Site-specific labeling and targeted delivery of proteins for the treatment of cancer
Inventors
Assignees
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Publication Number
US-9545449-B2
Publication Date
2017-01-17
Expiration Date
Abstract
The present invention relates to the formation of protein conjugates from proteins chemically modified for linkage to (1) anticancer drug pharmacophores, (2) ligands to biomarkers on cancer cell surfaces, (3) and/or another protein molecule. It provides and specifies new compositions, methods and combinations for tumor, and tumor vasculature targeting and cancer treatment.
Core Innovation
The invention relates to a pharmaceutical composition comprising a therapeutic compound having a structure according to formula (I). A protein multimer P includes 2, 3, or 4 proteins having solvent accessible thiol, in which at least one protein has at least 90% sequence identity to SEQ ID NO: 1. Each L-T moiety is site-specifically attached to an amino acid residue of P, and the compound according to formula (I) represents at least about 75% of biologically active proteins present in the composition.
The subunits in P are linked together via a chemical modification to the solvent accessible thiol and via specified linker linkages. The linking chemistry includes a linker having an R2-(CH2)m(OCH2CH2)p structure or a reaction between solvent accessible thiols in said subunits and a compound having the same structure.
The invention relates to cancer-targeted, site-specific protein conjugates and crosslinked multimeric proteins, including annexin family members, for delivery of therapeutic agents and/or biomarker ligands. The described protein conjugates include biomarker ligands and targeting peptides such as RGD, and include crosslinking strategies that yield defined crosslinked therapeutic protein structures.
Claims Coverage
The independent claim is directed to a pharmaceutical composition comprising a therapeutic compound of formula (I) with a site-specifically functionalized annexin/protein multimer P linked by specified linker structures, and representing a defined fraction of biologically active proteins. Three inventive features are identified across the consolidated claim coverage.
Site-specific L-T attachment on thiol-containing protein multimer with defined biologically active fraction
A pharmaceutical composition comprising a therapeutic compound having a structure according to formula (I), wherein P represents a multimer of proteins (2, 3, or 4) having a solvent accessible thiol, at least one protein having at least 90% sequence identity to SEQ ID NO: 1, each L independently being an organic linker group, each T independently being a therapeutic agent, a protein, or a ligand to a biomarker, and wherein each L-T moiety is site-specifically attached to an amino acid residue of P. The compound according to formula (I) represents at least about 75% of biologically active proteins present in the composition, and the proteins in P are linked via a chemical modification to the solvent accessible thiol.
Protein multimer subunit linkage using specified R2-PEG-based linker structures
A pharmaceutical composition in which subunits in P are linked together by a linker having the structure wherein R2 is (CH2)m(OCH2CH2)p with m being 1 to 8 and p being 0 to 1000, or by a linker formed through a reaction between solvent accessible thiols in the subunits and a compound having the structure wherein R2 is (CH2)m(OCH2CH2)p with m between 1 and 8 and p between 0 and 1000.
Therapeutic use in cancer
The pharmaceutical composition is administered in an effective amount for treating cancer in a patient.
The claim coverage centers on a formula (I) pharmaceutical composition containing a solvent-accessible thiol-containing protein multimer P with site-specific L-T attachment, crosslinking of subunits through defined R2-(CH2)m(OCH2CH2)p linker structures or thiol-reactive linker-forming reactions, and a therapeutic-use claim for treating cancer.
Stated Advantages
Improved in vivo stability versus maleimides.
The compound represents at least about 75% of biologically active proteins present in the composition.
The composition has a reduced effective conjugate dose versus unconjugated T.
Documented Applications
Treating cancer in a patient by administering an effective amount of the pharmaceutical composition.
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