Castration resistant prostate cancer
Inventors
POMBO-VILLAR, Esteban • Levitzki, Alexander • LANGUT, Yael • Zigler, Maya • Shir, Alexei • Kitas, Eric
Assignees
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Publication Number
US-11679160-B2
Publication Date
2023-06-20
Expiration Date
Abstract
The present invention relates to a polyplex for use in the treatment of castration resistant prostate cancer (CRPC) comprising a double stranded RNA (dsRNA) and a polymeric conjugate, wherein said polymeric conjugate consists of a linear polyethyleneimine (LPEl), one or more polyethylene glycol (PEG) moieties, one or more linkers and one or more targeting moieties, wherein said LPEl is covalently bound to one or more PEG moieties and each of said one or more PEG moieties is conjugated via one of the one or more linkers to one of the one or more targeting moieties, wherein each of said one or more targeting moieties is capable of binding to a cancer antigen, and wherein said cancer antigen is prostate surface membrane antigen (PSMA). Further, the invention relates to a pharmaceutical composition for use in the treatment of CRPC.
Core Innovation
The described invention treats castration resistant prostate cancer by administering an effective amount of a polyplex comprising double stranded RNA and a polymeric conjugate. The polymeric conjugate includes linear polyethyleneimine, one or more polyethylene glycol moieties, one or more linkers, and one or more targeting moieties, wherein linear polyethyleneimine is covalently bound to the polyethylene glycol moieties and each polyethylene glycol moiety is conjugated via a linker to a targeting moiety.
Each targeting moiety is capable of binding a cancer antigen, where the cancer antigen is prostate surface membrane antigen. Preferred embodiments include double stranded RNA as polyIC and structural constructs that attach prostate surface membrane antigen-targeting moieties to polyethylene glycol chains linked to linear polyethyleneimine.
The document further describes combinations involving immune cells, including T-TILs, tumor-specific engineered T cells, and PBMCs, together with the polyplex and pharmaceutical compositions. The disclosed embodiments include apoptosis, caspase-3 and PARP cleavage, cytokine induction including IP-10, RANTES, and IFN-β, direct and indirect bystander killing in co-cultures, and xenograft regression with PBMC reconstitution.
Claims Coverage
Two independent claims are identified, both directed to treating castration resistant prostate cancer by administering an effective amount of a dsRNA-containing polyplex where the polymeric conjugate consists of linear polyethyleneimine covalently bound to polyethylene glycol and connected through linkers to prostate surface membrane antigen-binding targeting moieties. The inventive features are centered on the polyplex composition architecture and prostate surface membrane antigen binding.
Psma-targeted dsrna polyplex with lpei-peg-linker-targeting architecture
A method of treating castration resistant prostate cancer by administering an effective amount of a polyplex comprising dsRNA and a polymeric conjugate, wherein the polymeric conjugate consists of linear polyethyleneimine, one or more polyethylene glycol moieties, one or more linkers and one or more targeting moieties, wherein linear polyethyleneimine is covalently bound to one or more polyethylene glycol moieties and each polyethylene glycol moiety is conjugated via one of the linkers to one of the targeting moieties.
Targeting moieties that bind psma
A method where each targeting moiety is capable of binding to a cancer antigen, and the cancer antigen is prostate surface membrane antigen.
Pharmaceutical composition containing dsrna polyplex with lpei-peg-linker-targeting architecture
A method of treating castration resistant prostate cancer by administering an effective amount of a pharmaceutical composition comprising a pharmaceutically acceptable carrier and a polyplex comprising dsRNA and a polymeric conjugate, wherein the polymeric conjugate consists of linear polyethyleneimine, one or more polyethylene glycol moieties, one or more linkers and one or more targeting moieties, wherein linear polyethyleneimine is covalently bound to the one or more polyethylene glycol moieties and each polyethylene glycol moiety is conjugated via one of the linkers to one of the targeting moieties.
Across the independent claims, the core claim coverage is the administration of a dsRNA polyplex where the polymeric conjugate uses covalently PEGylated linear polyethyleneimine connected through linkers to prostate surface membrane antigen-binding targeting moieties, either as direct polyplex administration or within a pharmaceutical composition containing a pharmaceutically acceptable carrier.
Stated Advantages
Targeted delivery and internalization of dsRNA/polyplex into PSMA-overexpressing CRPC cells.
Induction of apoptosis via polyIC.
Cytokine secretion and immune recruitment, including chemotaxis and immune activation outcomes.
Bystander effects and tumor regression in an androgen-resistant prostate cancer mouse model.
Reduced systemic toxicity versus naked polyIC.
Documented Applications
Treating castration resistant prostate cancer (CRPC) by administering an effective amount of a PSMA-targeted dsRNA polyplex, including treatment outcomes described in an androgen-resistant prostate cancer mouse model.
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