Soluble alpha-Klotho proteins, protein fragments, and uses thereof
Inventors
Assignees
Publication Number
US-12227777-B2
Publication Date
2025-02-18
Expiration Date
2039-01-11
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Abstract
Disclosed herein are modified soluble α-Klotho proteins and isolated fragments of wildtype soluble α-Klotho protein. Also disclosed are pharmaceutical compositions including the modified soluble α-Klotho proteins and/or isolated fragments of soluble α-Klotho protein and methods of their use in treating a subject.
Core Innovation
The invention discloses modified soluble α-Klotho proteins and isolated fragments of wildtype soluble α-Klotho protein. The modified proteins feature alterations within the KL2 extracellular domain—specifically, modifications in the receptor binding arm (RBA)—to substantially decrease or eliminate binding affinity for fibroblast growth factor receptor (FGFR)1c, FGFR3c, and/or FGFR4, while retaining the ability to bind FGF23. Pharmaceutical compositions containing these modified proteins, as well as isolated nucleic acid molecules, vectors, and host cells capable of expressing them, are also disclosed.
The central problem addressed is the need for effective inhibition of the FGF23 pathway for the long-term treatment of disorders related to phosphate metabolism, especially those involving excessive FGF23 signaling. Current therapeutic strategies, such as oral or intravenous phosphate supplementation, are inadequate for conditions involving renal phosphate wasting, and often lead to side effects or are impractical for chronic use. Thus, there is a significant demand for biologics that inhibit FGF23 signaling in inherited and acquired diseases associated with excessive FGF23 activity.
The invention provides modified soluble α-Klotho proteins that competitively bind FGF23 but are unable to form the functional FGF23-FGFR/α-Klotho ternary complex, thereby acting as FGF23 ligand traps and antagonizing the co-receptor activity of the wild-type protein. Isolated RBA fragments also serve as inhibitors by binding FGFR and blocking complex formation. Examples in the patent demonstrate that these modified proteins possess inhibitory activity in vitro and in vivo in relevant animal models.
Claims Coverage
The patent has two independent claims, each providing a distinct inventive feature involving modified soluble α-Klotho proteins with specific sequence modifications and functionalities.
Modified soluble α-Klotho protein with eliminated binding affinity for FGFRs
A modified soluble α-Klotho protein comprising a KL2 extracellular domain with a modification that eliminates binding affinity for FGFR1c, FGFR3c, and/or FGFR4 compared to wildtype soluble α-Klotho protein. The wildtype soluble α-Klotho is defined as comprising amino acids E34 to S981 of SEQ ID NO:1, while the modified variants include amino acid sequences E34 to S932 of SEQ ID NO:2 or E34 to S959 of SEQ ID NO:7.
Modified soluble α-Klotho protein possessing a modification compared to wildtype
A modified soluble α-Klotho protein possessing a modification as compared to wildtype soluble α-Klotho protein, where the modified protein comprises the amino acid sequence of E34 to S932 of SEQ ID NO:2 or E34 to S959 of SEQ ID NO:7.
The claims define the invention as modified soluble α-Klotho proteins with specific domain modifications that abolish their FGFR-binding capability, with precise sequence boundaries ensuring the described molecular functions.
Stated Advantages
The modified soluble α-Klotho proteins provide a strategy for inhibiting excessive FGF23 signaling, which is not adequately addressed by existing therapies, especially in conditions involving renal phosphate wasting.
The invention offers biologics that act as FGF23 ligand traps, enabling competitive inhibition of FGF23-mediated signaling both in vitro and in vivo.
The proteins described can raise serum phosphate and suppress disease-relevant gene expression in the kidney and heart, offering therapeutic utility where replacement therapy alone is insufficient.
Documented Applications
Treatment of diseases or disorders mediated by interaction of FGF23 with an FGFR/α-Klotho complex, including but not limited to autosomal dominant hypophosphatemic rickets (ADHR), X-linked hypophosphatemic rickets (XLH), tumor-induced osteomalacia (TIO), fibrous dysplasia (FD), and chronic kidney disease (CKD).
Treatment of renal phosphate wasting disorders by administering the modified soluble α-Klotho protein and/or the isolated fragment of wildtype soluble α-Klotho protein.
Treatment of one or more complications of chronic kidney disease (CKD), such as cardiovascular diseases including left ventricular hypertrophy (LVH) and/or vascular calcification.
Inhibition of FGF23/FGFR/α-Klotho ternary complex formation in patients with diseases or disorders mediated by interaction of FGF23 with an FGFR/α-Klotho complex.
Therapeutic use in hypophosphatemic conditions where FGF23 is not the primary cause, including refeeding syndrome, diabetic ketoacidosis, asthma exacerbations, chronic obstructive pulmonary disease, and post-kidney transplantation recovery.
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