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Assignees
Columbia University in the City of New York • William Marsh Rice University
Member
Rice UniversityRice University is a leading research university in Houston, Texas, recognized for its emphasis on scientific discovery, innovation, and interdisciplinary collaboration. The institution is committed to academic excellence, impactful research, and community engagement, offering robust undergraduate and graduate programs in engineering, natural sciences, social sciences, humanities, business, and the arts. Rice is distinguished by its history of collaboration with organizations such as NASA, fostering advances in space science, biotechnology, energy research, and artificial intelligence.
MemberColumbia UniversityColumbia UniversityColumbia University is a leading Ivy League research university in New York City, founded in 1754. It comprises undergraduate and graduate programs across 17+ schools, a world-renowned medical center, nearly 200 research centers and institutes, and extensive campus-life and student-services resources. Columbia supports broad disciplinary research (examples in the new content: extensive faculty-hosted publications and CVs such as those for Dustin R. Rubenstein), interdisciplinary initiatives (Columbia Climate School, Columbia Global Centers), and public events, conferences and workshops. Faculty labs and departmental pages host teaching and research materials (lecture notes, method papers, and open-access PDFs). Columbia also preserves and documents its technological and computing heritage: the IBM 650 Magnetic Drum Data Processing Machine was the first general-purpose computer installed and used at Columbia (Watson Scientific Computing Laboratory, installed beginning August 1955), and important early software work (e.g., the SOAP assembler) and intensive computing courses were developed and taught on these machines. Recent leadership transitions and active public programming continue alongside ongoing research expansion and global engagement. (Overview synthesized from Columbia University pages, faculty-hosted materials, and the Columbia Computing History archive.)
Rice University is a leading research university in Houston, Texas, recognized for its emphasis on scientific discovery, innovation, and interdisciplinary collaboration. The institution is committed to academic excellence, impactful research, and community engagement, offering robust undergraduate and graduate programs in engineering, natural sciences, social sciences, humanities, business, and the arts. Rice is distinguished by its history of collaboration with organizations such as NASA, fostering advances in space science, biotechnology, energy research, and artificial intelligence.
Columbia University is a leading Ivy League research university in New York City, founded in 1754. It comprises undergraduate and graduate programs across 17+ schools, a world-renowned medical center, nearly 200 research centers and institutes, and extensive campus-life and student-services resources. Columbia supports broad disciplinary research (examples in the new content: extensive faculty-hosted publications and CVs such as those for Dustin R. Rubenstein), interdisciplinary initiatives (Columbia Climate School, Columbia Global Centers), and public events, conferences and workshops. Faculty labs and departmental pages host teaching and research materials (lecture notes, method papers, and open-access PDFs). Columbia also preserves and documents its technological and computing heritage: the IBM 650 Magnetic Drum Data Processing Machine was the first general-purpose computer installed and used at Columbia (Watson Scientific Computing Laboratory, installed beginning August 1955), and important early software work (e.g., the SOAP assembler) and intensive computing courses were developed and taught on these machines. Recent leadership transitions and active public programming continue alongside ongoing research expansion and global engagement. (Overview synthesized from Columbia University pages, faculty-hosted materials, and the Columbia Computing History archive.)
Publication Number
US-12280115-B2
Publication Date
2025-04-22
Expiration Date
Abstract
Cytokine-bisphosphonate conjugates and methods of use thereof in muscle functions.
Core Innovation
Disclosed herein is a method for inhibiting, reducing and/or treating loss of muscle function comprising administering to a subject a pharmaceutical composition comprising a therapeutically effective amount of an agent that enhances Interleukin-6 (IL) release or activity, and optionally a pharmaceutically acceptable carrier or excipient; in certain exemplary embodiments the agent can be an IL-6 family cytokine conjugated to a bisphosphonate (IL6-BP).
A decline in muscle function is described as a devastating manifestation of aging that limits the ability of affected individuals to walk and perform elementary tasks, and osteocalcin (OCN) is described as a bone-derived hormone that is necessary and sufficient to increase muscle function; osteocalcin levels decline precipitously with age and replenishing OCN levels in aged mice restores their exercise capacity, but OCN's short half-life limits its development as a drug.
An IL-6 family cytokine-bisphosphonate conjugate is provided that comprises a bisphosphonate attached via one of its non-phosphonate R groups through a linking portion to an IL-6 family cytokine to target sustained IL-6 signaling to bone, thereby stimulating osteocalcin release and increasing exercise capacity; exemplary 1st and 2nd generation IL6-BP molecules and their engineering (including genetic code expansion and bioorthogonal click chemistry) are described, and experimental evidence in the specification indicates IL6-BP increases exercise capacity in an osteocalcin-dependent manner and produces a sustained increase in osteocalcin levels [procedural detail omitted for safety].
Claims Coverage
The independent claims disclose two primary inventive concepts covering (1) a class of cytokine-bisphosphonate conjugates with defined linkage chemistries and cytokine selections, and (2) a specific IL-6-bisphosphonate molecular conjugate.
Bisphosphonate linkage to IL-6 family cytokine
A cytokine-bisphosphonate conjugate comprising a bisphosphonate attached via one of its non-phosphonate R groups through a linking portion to an IL-6 family cytokine.
Azidophenylalanine-mediated triazole attachment
An embodiment where the cytokine comprises an azidophenylalanine residue and the triazole is composed from an azide group of the azidophenylalanine residue to form the bisphosphonate linkage.
Lysine-based Y linkage chemistries
An embodiment where the cytokine comprises a native lysine residue and Y comprises a nitrogen of the lysine sidechain, with Y selected from alkylimine, amide, urea, thiourea, sulfamidate, substituted benzo[d][1,2,3]triazin-4(3H)-one, or substituted 2-alkyliminoboronic acid, and attachment details as recited.
IL-6 family cytokine selection
The cytokine is selected from IL-6, Leptin, IL-11, ciliary neurotrophic factor (CNTF), leukemia inhibitory factor (LIF), oncostatin M (OSM), cardiotrophin 1 (CT-1), cardiotrophin-like cytokine (CLC), or IL-27.
Defined structural parameter ranges
Structural parameters for the conjugates include specified integer ranges for linker variables (e.g., l, m, n as recited in the specification) and defined substituents R1, R2, R3, R4, R5 as recited.
Specific IL-6-bisphosphonate molecular conjugate
A claimed embodiment comprising a specific IL-6-bisphosphonate conjugate molecule (and pharmaceutically acceptable salts thereof) in which IL-6 is interleukin-6.
Pharmaceutically acceptable salt of the IL-6 conjugate
The claimed IL-6-bisphosphonate conjugate is also claimed as a pharmaceutically-acceptable salt thereof.
The independent claims cover a class of cytokine-bisphosphonate conjugates defined by bisphosphonate linkage to IL-6 family cytokines via azidophenylalanine- or lysine-based chemistries, with specific structural parameter ranges and a claimed specific IL-6-bisphosphonate conjugate and its pharmaceutically acceptable salts.
Stated Advantages
Produces a long-lasting restoration or increase of exercise capacity in aged subjects.
Targets IL-6 signaling exclusively to bone to stimulate osteocalcin release while avoiding systemic IL-6 inflammatory effects.
Restores exercise capacity and/or reduces effects of sarcopenia and can prevent glucocorticoid-induced loss of exercise capacity.
A single dose can produce an increase in exercise capacity that endures for days, making it a promising drug candidate.
Documented Applications
Inhibiting, reducing and/or treating loss of muscle function.
Increasing exercise capacity in a subject having sarcopenia.
Treatment of subjects suffering from hip fracture, cancer, liver cirrhosis, Cushing's syndrome, Duchenne muscular dystrophy, a mitochondrial disease, kidney failure, diabetes, osteosarcopenia, or aging-associated loss of muscle function.
Use of an agent that enhances IL-6 release or activity in manufacturing a medicament for inhibiting or treating loss of muscle function.
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