Prevention and treatment of cast nephropathy
Inventors
Assignees
UAB Research Foundation • US Department of Veterans Affairs
Publication Number
US-8628781-B2
Publication Date
2014-01-14
Expiration Date
2031-04-01
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Abstract
Provided herein are polypeptides comprising or consisting essentially of a QSYDNTLSGSYVF (SEQ ID NO:1) or LSADSSGSYLYVF (SEQ ID NO:2) amino acid sequence. Also provided herein are methods of treating or preventing cast nephropathy in a subject. The methods comprise identifying a subject with or at risk of developing cast nephropathy and administering to the subject any of the polypeptides disclosed herein.
Core Innovation
Cast nephropathy, also known as myeloma kidney, is an inflammatory tubulointerstitial renal lesion occurring in multiple myeloma patients. It is characterized by intraluminal proteinaceous casts mainly found in the distal nephrons, which consist of light chain immunoglobulins and Tamm-Horsfall glycoprotein. These casts obstruct tubular fluid flow, causing inflammation, tubular atrophy, and ultimately leading to end-stage kidney failure. Renal failure from cast nephropathy can present acutely or as a chronic progressive disease at any multiple myeloma stage.
The invention provides polypeptides comprising or consisting essentially of QSYDNTLSGSYVF (SEQ ID NO:1) or LSADSSGSYLYVF (SEQ ID NO:2) amino acid sequences, optionally cyclized, that inhibit binding of light chain immunoglobulins to Tamm-Horsfall protein (THP). Methods of treating or preventing cast nephropathy involve identifying a subject with or at risk of developing the condition and administering these polypeptides or compositions containing them, which prevent the coaggregation of light chains and THP to reduce tubule obstruction.
Additional methods comprise administering antibodies or fragments thereof that inhibit binding of light chain immunoglobulins to THP, particularly antibodies targeting the CDR3 region of the light chain immunoglobulin, and nucleic acid sequences, including vectors encoding polypeptides or inhibitory nucleic acid molecules such as miRNA, siRNA, or antisense molecules that inhibit the expression of THP or light chains. These approaches are designed to mitigate renal failure by preventing the pathological interactions that form casts.
Claims Coverage
The claims include four aspects encompassing isolated polypeptides, their cyclization, cysteine modifications, and methods of treatment using these polypeptides.
Isolated polypeptides with specific amino acid sequences
An isolated polypeptide consisting essentially of the amino acid sequence QSYDNTLSGSYVF (SEQ ID NO:1) or LSADSSGSYLYVF (SEQ ID NO:2).
Cyclization of polypeptides for enhanced activity
The polypeptide is cyclized, enhancing its binding and inhibitory characteristics.
Addition of cysteine residues for cyclization
The cyclized polypeptide includes a first cysteine residue at the carboxy-terminal end and a second cysteine residue at the amino-terminal end to allow intramolecular disulfide bridge formation.
Method of treating cast nephropathy using the polypeptide
A method comprising identifying a subject with or at risk of developing cast nephropathy and administering a composition containing the specified polypeptide that inhibits binding of light chain immunoglobulin to Tamm-Horsfall protein.
The claims collectively cover isolated specific polypeptides and their cyclized forms with cysteine modifications, as well as therapeutic methods employing these polypeptides to inhibit pathological protein interactions in cast nephropathy.
Stated Advantages
Polypeptides selectively inhibit binding of nephrotoxic light chain immunoglobulins to Tamm-Horsfall protein, thereby preventing cast formation and tubular obstruction.
Cyclization of peptides increases inhibition efficiency at lower concentrations, improving therapeutic potential.
Using peptides or antibodies targeting the CDR3 domain offers specificity in blocking detrimental protein interactions causing renal failure.
The methods and compositions provide prophylactic and therapeutic applications to delay or reduce severity of cast nephropathy.
The peptides demonstrated efficacy in vivo by preventing acute kidney injury and improving renal function in a rat model.
Documented Applications
Treatment or prevention of cast nephropathy in subjects with or at risk due to multiple myeloma or other predispositions.
Therapeutic administration of polypeptides, antibodies, or nucleic acid molecules to inhibit binding of light chain immunoglobulins to Tamm-Horsfall protein to reduce renal failure.
Use in veterinary and human medicine for patients showing early signs or diagnosed with cast nephropathy or multiple myeloma-associated kidney injury.
Delivery routes including intravenous, intrarenal, intraperitoneal, topical, oral, or parenteral administration for localized or systemic treatment of kidney conditions related to cast nephropathy.
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