Peptide-containing linkers for antibody-drug conjugates
Inventors
Yurkovetskiy, Aleksandr V. • Bodyak, Natalya D. • Du, Bingfan • Gumerov, Dmitry R. • Kozytska, Mariya • Lowinger, Timothy B. • STEVENSON, Cheri A. • YIN, Mao
Assignees
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Publication Number
US-11964025-B2
Publication Date
2024-04-23
Expiration Date
Abstract
The present disclosure relates generally to antibody-drug conjugates comprising peptide-containing linkers and to methods of using these conjugates as therapeutics and/or diagnostics. Also disclosed herein are peptide-containing scaffolds useful to conjugate with a targeting moiety (e.g., an antibody), a drug, or both to produce the antibody-drug conjugates.
Core Innovation
The invention provides a conjugate of Formula (I) in which PBRM is an antibody or antibody fragment that binds to a target antigen and is connected to M_P through a divalent linker moiety L_P′. The corresponding monovalent moiety L_P contains a functional group W_P when not connected to PBRM, and the linker architecture includes defined attachment relationships, including L_M and optional multi-armed linker features.
The conjugate further includes a peptide moiety M_A containing from two to ten amino acids selected from glycine, serine, glutamic acid, aspartic acid, lysine, cysteine and stereoisomers and combinations thereof, together with a hydrophilic group T1 directly or indirectly attached to M_A. L3 is defined by carbonyl-containing structural motifs with attachment conditions through Y1 when L3 is absent, and the structure is parameterized by multiple integer ranges and substituent definitions.
The therapeutic agent D is specified as having a molecular weight of about 5 kDa or less, and each occurrence of L_D comprises a peptide connecting D to M_A and at least one cleavable bond such that when the bond is broken, D is released. The disclosure also refers to structural variants, linker substructures, and related conjugate formulae that maintain the same general antibody-linker-peptide-drug architecture.
Claims Coverage
The independent claim coverage centers on one Formula (I) conjugate with a target-binding antibody or antibody fragment (PBRM), a divalent linker architecture, a peptide moiety M_A, a hydrophilic group T1, and a cleavable drug-release linker L_D. The claim set presents one principal inventive framework with several defined structural features and substituent ranges.
Antibody-linked conjugate of Formula (I)
A conjugate of Formula (I) in which PBRM is an antibody or antibody fragment that binds to a target antigen, and L_P′ is a divalent linker moiety connecting PBRM to M_P, with the corresponding monovalent moiety L_P containing a functional group W_P when not connected to PBRM.
Functional group W_P and linker architecture
Each W_P independently is defined with ring A being optionally substituted C3-8 cycloalkyl or optionally substituted 5- to 12-membered heterocycloalkyl, and the conjugate includes defined attachment relationships through M_P and L_M, together with variable substituent patterns for R3, R4, R5, R20, and R21.
Peptide moiety M_A and hydrophilic group T1
M_A is a peptide moiety containing from two to ten amino acids selected from glycine, serine, glutamic acid, aspartic acid, lysine, cysteine and stereoisomers and combinations thereof, and T1 is a hydrophilic group directly or indirectly attached to M_A.
Cleavable drug-release linker L_D
Each occurrence of D is a therapeutic agent having a molecular weight ≤ about 5 kDa, and each occurrence of L_D comprises a peptide connecting D to M_A and at least one cleavable bond such that when the bond is broken, D is released.
Overall, the claims cover a Formula (I) conjugate that combines a target-binding PBRM with a defined divalent linker system, a peptide moiety M_A with an attached hydrophilic group T1, and a cleavable peptide linker L_D that releases therapeutic agent D.
Stated Advantages
Not explicitly described in patent.
Documented Applications
The patent provides examples described as suitable for conjugation/drug release in vitro or in vivo.
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