Methods and compositions for treating prostate cancer
Inventors
Shemi, Amotz • Khvalevsky, Elina Zorde • Gabai, Rachel Malka
Assignees
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Publication Number
US-9764035-B2
Publication Date
2017-09-19
Expiration Date
Abstract
Treatment of prostate cancer by regional and prolonged release of one or more nucleotide-based RNAi agents is provided.
Core Innovation
The disclosed invention relates to regional, prolonged release treatment of prostate cancer using millimeter-scale biodegradable drug delivery devices that implant a nucleotide-based RNA interference agent, such as an siRNA agent, within and/or with a biodegradable polymeric matrix. The device includes a matrix formed from a mixture of polylactic acid and polyglycolic acid, with the PLA:PGA ratio being 50:50 or being within 65:35 to 95:5 inclusive, and the RNAi agent is incorporated in the polymeric matrix and includes a sense strand and an antisense strand that target a prostate carcinoma gene.
The RNAi agent sense strand sequence is selected from SEQ ID NO: 23, SEQ ID NO: 30, SEQ ID NO: 15, SEQ ID NO: 22, and SEQ ID NO: 21. The disclosed RNAi strand features can further include structural and chemical characteristics such as 3′ dTdT overhangs and chemical modifications including 2′-OMe, with additional sequence-related options referenced in the document. The RNAi agent may also be provided with conjugation or complexation concepts such as cholesterol conjugation or cationic complexation.
The disclosure also addresses the problem of achieving regional treatment with delayed or prolonged release using biodegradable DDDs, while enabling release behavior sustained over extended periods. Device geometry and formulation features, including PLA:PGA ratio, polymer molecular weight, and additives/coatings, are used to control release profiles, including delayed or prolonged release behavior. Example release performance is described as achieving 95% release over about 3 to 24 months, supported by in vitro and in vivo testing referenced in the document.
Claims Coverage
Independent claim clm-00001 covers a millimeter-scale biodegradable PLA/PGA matrix DDD incorporating a prostate-carcinoma-targeting RNAi agent defined by sense/antisense strands, with the sense strand selected from specified SEQ ID NOs, and defines PLA:PGA ratio ranges. The excerpt also indicates dependent claims that further restrict the RNAi strand structure and define excipients/additives and performance/dosing constraints, including multi-month release and mg/kg/month dose ranges.
PLA/PGA millimeter-scale biodegradable RNAi DDD for prostate carcinoma
A millimeter-scale drug delivery device comprising a biodegradable polymeric matrix of PLA and PGA, wherein the PLA:PGA ratio is 50:50 or between 65:35 and 95:5 inclusive, and an RNAi agent incorporated within the biodegradable polymeric matrix, wherein the RNAi agent comprises a sense strand and an antisense strand targeting a prostate carcinoma gene.
Sense strand sequence selected from specified prostate carcinoma targets
The RNAi agent includes sense and antisense strand sequences that target a prostate carcinoma gene, wherein the sequence of the sense strand consists essentially of a sequence selected from the group consisting of SEQ ID NO: 23, SEQ ID NO: 30, SEQ ID NO: 15, SEQ ID NO: 22, and SEQ ID NO: 21.
Biodegradable matrix with trehalose
The device/formulation further includes trehalose in a specified range.
Biodegradable matrix with mannitol
The biodegradable matrix further includes mannitol in a specified amount range.
3′ dTdT overhang at the RNAi strands
The device is configured so that both the sense and antisense strands of the RNAi agent have a dTdT overhang at the 3′ end.
Multi-month release performance constraint
The device configuration is such that 95% of an RNAi agent is released over a time period between 3 and 24 months inclusive.
Dose constraint expressed as mg/kg/month
A treatment method includes determining the number of DDDs per treatment to achieve a dose of 0.008–0.065 mg/kg/month.
Across the independent coverage and indicated dependent refinements, the claims focus on a PLA/PGA millimeter-scale biodegradable DDD incorporating an RNAi agent with sense/antisense strands targeting prostate carcinoma genes, where the sense strand is defined by specified SEQ ID NOs, and where additional restrictions can define matrix excipients, RNAi strand structure, extended release, and mg/kg/month dosing constraints.
Stated Advantages
Enables delayed or prolonged release behavior for the RNAi agent, including sustained release performance with 95% release over about 3 to 24 months.
Documented Applications
Regional treatment of prostate cancer using millimeter-scale biodegradable drug delivery devices implanted to deliver an RNAi agent.
In vitro testing of release profiles and in vitro efficacy of multiple siRNA targets in PC3 cells using a viability assay.
Delayed/hibernation release behavior described in vitro and in vivo testing referenced in the document.
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