Near-IR light-cleavable conjugates and conjugate precursors
Inventors
Schnermann, Martin John • Nani, Roger Rauhauser • Gorka, Alexander Patrick
Assignees
US Department of Health and Human Services
Publication Number
US-10561729-B2
Publication Date
2020-02-18
Expiration Date
2037-08-07
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Abstract
Embodiments of near-infrared light-cleavable heptamethine cyanine-based conjugates, particularly targeting agent-drug conjugates, according to Formula I and conjugate precursors are disclosed. The disclosed targeting agent-drug conjugates are useful for targeted delivery and release of a drug. Methods of making and using the conjugates and precursors also are disclosed.
Core Innovation
This disclosure concerns conjugates, particularly targeting agent-drug conjugates comprising heptamethine cyanine fluorophores, conjugate precursors, and methods of making and using the conjugates. Embodiments of the disclosed conjugates undergo photodegradation when irradiated with near-infrared light, producing intramolecular cleavage and release of the drug. Some embodiments are fluorophores where fluorescence is lost upon photodegradation and drug release, enabling site-specific delivery and selective activation with concomitant drug release. Fluorescence levels of the administered conjugate may be monitored to visualize the location of the conjugate within a subject and as an indicator of drug release.
The background describes challenges with antibody-drug conjugates where existing linker strategies provide limited cleavage selectivity with site-specific delivery. Current approaches rely on intracellular processes and endogenous reactions with little tumor selectivity, leading to off-target drug release and dose-limiting toxicities. An appealing solution is developing antibody-drug cleavage chemistry reliant on an external stimulus applied in a site-specific manner. Near-infrared light (650-900 nm) offers unique potential due to significant tissue penetration, minimal toxicity, and clinical validation for diagnostic and therapeutic applications. Light-based therapeutic modalities have extensive history but lack extracellularly controlled site-selective drug release.
Claims Coverage
The patent contains multiple independent claims covering precursor compounds and conjugates with near-infrared light-cleavable properties, their structures, and methods of using them for targeted drug delivery and release.
Light-cleavable conjugates comprising heptamethine cyanine fluorophores, drugs, and targeting agents
Conjugates have a defined chemical structure according to Formula I comprising heptamethine cyanine fluorophores, a drug moiety linked via cleavable linkers, and a targeting agent, such as an antibody, enabling site-specific drug delivery upon near-IR light irradiation leading to drug release.
Structures tuning for wavelength-specific activation and targeting
Modifications of substituents R1 and R4 allow tuning of the activation wavelength from 690 nm to 740 nm, enabling deeper tissue penetration. Incorporation of sulfonated rings improves biodistribution and red-shifts effective cleavage wavelength. Targeting agents include antibodies such as panitumumab or trastuzumab.
Precursor compounds suitable for custom conjugation
Precursor compounds according to Formula IV feature reactive groups and linkers enabling conjugation to selected drugs and targeting agents. Protecting groups and functional substituents facilitate synthesis and customization of conjugates.
Methods for light-induced drug release and fluorescence monitoring
Methods involve providing conjugates and irradiating with near-infrared light at effective wavelengths (650-900 nm) and intensities, inducing cleavage and drug release. Fluorescence monitoring allows real-time assessment of drug release and targeted application of irradiation dose.
The claims comprehensively cover the chemical conjugates and their precursors, structural variations for improved targeting and wavelength tuning, and methods for use including targeted irradiation and fluorescence monitoring for controlled drug release.
Stated Advantages
The disclosed conjugates enable site-specific delivery and selective activation with controlled drug release via near-infrared light.
Fluorescence properties allow visualization of conjugate location and real-time monitoring of drug release.
Use of external light stimulus provides improved cleavage selectivity and minimizes off-target toxicities compared to endogenous enzymatic cleavage mechanisms.
Tunable chemical structures allow adjustment of activation wavelength for deeper tissue penetration.
Localized drug release enables effective bystander effects, potentially improving therapeutic efficacy on antigen-negative adjacent cells.
Documented Applications
Targeted delivery and controlled release of anti-cancer drugs to tumors using antibody-drug conjugates and near-infrared light to induce drug release.
Theranostic use for diagnosing tumor presence by fluorescence imaging and subsequent treatment via light-induced drug activation.
Ex vivo or in vitro diagnostic assays to detect target molecule binding and drug release using fluorescence and near-IR irradiation.
Customized conjugate preparation combining desired targeting agents and drugs for personalized therapy.
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