Compound for preparation of antibody-payload conjugate and use thereof

Patent metadata

Field	Value
Publication number	US-12296019-B2
Application number	US-202017424528-A
Country	US
Kind code	B2
Filing date	Jan 23, 2020
Priority date	Jan 23, 2019
Publication date	May 13, 2025
Grant date	May 13, 2025

Abstract

The present application relates to a novel linker for use in bioconjugation, comprising two or more electrophilic carbon atoms of a carbonyl group, and a click chemistry functional group and, more specifically, to a linker through which a compound, a peptide, and/or a protein can be directly and/or indirectly linked by a substitution reaction to a desired target molecule, that is, a target molecule.

First claim

What is claimed is:

1. An antibody-payload conjugate:

wherein, Ab is an antibody,
wherein n is an integer of 1 to 2,
wherein R″′ is C 1-6 alkylene, C 2-6 alkenylene, C 2-6 alkynylene, or C 1-6 heteroalkylene, wherein the heteroalkylene includes at least one selected from a group consisting of N, O, and S,
wherein B is one of a structure formed by a click chemistry reaction of a first click chemistry functional group and a second click chemistry functional group,
wherein the first click chemistry functional group and the second click chemistry functional group are independently selected from a group consisting of acetylene, transcyclooctene, cyclooctyne, dyarylcyclooctyne, methyl ester phosphine, norbornene, tetrazine, methylcyclopropene, azetine, cyanide, azide, and dibenzocyclooctyne, which can be reacted with each other,
wherein Am is an active moiety or a structure including the active moiety, wherein the active moiety comprises a drug molecule,
wherein Fp comprises a Fc binding peptide represented by DCAWHXGELVWCT (SEQ ID NO: 1)
wherein, D is aspartic acid, C is cysteine, A is alanine, W is tryptophan, H is histidine,
wherein X is 2,3-Diaminopropionic Acid (Dap) residue, 2,4-diaminobutyric acid (Dab) residue, ornithine (Orn) residue, or lysine (Lys) residue
wherein G is glycine, E is glutamate, L is leucine, V is valine, and T is threonine,
wherein, the cysteine at N-terminal and the cysteine at C-terminal are optionally linked to each other by a disulfide bond,
wherein the Fc binding peptide is linked to the antibody through an amino acid residue 6 of the Fc binding peptide,

wherein, Y 4 is NH, wherein Y 4 is derived from the amino acid residue 6 of the Fc binding peptide, wherein the amino acid residue 6 of the Fc binding peptide is X, and
wherein, the nitrogen atom linked to the Ab is derived from a lysine 246 of Fc region of the antibody or a lysine 248 of Fc region of the antibody.

2. The antibody-payload conjugate of claim 1 , wherein the Fc binding peptide is a peptide represented by DCAWHKGELVWCT (SEQ ID NO: 2).

3. The antibody-payload conjugate of claim 1 , wherein R″′ is C 1-5 alkylene, or C 1-5 heteroalkylene.

4. The antibody-payload conjugate of claim 1 , wherein R″′ is C 3 alkylene.

5. The antibody-payload conjugate of claim 1 , wherein the first click chemistry functional group is any one selected from norbornene, tetrazine, dibenzocyclooctyne, and azide,
wherein B is

or

and
wherein A 1 is linked to Fp and A 2 is linked to Am, or A 1 is linked to Am and A 2 is linked to Fp.

6. The antibody-payload conjugate of claim 1 ,
wherein n is 2, and
wherein, the nitrogen atom linked to the Ab is derived from the lysine 246 of Fc region of the antibody or the lysine 248 of Fc region of the antibody.

7. The antibody-payload conjugate of claim 1 ,
wherein n is 2,
wherein R″′ is C 3 alkylene,
wherein the Fc binding peptide is represented by DCAWHKGELVWCT (SEQ ID NO: 2),
wherein the first click chemistry functional group is norbornene, tetrazine, dibenzocyclooctyne, or azide,
wherein B is

or

wherein, the nitrogen atom linked to the Ab is derived from the lysine 246 of Fc region of the antibody or the lysine 248 of Fc region of the antibody, and
wherein A 1 is linked to Fp and A 2 is linked to Am, or A 1 is linked to Am and A 2 is linked to Fp.

8. The antibody-payload conjugate of claim 1 , wherein the drug molecule is one or more anticancer drug molecule.

9. The antibody-payload conjugate of claim 8 , wherein the anticancer drug molecule is a mertansine (DM 1).

10. The antibody-payload conjugate of claim 1 , wherein the drug molecules are two anticancer drug molecules.

11. A composition for treating a cancer, comprising an antibody-payload conjugate of claim 8 .

12. The composition of claim 11 , wherein the antibody is a trastuzumab, and wherein the cancer is a breast cancer.

Assignees

• Abtis Co Ltd
• Research & Business Found Sungkyunkwan Univ

Inventors

• Kim Ju Hwan
• Lee Tae Jin
• Chung Sang Jeon
• Lee Young Geun
• Seo Jin Woo

Classifications

• C07D207/46

  with hetero atoms directly attached to the ring nitrogen atom · CPC title

• A61P35/00

  Antineoplastic agents · CPC title

• A61K31/537

  spiro-condensed or forming part of bridged ring systems · CPC title

• A61K47/6889

  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 · CPC title

• A61K47/65 Primary

  Peptidic linkers, binders or spacers, e.g. peptidic enzyme-labile linkers · CPC title