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-8946379-B2
Publication Date
2015-02-03
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 present invention provides bladder cancer-specific ligand peptides comprising the amino acid sequence X1DGRX5GF (SEQ ID NO:1), wherein X1 and X5 are any amino acid, and the peptides bind to bladder cancer cells while binding minimally or not at all to normal bladder tissue or non-bladder tissue. These peptides can be used for imaging detection for diagnosis of bladder cancer, tumor localization to guide transurethral resection of bladder cancer, imaging detection for follow-up that can replace or complement costly cystoscopy, imaging detection of metastatic bladder cancer, and targeted therapy for superficial and metastatic bladder cancer.
Bladder cancer is a prevalent disease with high recurrence and progression rates despite current treatments such as transurethral resection and intravesical instillations. Monitoring with urine cytology has low sensitivity and cystoscopy is intrusive, uncomfortable, and costly. The invention addresses the need for improved, specific ligands for bladder cancer to enhance detection, localization, follow-up, and therapy using combinatorial chemistry technology, specifically one-bead one-compound (OBOC) combinatorial peptide libraries, to identify ligands that specifically bind bladder cancer cells.
The invention includes peptides that selectively bind bladder cancer cells and do not bind or minimally bind normal urothelial cells, with variations including D-amino acids, protecting groups, retro-inverso peptides, circularized peptides, and peptides conjugated to therapeutic or detectable moieties such as Fc regions of immunoglobulins, cytotoxins, fluorophores, radioisotopes, nanoparticles, and magnetic particles. Methods of use comprise detecting bladder cancer by contacting bladder tissue or cells, including urine samples, with these peptides conjugated to detectable labels and determining binding as indicative of bladder cancer presence or metastasis. Therapeutically, peptides can be linked to therapeutic moieties to inhibit growth, migration, or kill bladder cancer cells.
Claims Coverage
The claims describe multiple independent claims directed to bladder cancer-specific peptides with defined amino acid sequences, including compositions and methods of use. The inventive features focus on peptide composition, binding specificity, structural features, conjugation with therapeutic or detectable moieties, and methods for detection and treatment of bladder cancer.
Peptide composition with specific amino acid sequence and binding characteristics
A peptide comprising the amino acid sequence X1DGRX5GF (SEQ ID NO:2), wherein X1 is selected from Gln and Gly (and, in some claims, also Ala), and X5 is any amino acid other than cysteine, wherein the peptide is no longer than 25 amino acids in length, binds bladder cancer cells, and is recombinant and/or synthetic.
Structural modifications enhancing peptide properties
Peptides comprising one or more of: D-amino acid residues; protecting groups at one or both termini; two or more repeats of the X1DGRX5GF sequence; and N-terminal and/or C-terminal D-cysteine residues allowing circularization, with restrictions on combining certain modifications.
Specific amino acid substitutions at X5 position
Peptides wherein X5 is selected from Met, Lys, Gly, Ala, or Gly-Gly, providing variants with maintained binding properties.
Defined peptide sequences with demonstrated binding
Peptides having the amino acid sequences QDGRMGF (SEQ ID NO:5), QDGRKGF (SEQ ID NO:6), or QDGRKGGF (SEQ ID NO:7), with demonstrated selective binding to bladder cancer cells.
Selective binding to cancer cells over normal tissue
Peptides that do not bind to normal bladder tissue, ensuring specificity for cancer cells.
Conjugation to therapeutic moieties and detectable labels
Peptides linked to therapeutic moieties such as Fc immunoglobulin portions, cytotoxins, anticancer agents, or to detectable labels including beads, fluorophores, chemiluminescent moieties, magnetic or metal particles, nanoparticles, or radioisotopes for detection or treatment.
Formulation as nanoparticles
Peptides formulated as nanoparticles or magnetic nanoparticle-peptide conjugates to facilitate therapeutic or diagnostic applications.
Methods of detecting bladder cancer using labeled peptides
Methods of detecting bladder cancer by contacting bladder cells or tissue (in vitro, urine sample, or in vivo) with peptides linked to detectable labels and detecting binding to indicate cancer presence.
The claims cover novel bladder cancer-specific peptides with defined sequences and structures, their variants, conjugates to therapeutic or diagnostic agents, formulations, and methods for detection and treatment of bladder cancer using these peptides. The inventive features emphasize peptide specificity, structural modifications, and practical applications in diagnostics and therapy.
Stated Advantages
The bladder cancer-specific ligands can improve tumor localization to guide transurethral resection of bladder tumors, enhancing surgical outcomes.
They offer imaging detection methods that can replace or supplement costly and intrusive cystoscopy for diagnosis and follow-up of bladder cancer.
The ligands enable targeted therapy including intravesical instillation or intravenous injection to reduce recurrence and metastasis.
They have specificity for bladder cancer cells, minimizing binding to normal urothelial cells or other confounding cells, including those present in blood or inflamed tissue after BCG treatment.
Animal models such as dogs with naturally occurring bladder cancer can be used for preclinical studies due to similar ligand binding properties.
Documented Applications
Imaging detection for diagnosis of bladder cancer and tumor localization during transurethral resection.
Imaging detection of bladder cancer for follow-up after initial treatment, replacing or complementing cystoscopy.
Imaging detection of metastatic bladder cancer.
Targeted therapy of superficial and metastatic bladder cancer, including administration of peptide therapeutics or peptide-drug conjugates.
Detection of bladder cancer presence by contacting bladder cells or tissues, including cells from urine samples, with labeled peptides to detect binding indicating cancer.
Use in veterinary medicine for diagnosis and treatment of canine bladder cancer.
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