Bladder cancer specific ligand peptides
Inventors
Pan, Chong-xian • Zhang, Hongyong • Lam, Kit S. • Aina, Olulanu H.
Assignees
University of California • US Department of Veterans Affairs
Publication Number
US-10335365-B2
Publication Date
2019-07-02
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 are any amino acid, preferably excluding cysteine. These peptides selectively bind to bladder cancer cells while binding minimally or not at all to normal bladder or non-bladder tissues. The peptides are generally 7 to 10 amino acids in length and may include modifications such as D-amino acids, retro-inverso forms, circularization, repeats, and conjugation to other moieties like Fc portions or cytotoxins.
The problem being solved is the difficulty in diagnosing, localizing, and treating bladder cancer effectively due to the limitations of current methods such as intrusive cystoscopy, low sensitivity urine cytology, and costly procedures. Despite existing treatments like transurethral resection followed by chemotherapy or BCG, high recurrence and progression rates persist, necessitating long-term and costly monitoring. There is a need for bladder cancer-specific ligands that can be used for targeted imaging and therapy to improve diagnosis, tumor localization, treatment, and follow-up.
The invention leverages combinatorial chemistry technology, specifically one-bead one-compound (OBOC) peptide libraries, to identify ligands that bind selectively to bladder cancer cells. An illustrative ligand, PLZ4 (cQDGRMGFc), was identified which binds specifically to bladder transitional cell carcinoma lines and patient tumor samples but not to normal urothelial or other confounding cells. PLZ4 binds to integrin αvβ3 and αvβ5 expressed on bladder cancer cells and can be conjugated to imaging agents or therapeutic moieties for diagnostic and treatment uses. The peptides can also be used to inhibit bladder cancer cell growth, migration, and metastasis.
Claims Coverage
The patent includes three independent claims directed to methods of inhibiting or reducing bladder cancer cell growth using peptides with the sequence X1DGRX5GF linked to therapeutic moieties. The claims define the peptides with specific amino acid embodiments, length limitations, and modifications, as well as modes of administration and therapeutic moieties.
Bladder cancer-specific peptide sequence linked to therapeutic moiety
The peptide comprises the amino acid sequence X1DGRX5GF wherein X1 is Gln or Gly and X5 is any amino acid other than cysteine, and the peptide is no longer than 25 amino acids, recombinant or synthetic. The peptide binds bladder cancer cells and is linked to a therapeutic moiety that inhibits bladder cancer cell growth, migration, and metastasis.
Specific peptide amino acid variants and modifications
Inclusion of particular amino acid identities for X5 (Met, Lys, Gly, Ala, or Gly-Gly), peptide sequences (QDGRMGF, QDGRKGF, QDGRKGGF), flanking amino acid residues at termini, cysteine residues at termini, circularized peptides, nanoparticles, and magnetic nanoparticle conjugates.
Therapeutic moiety types and administration routes
Therapeutic moieties linked to the peptides include Fc portions of IgG, cytotoxins, anticancer agents, or radioisotopes. Administration routes include intravenous, intratumoral, intraurethral, and intravesical instillation.
The claims encompass methods of treating bladder cancer in subjects by administering synthetic or recombinant bladder cancer-specific peptides with defined amino acid sequences linked to therapeutic moieties. These peptides selectively bind bladder cancer cells and inhibit their growth and metastasis through various administration modalities and molecular conjugations.
Stated Advantages
The peptides provide tumor-specific localization aiding in precise tumor detection and resection guidance during surgery.
They enable imaging detection to replace or supplement costly and intrusive cystoscopy for diagnosis and follow-up.
The ligands facilitate targeted therapy to inhibit growth, migration, and metastasis of bladder cancer cells with potentially fewer off-target effects.
Use of canine bladder cancer models for preclinical studies allows evaluation in spontaneously occurring tumors with physiological relevance.
Documented Applications
Imaging detection for diagnosis and follow-up of bladder cancer, including tumor localization to guide transurethral resection.
Targeted therapy for superficial and metastatic bladder cancer using peptide conjugates linked to cytotoxins or anticancer agents.
Detection of bladder cancer cells in urine samples using peptide ligands linked to detectable labels.
In situ imaging of bladder cancer in tissue to facilitate detection and potential resection based on peptide binding.
Preclinical studies in canine bladder cancer models due to shared ligand binding properties with human bladder cancer cells.
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