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US-20260124317-A2 - Antibody Drug Conjugates

US20260124317A2US 20260124317 A2US20260124317 A2US 20260124317A2US-20260124317-A2

Abstract

Antibody-drug conjugate compounds comprising a linker and methods of using such compounds are provided.

Inventors

  • Charng-Sheng Tsai
  • Mei-Hsuan TSAI
  • Xiaodong Wei
  • Zewei Wang
  • Wei Luo
  • Ce Wang

Assignees

  • BEONE MEDICINES I GMBH

Dates

Publication Date
20260507
Application Date
20240627

Claims (20)

  1. 1 . A compound, wherein the compound is a compound of Formula (I): or a pharmaceutically acceptable salt tautomer, solvate, stereoisomer, enantiomer, isotopologue, or prodrug thereof, wherein BA is a binding agent selected from a humanized, chimeric, or human antibody or an antigen binding antibody fragment of an antibody; L is a covalent linker; PA is a payload residue; and subscript x is from 1 to 30.
  2. 2 - 10 . (canceled)
  3. 11 . A compound, wherein the compound is a compound of Formula (IIa), (IIb), or (IIc): or a pharmaceutically acceptable salt tautomer, solvate, stereoisomer, enantiomer, isotopologue, or prodrug thereof, wherein: RG 1 is a reactive group residue; RG 2 is an optional reactive group residue; SP 1 and SP 2 are independently, in each instance, an optional spacer group residue; HG is a hydrophilic residue; PAB is an optional self-immolative unit; subscript p is 0 or 1; AA 2 comprises formula (W) and AA 3 is a dipeptide residue of-valine-alanine-, -valine-citrulline-, or wherein R 6 is —CH 3 , or —(CH 2 ) 3 —NHC(═O)NH 2 ; or AA 3 is a tetrapeptide residue of-glycine-glycine-phenylalanine-glycine- or or a pharmaceutically acceptable salt tautomer, solvate, stereoisomer, enantiomer, isotopologue, or prodrug thereof, wherein: RG 1 is a reactive group residue; RG 2 is an optional reactive group residue; SP 1 and SP 2 are independently, in each instance, an optional spacer group residue; HG is a hydrophilic residue; PAB is an optional self-immolative unit; subscript p is 0 or 1; AA 2 comprises formula (W): and AA 1 is a dipeptide residue of-valine-alanine-, -valine-citrulline-, or wherein R 6 is —CH 3 , or —(CH 2 ) 3 —NHC(═O)NH 2 ; or AA 1 is a tetrapeptide residue of -glycine-glycine-phenylalanine-glycine- or or a pharmaceutically acceptable salt tautomer, solvate, stereoisomer, enantiomer, isotopologue, or prodrug thereof, wherein: RG 1 is a reactive group residue; SP 1 is an optional spacer group residue; PAB is an optional self-immolative unit; subscript p is 0 or 1; PA is a payload residue; and AA 3 is a dipeptide residue of-valine-alanine-, -valine-citrulline-, or wherein R 6 is —CH 3 , or —(CH 2 ) 3 —NHC(═O)NH 2 ; or AA 3 is a tetrapeptide residue of-glycine-glycine-phenylalanine-glycine- or
  4. 12 . The compound of claim 11 , wherein the compound is a compound of Formula (IIa): or a pharmaceutically acceptable salt tautomer, solvate, stereoisomer, enantiomer, isotopologue, or prodrug thereof.
  5. 13 . The compound of claim 11 , wherein the compound is a compound of Formula (IIb): or a pharmaceutically acceptable salt tautomer, solvate, stereoisomer, enantiomer, isotopologue, or prodrug thereof.
  6. 14 . The compound of claim 11 , wherein the compound is a compound of Formula (IIc): or a pharmaceutically acceptable salt tautomer, solvate, stereoisomer, enantiomer, isotopologue, or prodrug thereof.
  7. 15 . The compound of claim 11 , wherein RG 1 is
  8. 16 . The compound claim 11 , wherein RG 1 is wherein EWG is an electron withdrawing group selected from the group consisting of —CN, halogen, —CF 3 , —C(═O)OR 1 , and —C(═O)R 1 , and R 1 is substituted or unsubstituted alkyl, substituted or unsubstituted cycloalkyl, substituted or unsubstituted aryl, substituted or unsubstituted heterocycloalkyl, or substituted or unsubstituted heteroaryl.
  9. 17 . The compound of claim 11 , wherein RG 1 is
  10. 18 . The compound of claim 11 , wherein RG 1 is wherein EWG is an electron withdrawing group selected from —CN, halogen, —CF 3 , —C(═O)OR 1 , and —C(═O)R 1 , and R 1 is substituted or unsubstituted alkyl, substituted or unsubstituted cycloalkyl, substituted or unsubstituted aryl, substituted or unsubstituted heterocycloalkyl, or substituted or unsubstituted heteroaryl.
  11. 19 . The compound of claim 11 , wherein SP 1 is —(CH 2 ) n1 —C(═O)—, —(CH 2 CH 2 O) n2 —CH 2 CH 2 —C(═O)—, —CH[—(CH 2 ) n3 —COOH]—C(═O)—, —CH 2 —C(═O)—NH—(CH 2 ) n4 —C(═O)—, —CH 2 —C(═O)—NH—(CH 2 ) n3 —C(═O)—NH—(CH 2 ) n4 —C(═O)—, or C(═O)—(CH 2 ) n5 —C(═O)—, wherein each of n1, n2, n3, n4, and n5 independently represents an integer of 1 to 8.
  12. 20 . The compound of claim 11 , wherein SP 2 is —(CH 2 ) n6 —; and n6 represents an integer of 1 to 8.
  13. 21 . The compound of claim 11 , wherein RG 2 is a bond, —C(═O)—NH—, or —NHC(═O)—.
  14. 22 . The compound of claim 11 , wherein HG is wherein each n7 is independently 1-15; each n8 is independently 0 or 1; each n9 is independently 1 or 2; each n10 is independently an integer of 4 to 16; each n11 is independently an integer of 0 to 5; n12 is an integer of 0 to 3; d is 0-3; R 2 is H or Me; R 3 is —OH, —NH 2 , —NHCH 2 —CH 2 -(PEG) x -OH, or —NHCH 2 —CH 2 -(PEG) x -OMe; R 4 is OH or NH 2 ; and each of X, Y, and Z is independently —CH 2 —, —NH—, —S— or —O—.
  15. 23 . The compound of claim 11 , wherein HG is —NHSO 2 NH 2 , —SO 3 H, —SO 2 NH 2 , or —PO 3 H 2 , and RG 2 is a bond.
  16. 24 . The compound of claim 11 , wherein PAB represents —NH—CH 2 —O—, formula (Y1): or formula (Y2): wherein the indicates the bond through which the PAB is bonded to the adjacent groups in the formula.
  17. 25 . The compound of claim 11 , wherein each PA independently represents formula (D1): wherein each of R 4 , R 5a , and R 5b is independently hydrogen, sugar residue, substituted or unsubstituted inorganic or organic acid residue, substituted or unsubstituted C 1-8 alkyl, substituted or unsubstituted cycloalkyl, substituted or unsubstituted non-aromatic heterocyclyl, substituted or unsubstituted cycloalkylalkyl, or substituted or unsubstituted heterocyclylalkyl; or R 5a and R 5b together with the atoms to which they are attached, form a substituted or unsubstituted cycloalkyl or substituted or unsubstituted non-aromatic heterocyclyl.
  18. 26 . The compound of claim 11 , wherein each PA independently represents formula (D2): wherein ring B is a substituted or unsubstituted cycloalkyl, substituted or unsubstituted aryl, substituted or unsubstituted heterocyclyl, or substituted or unsubstituted heteroaryl.
  19. 27 . The compound of claim 11 , wherein each PA independently represents formula (E1): wherein each of R 7 and R 8 is, independently, hydrogen, halogen, or alkyl.
  20. 28 . (canceled)

Description

1. CROSS-REFERENCE TO RELATED APPLICATIONS This application is a continuation of International Application No. PCT/CN2022/142310, filed on Dec. 27, 2022, which claims priority to International Application No. PCT/CN2022/088762, filed on Apr. 24, 2022, International Application No. PCT/CN2022/086931, filed on Apr. 14, 2022, and International Application No. PCT/CN2021/142037, filed on Dec. 28, 2021, the disclosures of each of which are hereby incorporated by reference in their entireties. 2. FIELD Provided herein are novel proteins, e.g., antibody, drug conjugates comprising hydrophilic solubilizing groups and/or linkers comprising hydrophilic solubilizing groups, and methods for treating diseases, disorders, and conditions comprising administering the protein drug conjugates comprising hydrophilic solubilizing groups and/or linkers thereof. 3. SEQUENCE LISTING The instant application contains a Sequence Listing, which has been submitted electronically in XML format and is hereby incorporated by reference in its entirety. Said XML copy, created on Dec. 22, 2022, is named “BGB36201-01PCT_Seql.xml” and is 10,403 bytes in size. 4. BACKGROUND Antibody-drug conjugates (ADCs) are antibodies that are operably linked to a biologically active small molecule, also known as a toxin or payload. ADCs deliver a potent payload selectively to target-expressing cells, leading to a potential reduction of off-target side effects and/or toxicity and improved therapeutic index. The lipophilic nature of many payloads (i.e., drugs) can adversely affect the properties of the ADC to the extent that the payloads are not efficiently delivered to the target cells. Low bioavailability of lipophilic payloads can narrow therapeutic windows for ADC treatment. Furthermore, the hydrophobic nature of payloads can present challenges to their conjugation to antibodies, a reaction performed in aqueous conditions. Thus, there is an ongoing need for the development of hydrophilic linkers for protein conjugates, e.g., ADCs, which would allow for the feasibility of conjugating lipophilic payloads, improved modulation of biological targets, improved bioavailability, and improved therapeutic window. Monoclonal antibody (mAb) therapies are gaining momentum as an adjunct and front-line treatments for cancer. Successes of mAb therapies like AVASTIN™ (anti-VEGF) for colon cancer, RITUXAN™ (Rituximab; anti-CD20) for Non-Hodgkin's Lymphoma and HERCEPTIN™ (anti-Her2) for breast cancer have demonstrated that unconjugated antibodies can improve patient survival without the incidence of significantly increased toxicity. Monoclonal antibodies can be conjugated to a therapeutic agent to form an antibody-drug conjugate. For example, the HERCEPTIN™ antibody mentioned above was conjugated with a maytansine payload to form the ADC KADCYLA™. ADCs can exhibit increased efficacy, as compared to an unconjugated antibody. The linkage of the antibody to the drug can be direct, or indirect via a linker. The linker can be cleavable or non-cleavable. One of the components believed to be important for developing effective and well-tolerated ADCs is the composition and stability of the linker. For some types of ADCs, the linker desirably provides serum stability, yet selectively releases the drug within the target cell. Attachment of a linker to a mAb can be accomplished in a variety of ways, such as through surface lysines, reductive coupling to oxidized carbohydrates, and through cysteine residues liberated by reducing interchain disulfide linkages. A variety of ADC linkage systems have been described in the literature, including hydrazone, disulfide, and peptide-based linkages. Some hydrazone and disulfide-based linkers can be labile in circulation, resulting in the undesired release of the drug outside the targeted tissue. It is believed that this premature release of drug can lead to systemic toxicity or organ-specific toxicity and/or less than optimal therapeutic efficacy. Peptide-based linker strategies can provide linkers of higher stability; however, the increased associated hydrophobicity of some linkers can lead to aggregation, particularly with strongly hydrophobic drugs. Such aggregation can lead to a number of undesired effects such as precipitation of the ADC, difficulty in administration, and non-specific uptake of the ADCs into non-targeted tissues, potentially affecting non-target toxicity and reducing efficacy. Exatecan is a drug which is a structural analog of camptothecin with antineoplastic activity. See Abou-Alfa et al., “Randomized Phase III Study of Exatecan and Gemcitabine Compared with Gemcitabine Alone in Untreated Advanced Pancreatic Cancer,” Journal of Clinical Oncology, 24 (27): 4441-7, Sep. 20, 2006. Monomethyl auristatin E (MMAE) is a synthetic antineoplastic agent. Because of its toxicity, it cannot be used as a drug itself. MMAE is actually desmethyl-auristatin E; that is, the N-terminal amino group has only one methyl substituent instead of t