C07D; cyclic dipeptides not having in their molecule any other peptide link than those which form their ring, e.g. piperazine-2,5-diones, C07D; ergot alkaloids of the cyclic peptide type C07D519/02; macromolecular compounds having statistically distributed amino acid units in their molecules, i.e. when the preparation does not provide for a specific; but for a random sequence of the amino acid units, homopolyamides and block copolyamides derived from amino acids C08G69/00; macromolecular products derived from proteins C08H1/00; preparation of glue or gelatine C09H; single cell proteins, enzymes C12N; genetic engineering processes for obtaining peptides C12N15/00; compositions for measuring or testing processes involving enzymes C12Q; investigation or analysis of biological material G01N33/00)

## Abstract

A drug conjugate is provided herein. The conjugate comprises a protein based recognition-molecule (PBRM) and a polymeric scaffold having one or more -LD-D, the PBRM being connected to the polymeric scaffold by LP, wherein the polymeric scaffold comprises a linear, branched or cyclic polymer having four or more —OH groups. Each occurrence of D is independently a therapeutic agent having a molecular weight ≦5 kDa. LD and LP are linkers connecting the therapeutic agent and PBRM to the polymeric scaffold respectively. Also disclosed are polymeric scaffolds useful for conjugating with a PBRM to form a polymer-drug-PBRM conjugate described herein, compositions comprising the conjugates, methods of their preparation, and methods of treating various disorders with the conjugates or their compositions.

## Claims

### Claim 1

A polymeric scaffold useful to conjugate with a protein based recognition-molecule (PBRM), the scaffold comprising a linear, branched or cyclic polymer having one or more —OH groups connected to the polymer, one or more
connected to the polymer, and one or more
connected to the polymer, wherein:
the polymer is a hydroxyl polymer having a molecular weight ranging from 2 kDa to 300 kDa and the polymer is not a polyacetal or a polyketal,
each occurrence of D is independently a therapeutic agent having a molecular weight ≦5 kDa;
LD1 is a carbonyl-containing moiety;
each occurrence of
independently is a first linker that contains a biodegradable bond so that when the bond is broken, D is released in an active form for its intended therapeutic effect; in which each u is 1, and the
between LD1 and D denotes direct or indirect attachment of D to LD1; and
each occurrence of
independently is a second linker not yet connected to PBRM, in which LP2 is a moiety containing a functional group that is capable of forming a covalent bond with a functional group of a PBRM, each u is 1, and the
between LD1 and LP2 denotes direct or indirect attachment of LP2 to LD1, and each occurrence of the second linker is distinct from each occurrence of the first linker.

### Claim 2 (depends on 1)

The polymeric scaffold of claim 1 being of Formula (Ibb):
wherein:
m is an integer from 1 to 2200,
m1 is an integer from 1 to 660,
m2 is an integer from 1 to 300,
m3 is an integer from 1 to 110, and
the sum of m, m1, m2 and m3 ranges from 4 to about 2200.

### Claim 3 (depends on 1)

The scaffold of claim 1, further comprising a PBRM connected to the polymeric carrier via LP2.

### Claim 4 (depends on 3)

The scaffold of claim 3, being of Formula (Icc):
wherein:
between LP2 and PBRM denotes direct or indirect attachment of PBRM to LP2,
each occurrence of PBRM independently has a molecular weight of less than 200 kDa;
m is an integer from 1 to 2200,
m1 is an integer from 1 to 660,
m2 is an integer from 1 to 300,
m3 is an integer from 0 to 110,
m4 is an integer from 1 to 60; and
the sum of m, m1, m2, m3 and m4 ranges from 4 to 2200.

### Claim 5 (depends on 3)

The scaffold of claim 3, wherein the scaffold comprises one or more D-carrying polymeric carriers, each independently having Formula (Idd), connected to the PBRM:
wherein:
the PBRM has a molecular weight of greater than 40 kDa;
the terminal
attached to LP2 denotes direct or indirect attachment of LP2 to PBRM such that the D-carrying polymeric carrier is connected to the PBRM,
m is an integer from 1 to 300,
m1 is an integer from 1 to 140,
m2 is an integer from 1 to 40,
m3 is an integer from 0 to 18,
m4 is an integer from 1 to 10; and
the sum of m, m1, m2, m3, and m4 ranges from 4 to 300;
provided that the total number of LP2 attached to the PBRM is 10 or less.

### Claim 6 (depends on 1)

The scaffold of claim 1, wherein LD1 comprises —X—(CH2)v—C(═O)— with X directly connected to the carbonyl group of —(O)u—C(═O), in which X is CH2, O, or NH, and v is an integer from 1 to 6.

### Claim 7 (depends on 1)

The scaffold of claim 1, wherein the scaffold has a molecular weight ranging from 2 kDa to 40 kDa when the PBRM has a molecular weight of greater than 40 kDa or a molecular weight ranging from 20 kDa to 300 kDa when the PBRM has a molecular weight of less than 200 kDa.

### Claim 8 (depends on 2)

The scaffold of claim 2, wherein LD1 comprises —X—(CH2)v—C(═O)— with X directly connected to the carbonyl group of —(O)u—C(═O), in which X is CH2, O, or NH, and v is an integer from 1 to 6.

### Claim 9 (depends on 4)

The scaffold of claim 4, wherein LD1 comprises —X—(CH2)v—C(═O)— with X directly connected to the carbonyl group of —(O)u—C(═O), in which X is CH2, O, or NH, and v is an integer from 1 to 6.

### Claim 10 (depends on 5)

The scaffold of claim 5, wherein LD1 comprises —X—(CH2)v—C(═O)— with X directly connected to the carbonyl group of —(O)u—C(═O), in which X is CH2, O, or NH, and v is an integer from 1 to 6.

### Claim 11 (depends on 2)

The scaffold of claim 2, wherein the scaffold has a molecular weight ranging from 2 kDa to 40 kDa when the PBRM has a molecular weight of greater than 40 kDa or a molecular weight ranging from 20 kDa to 300 kDa when the PBRM has a molecular weight of less than 200 kDa.

### Claim 12 (depends on 4)

The scaffold of claim 4, wherein the scaffold has a molecular weight ranging from 2 kDa to 40 kDa when the PBRM has a molecular weight of greater than 40 kDa or a molecular weight ranging from 20 kDa to 300 kDa when the PBRM has a molecular weight of less than 200 kDa.

### Claim 13 (depends on 5)

The scaffold of claim 5, wherein the scaffold has a molecular weight ranging from 2 kDa to 40 kDa when the PBRM has a molecular weight of greater than 40 kDa or a molecular weight ranging from 20 kDa to 300 kDa when the PBRM has a molecular weight of less than 200 kDa.

### Claim 14 (depends on 6)

The scaffold of claim 6, wherein the scaffold has a molecular weight ranging from 2 kDa to 40 kDa when the PBRM has a molecular weight of greater than 40 kDa or a molecular weight ranging from 20 kDa to 300 kDa when the PBRM has a molecular weight of less than 200 kDa.