Albumin binding peptide-drug (AlBiPeD) conjugates and methods of making and using same
Inventors
Chilkoti, Ashutosh • Yousefpour, Parisa
Assignees
Publication Number
US-12296018-B2
Publication Date
2025-05-13
Expiration Date
2039-01-25
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Abstract
Described herein are albumin binding peptide drug (AlBiPeD) conjugates comprising a small molecule linked to an albumin binding domain (ABD) via a pH-sensitive linker and methods of purifying and using the same.
Core Innovation
The invention provides albumin binding peptide-drug (AlBiPeD) conjugates comprising a small molecule, such as a chemotherapeutic agent, linked to an albumin binding domain (ABD) via a pH-sensitive linker. The ABD facilitates binding to endogenous albumin in vivo, thereby improving the pharmacokinetics and biodistribution of the coupled small molecule. The linker may include specific amino acid sequences providing site-specific attachment and controlled drug release.
This delivery system addresses the problem of traditional small molecule agents, which have short circulation half-lives, low solubility, and poor tumor selectivity—leading to systemic toxicities and limited maximum dosages. Prior attempts using macromolecular or nanoparticulate carriers have suffered from difficult optimization and unpredictable interactions with serum proteins and the immune system.
The AlBiPeD conjugate, particularly exemplified by an ABD-doxorubicin (ABD-Dox) construct, demonstrates an extended plasma half-life, high solubility, and enhanced tumor accumulation compared to free drug or current clinical prodrugs such as aldoxorubicin. The system allows efficient in vivo tumor targeting, pH-controlled drug release, and can be modularly adapted to various small molecules, imaging agents, and engineered ABD variants.
Claims Coverage
The patent claims five independent inventive features spanning composition, method of use, and purification methods.
Albumin binding domain-small molecule composition with specific linker and solubility
A composition comprising: - An albumin binding domain (ABD) consisting of the amino acid sequence of SEQ ID NO:1. - A linker attached to the C terminus of the ABD, the linker consisting of (CGG)z (SEQ ID NO:3), where z is 1, 2, 3 or 4, with cysteine N-terminus coupled to the ABD. - One or two chemotherapeutic molecules (doxorubicin, paclitaxel, or docetaxel), each coupled to a cysteine thiol in the linker via a 3,3′-N-[ε-maleimidocaproic acid] hydrazide moiety. - The composition exhibiting aqueous solubility of up to 4 mg molecule equivalent/mL.
Method of killing cancer cells with the albumin binding peptide-drug conjugate
A method comprising contacting cancer cells (colon or pancreatic cancer cells) with an effective amount of the composition containing the ABD (SEQ ID NO:1), (CGG)z linker, and conjugated chemotherapeutic, as previously described.
Method of treating colon or pancreatic cancer using the ABD-drug conjugate
A method comprising administering to a subject with colon cancer or pancreatic cancer a therapeutically effective amount of the described ABD-linker-chemotherapeutic conjugate.
Method of purifying the ABD-drug composition using a cleavable elastin-like polypeptide conjugate
A method comprising: 1. Forming a conjugate with an elastin-like polypeptide (Tt above 50°C) and the ABD-drug composition, where the composition is conjugated to a first end of the elastin-like polypeptide via a cleavable amino acid sequence. 2. Treating the conjugate with an enzyme, chemical, or both, that cleaves the amino acid sequence. 3. Separating the ABD-drug composition from the elastin-like polypeptide.
In summary, the inventive features include a novel ABD-small molecule conjugate with defined linker and solubility, methods for cancer cell killing and treatment, and a specific enzymatic or chemical purification technique using elastin-like polypeptides.
Stated Advantages
Improves the pharmacokinetics and biodistribution of small molecule drugs, resulting in extended plasma half-life and enhanced tumor accumulation.
Enables targeted delivery of chemotherapeutics and imaging agents to tumors, minimizing premature systemic toxicity by providing pH-dependent release in acidic tumor environments.
Allows high aqueous solubility of drug-conjugates at physiological pH, overcoming solubility limitations of other prodrugs like aldoxorubicin.
Permits site-specific conjugation and modular adaptation to different drugs or diagnostic agents via recombinant engineering of the ABD.
Facilitates efficient, high-yield purification of recombinant conjugates from E. coli without need for chromatographic steps.
Documented Applications
Killing cancer cells in vitro and in vivo by delivering an effective amount of the ABD-chemotherapeutic conjugate.
Treating diseases or disorders in a subject, specifically including cancer, with the ABD-drug compositions administered therapeutically.
Targeted treatment of various cancer types and subtypes, including carcinomas, sarcomas, lymphomas, leukemias, and specifically colon cancer and pancreatic cancer.
Use in delivering imaging agents for diagnostic applications, utilizing the ABD composition for improved biodistribution of imaging moieties.
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