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WO-2026092705-A1 - DRUG FOR TREATING URINARY SYSTEM DISEASES

WO2026092705A1WO 2026092705 A1WO2026092705 A1WO 2026092705A1WO-2026092705-A1

Abstract

Provided is a drug for treating urinary system diseases. Specifically provided is a complex, comprising a carrier protein, and a functional molecule used for the diagnosis, prevention and/or treatment of urinary system diseases. The carrier protein is selected from a mutant DIIIbV of a subdomain structure (for example, DIIIb) of albumin domain III, an albumin domain III DIIIV containing the mutant, and multimers of the DIIIbV or DIIIV. The carrier protein exhibits an excellent transmucosal efficiency, can achieve transmucosal administration by means of pulmonary administration and gastrointestinal administration, and exhibits long-acting and sustained-release characteristics in the body. By means of the modes such as fusion expression and chemical grafting, etc., the functional molecule used for the diagnosis, prevention and/or treatment of urinary system diseases is carried, so as to achieve transmucosal drug delivery, thereby achieving targeted diagnosis and treatment of urinary system diseases.

Inventors

  • TIAN, RUI
  • XIE, Shiqiang
  • HAN, Dandan
  • FENG, XIN
  • YANG, Shengren
  • XIA, NINGSHAO

Assignees

  • 翔安创新实验室
  • 厦门大学

Dates

Publication Date
20260507
Application Date
20251031
Priority Date
20241031

Claims (20)

  1. A complex comprising a carrier protein and a functional molecule for the diagnosis, prevention, and/or treatment of urinary system diseases; The carrier protein is selected from the DIIIbV mutant of the albumin third domain substructure (e.g., DIIIb), the albumin third domain DIIIV containing the mutant, and the DIIIbV or DIIIV multimer.
  2. The complex of claim 1, compared with the wild type, comprises one or more (e.g., 40-50, 30-40, 20-30, 15-20, 10-15, 5-10, 1-5) amino acid insertions, substitutions, deletions and/or mutations. Preferably, the inserted, substituted, deleted, and/or mutated amino acids correspond to the amino acids at positions 467 to 585 of SEQ ID NO:1; More preferably, the inserted, substituted, deleted and/or mutated amino acids correspond to the amino acids at positions 497 to 585 of SEQ ID NO:1; More preferably, the inserted, substituted, deleted and/or mutated amino acids correspond to the amino acids at positions 500 to 573 of SEQ ID NO:1.
  3. The complex of claim 1 or 2, wherein the DIIIbV or DIIIV: (1) Compared with the wild type, it has a higher FcRn affinity under acidic or weakly acidic conditions; preferably, the FcRn affinity Kd value of the DIIIV is at the level of 10⁻⁶ M, 10⁻⁷ M, 10⁻⁸ M, 10⁻⁹ M, 10⁻¹⁰ or 10⁻¹¹ M; preferably, the FcRn affinity Kd value of the DIIIbV is at the level of 10⁻⁶ M, 10⁻⁷ M, 10⁻⁸ M, 10⁻⁹ M, 10⁻¹⁰ or 10⁻¹¹ M. (2) Mutations containing 1, 2, 3, 4, 5, 6, 7, 8, 9, 10, 11, 12, 13, 14, 15 or more amino acids compared to the wild type; (3) Contains a mutation at one or more amino acid sites selected from the following: corresponding to amino acids 500, 505, 523, 524, 527, 528, 531, 547, 509, 510, 498, 512 and 573 of natural albumin having the amino acid sequence shown in SEQ ID NO:1. (4) The mutation is a conserved mutation; (5) The DIII portion comprises a fragment of natural albumin corresponding to amino acids 467 to 585 of SEQ ID NO:1; Preferably, the amino acid mutations contained in DIIIbV or DIIIV are located at positions 523 and 573; Preferably, the amino acid mutations contained in DIIIbV or DIIIV are located at positions 505, 523, 547, and 573; Preferably, the amino acid mutations in DIIIbV or DIIIV are located at positions 500, 505, 523, 524, 527, 528, 531, 547, and 573; or, (6) Any combination of the above.
  4. The complex according to any one of claims 1-3, wherein the DIIIbV or DIIIV: (1) The 500th amino acid in the natural albumin having the amino acid sequence shown in SEQ ID NO:1 is L or D; (2) The amino acid at position 505 of the natural albumin having the amino acid sequence shown in SEQ ID NO:1 is Q, N or T; (3) The amino acid at position 523 of natural albumin having the amino acid sequence shown in SEQ ID NO:1 is L or M; (4) The amino acid at position 524 of natural albumin having the amino acid sequence shown in SEQ ID NO:1 is L; (5) The amino acid at position 527 of natural albumin having the amino acid sequence shown in SEQ ID NO:1 is K; (6) The amino acid at position 528 of natural albumin having the amino acid sequence shown in SEQ ID NO:1 is H or Y; (7) The amino acid at position 531 of natural albumin having the amino acid sequence shown in SEQ ID NO:1 is L; (8) The amino acid at position 547 of natural albumin having the amino acid sequence shown in SEQ ID NO:1 is A or C; (9) The amino acid at position 509 of natural albumin having the amino acid sequence shown in SEQ ID NO:1 is L; (10) The amino acid at position 510 of the natural albumin having the amino acid sequence shown in SEQ ID NO:1 is R or N; (11) The amino acid at position 498 of natural albumin having the amino acid sequence shown in SEQ ID NO:1 is E; (12) The amino acid at position 512 of natural albumin, which corresponds to the amino acid sequence shown in SEQ ID NO:1, is G; (13) The amino acid at position 573 of the natural albumin having the amino acid sequence shown in SEQ ID NO:1 is any amino acid other than K (e.g., P); or, (14) The amino acid at position 508 of natural albumin having the amino acid sequence shown in SEQ ID NO:1 is L; (15) Any combination of the above.
  5. The complex of claim 4, wherein the DIIIbV or DIIIV: (1) The amino acid at the 500th position is mutated from K to L or D; (2) The amino acid at position 505 is mutated from E to Q, N or T; (3) The amino acid at the 523rd position is mutated from I to L or M; (4) The amino acid at position 524 is mutated from K to L; (5) The amino acid at position 527 is mutated from T to K; (6) The amino acid at the 528th position is mutated from A to H or Y; (7) The amino acid at position 531 is mutated from E to L; (8) The amino acid at position 547 is mutated from V to A or C; (9) The amino acid at position 509 is mutated from F to L; (10) The amino acid at the 510th position is mutated from H to R or N; (11) The amino acid at position 498 is mutated from V to E; (12) The amino acid at the 512th position is mutated from D to G; (13) The amino acid at the 573rd position is mutated from K to any amino acid other than K (e.g., P); (14) The amino acid at position 508 is mutated from T to L; or, (15) Any combination of the above; Preferably, the mutations contained in DIIIbV or DIIIV are I523G and K573P; Preferably, the DIIIbV or DIIIV contains mutations of E505Q, I523G, V547A and K573P; Preferably, the DIIIbV or DIIIV contains mutations of K500L, E505Q, I523L, K524L, T527K, A528H, E531L, V547A and K573P.
  6. The complex according to any one of claims 1-5, wherein, The wild type of DIII or DIIIb is derived from natural serum albumin of mammals; preferably, the mammals are selected from humans, chimpanzees, gorillas, rhesus monkeys, rabbits, mice, rats, hamsters, cattle, horses, donkeys, goats, sheep, dogs, guinea pigs and pigs; preferably, the wild type of DIII or DIIIb is derived from natural human serum albumin. Preferably, the natural human serum albumin comprises, or is composed of, the amino acid sequence shown in SEQ ID NO:1; Preferably, the natural human serum albumin DIII comprises, or is composed of, the amino acid sequence shown in SEQ ID NO:2; Preferably, the natural human serum albumin DIIIb contains, or is composed of, the amino acid sequence shown in SEQ ID NO:4.
  7. The complex according to any one of claims 1-6, wherein the DIIIbV is selected from the amino acid sequences shown in SEQ ID NO: 36-40; Preferably, the DIIIV is selected from the amino acid sequences shown in SEQ ID NO: 5-35; Preferably, the DIIIV has the amino acid sequence shown in SEQ ID NO:5.
  8. The complex according to any one of claims 1-7, wherein the carrier protein further comprises an albumin first domain DI, a portion thereof, a derivative thereof, or a mutant thereof, and/or an albumin second domain DII, a portion thereof, a derivative thereof, or a mutant thereof; Preferably, the DI and DII are each independently derived from the natural serum albumin of mammals; preferably, the mammals are selected from humans, chimpanzees, gorillas, rhesus monkeys, rabbits, mice, rats, hamsters, cattle, horses, donkeys, goats, sheep, dogs, guinea pigs and pigs; preferably, the mammals are humans.
  9. The complex according to any one of claims 1-8, wherein the polymer is a homo- or hetero-dimer, trimer, tetramer or any polymer that can exist stably in physiological solutions of DIIIbV or DIIIV.
  10. The complex according to any one of claims 1-9, wherein the urinary tract disease is kidney injury, urinary tract inflammation, or urinary tract cancer; Preferably, the urinary tract inflammation is selected from allergic inflammation such as glomerulonephritis; urinary tract infections such as renal tuberculosis, pyelonephritis, cystitis, and urethritis; Preferably, the urinary system tumor is selected from renal cancer, urothelial carcinoma such as renal pelvis cancer, ureter cancer, bladder cancer, and urethral cancer. Preferably, the kidney injury is selected from acute kidney injury, acute kidney disease, chronic kidney disease, or complications of other chronic diseases and autoimmune diseases (e.g., diabetic nephropathy, systemic lupus erythematosus nephropathy, IgA nephropathy); Preferably, the urinary system disease is selected from kidney disease, ureteral disease, bladder disease, and urethral disease; Preferably, the kidney disease is selected from kidney injury (e.g., acute kidney injury), glomerular disease, tubulointerstitial disease, and renal cancer; preferably, the glomerular disease is selected from nephritis syndrome, nephrotic syndrome, and diabetic glomerular lesions (e.g., diabetic nephropathy); preferably, the tubulointerstitial disease is selected from tubulointerstitial nephritis (e.g., acute or chronic tubulointerstitial nephritis), acute pyelonephritis, acute tubular necrosis, acute renal papillary necrosis, obstructive or reflux nephropathy, nephrocalcinosis, pyonephrosis, and renal or perirenal abscess.
  11. The complex according to any one of claims 1-10, wherein the functional molecule is selected from diagnostic reagents, imaging agents, therapeutic radionuclides, or macromolecular or small molecule drugs, such as peptides, proteins, antibodies, nanobodies, nucleic acid drugs, or chemotherapeutic drugs; preferably, the peptide or protein is a peptide chain or a cyclic peptide; preferably, the antibody is a monoclonal antibody or its antigen-binding fragment; the nucleic acid drug is mRNA or a protein-nucleic acid complex; Preferably, the drug is an anti-inflammatory, anti-apoptotic, or anti-oxidative stress drug for the urinary system disease; preferably, the drug is selected from amifostine, cimetidine, glutathione, RNLS agonists (e.g., RP81), cortisone, curcumin, dexamethasone, and MMAE. Preferably, the diagnostic reagent is selected from substances highly expressed or secreted by the renal system (such as interleukin, intrinsic factor-vitamin B12 receptor (cubilin), low-density lipoprotein receptor-associated protein 2 (megalin), kidney injury-associated molecule (KIM-1), neutrophil gelatinase-associated lipotransferase (NGAL), and other proteins). Preferably, the imaging agent is selected from cyanine dyes such as IR-780 and IR-783, and other photosensitizers; Preferably, the therapeutic nuclide is selected from 64Cu , 18F , 68Ga , 177Lu , 125I , 90Y , 89Sr , 32P , and 233Ra .
  12. The complex according to any one of claims 1-11, wherein the carrier protein and the functional molecule are directly linked or linked through a linker; Preferably, the connector is a cuttable or non-cuttable connector; preferably, the cuttable connector is of the acid-cleaving type, disulfide bond-cleaving type, protease-cleaving type, glycosidase-cleaving type, or phosphatase-cleaving type; preferably, the connector is selected from DBCO-NHS ester, Sulfo-SMCC sodium, CL2 linker, DSP Cross linker, Mc-Val-Cit-PABC-PNP, Val-Cit-PAB, MC-Val-Cit-PAB, MAC glucuronide linker-2, Fmoc-PEA, Mal-PEG4-OH, 3-Mercaptopropionic acid NHS ester, and tBoc-NH-PEG-NH 2 .
  13. The complex according to any one of claims 1-12, wherein the carrier protein and the functional molecule are coupled by gene fusion or chemical methods to form the complex.
  14. A nucleic acid molecule encoding the complex according to any one of claims 1-13; Preferably, the complex is a fusion protein.
  15. A vector comprising the nucleic acid molecule of claim 14; preferably, the vector is an expression vector; Preferably, the vector is a vector of eukaryotic bacteria (e.g., pPIC9K, pCDNA3.4).
  16. A host cell comprising the nucleic acid molecule of claim 14 or the vector of claim 15; Preferably, the cells are eukaryotic cells or prokaryotic cells; Preferably, the eukaryotic cells are yeast cells (e.g., Saccharomyces cerevisiae, Pichia pastoris) and 293T cells; Preferably, the prokaryotic cells are Escherichia coli cells, Bacillus subtilis cells, or any combination thereof.
  17. A delivery combination or pharmaceutical composition comprising the complex according to any one of claims 1-13; Preferably, the delivery combination or pharmaceutical composition is delivered intravenously; Preferably, the delivery combination or pharmaceutical composition is delivered via nasal or oral inhalation, preferably via nasal delivery, such as nasal drops, nasal spray, or a combination thereof; Preferably, the complex is delivered to the mucosal surface of the subject (e.g., oral mucosa, nasal mucosa, tracheal mucosa, eyelid mucosa, vaginal mucosa); Preferably, the delivery combination or pharmaceutical composition further comprises one or more mucosal adhesives to enhance the residence time of the effector molecules on the mucosal surface of the subject; Preferably, the delivery combination or pharmaceutical composition is an aerosol, powder inhaler, spray, or other dosage form suitable for inhalation administration; Preferably, the pharmaceutical composition contains one or more pharmaceutically acceptable excipients.
  18. Use of the complex of any one of claims 1-13, the delivery combination of claim 17, or the pharmaceutical composition in the preparation of a medicament for treating urinary system diseases; Preferably, the urinary system disease is kidney damage, urinary system inflammation, or urinary system cancer; Preferably, the urinary tract inflammation is selected from allergic inflammation such as glomerulonephritis; urinary tract infections such as renal tuberculosis, pyelonephritis, cystitis, and urethritis; Preferably, the urinary system tumor is selected from renal cancer, urothelial carcinoma such as renal pelvis cancer, ureter cancer, bladder cancer, and urethral cancer. Preferably, the kidney injury is selected from acute kidney injury, acute kidney disease, chronic kidney disease, or complications of other chronic diseases and autoimmune diseases (e.g., diabetic nephropathy, systemic lupus erythematosus nephropathy, IgA nephropathy); Preferably, the kidney disease is selected from kidney injury (e.g., acute kidney injury), glomerular disease, tubulointerstitial disease, and renal cancer. In some embodiments, the glomerular disease is selected from nephritis syndrome, nephrotic syndrome, and diabetic glomerulonephropathy (e.g., diabetic nephropathy). In some embodiments, the tubulointerstitial disease is selected from tubulointerstitial nephritis (e.g., acute or chronic tubulointerstitial nephritis), acute pyelonephritis, acute tubular necrosis, acute renal papillary necrosis, obstructive or reflux nephropathy, nephrocalcinosis, pyonephrosis, and renal or perirenal abscess.
  19. The complex according to any one of claims 1-13, the delivery combination or pharmaceutical composition according to claim 17, is for treating urinary system diseases; Preferably, the urinary system disease is kidney damage, urinary system inflammation, or urinary system cancer; Preferably, the urinary tract inflammation is selected from allergic inflammation such as glomerulonephritis; urinary tract infections such as renal tuberculosis, pyelonephritis, cystitis, and urethritis; Preferably, the urinary system tumor is selected from renal cancer, urothelial carcinoma such as renal pelvis cancer, ureter cancer, bladder cancer, and urethral cancer. Preferably, the kidney injury is selected from acute kidney injury, acute kidney disease, chronic kidney disease, or complications of other chronic diseases and autoimmune diseases (e.g., diabetic nephropathy, systemic lupus erythematosus nephropathy, IgA nephropathy); Preferably, the kidney disease is selected from kidney injury (e.g., acute kidney injury), glomerular disease, tubulointerstitial disease, and renal cancer. In some embodiments, the glomerular disease is selected from nephritis syndrome, nephrotic syndrome, and diabetic glomerulonephropathy (e.g., diabetic nephropathy). In some embodiments, the tubulointerstitial disease is selected from tubulointerstitial nephritis (e.g., acute or chronic tubulointerstitial nephritis), acute pyelonephritis, acute tubular necrosis, acute renal papillary necrosis, obstructive or reflux nephropathy, nephrocalcinosis, pyonephrosis, and renal or perirenal abscess.
  20. A method of treating a urinary tract disease includes administering an effective amount of the complex of any one of claims 1-13, the delivery combination of claim 17, or the pharmaceutical composition to a subject in need of the treatment. Preferably, the urinary system disease is kidney damage, urinary system inflammation, or urinary system cancer; Preferably, the urinary tract inflammation is selected from allergic inflammation such as glomerulonephritis; urinary tract infections such as renal tuberculosis, pyelonephritis, cystitis, and urethritis; Preferably, the urinary system tumor is selected from renal cancer, urothelial carcinoma such as renal pelvis cancer, ureter cancer, bladder cancer, and urethral cancer. Preferably, the kidney injury is selected from acute kidney injury, acute kidney disease, chronic kidney disease, or complications of other chronic diseases and autoimmune diseases (e.g., diabetic nephropathy, systemic lupus erythematosus nephropathy, IgA nephropathy); Preferably, the kidney disease is selected from kidney injury (e.g., acute kidney injury), glomerular disease, tubulointerstitial disease, and renal cancer. In some embodiments, the glomerular disease is selected from nephritis syndrome, nephrotic syndrome, and diabetic glomerulonephropathy (e.g., diabetic nephropathy). In some embodiments, the tubulointerstitial disease is selected from tubulointerstitial nephritis (e.g., acute or chronic tubulointerstitial nephritis), acute pyelonephritis, acute tubular necrosis, acute renal papillary necrosis, obstructive or reflux nephropathy, nephrocalcinosis, pyonephrosis, and renal or perirenal abscess.

Description

Medications used to treat urinary system diseases This application is based on and claims priority to Chinese patent application No. 202411547095.9, filed on October 31, 2024, the disclosure of which is incorporated herein by reference in its entirety. Technical Field This application relates to the field of biological agents, specifically to drugs for the treatment of urinary system diseases. Background Technology Mucosa, as the first line of defense in the body's immune system, is widely distributed in the oral cavity, nasal cavity, eyes, gastrointestinal tract, vagina, and respiratory tract. It is a membranous structure composed of epithelial and connective tissues; the epithelial portion is called the epithelium, which is richly supplied with blood vessels and nerves and covered by mucus. Mucosal drug delivery systems are a novel drug delivery method that delivers drugs, along with suitable carrier materials, to the mucosal site for local action or absorption into the systemic circulation to induce systemic therapeutic effects. Mucosal drug delivery offers several advantages: First, compared to oral administration, drugs are absorbed into the systemic circulation through the mucosa, bypassing the liver and effectively avoiding the first-pass effect. Second, the limited types and quantities of enzymes in the mucosa result in relatively low enzymatic degradation activity of drugs, increasing drug stability. Furthermore, local administration increases drug concentration at the site of action, thereby improving bioavailability. Finally, local application makes the drug delivery process more convenient, allowing patients to self-administer the procedure and improving patient compliance. These advantages make mucosal drug delivery a promising area for drug delivery. The kidneys are crucial organs for maintaining homeostasis, performing vital physiological functions such as filtering blood, eliminating metabolic waste, regulating water and electrolyte balance, and secreting hormones. The complexity of their structure and function determines the challenges and unique characteristics of targeted drug delivery. The inherent physiological characteristics of the kidneys present technical obstacles to drug delivery. For a long time, targeted drug delivery to the kidneys has faced two major challenges: First, as a vital metabolic organ, drugs entering the bloodstream are rapidly excreted by the kidneys, resulting in the elimination of drugs before reaching effective concentrations. This necessitates frequent dosing to maintain local effective drug concentrations, increasing the burden on patients and potentially raising the risk of adverse drug reactions. Second, the complex hierarchical structure and physiological barriers of the kidneys (such as the glomerular filtration barrier and the renal tubular epithelial cell barrier) make it difficult for exogenous drugs to accurately penetrate and accumulate in key diseased areas such as the renal tubules, leading to low drug utilization and limited therapeutic efficacy. Therefore, a targeted drug delivery system capable of effective kidney-targeting is needed to address the current challenges in kidney disease treatment. Summary of the Invention The research unexpectedly discovered a protein with affinity for the neonatal Fc receptor (FcRn), which can efficiently deliver various payloads (small molecule drugs, proteins, nucleic acids, etc.). Administered via the mucosal system or blood, it can be reabsorbed into the bloodstream through the proximal renal tubules, thus achieving long-term kidney targeting. Depending on different needs, it can be administered via nasal spray, bronchial administration, oral mucosa, gastrointestinal mucosa, or blood, providing a new tool for the precise diagnosis, long-term monitoring, and efficient treatment of kidney diseases. The neonatal Fc receptor (FcRn) is the receptor for human serum albumin (HSA), mediating lysosomal escape of HSA to enable long-term circulation of albumin in vivo. The FcRn protein structure consists of a heterodimer composed of a non-covalently bound α-chain and β2-microglobulin. It is widely expressed in various epithelial cells, endothelial cells, and immune cells in vivo, and is highly expressed on the surface of mucosal epithelial cells (such as the nasal airway and olfactory epithelium). By constructing FcRn mutants with different affinities (high or low affinity) and employing high-throughput screening methods, a high-affinity albumin DIII mutant of FcRn was identified as a renal targeting warhead. This high-affinity mutant exhibits excellent transmucosal efficiency and demonstrates long-acting, sustained-release characteristics. Through fusion expression and chemical grafting, the identified high-affinity mutant and functional molecules, such as small molecule compounds, peptides or proteins, and nucleic acid molecules, that can be used for the diagnosis, prevention, and/or treatment of kidney diseases were f