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Assignees
Member
Johns Hopkins UniversityFounded in 1876, Johns Hopkins University is recognized as the first research university in the United States. It advances interdisciplinary education, high-impact research, and global outreach, supporting knowledge translation, technological innovation, and community partnerships. The university fosters academic excellence, innovation incubation, outreach, and inclusion across multiple campuses in Baltimore, integrating into the city's social, economic, and cultural life.
Founded in 1876, Johns Hopkins University is recognized as the first research university in the United States. It advances interdisciplinary education, high-impact research, and global outreach, supporting knowledge translation, technological innovation, and community partnerships. The university fosters academic excellence, innovation incubation, outreach, and inclusion across multiple campuses in Baltimore, integrating into the city's social, economic, and cultural life.
Publication Number
US-12691158-B2
Publication Date
2026-07-28
Expiration Date
Abstract
The present invention relates to the field of cancer. More specifically, the present invention provides compositions and methods for treating cancer using albumin-proaerolysin prodrugs. Accordingly, in one aspect, the present invention provides prodrug compositions. In certain embodiments, a prodrug composition comprises a prostate-specific antigen (PSA)-activated pro-aerolysin (PA), wherein a PSA cleavable linker replaces the native furin cleavage site within PA; and human serum albumin (HSA) or a fragment thereof fused to the N-terminus of the PSA-activated PA.
Core Innovation
The invention relates to a PSA-activated pro-aerolysin prodrug composition for treating prostate cancer or benign prostatic hyperplasia in a subject. The prodrug composition comprises prostate-specific antigen-activated pro-aerolysin, wherein a PSA cleavable linker replaces the native furin cleavage site, and human serum albumin, or a fragment thereof, fused to the N-terminus of the PSA-activated pro-aerolysin with a linker sequence comprising at least one PSA cleavable site.
PSA-mediated activation is used, where tumor-associated enzymatically active PSA cleaves the HSA linker and activates pro-aerolysin to generate aerolysin heptameric pores that produce selective cytotoxicity in metastatic prostate cancer. The approach leverages enhanced permeability and retention to support tumor selectivity.
The design addresses systemic and non-specific toxicity by being intended to reduce binding of the prodrug to GPI-anchored proteins on normal cells, thereby lowering non-specific toxicity in subject tissues as compared to administration of the PSA-activated pro-aerolysin alone. The document also indicates extension to protease-activated variants using other cleavage sites such as PSMA and HK2.
Claims Coverage
The relevant independent claim covers one inventive combination: a systemic method of treating prostate cancer or BPH using a PSA-activated albumin-fused pro-aerolysin prodrug composition with a PSA cleavable linker replacing a native furin cleavage site and reduced binding to GPI-anchored proteins on normal cells.
Systemic treatment using a PSA-activated pro-aerolysin with a furin-to-PSA cleavable linker replacement
Administering systemically an effective amount of a prodrug composition that includes prostate-specific antigen-activated pro-aerolysin in which a PSA cleavable linker replaces the native furin cleavage site.
Albumin fusion to the N-terminus of PSA-activated pro-aerolysin via a PSA-cleavable linker
Human serum albumin, or a fragment thereof, is fused to the N-terminus of the PSA-activated pro-aerolysin with a linker sequence comprising at least one PSA cleavable site.
Lower non-specific toxicity via non-binding to GPI-anchored proteins on normal cells
The prodrug composition does not bind to GPI-anchored proteins on normal cells, thereby lowering non-specific toxicity in subject tissues compared to administration of the PSA-activated pro-aerolysin alone.
The independent claim combines the PSA-cleavable linker replacement, the HSA fusion at the N-terminus, systemic administration, and the specified reduction in binding to GPI-anchored proteins on normal cells.
Stated Advantages
Lowers non-specific toxicity in subject tissues compared to administration of the PSA-activated pro-aerolysin alone by not binding to GPI-anchored proteins on normal cells.
Selective cytotoxicity in metastatic prostate cancer via PSA-mediated activation producing aerolysin heptameric pores.
Tumor selectivity supported by enhanced permeability and retention.
Documented Applications
Treating prostate cancer in a subject by systemically administering the PSA-activated albumin-fused pro-aerolysin prodrug composition.
Treating benign prostatic hyperplasia in a subject by systemically administering the PSA-activated albumin-fused pro-aerolysin prodrug composition.
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