Potentiation of anticancer agents
Inventors
Beliveau, Richard • Demeule, Michel • Che, Christian • Regina, Anthony
Assignees
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Publication Number
US-8969310-B2
Publication Date
2015-03-03
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 provides peptide carriers derived from aprotinin, including Angiopep-1 and Angiopep-2. In particular, Angiopep-2 (SEQ ID NO:97) is used as a polypeptide carrier to conjugate paclitaxel molecules to increase anticancer drug potency and modify pharmacokinetics. The described approach includes conjugates discussed in relation to bypassing P-glycoprotein (P-gp)/MDR1 efflux.
Paclitaxel conjugates are described as Angiopep-2 conjugates in which one to three paclitaxel molecules are conjugated to the Angiopep-2 polypeptide at specified NH group positions, including the amino terminal amine or amino groups on lysine at positions 10 or 15 of Angiopep-2. The partial content reports that these conjugates accumulate in brain/target tissues, including tumoral brain, and show potency in vitro comparable to unconjugated Taxol while showing enhanced efficacy in vivo.
The partial content further describes formulation aspects that improve solubility and tolerability by including macrogol 15 hydroxystearate (Solutol® HS15) in the formulations. It is reported that the use of Solutol HS15 enables higher dosing with reduced toxicity versus paclitaxel. Diagnostic uses are also discussed, including label transport/detection, and receptor involvement is described via LRP and RAP.
Claims Coverage
The document provides two independent claim sets that share the same core structure: a conjugate of Angiopep-2 (SEQ ID NO:97) with one to three paclitaxel molecules plus macrogol 15 hydroxystearate (Solutol® HS15), with additional dependents further constraining formulation excipients and Angiopep-2 polypeptide properties. The independent claims thus cover both the conjugate definition and the Solutol HS15 formulation component, while the key inventive features are the specified conjugation geometry and the specific Angiopep-2 sequence reference.
Angiopep-2 paclitaxel conjugate defined by SEQ ID NO:97
A conjugate, or a pharmaceutically acceptable salt thereof, comprising a polypeptide comprising the amino acid sequence of Angiopep-2 (SEQ ID NO:97) and one to three paclitaxel molecules conjugated to said polypeptide.
Paclitaxel conjugation at specified NH group positions on Angiopep-2
Each of said paclitaxel molecules is conjugated to said Angiopep-2 as shown below, wherein the NH group is either the amino terminal amine or an amino group on a lysine at position 10 or position 15 of Angiopep-2.
Solutol HS15 formulation component
The pharmaceutical composition/composition further comprising macrogol 15 hydroxystearate (Solutol® HS 15).
Across the independent claims, coverage centers on an Angiopep-2 (SEQ ID NO:97) polypeptide conjugate bearing one to three paclitaxel molecules attached through NH group positions defined as either the amino terminal amine or lysine at positions 10 or 15, formulated with macrogol 15 hydroxystearate (Solutol® HS 15).
Stated Advantages
Increase anticancer drug potency.
Modify pharmacokinetics by bypassing P-gp (MDR1) efflux.
Accumulate in brain/target tissues, including tumoral brain.
Show enhanced efficacy in vivo compared with unconjugated Taxol.
Improve formulation solubility and tolerability.
Enable higher dosing with reduced toxicity versus paclitaxel.
Documented Applications
Anticancer drug delivery/use of Angiopep-2/paclitaxel conjugates with reported in vivo tumor growth inhibition in glial tumor models.
Diagnostic uses including label transport/detection.
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