Search

CN-122028936-A - Antibody-drug conjugates

CN122028936ACN 122028936 ACN122028936 ACN 122028936ACN-122028936-A

Abstract

The present disclosure relates to drug-linker systems for antibody-drug conjugates and antibody-drug conjugates comprising the same.

Inventors

  • P Hoge
  • N. Weiyar

Assignees

  • ADC疗法责任有限公司

Dates

Publication Date
20260512
Application Date
20241016
Priority Date
20231017

Claims (20)

  1. 1. An antibody-drug conjugate having the structure (1) (1) Wherein: AB is a cell binding agent, such as an antibody; n is an integer in the range of 5 to 8; L 1 is a linker; l 2 is a linker; L 3 is a linker; a. b and c are independently 0 or 1; Z is a linking group obtained by a metal-free click reaction or by thiol conjugation or by transglutaminase-mediated deamidation; or Z is absent, wherein a and b are 0, and the N-terminus of the polyglycine is directly bonded to AB in the absence of a sortase recognition sequence motif; x is an integer in the range of 1 to 8.
  2. 2. The antibody-drug conjugate of claim 1, wherein D is irinotecan, optionally wherein the drug linker is capable of cleaving under cellular conditions to release the irinotecan having the following formula (D 1 ): (D 1 ) 。
  3. 3. The antibody-drug conjugate of claim 1 or 2, wherein L 3 comprises a cathepsin-cleavable peptide or legumain-cleavable peptide.
  4. 4. The antibody-drug conjugate of any preceding claim, wherein L 3 is , The antibody-drug conjugate has the structure (1 a) (1a) Wherein: AB is a cell binding agent, such as an antibody; n is an integer in the range of 5 to 8; L 1 is a linker; l 2 is a linker; L 3a is a linker; a. b and d are independently 0 or 1; Z is a linking group obtained by a metal-free click reaction or by thiol conjugation or by transglutaminase-mediated deamidation; Or Z is absent, wherein a and b are 0, and the N-terminus of the polyglycine is directly conjugated to AB in the absence of a sortase recognition sequence motif; d is the drug payload; p is an integer in the range of 1 to 5; Each R 11 is independently an amino acid side chain; x is an integer in the range of 1 to 8.
  5. 5. The antibody-drug conjugate of any preceding claim, wherein L 3 comprises a self-sacrificing group.
  6. 6. The antibody-drug conjugate of claim 4 or 5 having the structure (1 b) (1b) Wherein: AB is a cell binding agent, such as an antibody; n is an integer in the range of 5 to 8; L 1 is a linker; l 2 is a linker; a and b are independently 0 or 1; Z is a linking group obtained by a metal-free click reaction or by thiol conjugation or by transglutaminase-mediated deamidation; or Z is absent, wherein a and b are 0, and the N-terminus of the polyglycine is directly bonded to AB in the absence of a sortase recognition sequence motif; d is the drug payload; p is an integer in the range of 0 to 5; Each R 11 is independently an amino acid side chain; a is an optionally substituted 5-or 6-membered aromatic or heteroaromatic ring; R 21 is selected from H, R 22 , C (O) OH and C (O) R 22 , wherein R 22 is C 1 -C 24 (hetero) alkyl, C 3 -C 10 (hetero) cycloalkyl, C 2 -C 10 (hetero) aryl, C 3 -C 10 alkyl (hetero) aryl and C 3 -C 10 (hetero) arylalkyl, optionally substituted with and optionally interrupted by one or more heteroatoms selected from O, S and NR 23 , wherein R 23 is independently selected from the group consisting of hydrogen and C 1 -C 4 alkyl, X is an integer in the range of 1 to 8.
  7. 7. The antibody-drug conjugate of any preceding claim, wherein the peptide (NH-CR 11 -CO) p is selected from Val-Cit、Glu-Val-Cit、Val-Ala、Val-Lys、Val-Arg、Aclys-Val-Cit、Aclys-Val-Ala、Glu-Val-Ala、Asp-Val-Ala、Phe-Gly、Phe-Cit、Phe-Ala、Phe-Lys、Phe-Arg、Ala-Lys、Leu-Cit、Ile-Cit、Trp-Cit、Ala-Ala-Asn、Asn-Asn、Ala-Asn and Lys at each occurrence, optionally selected from Val-Cit, glu-Val-Cit, val-Ala, glu-Val-Ala, val-Lys, phe-gly, phe-Cit, phe-Ala, phe-Lys, ala-Asn, optionally Val-Cit or Val-Ala.
  8. 8. The antibody-drug conjugate of any preceding claim, wherein the linking group Z is obtainable by a metal-free click reaction and comprises a triazole moiety or the group Z is obtainable by thiol conjugation comprising a succinimidyl ring or a ring-opened succinamide derivative thereof.
  9. 9. The antibody-drug conjugate of any preceding claim having the structure (1 c) (1c) Z, L 2 、L 3 , D, b, c, n and x are as defined in any preceding claim; e is an integer in the range of 0 to 20; Su is a monosaccharide; g is a monosaccharide moiety; GlcNAc is an N-acetylglucosamine moiety; fuc is a fucose moiety; m is 0 or 1.
  10. 10. The antibody-drug conjugate of any preceding claim, wherein L 2 does not comprise a (poly) ethylene glycol linker.
  11. 11. The antibody-drug conjugate of any preceding claim, wherein L 2 is selected from- (CR 1 R 2 )y-、-(CR 1 R 2 ) y-C (O) -and-C (O) - (CR 1 R 2 ) y-C (O) -, wherein y is an integer in the range of 0 to 6, wherein one or more CR 1 R 2 can be optionally replaced by NR 1 , R 1 and R 2 are independently selected from H, R 2a , C (O) OH and C (O) R 2a , wherein R 2a is selected from optionally substituted C 1 -C 6 (hetero) alkyl, C 3 -C 10 (hetero) cycloalkyl, C 6 -C 10 (hetero) aryl, C 7 -C 14 alkyl (hetero) aryl and C 7 -C 14 (hetero) arylalkyl.
  12. 12. A method for synthesizing the antibody-drug conjugate of any one of claims 1 to 11, comprising reacting (I) A modified antibody having the structure AB- ((L 1 ) a -F) x, wherein: AB is a cell binding agent, such as an antibody; L 1 is a linker; a is 0 or 1; F is a click probe capable of reacting with Q in a metal-free click reaction, or a thiol or precursor thereof, or an acyl donor capable of reacting with Q in transglutaminase-mediated transamidation; x is an integer in the range of 1 to 8; And (3) with Linker-drug construct according to structure (5): Wherein: Q is a click probe capable of a metal-free click reaction, or a thiol-reactive probe, or an acyl acceptor probe capable of reacting with an acyl donor F in transglutaminase-mediated transamidation; L 2 、L 3 , D, n, b and c are as defined in any preceding claim; To form an antibody-drug conjugate, wherein the drug is covalently linked to the antibody via a linking group Z formed by a metal-free click reaction between Q and F, or by thiol-binding between Q and F, or by transglutaminase-mediated transamidation between Q and F.
  13. 13. The method of claim 12, wherein the click probe Q comprises a cycloalkyne moiety, a cycloalkene moiety, or a tetrazine moiety.
  14. 14. The method of claim 12, wherein the thiol-reactive probe Q comprises or is a maleimide moiety.
  15. 15. The method according to any one of claims 12 to 14, wherein the click probe F is selected from the group consisting of azide, tetrazine, triazine, nitrone, nitrile oxide, nitrilimine, diazo compound, o-quinone, dioxythiophene, sydney ketone, alkyne and cyclic olefin, the click probe F preferably being an azide moiety, and/or wherein the click reaction is a1, 3-dipolar cycloaddition or a (4+2) cycloaddition, or F is a thiol, and/or wherein the thiol conjugation is a Michael addition or a nucleophilic substitution.
  16. 16. The method of any one of claims 12 to 15, wherein AB- ((L 1 ) a-F) x is according to structure (6): (6) Wherein F and x are as defined in any preceding claim; e is an integer in the range of 0 to 10; Su is a monosaccharide; g is a monosaccharide moiety; GlcNAc is an N-acetylglucosamine moiety; fuc is a fucose moiety; m is 0 or 1.
  17. 17. A linker-drug construct according to structure (5): (5) Wherein: Q is a click probe capable of a metal-free click reaction, or a thiol-reactive probe, or an acyl acceptor probe capable of reacting with an acyl donor F in transglutaminase-mediated transamidation; l 2 、L 3 , D, n, b and c are as defined in any preceding claim.
  18. 18. The linker-drug construct of claim 17 wherein the click probe Q comprises a cycloalkyne moiety, a cycloalkene moiety, or a tetrazine moiety.
  19. 19. The linker-drug construct of claim 17 wherein the thiol-reactive probe Q comprises or is a maleimide moiety.
  20. 20. A pharmaceutical composition comprising the antibody-drug conjugate of any one of claims 1 to 11 and a pharmaceutically acceptable carrier.

Description

Antibody-drug conjugates Technical Field The present invention relates to the field of antibody-drug conjugates, in particular to antibody-drug conjugates with a polyglycine linker. Background Antibody-drug conjugates (ADCs) are essentially targeted delivery of active drugs to a particular cell site of choice, and are an effective method for treating a variety of diseases, with many beneficial aspects compared to systemic delivery of the same drug. In the ADC field, chemical linkers are typically employed to attach drugs to antibodies. Such linkers are required to possess a number of key properties, including the requirement that they remain stable in plasma for a long period of time after drug administration. The stable linker is capable of localizing the ADC to a desired site or cell in the body and preventing premature release of the payload in the circulation, which would indifferently induce a variety of undesired biological responses, thereby reducing the therapeutic index of the ADC. After internalization, the ADC should be processed to effectively release the payload so that it can bind to its target. Disclosure of Invention The inventors have surprisingly found that linkers with a polyglycine system are well suited for use in metal-free click-reaction chemistry or thiol conjugation, or transglutaminase-mediated transamidation, to conjugate a drug payload to an antibody, resulting in an antibody-drug conjugate that exhibits no or negligible aggregation propensity. The resulting ADCs were found to exhibit significant in vivo efficacy. Thus, the inventors were able for the first time to prepare an ADC with a payload that exhibited efficacy on the same order of magnitude as the most effective antibody-drug conjugates known to date, in particular the antibody-isatecan (exatecan) conjugate, while showing no aggregation at all. The resulting ADCs were also found to exhibit improved conjugation efficiency. The present invention relates firstly and most importantly to an antibody-drug conjugate having structure (1) (1) Wherein: AB is a cell binding agent, such as an antibody; n is an integer in the range of 5 to 8; L 1 is a linker; l 2 is a linker; L 3 is a linker; a. b and c are independently 0 or 1; Z is a linking group obtained by a metal-free click reaction or by thiol conjugation or by transglutaminase-mediated deamidation; or Z is absent, wherein a and b are 0, and the N-terminus of the polyglycine is directly bonded to AB in the absence of a sortase recognition sequence motif; d is the drug payload; x is an integer in the range of 1 to 8. The invention further relates to a method for synthesizing an antibody-drug conjugate according to the invention, a linker-drug construct suitable for use in the method according to the invention, a medical use of an antibody-drug conjugate according to the invention, and a pharmaceutical composition comprising an antibody-drug conjugate according to the invention. Detailed Description Definition of the definition The verb "to comprise" and its conjugations as used in this specification and in the claims is used in its non-limiting sense to mean that items following the word are included, but items not specifically mentioned are not excluded. Furthermore, reference to an element by the indefinite article "a" or "an" does not exclude the possibility that more than one of the element is present, unless the context clearly requires that there be one and only one of the elements. The indefinite article "a" or "an" thus generally means "at least one of". The compounds disclosed in the present specification and claims may contain one or more asymmetric centers and the compounds may exist in different diastereomers and/or enantiomers. Unless otherwise indicated, the description of any compound in this specification and claims is intended to include all diastereomers and mixtures thereof. In addition, unless otherwise indicated, the description of any compound in this specification and claims is intended to include individual enantiomers, as well as any mixtures of enantiomers (racemic or otherwise). While the structure of the compounds is depicted as a particular enantiomer, it is to be understood that the application is not limited to that particular enantiomer. The compounds may exist in different tautomeric forms. Unless otherwise indicated, compounds according to the application are intended to include all tautomeric forms. Where the structure of a compound is depicted as a particular tautomer, it is to be understood that the application is not limited to that particular tautomer. The compounds disclosed in the present specification and claims may further exist in the form of R and S stereoisomers. Unless otherwise indicated, the description of any compound in this specification and claims is intended to include the individual R stereoisomers and the individual S stereoisomers of the compound, as well as mixtures thereof. While the structure of the compounds is depicte