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JP-2026076188-A - Antibody-drug conjugates

JP2026076188AJP 2026076188 AJP2026076188 AJP 2026076188AJP-2026076188-A

Abstract

[Problem] To provide an antibody-drug conjugate containing a STING modulator that is useful for stimulating an immune response in subjects that require stimulation of the immune response. [Solution] Compound of formula (I): or by a pharmaceutically acceptable salt thereof. [In the formula, a is an integer from 1 to 20, Ab is an anti-CCR2 antibody, an anti-CCR2 antibody fragment, or an anti-CCR2 antigen-binding fragment, D is a guanine base, a guanine base derivative, an adenine base, or a STING activity modulator containing an amino group on an adenine base derivative, and L is a linker covalently bonded to Ab and also to the amino group on D.] [Selection Diagram] None

Inventors

  • シュ、ヘ
  • イ、ホン ミョン
  • アーレント、クリストファー

Assignees

  • 武田薬品工業株式会社

Dates

Publication Date
20260511
Application Date
20251226
Priority Date
20201109

Claims (20)

  1. Compound of formula (I): or a pharmaceutically acceptable salt thereof. [In the formula, a is an integer between 1 and 20. Ab is an anti-CCR2 antibody, an anti-CCR2 antibody fragment, or an anti-CCR2 antigen-binding fragment. D is a modulator of STING activity, comprising a guanine base, a guanine base derivative, an adenine base, or an adenine base derivative with an amino group. L is a linker that is covalently bonded to Ab and also to the aforementioned amino group on D.
  2. The compound according to claim 1, wherein D-L is represented by formula (Ia), or a pharmaceutically acceptable salt thereof. [In the formula: This indicates the connection point to Ab, b is an integer between 1 and 20. m is 0, 1, 2, 3, or 4. n is either 0 or 1, Each R1 is independently selected from C1 - C4 alkyl, O- C1 - C4 alkyl, and halogen. R2 is selected from C1 - C4 alkyl and -( CH2CH2O ) s - CH3 [wherein s is an integer from 1 to 10]. R3 and R3 ' are independently selected from hydrogen and C1 - C3 alkyl, respectively. L1 is a linker fragment that can be cut.
  3. a is an integer from 1 to 8, b is an integer between 1 and 10, The compound according to claim 2, or a pharmaceutically acceptable salt thereof, wherein m is 0.
  4. m is 0, n is 0, The compound according to claim 2 or 3, or a pharmaceutically acceptable salt thereof, wherein R3 and R3 ' are each hydrogen.
  5. L1 is The compound according to any one of claims 2 to 4, or a pharmaceutically acceptable salt thereof. [In the formula: This is the bond point to the nitrogen atom in equation (Ia), is a connection point to Ab, t is an integer between 1 and 10. W either does not exist or is a self-sacrificing element. Z is either absent or a peptide of 2 to 5 amino acids. U and U' are either non-existent or spacers, independently. Q is a heterodifunctional group. However, it is not possible for both W and Z to be absent.
  6. W is The compound according to claim 5, or a pharmaceutically acceptable salt thereof, wherein the self-sacrificing group is selected from the above. [In the formula: This is a bonding point to the carbonyl group, This is a connection point to Z.
  7. W The compound according to claim 5 or 6, or a pharmaceutically acceptable salt thereof.
  8. W The compound according to any one of claims 5 to 7, or a pharmaceutically acceptable salt thereof.
  9. A compound according to any one of claims 5 to 8, wherein Z is a peptide that can be cleaved by an enzyme, or a pharmaceutically acceptable salt thereof.
  10. A compound according to any one of claims 5 to 9, or a pharmaceutically acceptable salt thereof, wherein Z is cleavable by cathepsin.
  11. The compound according to any one of claims 5 to 10, or a pharmaceutically acceptable salt thereof, wherein Z is a two-amino acid peptide selected from Val-Cit, Cit-Val, Val-Ala, Ala-Val, Phe-Lys, and Lys-Phe.
  12. A compound according to any one of claims 5 to 11, or a pharmaceutically acceptable salt thereof, wherein Z is Al-Val or Val-Ala.
  13. U' does not exist, and U is A compound according to any one of claims 5 to 12, selected from, or a pharmaceutically acceptable salt thereof. [In the formula: is a connection point to Z, is a connection point to Q, p is an integer from 1 to 6, q is an integer between 1 and 20. X is O, or -CH2- , Each r is independently either 0 or 1.
  14. U' does not exist, and U is The compound according to any one of claims 5 to 13, or a pharmaceutically acceptable salt thereof.
  15. The compound according to any one of claims 5 to 14, or a pharmaceutically acceptable salt thereof, wherein Q is a heterobifunctional group and is bound to U', or, if U' is absent, is bound to Ab by chemical or enzyme-mediated conjugation.
  16. Q is A compound according to any one of claims 5 to 15, selected from, or a pharmaceutically acceptable salt thereof. [During the ceremony It is either a connection point to U, or, if U does not exist, a connection point to Z. It is either a connection point to U', or, if U' does not exist, a connection point to Ab.
  17. Q is The compound according to any one of claims 5 to 16, or a pharmaceutically acceptable salt thereof.
  18. A compound according to any one of claims 5 to 17, or a pharmaceutically acceptable salt thereof, wherein t is 1.
  19. A compound according to any one of claims 2 to 18, or a pharmaceutically acceptable salt thereof, wherein R2 is -CH3 and R3 and R3 ' are each hydrogen.
  20. A compound according to any one of claims 1 to 19, wherein a is 2 to 6, or a pharmaceutically acceptable salt thereof.

Description

This disclosure provides antibody-drug conjugates comprising STING modulators. Compositions comprising antibody-drug conjugates are also provided. The compounds and compositions are useful for stimulating immune responses in subjects requiring stimulation of an immune response. Antibody-drug conjugates (ADCs), a rapidly growing class of targeted therapies, represent a novel and promising approach to improving drug selectivity and cytotoxic activity. These therapeutic agents consist of an antibody (or antibody fragment) capable of binding to a payload drug to form an immune complex. The antibody instructs the ADC to bind to targeted cells. The ADC can then internalize and release its payload, delivering therapeutic effects to the cells. Because the ADC is directed to its targeted cells, the side effects of the conjugated drug may be lower than those seen when the drug is administered systemically. The adapter protein STING (an interferon gene stimulant) has been shown to play a role in the innate immune system. Activating the STING pathway triggers an immune response that leads to the production of specific killer T cells that shrink tumors, conferring long-lasting immunity and preventing tumor recurrence. The activated STING pathway also contributes to antiviral responses by producing antiviral and pro-inflammatory cytokines that fight viruses and mobilize both the innate and adaptive immune systems, resulting in long-lasting immunity against pathogenic viruses. Due to its potential therapeutic effects in enhancing both innate and adaptive immune responses, STING is an attractive target for drug discovery. Cyclic dinucleotides can function as STING agonists and have been tested in clinical trials. However, their anionic properties result in poor membrane permeability, which can limit their ability to involve STING intracellularly, often leading to the unwanted distribution of these compounds in the bloodstream. There is a continued need for novel STING agonists, as well as improved methods for delivering these agonists to target cells. In the first aspect, this disclosure relates to formula (I): or provide a pharmaceutically acceptable salt thereof in the formula. a is an integer between 1 and 20. Ab is an anti-CCR2 antibody, an anti-CCR2 antibody fragment, or an anti-CCR2 antigen-binding fragment. D is a modulator of STING activity, containing an amino group on a guanine base, a guanine base derivative, an adenine base, or an adenine base derivative. L is a linker covalently bonded to Ab and also to the amino group on D. In the first embodiment of the first aspect, the present disclosure provides a compound of formula (I) or a pharmaceutically acceptable salt thereof, wherein D-L is represented by formula (Ia), During the ceremony: This indicates the connection point to Ab. b is an integer between 1 and 20. m is 0, 1, 2, 3, or 4. n is either 0 or 1. Each R1 is independently selected from C1 - C4 alkyl, O- C1 - C4 alkyl, and halogen. R2 is selected from C1 - C4 alkyl and -( CH2CH2O ) s - CH3 [wherein s is an integer from 1 to 10]. R3 and R3 ' are independently selected from hydrogen and C1 - C3 alkyl, respectively. L1 is a linker fragment that can be cut. In a second embodiment of the first aspect, the present disclosure provides a compound of formula (I) or a pharmaceutically acceptable salt thereof, wherein D-L is represented by formula (Ia), where: a is an integer between 1 and 8. b is an integer between 1 and 10. m is 0. In a third embodiment of the first aspect, the present disclosure provides a compound of formula (I) or a pharmaceutically acceptable salt thereof, wherein D-L is represented by formula (Ia), where: m is 0, n is 0, R3 and R3 ' are both hydrogen atoms. In a third embodiment of the first aspect, the disclosure provides a compound of formula (I) or a pharmaceutically acceptable salt thereof, wherein D-L is represented by formula (Ia), and L1 is And, During the ceremony, This is the bond point to the nitrogen atom in equation (Ia), This is a connection point to Ab, t is an integer between 1 and 10. W either does not exist or is a self-sacrificing element. Z is either absent or a peptide consisting of 2 to 5 amino acids. U and U' are either non-existent or spacers, respectively. Q is a heterodifunctional group. However, it is not possible for both W and Z to be absent. In the fourth embodiment of the first aspect, W is: It is a self-sacrificing base selected from, During the ceremony: This is a bonding site to the carbonyl group. This is a connection point to Z. In the fifth embodiment of the first aspect, W is: That is the case. In the sixth embodiment of the first aspect, W is: That is the case. In the seventh embodiment of the first aspect, Z is a peptide that can be cleaved by an enzyme. In the eighth embodiment of the first aspect, Z is cleavable by cathepsin. In the ninth embodiment of the first aspect, Z is a two-amino acid peptide selected from Val-Cit, Cit-Val, Val-Ala, Ala-Val, Phe