Potentiation of anticancer agents
Inventors
Béliveau, Richard • Demeule, Michel • Che, Christian • Regina, Anthony
Assignees
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Publication Number
US-9713646-B2
Publication Date
2017-07-25
Expiration Date
Abstract
The present invention relates to carriers, conjugate and pharmaceutical compositions and their use to increase the potency of drugs and to modify the pharmacokinetics of compounds. More particularly, the present invention relates to conjugates comprising the carrier described herein and their use in the treatment and diagnostic of cancer.
Core Innovation
The invention relates to a cancer-treatment and diagnostic platform in which aprotinin-derived peptide carriers, including Angiopep-1 and Angiopep-2, are conjugated to anticancer drugs. The peptide carrier is used with a pharmaceutically acceptable carrier to form pharmaceutical compositions for cancer cell growth inhibition and related diagnostic and detection uses.
The described problem is multiple drug resistance, including efflux by P-glycoprotein (P-gp/MDR1), which is linked to resistance to anticancer agents. The background highlights P-gp efflux in brain capillaries and motivates altering pharmacokinetics and biodistribution to improve delivery to tumors, including brain metastases.
The core of the approach is a conjugate comprising a polypeptide having the amino acid sequence of Angiopep-2, with an anticancer agent conjugated to the polypeptide. The platform includes conjugate designs and formulations intended to modify pharmacokinetics and promote intracellular accumulation, including in P-gp-expressing/MDR cells, with receptor-related interactions involving LRP and RAP described as mechanisms for transport and accumulation.
Claims Coverage
Independent claim clm-00001 covers a method of inhibiting cancer cell growth by administering a pharmaceutical composition containing a conjugate of an Angiopep-2 polypeptide and an anticancer agent, together with a pharmaceutically acceptable carrier, in an amount sufficient for inhibition. The provided claim set includes six inventive features, with dependent claims further refining sequence, payload load, attachment site, selectable anticancer agents, and solubilizer options.
Angiopep-2 polypeptide–anticancer agent conjugate administration for cancer cell growth inhibition
A method comprising administering to a patient having cancer a pharmaceutical composition comprising a conjugate with a polypeptide comprising the amino acid sequence of Angiopep-2 and an anticancer agent conjugated to the polypeptide, together with a pharmaceutically acceptable carrier, in an amount sufficient to inhibit cancer cell growth.
Angiopep-2 sequence limitation to the polypeptide consisting of the Angiopep-2 amino acid sequence
The method of inhibiting cancer cell growth wherein the polypeptide consists of the amino acid sequence of Angiopep-2.
Quantitative constraint on anticancer agent load per Angiopep-2 polypeptide
The method wherein one to three anticancer agents are conjugated to the polypeptide.
Defined NH-group conjugation attachment sites on Angiopep-2
The method wherein the anticancer agent is conjugated via an NH group that is either the amino terminal amine or an amino group on lysine at position 10 or 15 of the Angiopep-2 sequence.
Selectable anticancer agent payload restricted to specified agents
The method wherein the anticancer agent is selected from paclitaxel, vinblastine, vincristine, etoposide, doxorubicin, cyclophosphamide, doclitaxel, melphalan, or chlorambucil.
Formulation solubilizer limited to a poly-oxyethylene ester of a fatty acid
The method wherein the pharmaceutical composition includes a solubilizer that is a poly-oxyethylene ester of a fatty acid.
The claim coverage centers on administering an Angiopep-2 polypeptide–anticancer agent conjugate in a pharmaceutically acceptable formulation for inhibition of cancer cell growth, with further limitations on sequence, number of drug molecules, conjugation attachment sites, choice of anticancer agents, and solubilizer class.
Stated Advantages
Increase drug potency and alter pharmacokinetics/biodistribution.
Bypass P-gp efflux to enhance delivery to tumors, including brain metastases.
Promote intracellular accumulation, including in P-gp-expressing/MDR cells.
Maintain similar in vitro mechanism while improving cytotoxicity/potency in vitro.
Enhance in vivo tumor growth inhibition.
Improve distribution to brain and lung.
Increase solubility and blood bioavailability (AUC increases reported).
Reduce toxicity compared to paclitaxel, with improved tolerability observations described.
Documented Applications
Cancer treatment using Angiopep-2 polypeptide–anticancer agent conjugates to inhibit cancer cell growth, including delivery targeted to brain and tumoral brain, including brain metastases.
Diagnostic and detection uses using labels, including isotope, fluorescent, and reporter molecules.
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