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EP-4735049-A1 - BIOACTIVE CONJUGATES, PREPARATION METHOD AND USE THEREOF

EP4735049A1EP 4735049 A1EP4735049 A1EP 4735049A1EP-4735049-A1

Abstract

Compounds of formula (Ia) are provided, wherein Conjugator is a group capable of bonding a BA and joining the BA to the rest of the compound, Cleavable and Linker together include at least one site for enzymatic cleavage and provide distance between Conjugator and Payload, Payload is a cytotoxic agent, and BA is a binding agent selected from a humanized, monoclonal, chimeric, or human antibody or an antigen-binding fragment thereof.

Inventors

  • TSAI, Charng-Sheng
  • TSAI, Mei-Hsuan
  • WEI, Xiaodong
  • LUO, WEI
  • WU, LIMING

Assignees

  • Beone Medicines I GmbH

Dates

Publication Date
20260506
Application Date
20240628

Claims (20)

  1. A compound of formula (Ia) : or a pharmaceutically acceptable salt, tautomer, solvate, or stereoisomer thereof, wherein: BA is a binding agent selected from a humanized, monoclonal, chimeric, or human antibody or an antigen-binding fragment thereof; Conjugator has formula (II) or (III) : wherein: U is a bond, heteroarylene, or arylene; V is a bond or -C≡C- (CH 2 ) n -; n is an integer between 0 and 10 inclusive; W 2 is -C (=O) -, -NH-, or -O-; RG is - (succinimid-3-yl-N) -, or RS is -NR 1a R 1b ; each of R 1a and R 1b is, independently, H or substituted or unsubstituted C 1-4 alkyl; RE is a bond, -O-, -OC (=O) -, -OC (=O) NR 6 -, –NHC (=O) NR 6 -, -OS (=O) 2 NR 6 -, -NHS (=O) 2 NR 6 -, or -OC (=O) NHS (=O) 2 NR 6 -; R 6 is H or substituted or unsubstituted C 1-4 alkyl; W 3 is -C (=O) -, -NH-, or -O-; each of s and t is, independently, 1 or 2; indicates a point of covalent attachment within the compound, and *marks the bond where Conjugator connects to BA; Linker has formula (IV) : wherein: HG is a hydrophilic residue, and **marks the bond where Linker connects to Conjugator; Cleavable has formula (V) : wherein: each R 2 is independently hydrogen, a halogen, substituted or unsubstituted C 1-4 alkyl, -CN, or -NO 2 , and ****marks the bond where Cleavable connects to Linker; Payload is a payload residue; and x is from 1 to 15 inclusive.
  2. The compound of claim 1, wherein Cleavable has the following formula:
  3. A compound of Formula (Ib) : or a pharmaceutically acceptable salt, tautomer, solvate, or stereoisomer thereof, wherein: BA is a binding agent selected from a humanized, monoclonal, chimeric, or human antibody or an antigen-binding fragment thereof; Conjugator has formula (II) or (III) : wherein: U is a bond, heteroarylene, or arylene; V is a bond or -C≡C- (CH 2 ) n -; n is an integer between 0 and 10 inclusive; W 2 is -C (=O) -, -NH-, or -O-; RG is - (succinimid-3-yl-N) -, or RS is -NR 1a R 1b ; each of R 1a and R 1b is, independently, H or substituted or unsubstituted C 1-4 alkyl; RE is a bond, -O-, -OC (=O) -, -OC (=O) NR 6 -, -NHC (=O) NR 6 -, -OS (=O) 2 NR 6 -, -NHS (=O) 2 NR 6 -, or –OC (=O) NHS (=O) 2 NR 6 -; R 6 is H or substituted or unsubstituted C 1-4 alkyl; W 3 is -C (=O) -, -NH-, or -O-; each of s and t is, independently, 0, 1, or 2; indicates a point of covalent attachment within the compound, and *marks the bond where Conjugator connects to BA; Cleavable has formula (Va) , (Vb) , or (Vc) : wherein: each R 2 is, independently, hydrogen, halogen, substituted or unsubstituted C 1-4 alkyl, -CN, or -NO 2 , ***marks the bond where Cleavable connects to Conjugator, and ****marks the bond where Cleavable connects to Linker; Linker has formula (IV’) : wherein HG is a hydrophilic residue, and **! marks the bond where Linker connects to Cap; Cap is CH 3 C (=O) -, CH 3 - (CH 2 ) b -O- (CH 2 CH 2 O) a - (CH 2 CH 2 ) d -C (=O) -, CH 3 - (CH 2 ) b -O- (CH 2 CH 2 O) a - (CH 2 CH 2 ) d -NH-C (=O) -, CH 3 (C (=O) N (CH 3 ) CH 2 ) a C (=O) -, -NH- (CH 2 CH 2 O) a - (CH 2 ) b CH 3 , or – (N (CH 3 ) (CH 2 ) c C (=O) ) a NH 2 , wherein: a is an integer between 1 and 18 inclusive, each of b and d is, independently, 0, 1, or 2, and c is an integer between 1 and 4 inclusive; Payload is a payload residue; and x is from 1 to 15 inclusive.
  4. The compound of claim 3, wherein Cleavable has one of the following formulas:
  5. The compound of claim 3 or 4, wherein Cap is CH 3 C (=O) -, CH 3 - (CH 2 ) b -O- (CH 2 CH 2 O) a - (CH 2 CH 2 ) d -C (=O) -, or CH 3 (C (=O) N (CH 3 ) CH 2 ) a C (=O) -.
  6. The compound of claim 5, wherein Cap is CH 3 C (=O) -CH 3 -O- (CH 2 CH 2 O) 11 - (CH 2 CH 2 ) -C (=O) -, or -CH 3 (C (=O) N (CH 3 ) CH 2 ) 12 C (=O) -.
  7. A compound of Formula (Ic) : or a pharmaceutically acceptable salt, tautomer, solvate, or stereoisomer thereof, wherein: BA is a binding agent selected from a humanized, monoclonal, chimeric, or human antibody or an antigen-binding fragment thereof; Conjugator is has formula (II) or (III) : wherein; U is a bond, heteroarylene, or arylene; V is a bond or -C≡C- (CH 2 ) n -; n is an integer between 0 and 10 inclusive; W 2 is -C (=O) -, -NH-, or -O-; RG is - (succinimid-3-yl-N) -, or RS is an amino group or -NR 1a R 1b ; each of R 1a and R 1b is, independently, H or substituted or unsubstituted C 1-4 alkyl; RE is a bond, -O-, -OC (=O) -, -OC (=O) NR 6 -, -NHC (=O) NR 6 -, -OS (=O) 2 NR 6 -, -NHS (=O) 2 NR 6 -, or –OC (=O) NHS (=O) 2 NR 6 -; R 6 is H or substituted or unsubstituted C 1-4 alkyl; W 3 is -C (=O) -, -NH-, or -O-; each of s and t is, independently, 0, 1, or 2; indicates a point of covalent attachment within the compound, and *marks the bond where Conjugator connects to BA; Linker has formula (IV) : wherein: HG is a hydrophilic residue, and; **marks the bond where Linker connects to Conjugator; Cleavable has formula (Va’) , (Vb’) , or (Vc’) : wherein: each R 2 is, independently, hydrogen, halogen, substituted or unsubstituted C 1-4 alkyl, -CN, or -NO 2 , ***! marks the bond where Cleavable connects to Cap, and ****marks the bond where Cleavable connects to Linker; Cap is CH 3 C (=O) -, CH 3 - (CH 2 ) b -O- (CH 2 CH 2 O) a - (CH 2 CH 2 ) d -C (=O) -, -C (=O) - (CH 2 CH 2 O) a - (CH 2 ) b CH 3 , CH 3 (C (=O) N (CH 3 ) CH 2 ) a C (=O) -, -NH- (CH 2 CH 2 O) a - (CH 2 ) b CH 3 , or – (N (CH 3 ) (CH 2 ) c C (=O) ) a NH 2 ; a is an integer between 1 and 18 inclusive; each of b and d, independently, is 0, 1, or 2; c is an integer between 1 and 4 inclusive; Payload is a payload residue; and x is from 1 to 15 inclusive.
  8. The compound of claim 7, wherein Cleavable has one of the following formulas:
  9. The compound of claim 7 or 8, wherein Cap is -NH- (CH 2 CH 2 O) a - (CH 2 ) b CH 3 or – (N (CH 3 ) (CH 2 ) c C (=O) ) a NH 2 .
  10. The compound of claim 9, wherein Cap is -NH- (CH 2 CH 2 O) 12 -CH 3 or – (N (CH 3 ) CH 2 C (=O) ) 12 NH 2 .
  11. A compound of Formula (Id) : or a pharmaceutically acceptable salt, tautomer, solvate, or stereoisomer thereof, wherein: BA is a binding agent selected from a humanized, monoclonal, chimeric, or human antibody or an antigen-binding fragment thereof; Conjugator is has formula (II) or (III) : wherein: U is a bond, heteroarylene, or arylene; V is a bond or -C≡C- (CH 2 ) n -; n is an integer between 0 and 10 inclusive; W 2 is -C (=O) -, -NH-, or -O-; RG is - (succinimid-3-yl-N) -, or RS is -NR 1a R 1b ; each of R 1a and R 1b is, independently, H or substituted or unsubstituted C 1-4 alkyl; RE is a bond, -O-, -OC (=O) -, -OC (=O) NR 6 -, -NHC (=O) NR 6 -, -OS (=O) 2 NR 6 -, -NHS (=O) 2 NR 6 -, or –OC (=O) NHS (=O) 2 NR 6 -; R 6 is H or substituted or unsubstituted C 1-4 alkyl; W 3 is -C (=O) -, -NH-, or -O-; each of s and t is, independently, 0, 1, or 2; indicates a point of covalent attachment within the compound, and *marks the bond where Conjugator connects to BA; Linker has formula (IV’) : wherein: HG is a hydrophilic residue, and **! marks the bond where Linker connects to Cap; Cleavable has formula (Va”) , (Vb”) , or (Vc”) : wherein: each R 2 is, independently, hydrogen, halogen, substituted or unsubstituted C 1-4 alkyl, -CN, or -NO 2 , *** marks the bond where Cleavable connects to Brancher, and ****marks the bond where Cleavable connects to Linker; Cap is CH 3 C (=O) -, CH 3 - (CH 2 ) b -O- (CH 2 CH 2 O) a - (CH 2 CH 2 ) d -C (=O) -, -C (=O) - (CH 2 CH 2 O) a - (CH 2 ) b CH 3 , CH 3 (C (=O) N (–H 3 ) CH 2 ) a C (=O) -, -NH- (CH 2 CH 2 O) a - (CH 2 ) b CH 3 , or - (N (CH 3 ) (CH 2 ) c C (=O) ) a NH 2 , wherein a is an integer between 1 and 18 inclusive; each of b and d is, independently, 0, 1, or 2, and c is an integer between 1 and 4 inclusive; Brancher has formula (XIIa) , (XIIa1) , (XIIb) or (XIIb1) : wherein: hydrophile is -NH- (CH 2 CH 2 O) a1 - (CH 2 ) b1 CH 3 , –-C (=O) NH 2 , -C (=O) - (CH 2 CH 2 O) a1 - (CH 2 ) b1 CH 3 , or - (N (CH 3 ) (CH 2 ) c1 C (=O) ) a1 NH 2 , marks the bond where Brancher connects to Conjugator, marks the bond where Brancher connects to Cleavable, a1 is an integer between 1 and 18 inclusive, b1 is 0, 1, or 2; and each of c1, p, and q is, independently, an integer between 1 and 4 inclusive, Payload is a payload residue; and x is from 1 to 15.
  12. The compound of claim 11, wherein Cleavable has one of the following formulas:
  13. The compound of claim 11 or 12, wherein a1 is 12, b1 is 0, c1 is 1, p is 2, and q is 2 or 4.
  14. The compound of any one of claims 11 to 13, wherein Brancher has one of the following formulas:
  15. The compound of any one of claims 11 to 14, wherein hydrophile is -C (=O) - (CH 2 CH 2 O) a1 -CH 3 or - (N (CH 3 ) -CH 2 -C (=O) ) a1 NH 2 , and a1 is an integer between 10 and 16 inclusive.
  16. The compound of claim 15, wherein a1 is 12.
  17. The compound of any one of claims 11 to 16, wherein Cap is CH 3 C (=O) -.
  18. The compound of any one of claims 1-17, wherein Conjugator has formula (II) .
  19. The compound of claim 18, wherein U is arylene.
  20. The compound of claim 19, wherein U is phenylene.

Description

BIOACTIVE CONJUGATES, PREPARATION METHOD AND USE THEREOF CROSS REFERENCE TO RELATED APPLICATION This application claims priority to International Application No. PCT/CN2023/104058, filed June 29, 2023, the disclosure of which is hereby incorporated by reference in its entirety FIELD Provided herein are antibody drug conjugate platforms and antibody drug conjugates (ADCs) comprising the platforms and an antibody, or antigen-binding fragment thereof, as well as uses of the ADC platforms and ADCs. SEQUENCE LISTING This application contains a Sequence Listing, which has been submitted electronically in XML format. The XML file is entitled “01368-0075-00PCT-ST26. xml, ” was created on June 20, 2024, and is 8, 226 bytes in size. The Sequence Listing is incorporated herein by reference in its entirety. BACKGROUND Antibody-drug conjugates (ADC) include an antibody against a tumor antigen linked to a biologically active small molecule such as a toxin or payload (i.e., a drug) . ADCs selectively deliver the payload to cells expressing the tumor antigen. The payload monomethyl auristatin E (MMAE) is an antimitotic agent that inhibits cell division. ADCs including MMAE can be highly hydrophobic, leading to aggregation of ADCs with high drug-to-antibody ratios (DAR) and non-specific uptake of the ADCs. ADCs including MMAE can be unstable, leading to deconjugation, premature payload release, poor pharmacokinetic profiles, and off-target effects. ADCs employing other payloads can suffer from the same deficiencies. The linker component of ADCs, including the portion that directly conjugates with an antibody, is one important feature in developing optimized therapeutic agents that are highly active at well-tolerated doses. The electrophilic maleimide functional group has been used to join linkers with a free thiol of an antibody. In vivo, the conjugation product is subject to slow elimination, thus reversing the conjugation reaction and leaving the maleimide of an ADC free to transfer to any other available thiol, including those from serum albumin in plasma. There is an ongoing need for the development of new linkers for use with MMAE and other payloads in ADCs that would resist deconjugation and premature payload release, and allow for increased DAR, increased stability in circulation, improved pharmacokinetics, and improved efficacy. The present disclosure satisfies these needs. BRIEF SUMMARY Provided herein are antibody drug conjugate platforms and antibody drug conjugates (ADCs) . Also provided are uses of the ADC platforms to prepare ADCs. In some embodiments, provided herein are ADC compounds of formula (Ia) : or a pharmaceutically acceptable salt, tautomer, solvate, or stereoisomer thereof, wherein: BA is a binding agent selected from a humanized, monoclonal, chimeric, or human antibody or an antigen-binding fragment thereof; Conjugator is selected from formula (II) and (III) : wherein: U is a bond, heteroarylene, or arylene; V is a bond or -C≡C- (CH2) n-; n is an integer between 0 and 10 inclusive; W2 is -C (=O) -, -NH-, or -O-; RG is- (succinimid-3-yl-N) -, or RS is -NR1aR1b; each of R1a and R1b is, independently, H or substituted or unsubstituted C1-4 alkyl; RE is a bond, -O-, -OC (=O) -, -OC (=O) NR6-, -NHC (=O) NR6-, -OS (=O) 2NR6-, -NHS (=O) 2NR6-, or -OC (=O) NHS (=O) 2NR6-; R6 is H or substituted or unsubstituted C1-4 alkyl; W3 is -C (=O) -, -NH-, or -O-; each of s and t is, independently, 1 or 2; indicates a point of covalent attachment within the compound, and *marks the bond where Conjugator connects to BA; Linker has formula (IV) : wherein: HG is a hydrophilic residue, and **marks the bond where Linker connects to Conjugator; Cleavable has formula (V) : wherein: each R2 is independently hydrogen, a halogen, substituted or unsubstituted C1-4 alkyl, -CN, or -NO2, and ****marks the bond where Cleavable connects to Linker; Payload is a payload residue; and x is from 1 to 15 inclusive. In some embodiments, provided herein are ADC compounds of formula (Ib) : or a pharmaceutically acceptable salt, tautomer, solvate, or stereoisomer thereof, wherein: BA is a binding agent selected from a humanized, monoclonal, chimeric, or human antibody or an antigen-binding fragment thereof; Conjugator is selected from formula (II) and (III) : wherein: U is a bond, heteroarylene, or arylene; V is a bond or -C≡C- (CH2) n-; n is an integer between 0 and 10 inclusive; W2 is -C (=O) -, -NH-, or -O-; RG is- (succinimid-3-yl-N) -, or RS is -NR1aR1b; each of R1a and R1b is, independently, H or substituted or unsubstituted C1-4 alkyl; RE is a bond, -O-, -OC (=O) -, -OC (=O) NR6-, -NHC (=O) NR6-, -OS (=O) 2NR6-, -NHS (=O) 2NR6-, or –OC (=O) NHS (=O) 2NR6-; R6 is H or substituted or unsubstituted C1-4 alkyl; W3 is -C (=O) -, -NH-, or -O-; each of s and t is, independently, 0, 1, or 2; indicates a point of covalent attachment within the compound, and *marks the bond where Conjugator connects to BA; Cleavable has formula (Va) , (Vb) , or