Multi-arm polymeric alkanoate conjugates
Inventors
Kozlowski, Antoni • McManus, Samuel P. • Riggs-Sauthier, Jennifer • Shen, Xiaoming • Zhang, Wen
Assignees
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Publication Number
US-11672776-B2
Publication Date
2023-06-13
Expiration Date
Abstract
Among other aspects, provided herein are multi-armed polymer conjugates comprising an alkanoate-linker, compositions comprising such conjugates, and related methods of making and administering the same. Methods of treatment employing such conjugates and related uses are also provided. The conjugates are prepared with high drug loading efficiencies.
Core Innovation
The invention relates to multi-arm polymer conjugates in which incomplete substitution can occur, and it addresses losses of drug loading attributed to failure of covalent attachment and loss of drug after ester formation via azlactone/hydrolysis pathways. The disclosure frames the problem in terms of multi-armed PEG-drug conjugates having less than full loading, including conjugate species in which some arms lack drug.
A multi-armed polymer prodrug conjugate framework is described in which a multi-arm water-soluble non-peptidic polymer is attached to an organic core via a linker, with an optional spacer. An alkanoate segment forms hydrolytically degradable ester bonds to release small-molecule drug residues through ester cleavage, where the residue is a hydroxyl-containing taxane or hydroxyl-containing camptothecin having a molecular weight of less than about 800 daltons, and attachment occurs at a hydroxyl oxygen.
The conjugate structure is defined by parameters including arm count, polymer arm repeat content, and alkanoate structural parameters with substituted alpha/beta positions to control steric effects. The disclosure emphasizes achieving high drug loading and limiting impurities compared with earlier glycine/carboxymethylene-linked conjugates, including discussion of docetaxel, irinotecan, and SN-38 conjugate species, including cases where some arms have no drug.
Claims Coverage
The claim coverage centers on one independent multi-arm polymer conjugate structure, with dependent claims refining the linkage, substituent options, molecular-weight range, and drug residue identity. The inventive coverage focuses on a defined PEG-type polymer repeat unit framework, covalent attachment of a hydroxyl-containing taxane or camptothecin residue through a hydroxyl oxygen, and quantitative constraints on the polymer and substituents.
Multi-arm polymer conjugate with defined polymer repeat unit and hydroxyl-oxygen attachment
A multi-arm polymer conjugate having a defined polymer repeat unit, a covalent linkage, defined substituent options, arm-count and polymer-length parameters, and a residue of a hydroxyl-containing taxane or hydroxyl-containing camptothecin having a molecular weight of less than about 800 daltons, attached at a hydroxyl oxygen.
The claim coverage centers on a single independent conjugate structure defined by the polymer repeat unit, a covalent linkage choice, defined substituent options, arm-count and polymer-length parameters, and attachment of a low-molecular-weight hydroxyl-containing taxane or camptothecin residue through a hydroxyl oxygen. Dependent claims further narrow the polymer molecular-weight range, specify particular taxane residues, set overall molecular-weight constraints, and tie the conjugate to therapeutic use in mammalian cancer treatment.
Stated Advantages
Improved loading and reduced impurities compared with earlier glycine/carboxymethylene-linked conjugates.
High drug loading is emphasized, including drug loading values described as greater than about 92% and up to about 100% in the discussion.
Reduced toxicity is mentioned in connection with the improved conjugate performance and in vivo anti-cancer activity.
Sustained systemic exposure and terminal half-life, supported by docetaxel exposure and pharmacokinetics characterization.
Antitumor activity in solid tumors, supported by in vivo examples.
Reduction of myelosuppression.
Documented Applications
Pharmaceutical compositions comprising the multi-arm polymer conjugate, as defined in the claims.
A method of treating cancer in a mammalian subject by administering a therapeutically effective amount of the conjugate over a time effective to inhibit growth of one or more cancerous solid tumors.
Use directed to cancerous solid tumors, including broad indications and cancer types addressed in the in vivo examples.
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