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EP-4736883-A1 - CONJUGATE FOR PREVENTING AND TREATING VIRAL INFECTION AND USE THEREOF

EP4736883A1EP 4736883 A1EP4736883 A1EP 4736883A1EP-4736883-A1

Abstract

The present invention relates to conjugates for the preventing and treating of viral infections and use thereof, and more specifically to a conjugate of protein and anti-influenza compound of formula I-A or I-B, or a pharmaceutically acceptable salt, ester, isomer, solvate, prodrug, or isotopically labeled compound thereof, wherein each symbol is as defined herein. The conjugates or intermediate compounds of the present invention exhibit significant anti-influenza virus activity, while also have excellent in vitro / in vivo pharmacokinetic properties and safety, indicating high prospects for clinical application.

Inventors

  • SONG, Guowei
  • WU, Jimzhen
  • CHUN, Sophia Siufei
  • SONG, Zhidong
  • PENG, CHENG
  • GAO, Guanglin
  • WU, JIN
  • GAO, Fan
  • GAO, Zhao
  • ZOU, Gang
  • YIE, Junmin

Assignees

  • Shanghai Ark Biopharmaceutical Co. Ltd.

Dates

Publication Date
20260506
Application Date
20240628

Claims (20)

  1. A conjugate represented by structure of Formula I-A or Formula I-B, or a pharmaceutically acceptable salt, ester, isomer, solvate, prodrug, or isotopically labeled compound thereof: wherein, m is 1 or 2; n is an integer from 1 to 20, and preferably an integer of 1, 2, 3, 4, 5, 6, 7, or 8; w is an integer from 0 to 8; for example, 0, 1, 2, 3, 4, or 5; L is a linker; E is selected from an antibody or antibody fragment, Fc domain monomer, Fc domain, Fc binding peptide, albumin, or albumin-binding peptide; each of R 1a , R 2a , R 3a , R 5a , R 6a , R 7a , R 9a and R 10a is independently selected from hydrogen, deuterium, hydroxyl, -O-C 1-6 alkyl, hydroxylC 1-6 alkyl-, C 1-6 alkyl-, C 3-8 cycloalkyl-, C 3-8 heterocycloalkyl-, C 6 -C 15 aryl, 5 to 15-membered heteroaryl, halogen, cyano, and amino; R 1a and R 2a may together form C 3-8 cycloalkyl or C 3-8 heterocycloalkyl; or R 5a and R 6a may together form C 3-8 cycloalkyl or C 3-8 heterocycloalkyl; or R 9a and R 10a may together form C 3-8 cycloalkyl or C 3-8 heterocycloalkyl, wherein said C 3-8 cycloalkyl or C 3-8 heterocycloalkyl may be optionally substituted with a substituent selected from halogen and hydroxyl; each of R 4a and R 8a is independently selected from H, C 1-6 alkyl, C 3-8 cycloalkyl or C 3-8 heterocycloalkyl; x is 1 or 2; y is an integer from 1 to 20, and preferably an integer of 1, 2, 3, 4, 5, 6, 7, or 8; z is an integer from 0 to 8; for example, 0, 1, 2, 3, 4, or 5; q is 0, 1, 2, 3 or 4; each of R 1' , R 2' , R 3' , R 4' and R 5' is independently selected from hydrogen, deuterium, hydroxyl, -O-C 1-6 alkyl, hydroxylC 1-6 alkyl, C 1-6 alkyl, C 3-8 cycloalkyl, C 3-8 heterocycloalkyl, C 6 -C 15 aryl, 5 to 15-membered heteroaryl, halogen, cyano, and amino; or R 1' and R 2' may together form C 3-8 cycloalkyl or C 3-8 heterocycloalkyl; or, two adjacent R 3' may form C 3-8 cycloalkyl, C 3-8 heterocycloalkyl, C 6 -C 15 aryl, or 5 to 15-membered heteroaryl.
  2. The conjugate according to claim 1, or the pharmaceutically acceptable salt, ester, isomer, solvate, prodrug, or isotopically labeled compound thereof, wherein L is a linker represented by the structure of formula I-3a, comprising L 1 and L 2a , the left and right ends of L 1 are linked to the drug moiety, and the upper end of L 2a is linked to - NR 8a , wherein, L 1 is selected from the following structure: wherein, W is selected from O, S, NR b , CH 2- or absence; each of R a and R b is independently selected from H, optionally substituted C 1 -C 20 alkyl, and optionally substituted C 2 -C 20 alkenyl; and preferably selected from H and methyl, and more preferably methyl; each of y 1 and y 2 is independently 0, 1, 2, 3, 4, 5, or 6; preferably, L 1 is selected from the following structures: Structure of L 1
  3. The conjugate according to claim 1 or 2, or the pharmaceutically acceptable salt, ester, isomer, solvate, prodrug, or isotopically labeled compound thereof, wherein L 2a is of the structure of formulas L2-1a to L2-7a: L 2a structure No. Structure Formula L2-1a Formula L2-2a Formula L2-3a Formula L2-4a Formula L2-5a Formula L2-6a Formula L2-7a wherein, Z is selected from NR, S and O; R groups are each independently selected from hydrogen, deuterium, optionally substituted C 1 -C 20 alkyl, optionally substituted C 2 -C 20 alkenyl, optionally substituted C 3 -C 20 cycloalkyl, optionally substituted 3 to 20-membered heterocycloalkyl, optionally substituted C 6 -C 15 aryl, and optionally substituted 5 to 15-membered heteroaryl; s and t are integers from 1 to 20; for example, 1, 2, 3, 4, 5, 6, 7, 8, 9, 10, 11, or 12; and y is 0 or 1.
  4. The conjugate according to any one of claims 1 to 3, or the pharmaceutically acceptable salt, ester, isomer, solvate, prodrug, or isotopically labeled compound thereof, wherein L 2a is selected from Formula L2-1a, L2-5a, and L2-7a, Z is O, R is H, s and t are integers selected from 3 to 10, preferably, s and t are 4 or 8, respectively.
  5. The conjugate according to any one of claims 1 to 4, or the pharmaceutically acceptable salt, ester, isomer, solvate, prodrug, or isotopically labeled compound thereof, wherein the S atom on E comes from the cysteine (cys) residue or disulfide bond in E; preferably, E is an antibody or an antibody fragment thereof, a Fc domain monomer, a Fc domain, a Fc binding peptide, albumin, or an albumin-binding peptide, for example, the Fc domain monomer comprises or consists of any of the amino acid sequences set forth in SEQ ID Nos. 1-81, or an amino acid sequence having at least 95%, 96%, 97%, 98%, or 99% identity thereto; preferably, it comprises or consists of an amino acid sequence selected from any one of SEQ ID NO: 9, SEQ ID NO: 10, SEQ ID NO: 11, SEQ ID NO: 33, SEQ ID NO: 36, SEQ ID NO: 37, SEQ ID NO: 38, SEQ ID NO: 41, SEQ ID NO: 42, SEQ ID NO: 43, SEQ ID NO: 44, SEQ ID NO: 45, SEQ ID NO: 46, SEQ ID NO: 51, SEQ ID NO: 52, SEQ ID NO: 53, SEQ ID NO: 54, SEQ ID NO: 55, SEQ ID NO: 56, SEQ ID NO: 57, SEQ ID NO: 59, SEQ ID NO: 65, SEQ ID NO: 66, SEQ ID NO: 67, SEQ ID NO: 68, SEQ ID NO: 69, SEQ ID NO: 70, SEQ ID NO: 71, and SEQ ID NO: 72.
  6. The conjugate according to any one of claims 1 to 5, or the pharmaceutically acceptable salt, ester, isomer, solvate, prodrug, or isotopically labeled compound thereof, wherein the conjugate is of a structure of formula I-A.
  7. The conjugate according to any one of claims 1 to 5, or the pharmaceutically acceptable salt, ester, isomer, solvate, prodrug, or isotopically labeled compound thereof, wherein the conjugate is of a structure of formula I-B.
  8. The conjugate according to claim 6, or the pharmaceutically acceptable salt, ester, isomer, solvate, prodrug, or isotopically labeled compound thereof, wherein the structure between L and E is selected from the following structure: wherein, each of R 1a , R 2a , R 3a , R 5a , R 6a , R 7a , R 9a and R 10a is independently selected from hydrogen, deuterium, -O-C 1-6 alkyl, hydroxylC 1-6 alkyl-, C 1-6 alkyl- and C 3-8 cycloalkyl-; or, R 1a and R 2a may together form C 3-8 cycloalkyl; or, R 5a and R 6a may together form C 3-8 cycloalkyl; or, R 9a and R 10a may together form C 3-8 cycloalkyl, wherein said C 3-8 cycloalkyl is optionally substituted with a substituent selected from halogen and hydroxyl; each of R 4a and R 8a is independently selected from H, C 1-6 alkyl, and C 3-8 cycloalkyl; and w is 0, 1 or 2; preferably, each of R 1a , R 3a , R 4a , R 5a , R 7a , R 9a , and R 10a is independently hydrogen; each of R 2a , R 6a and R 8a is independently selected from hydrogen, C 1-6 alkyl, and C 3-8 cycloalkyl; and w is 0; more preferably, the structure of formula I-4a is selected from:
  9. The conjugate according to any one of claims 1 to 5, or the pharmaceutically acceptable salt, ester, isomer, solvate, prodrug, or isotopically labeled compound thereof, characterized that the conjugate is selected from the compounds represented by the structures of formula C-1a to formula C-27a: No. Structure of conjugate C-1a C-2a C-3a C-4a C-5a C-6a C-7a C-8a C-9a C-10a C-11a C-12a C-13a C-14a C-15a C-16a C-17a C-18a C-19a C-20a C-21a C-22a C-23a C-24a C-25a C-26a C-27a wherein, m, n, x, y, and E are as defined in any one of claims 1-5.
  10. The conjugate according to any one of claims 1 to 9, or the pharmaceutically acceptable salt, ester, isomer, solvate, prodrug, or isotopically labeled compound thereof, wherein the ratio of n to m ranges from 1 to 20, preferably from 2 to 10, such as 2, 3, 4, 5, 6, 7, 8, 9, or 10.
  11. The conjugate according to any one of claims 1 to 10, or the pharmaceutically acceptable salt, ester, isomer, solvate, prodrug, or isotopically labeled compound thereof, which has an average DAR value between 0.5 and 10.0, such as 2.0-4.5 or 4.8-8.5.
  12. The conjugate according to any one of claims 1 to 11, or the pharmaceutically acceptable salt, ester, isomer, solvate, prodrug, or isotopically labeled compound thereof, wherein E comprises an Fc domain monomer or an Fc domain comprising said Fc domain monomer, wherein said Fc domain monomer comprises or consists of: any one of the amino acid sequences set forth in SEQ ID Nos. 1-81, or an amino acid sequence having at least 95%, 96%, 97%, 98% or 99% identity thereto.
  13. The conjugate according to any one of claims 1 to 12, or the pharmaceutically acceptable salt, ester, isomer, solvate, prodrug, or isotopically labeled compound thereof, wherein E is capable of recognizing viral surface antigens, such as CR6261, CR8020, MEDI8897, Palivizumab, SD38, etc.; or the Fc domain monomer may be an Fc domain monomer of any antibody subtype of immunoglobulin (e.g., IGHG1*01 (such as G1m(za)), IGHG1*07 (such as G1m(zax)), IGHG1*04 (such as G1m(zav)), IGHG1*03 (G1m(f)), IGHG1*08 (such as G1m(fa)), IGHG2*01, IGHG2*02, IGHG2*06, IGHG3*01, IGHG3*04, IGHG3*05, IGHG3*09, IGHG3*10, IGHG3*11, IGHG3*12, IGHG3*06, IGHG3*07, IGHG3*08, IGHG3*13, IGHG3*03, IGHG3*14, IGHG3*15, IGHG3*16, IGHG3*17, IGHG3*18, IGHG3*19, IGHG2*04, IGHG4*01, IGHG4*02, IGHG4*03).
  14. The conjugate according to any one of claims 1 to 13, or the pharmaceutically acceptable salt, ester, isomer, solvate, prodrug, or isotopically labeled compound thereof, wherein the conjugate has the following structure: wherein E is as defined in any one of claims 1-13; preferably, wherein E is SEQ ID NO: 67, SEQ ID NO: 69 or SEQ ID NO: 71; and wherein m and n are as defined in claim 1, and m is preferably 1.
  15. The conjugate according to any one of claims 1 to 14, or the pharmaceutically acceptable salt, ester, isomer, solvate, prodrug, or isotopically labeled compound thereof, wherein the carbon to which the group is linked or the carbon to which the group corresponding to is linked is in R or S configuration, and preferably R configuration.
  16. A compound represented by structure of formula I-5a or I-6a, or a pharmaceutically acceptable salt, ester, isomer, solvate, prodrug, or isotopically labeled compound thereof, wherein each symbol is as defined in any one of claims 1-15; wherein each symbol is as defined in any one of claims 1-15.
  17. The compound according to claim 16, or the pharmaceutically acceptable salt, ester, isomer, solvate, prodrug, or isotopically labeled compound thereof, wherein the compounds have the structures of formulas C-Inter-1 to formula C-Inter-12: Intermediate No. Structure of intermediate C-Inter-1 C-Inter-2 C-Inter-3 C-Inter-4 C-Inter-5 C-Inter-6 C-Inter-7 C-Inter-8 C-Inter-9 C-Inter-10 C-Inter-11 C-Inter-12
  18. A method for preparing the conjugate of formula I-A according to any one of claims 1-15, wherein each symbol is as defined in any one of claims 1-15; the method comprises the following steps: Step 1, dissolving (E) m in a buffer solution, wherein E and m are as defined in any one of claims 1-15; then, a reducing agent (such as TCEP, DTT) is added to reduce the disulfide bond in (E) m , to obtain a compound of formula II-1 with thiol residues, wherein E, m, and n are as defined in any one of claims 1-15; Step 2, adding a buffer solution containing 6-14 molar equivalents of compound of formula I-5a to compound of formula II-1, wherein each symbol is as defined in formula I-A; under the condition of pH 5.5-7.0 (e.g., 5.8-6.8, 6.0-6.6), the Michael addition reaction is carried out for 0.5-10 hours, preferably 0.5-2 hours; then, 3-7 molar equivalents of the buffer solution of compound of formula I-5a are added in batches (e.g., 1-2 batches), and the reaction is continued for 0.5-10 hours (preferably 0.5-2 hours) to obtain the conjugate of formula I-3b, wherein each symbol is as defined in formula I-A; Step 3, adjusting the pH of the solution containing the conjugate of formula I-3b to 7-8 (e.g., 7.1-7.9, 7.3-7.7), and then performing a hydrolysis reaction to obtain the final conjugate of formula I-A; or, the method for preparing the conjugate of formula I-B according to any one of claims 1-15, wherein each symbol is as defined in any one of claims 1-15; the method comprises the following steps: Step 1, dissolving (E) m in a buffer solution, wherein E and m are as defined in any one of claims 1-15, and adding a reducing agent (such as TCEP, DTT) to reduce the disulfide bond in (E) m , to obtain a compound of formula II-1 with thiol residues, wherein E, m, and n are as defined in any one of claims 1-15; Step 2, adding a buffer solution containing 6-14 molar equivalents of compound of formula I-6a to compound of formula II-1, wherein each symbol is as defined in the formula I-B; the Michael addition reaction is carried out under the condition of pH 5.5-8 (e.g., 5.8-7.6, 6.0-7.5), to obtain the conjugate of formula I-B.
  19. A pharmaceutical composition, comprising the conjugate of formula I-A or formula I-B according to any one of claims 1-15, or the compound of formula I-5a or I-6a according to claim 16 or claim 17, or the pharmaceutically acceptable salt, ester, isomer, solvate, prodrug, or isotopically labeled compound thereof, and optionally one or more other therapeutic agents, such as chemotherapeutic agents, angiogenesis inhibitors, cytokines, cytotoxic agents, other antibodies, small molecule drugs, or immunomodulators (e.g., immune checkpoint inhibitors or agonists), and optionally a pharmaceutically acceptable excipient.
  20. A method for preventing or treating patients infected with viruses or patients who may be at risk of being infected with viruses, comprising the step of administering to the patients, for example, by injection, an effective dose of any of the conjugates of formula I-A or formula I-B according to any one of claims 1-15, or the compound of formula I-5a or I-6a according to claim 16 or claim 17, or the pharmaceutically acceptable salt, ester, isomer, solvate, prodrug, or isotopically labeled compound thereof.

Description

Field of the invention The present invention relates to conjugates of antiviral drugs against influenza (Flu) viruses and antibodies or their constant region Fc. Specifically, the present invention relates to compounds comprising antibodies or their constant region Fc covalently conjugated to small molecule inhibitors of viral surface proteins or inhibitor peptide drugs and intermediate compounds thereof, as well to pharmaceutical compositions or drugs comprising these compounds, and their use for the prevention and/or treatment of related viral infections. Background of the invention Influenza virus causes approximately 3 to 5 million severe infections globally each year, with around 500,000 deaths (Luliano et al., 2018, Lancet 391: 1285-1300). Although most healthy individuals recover spontaneously from the infection within one to two weeks, for the elderly, those with chronic diseases, and individuals with compromised immune systems, influenza virus infection can progress to life-threatening severe infections and complications, such as pneumonia. Developing treatments against influenza viruses remains a persistent challenge for humanity. Although antiviral drugs and preventive vaccines are currently available on the market, small molecule anti-influenza drugs typically need to be administered within 48 hours of symptom onset to achieve clinical benefits. Furthermore, due to the high variability of influenza viruses, resistant strains to commonly used drugs have been identified. Therefore, there is a need to develop more effective and long-lasting therapies for the treatment and/or prevention of influenza virus infection. Influenza viruses are a type of negative strand, segmented RNA viruses belonging to the Orthomyxoviridae family, and include influenza virus A, B, and C. Among these, infections are primarily caused by influenza A and B viruses in humans. Influenza viruses infect respiratory epithelial cells. The first step of this process involves the adsorption to host cells mediated by the viral surface receptor binding protein (hemagglutinin (HA protein), in the case of influenza proteins). Subsequently, under the action of the hemagglutinin, the viral envelope and cell membrane fuse, and the influenza virus genome segments and the viral RNA-dependent RNA polymerase complex are subsequently released into the cells. The RNA-dependent RNA polymerase complex of the virus uses genome fragments as templates to synthesize new progeny virus particles within the cell. The newly synthesized virus particles are released outside the cell through cell lysis or budding. For influenza viruses, the complete release of progeny viruses relies on the neuraminidase (NA) to cleave sialic acid residues on the cell surface. Neuraminidase inhibitors, which target the neuraminidase of influenza viruses to reduce virus spread, have been approved for clinical use, including oseltamivir (Tamiflu™), zanamivir (Relenza™), and peramivir (Rapivab™). Patients who have undergone organ transplants or those with cancer, due to their suppressed immune systems, are unable to effectively eliminate viruses. After being infected with the influenza viruses, the viruses tend to replicate for a longer period in their bodies, thereby increasing the likelihood of developing drugresistant strains. Such findings have already been observed clinically. Meanwhile, the problem of influenza drug resistance in ordinary patients is also a significant challenge in medication use. Therefore, more effective new methods and therapeutic agents for treating influenza are needed. Description of the invention In one aspect, the present invention provides a conjugate, or a pharmaceutically acceptable salt, ester, isomer, solvate, prodrug, or isotopically labeled compound thereof, comprising an anti-influenza small molecule compound conjugated to a protein (also referred to as "conjugate of protein and anti-influenza compound "), which exhibits significant anti-influenza virus activity. In some embodiments, the present invention provides a conjugate represented by a structure of Formula I-A or Formula I-B, or a pharmaceutically acceptable salt, ester, isomer, solvate, prodrug, or isotopically labeled compound thereof: wherein, m is 1 or 2;n is an integer from 1 to 20, and preferably an integer of 1, 2, 3, 4, 5, 6, 7, or 8;w is an integer from 0 to 8; for example, 0, 1, 2, 3, 4, or 5;L is a linker;E is selected from an antibody or antibody fragment, Fc domain monomer, Fc domain, Fc binding peptide, albumin, or albumin-binding peptide;each of R1a, R2a, R3a, R5a, R6a, R7a, R9a and R10a is independently selected from H, deuterium, hydroxyl, - O-C1-6 alkyl, hydroxylC1-6 alkyl-, C1-6 alkyl-, C3-8 cycloalkyl-, C3-8 heterocycloalkyl-, C6-C15 aryl, 5 to 15-membered heteroaryl, halogen, cyano, and amino; R1a and R2a may together form C3-8 cycloalkyl or C3-8 heterocycloalkyl;or R5a and R6a may together form C3-8 cycloalkyl or C3-8 heterocycloalkyl;or R9a and R10a may toge