Nectin-4 antibody conjugates and uses thereof
Inventors
Baum, Peter R. • DuBose, Robert • Odegard, Valerie • STEVENS, Brenda • Tan, Philip
Assignees
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Publication Number
US-12364768-B2
Publication Date
2025-07-22
Expiration Date
Abstract
The present disclosure provides conjugates of anti-Nectin-4 antibodies or antigen binding fragments thereof to a myeloid cell agonist, compositions comprising the conjugates, and methods of treating cancer with the conjugates. The present disclosure also provides for anti-Nectin-4 antibodies or antigen binding fragments thereof and method for using the antibodies or antigen binding fragments thereof in treating cancer.
Core Innovation
The disclosed subject matter relates to an isolated monoclonal antibody, or an antigen-binding fragment thereof, that specifically binds to Nectin-4. The antibody comprises a heavy chain variable region and a light chain variable region defined by specified CDR amino acid sequences identified by SEQ ID NOs, including multiple alternative VH and VL CDR sequence sets.
The disclosure further describes anti-Nectin-4 immunoconjugate and conjugate linker architectures in which a Nectin-4-binding antibody is covalently linked via a linker to a myeloid cell agonist, a TLR7 agonist, or a TLR8 agonist. The linkers include cleavable and non-cleavable embodiments, lysosomally cleavable peptidic linker examples, beta-glucuronic acid-based and beta-galactoside-based moieties, and self-immolative spacer concepts such as PABA/PABC.
Additional structural definitions are provided for conjugate components and reactive moieties, including maleimide, alpha-halo carbonyl, succinimide and hydrolyzed succinimide forms, bridged disulfide approaches, and broad linker and attachment-site variability through formulas and substituent ranges. The disclosure also includes benzazepine and aminobenzazepine-based conjugatable small-molecule frameworks, TLR7/8 and related immune-stimulatory compound types, and Formula (A-L-Dx) and related embodiments.
Claims Coverage
The consolidated claim coverage centers on one inventive feature set: an isolated monoclonal antibody, or an antigen-binding fragment thereof, that specifically binds to Nectin-4 and is defined by multiple alternative VH and VL CDR amino-acid sequence sets. No independent claim text for the linker or conjugate architectures is explicitly provided.
Nectin-4 binding antibody defined by VH and VL CDR sequences
An isolated monoclonal antibody, or an antigen-binding fragment thereof, that specifically binds to Nectin-4, comprising a heavy chain variable region and a light chain variable region, with VH-CDR1, VH-CDR2, and VH-CDR3 and VL-CDR1, VL-CDR2, and VL-CDR3 amino acid sequences specified by SEQ ID NOs, including multiple alternative CDR sequence sets.
The claimed inventive feature is a Nectin-4-specific isolated monoclonal antibody, or antigen-binding fragment, defined by particular VH and VL CDR amino-acid sequences across multiple alternative SEQ ID NO sets.
Stated Advantages
Promoting hydrolysis and improving plasma stability.
Addressing bystander effects and nonspecific toxicities.
Conjugates induce TNF-α in PBMC co-cultures with Nectin-4+ tumor cells.
Conjugates increase tumor chemokines and cytokines.
Conjugates show in vivo tumor control in human Nectin-4-expressing mouse models.
Conjugates demonstrate binding-blocking (TIGIT-Fc blocking).
Self-stabilizing linker design prevents maleimide reverse reaction.
Bridged disulfide approaches provide claimed stability improvements and homogeneous DAR4 conjugate.
Hydrophilic glycosides mitigate aggregation in immune-stimulatory antibody conjugates.
Documented Applications
Immune-stimulatory antibody conjugates using structural linker concepts, including non-cleavable linkers whose payload release is triggered after antibody degradation in lysosomal compartments following internalization.
Conjugates involving immune-stimulatory compounds, including TLR7 agonist and TLR8 agonist contexts.
Cancer treatment using anti-Nectin-4 antibody immunoconjugates, including subcutaneous administration and pharmaceutical compositions.
Use in treatment of cancers with excess Nectin-4, including urothelial cancer, triple negative breast cancer, NSCLC, HNSCC, cervical cancer, pancreatic adenocarcinoma, esophageal adenocarcinoma, and uterine corpus endometrial carcinoma.
PBMC co-culture with Nectin-4+ tumor cells to evaluate induction of TNF-α and increases in tumor chemokines and cytokines.
In vivo tumor control evaluation in human Nectin-4-expressing mouse models.
Binding-blocking assessment using TIGIT-Fc blocking.
Immune-stimulatory antibody conjugate use involving an anti-Nectin-4 antibody and an immune-stimulatory compound, including a context described as a myeloid cell agonist.
Preclinical and pharmacodynamic assessment contexts, including tumor growth delay, cytokine and chemokine changes in tumors, and NHP pharmacodynamic markers.
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