Bladder cancer specific ligand peptides
Inventors
Pan, Chong-xian • Zhang, Hongyong • Lam, Kit S. • Aina, Olulanu H.
Assignees
US Department of Veterans Affairs
Publication Number
US-9539340-B2
Publication Date
2017-01-10
Expiration Date
2030-09-23
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Abstract
The present invention is directed to bladder cancer specific ligand peptides, comprising the amino acid sequence X1DGRX5GF (SEQ ID NO:1), and methods of their use, e.g., for imaging detection for diagnosis of bladder, tumor localization to guide transurethral resection of bladder cancer, imaging detection of bladder cancer for follow-up after the initial treatment that can replace or complement costly cystoscopy, imaging detection of metastatic bladder cancer, and targeted therapy for superficial and metastatic bladder cancer.
Core Innovation
The invention provides bladder cancer specific ligand peptides comprising the amino acid sequence X1DGRX5GF (SEQ ID NO:1), where X1 and X5 represent any amino acid, and their methods of use. These peptides selectively bind to bladder cancer tissue while binding minimally or not at all to normal bladder tissue or non-bladder tissues. The invention includes synthetic and recombinant peptides no longer than 10 amino acids, which may be circularized or contain flanking cysteine residues. These peptides can also be linked to a variety of therapeutic or detectable moieties.
The problem being addressed is the difficulty in diagnosing and treating bladder cancer effectively due to limitations with current methods. Approximately 75% of bladder cancer patients present at non-invasive stages but face high recurrence and progression rates despite treatments. Current diagnostic methods such as urine cytology have low sensitivity (~35%) and cystoscopy is intrusive, uncomfortable, and costly. There is a need for more specific, sensitive, and less invasive diagnostic tools and more targeted therapies.
Claims Coverage
The patent contains multiple independent claims directed to methods of inhibiting bladder cancer cell growth using specific peptides linked to therapeutic moieties.
Peptide-based targeting of bladder cancer cells linked to therapeutic moieties
A method comprising contacting bladder tissue with a peptide comprising the sequence X1DGRX5GF (SEQ ID NO:2) where X1 is Gln or Gly and X5 is any amino acid except cysteine, the peptide being no longer than 25 amino acids and recombinant and/or synthetic, linked to a therapeutic moiety that inhibits or kills bladder cancer cells.
Peptides with defined amino acid substitutions and structural modifications linked to therapeutics
A method comprising contacting bladder tissue with a peptide comprising the amino acid sequence X1DGRX5GF (SEQ ID NO:2), wherein X1 is Gln, Gly or Ala, and the peptide includes one or more of: D-amino acids, protecting groups at termini, multiple repeats of the sequence, or is circularized with terminal D-cysteines, linked to a therapeutic moiety inhibiting bladder cancer cell growth.
Short peptides no longer than 10 amino acids linked to therapeutic moieties for bladder cancer inhibition
A method comprising contacting bladder tissue with a recombinant and/or synthetic peptide no longer than 10 amino acids, comprising the sequence X1DGRX5GF where X1 is Gln or Gly and X5 is not cysteine, linked to a therapeutic moiety that inhibits bladder cancer cell growth.
The claims cover methods of treating bladder cancer by administering peptides of specific sequences and lengths, linked to various therapeutic agents, with defined amino acid variations and modifications enabling specific binding and therapeutic effects on bladder cancer cells.
Stated Advantages
The peptides can be used for tumor localization to guide transurethral resection of bladder cancer.
They enable imaging detection for diagnosis and follow-up after initial bladder cancer treatment, potentially replacing or complementing costly cystoscopy.
They allow imaging detection of metastatic bladder cancer.
They can be used for targeted therapy for superficial and metastatic bladder cancer.
The peptides show specificity by binding bladder cancer cells but not normal cells or confounding cells, such as fibroblasts or blood cells.
The peptides retain binding ability in acidic urine environments relevant to bladder cancer diagnosis and therapy.
Conjugation to imaging agents enables in vivo tumor visualization in mouse xenografts, supporting diagnostic applications.
Documented Applications
Imaging detection for diagnosis of bladder cancer.
Tumor localization to guide transurethral resection of bladder cancer (TURBT).
Imaging detection of bladder cancer for follow-up after initial treatment.
Replacement or complement to cystoscopy for bladder cancer monitoring.
Imaging detection of metastatic bladder cancer.
Targeted therapy for superficial and metastatic bladder cancer, including conjugation to cytotoxins, anticancer agents, radioisotopes, or Fc portions of immunoglobulins.
Use in mammalian subjects including humans, non-human primates, and dogs.
Use of canine bladder cancer models for preclinical studies.
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