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US-20260124212-A1 - MAYTANSINOID DERIVATIVES WITH SELF-IMMOLATIVE PEPTIDE LINKERS AND CONJUGATES THEREOF

US20260124212A1US 20260124212 A1US20260124212 A1US 20260124212A1US-20260124212-A1

Abstract

The invention relates to novel cell-binding agent-maytansinoid conjugate having a self-immolative peptide linker and more specifically to conjugates of formula (I). The invention also provides novel maytansinoid compounds of formula (II), (III), (IV) or (V). The invention further provides compositions and methods useful for inhibiting abnormal cell growth or treating a proliferative disorder in a mammal using the compounds or conjugates of the invention.

Inventors

  • Wayne C. Widdison

Assignees

  • IMMUNOGEN, INC.

Dates

Publication Date
20260507
Application Date
20250811

Claims (20)

  1. 1 - 36 . (canceled)
  2. 37 . A compound represented by the following formula: or a pharmaceutically acceptable salt thereof, wherein: L 2 ′ is represented by the following structural formulas: wherein: R x , R y , R x′ and R y′ are all H; l and k are each independently an integer from 1 to 10; J CB ′ is —C(═O)OH or —COE; A is an amino acid or a peptide comprising 2 to 20 amino acids; R 1 and R 2 are each independently H or a C 1-3 alkyl; L 1 is a spacer; and D-L 1 -SH is a cytotoxic agent.
  3. 38 . The compound of claim 37 , wherein one of R 1 and R 2 is H, and the other one is Me; or R 1 and R 2 are both H.
  4. 39 . The compound of claim 37 , wherein L 1 is -L 1 ′ C(═O)—; and L 1 ′ is an alkylene or a cycloalkylene;
  5. 40 . The compound of claim 39 , wherein L 1 is —CR 3 R 4 —(CH 2 ) 1-8 —C(═O)—; and R 3 and R 4 are each independently H or Me.
  6. 41 . The compound of claim 40 , wherein R 3 and R 4 are both Me.
  7. 42 . The compound of claim 39 , wherein L 1 is —(CH 2 ) 4-6 —C(═O)—.
  8. 43 . The compound of claim 37 , wherein l and k are each independently an integer an integer from 2 to 6.
  9. 44 . The compound of claim 37 , wherein A is a peptide cleavable by a protease.
  10. 45 . The compound of claim 44 , wherein A is a peptide cleavable by a protease expressed in tumor tissue.
  11. 46 . The compound of claim 45 , wherein A is a peptide having an amino acid that is covalent linked with —NH—CR 1 R 2 —S-L 1 -D selected from the group consisting of Ala, Arg, Asn, Asp, Cit, Cys, selino-Cys, Gln, Glu, Gly, Ile, Leu, Lys, Met, Phe, Pro, Ser, Thr, Trp, Tyr and Val, each independently as L or D isomer.
  12. 47 . The compound of claim 46 , wherein the amino acid connected to —NH—CR 1 R 2 —S-L 1 -D is an L amino acid.
  13. 48 . The compound of claim 37 , wherein A is selected from the group consisting of Gly-Gly-Gly, Ala-Val, Val-Ala, D-Val-Ala, Val-Cit, D-Val-Cit, Val-Lys, Phe-Lys, Lys-Lys, Ala-Lys, Phe-Cit, Leu-Cit, Ile-Cit, Phe-Ala, Phe-N 9 -tosyl-Arg, Phe-N 9 -nitro-Arg, Phe-Phe-Lys, D-Phe-Phe-Lys, Gly-Phe-Lys, Leu-Ala-Leu, Ile-Ala-Leu, Val-Ala-Val, Ala-Ala-Ala, D-Ala-Ala-Ala, Ala-D-Ala-Ala, Ala-Ala-D-Ala, Ala-Leu-Ala-Leu (SEQ ID NO: 1), β-Ala-Leu-Ala-Leu (SEQ ID NO: 2), Gly-Phe-Leu-Gly (SEQ ID NO: 3), Val-Arg, Arg-Arg, Val-D-Cit, Val-D-Lys, Val-D-Arg, D-Val-Cit, D-Val-Lys, D-Val-Arg, D-Val-D-Cit, D-Val-D-Lys, D-Val-D-Arg, D-Arg-D-Arg, Ala-Ala, Ala-D-Ala, D-Ala-Ala, D-Ala-D-Ala, Ala-Met, Gln-Val, Asn-Ala, Gln-Phe, Gln-Ala, D-Ala-Pro, and D-Ala-tBu-Gly, wherein the first amino acid in each peptide is connected to L 2 group and the last amino acid in each peptide is connected to —NH—CR 1 R 2 —S-L 1 -D.
  14. 49 . The compound of claim 48 , wherein A is Ala-Ala-Ala, Ala-D-Ala-Ala, Ala-Ala, D-Ala-Ala, Val-Ala, D-Val-Ala, D-Ala-Pro, or D-Ala-tBu-Gly.
  15. 50 . The compound of claim 37 , wherein D is represented by the following formula:
  16. 51 . The compound of claim 37 , wherein the compound is represented by the following formula: or a pharmaceutically acceptable salt thereof, wherein: R 3 and R 4 are each independently H or Me; m1, m3, n1, r1, s1, and t1 are each independently an integer from 1 to 6; m2, n2, r2, s2 and t2 are each independently an integer from 1 to 7; t3 is an integer from 1 to 12; J CB ′ is —C(═O)OH or —COE; D 1 is represented by the following formula:
  17. 52 . The compound of claim 51 , wherein A is Ala-Ala-Ala, Ala-D-Ala-Ala, Ala-Ala, D-Ala-Ala, Val-Ala, D-Val-Ala, D-Ala-Pro, or D-Ala-tBu-Gly.
  18. 53 . The compound of claim 51 , wherein R 3 and R 4 are both Mc.
  19. 54 . The compound of claim 51 , wherein R 3 and R 4 are both H.
  20. 55 . The compound of claim 51 , wherein the compound is represented by the following formula: or a pharmaceutically acceptable salt thereof, wherein: A is Ala-Ala-Ala, Ala-D-Ala-Ala, Ala-Ala, D-Ala-Ala, Val-Ala, D-Val-Ala, D-Ala-Pro, or D-Ala-tBu-Gly, J CB ′ is —C(═O)OH or —COE; and D 1 is represented by the following formula:

Description

RELATED APPLICATIONS This application is a continuation application of U.S. application Ser. No. 17/406,326, filed on Aug. 19, 2021, which is a continuation application of U.S. application Ser. No. 16/692,743, filed Nov. 22, 2019, which is a divisional application of U.S. application Ser. No. 15/906,416, filed on Feb. 27, 2018, which claims the benefit of the filing date, under 35 U.S.C. § 119 (e), of U.S. Provisional Application No. 62/465,118, filed on Feb. 28, 2017, and U.S. Provisional Application No. 62/480,209, filed on Mar. 31, 2017. The entire contents of each of the above-referenced applications are incorporated herein by reference. SEQUENCE LISTING The 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 Jul. 7, 2025, is named “121162-04205.xml” and is 68,905 bytes in size. The sequence listing contained in this .XML file is part of the specification and is hereby incorporated by reference herein in its entirety. BACKGROUND OF THE INVENTION Antibody-drug conjugates (ADC) are emerging as a powerful class of anti-tumor agents with efficacy across a range of cancers. ADCs are commonly composed of three distinct elements: a cell-binding agent; a linker; and a cytotoxic agent. The linker component of ADC is an important element in developing targeted anti-cancer agents that possess an optimal therapeutic window, i.e., high activity at a low, non-toxic dose. Therefore, there is a need for ADCs having new class of linker component. SUMMARY OF THE INVENTION The present invention is directed to a cell-binding agent-cytotoxic agent conjugate represented by the following formula: or a pharmaceutically acceptable salt thereof, wherein: CB is a cell-binding agent;L2 is absent or a spacer;A is an amino acid residue or a peptide comprising 2 to 20 amino acid residues;R1 and R2 are each independently H or a C1-3alkyl;L1 is a spacer;D-L1-SH is a cytotoxic agent; andq is an integer from 1 to 20. The present invention is also directed to a compound of formula (II): or a pharmaceutically acceptable salt thereof, wherein: L2′ is absent or a spacer bearing a reactive moiety that can form a covalent bond with a cell-binding agent;A is an amino acid or a peptide comprising 2 to 20 amino acids;R1 and R2 are each independently H or a C1-3alkyl;L1 is a spacer;D-L1-SH is a cytotoxic agent; andq is an integer from 1 to 20. Also included in the present invention is a compound of formula (III): or a pharmaceutically acceptable salt thereof, wherein: A′ is an amino acid or a peptide comprising 2 to 20 amino acids;R1 and R2 are each independently H or a C1-3alkyl;L1 is a spacer;D-L1-SH is a cytotoxic agent; andq is an integer from 1 to 20. The present invention is also directed to a compound of formula (IV): or a pharmaceutically acceptable salt thereof, wherein: L3 is represented by the following formula: Rx′ and Ry′ for each occurrence, are independently H, —OH, halogen, —O—(C1-4 alkyl), —SO3H, —NR40R41R42+, or a C1-4 alkyl optionally substituted with —OH, halogen, SO3H or NR40R41R42+, wherein R40, R41 and R42 are each independently H or a C1-4 alkyl;k is an integer from 1 to 10;A is an amino acid or a peptide comprising 2 to 20 amino acids;R1 and R2 are each independently H or a C1-3alkyl;L1 is a spacer;D-L1-SH is a cytotoxic agent; andq is an integer from 1 to 20. The present invention also directs to a composition (e.g., a pharmaceutical composition) comprising a conjugate (e.g., a conjugate of formula (I)) or a compound (e.g., a compound of formula (II), (III) or (IV)) and a carrier (a pharmaceutically acceptable carrier). The present invention also includes a composition (e.g., a pharmaceutical composition) comprising a conjugate (e.g., a conjugate of formula (I)) or a compound (e.g., a compound of formula (II), (III) or (IV)) described herein and a carrier (a pharmaceutically acceptable carrier), further comprising a second therapeutic agent. The present compositions are useful for inhibiting abnormal cell growth or treating a proliferative disorder in a mammal (e.g., human). The present compositions are useful for treating conditions such as cancer, rheumatoid arthritis, multiple sclerosis, graft versus host disease (GVHD), transplant rejection, lupus, myositis, infection, immune deficiency such as AIDS, and inflammatory diseases in a mammal (e.g., human). The present invention also includes a method of inhibiting abnormal cell growth or treating a proliferative disorder in a mammal (e.g., human) comprising administering to said abnormal cell or said mammal a therapeutically effective amount of a conjugate (e.g., a conjugate of formula (I)) or a compound (e.g., a compound of formula (II), (III) or (IV)) or a composition thereof, alone or in combination with a second therapeutic agent. BRIEF DESCRIPTION OF THE FIGURES FIG. 1 depicts Ab-sSPDB-DM4 conjugates tested and