# US 11,027,022 B2 · Conjugates and conjugating reagents

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- Number: US 11,027,022 B2
- Document ID: US11027022B2
- Status: Granted
- Kind: B2
- Application number: 16/097,864
- Filed: 2017-05-19
- Published: 2019-05-09
- Granted: 2021-06-08
- Earliest claimed: 2016-05-20
- Assignees: Polytherics Limited
- Applicants: Polytherics Limited
- Inventors: Antony Godwin
- Web page: https://patentgrep.com/patent/US11027022B2

## CPC

- A61K 47/6951: {using cyclodextrin (cyclodextrins used as simple excipients A61K47/40)}
- A61K 31/404: Indoles, e.g. pindolol
- A61K 31/5365: ortho- or peri-condensed with heterocyclic ring systems
- A61K 47/6817: {Toxins}
- A61K 47/6849: {the antibody targeting a receptor, a cell surface antigen or a cell surface determinant}
- A61K 47/6889: {Conjugates wherein the antibody being the modifying agent and wherein the linker, binder or spacer confers particular properties to the conjugates, e.g. peptidic enzyme-labile linkers or acid-labile linkers, providing for an acid-labile immuno conjugate wherein the drug may be released from its antibody conjugated part in an acidic, e.g. tumoural or environment}
- A61P 35/00: Antineoplastic agents
- 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)
- A61P: SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS

## Abstract

A conjugate of a protein or peptide conjugated to a therapeutic, diagnostic or labelling agent via a linker, in which the linker includes a protein or peptide bonding portion having the general formula: in which Pr represents said protein or peptide, each Nu represents a nucleophile present in or attached to the protein or peptide, each of A and B independently represents a C1-4alkylene or alkenylene chain, and W′ represents an electron withdrawing group or a group obtained by reduction of an electron withdrawing group; and in which the linker also includes a cyclodextrin. The invention also provides reagents for making such conjugates.

## Claims

### Claim 1

A conjugate of a protein or peptide conjugated to a therapeutic agent via a linker, in which the linker also includes a cyclodextrin, and in which the cyclodextrin is present as a pendant group which is tethered to the backbone of the linker, wherein the conjugate is represented schematically by the formula:
in which:
D represents said therapeutic agent,
F′ represents a group of formula I:
in which Pr represents said protein or peptide, each Nu represents a sulfur atom or amine group present in or attached to the protein or peptide, each of A and B independently represents a C1-4alkylene or alkenylene chain, and W′ represents a keto group —CO—, an ester group —O—CO—, a sulfone group —SO2—, or a group obtained by reduction of one of these groups; and CD represents said cyclodextrin.

### Claim 2 (depends on 1)

A conjugate as claimed in claim 1, in which the cyclodextrin is α-cyclodextrin, β-cyclodextrin, or γ-cyclodextrin.

### Claim 3 (depends on 1)

A conjugate as claimed in claim 1, in which the cyclodextrin is bonded to the rest of the linker via the 3- or the 6-position of a cyclic glucose group.

### Claim 4 (depends on 1)

A conjugate as claimed in claim 1, in which the cyclodextrin is monocyclic.

### Claim 5 (depends on 1)

A conjugate as claimed in claim 1, in which the linker includes a portion
wherein AA represents a protease-specific amino acid sequence.

### Claim 6 (depends on 1)

A conjugate as claimed in claim 1, in which the protein or peptide is an antibody or an antibody fragment.

### Claim 7 (depends on 1)

A conjugate as claimed in claim 1, wherein the group of formula (I) is a group of formula (Ia):

### Claim 8 (depends on 7)

A conjugate as claimed in claim 7, wherein the group of formula (Ia) is a group of formula (Ib) or (Ic):

### Claim 9 (depends on 1)

A conjugate as claimed in claim 1, in which each Nu represents a sulfur atom present in a cysteine residue present in the protein or peptide.

### Claim 10 (depends on 1)

A conjugate as claimed in claim 1, which has the formula:

### Claim 11 (depends on 1)

A process for the preparation of a conjugate as claimed in claim 1, which comprises reacting a protein or peptide with a conjugating reagent comprising a therapeutic agent and a linker in which the linker also includes a cyclodextrin, and in which the cyclodextrin is present as a pendant group which is tethered to the backbone of the linker, wherein the conjugate reagent is represented schematically by the formula:
in which: D represents said therapeutic agent,
CD represents said cyclodextrin, and
F is capable of reacting with sulfur atom or amine group present in or attached to the protein or peptide and F represents a group of formula (II) or (II′):
in which W represents a keto group —CO, an ester group —O—CO—, or a sulfone group —SO2—;
each of A and B independently represents a C1-4alkylene, or alkenylene chain, m is 0 to 4, and
each L independently represents a leaving group selected from —SP, —OP, —SO2P, —OSO2P, —N+PR2R3, halogen, or —OØ, in which P represents a hydrogen atom, C1-6alkyl, phenyl, or C1-6alkyl-phenyl group, or is a group which includes a portion —(CH2CH2O)n— in which n is a number of two or more, and each of R2 and R3 independently represents a hydrogen atom, a C1-4alkyl group, or a group P, and Ø represents a substituted phenyl, group, containing at least one substituent selected from the group consisting of —CN, —NO2, —CF3, —CO2Ra, —COH, —CH2OH, —CORa, —ORa, —OCORa, —OCO2Ra, —SRa, —SORa, —SO2Ra, —NRaCORa, —NRaCO2Ra, —NO, —NHOH, —NRa OH, —CH═N—NRa CORa, —N+Ra3, halogen, —CH≡CRa, and —C═CRa2 in which each Ra represents a hydrogen atom, C1-6alkyl, phenyl, or C1-6alkyl-phenyl group.

### Claim 12 (depends on 1)

A pharmaceutical composition which comprises a conjugate as claimed in claim 1 together with a pharmaceutically acceptable carrier, and optionally together with a further active ingredient.

### Claim 13 (depends on 1)

A conjugate as claimed in claim 1, in which the therapeutic agent is an auristatin, a maytansinoid or a duocarmycin.