Monoclonal antibodies that specifically bind to matrilin-3 and their use
Inventors
Baron, Jeffrey • Cheung, Crystal Sao Fong • Lui, Julian Chun Kin • Dimitrov, Dimiter • Zhu, Zhongyu
Assignees
US Department of Health and Human Services
Publication Number
US-10954291-B2
Publication Date
2021-03-23
Expiration Date
2035-01-14
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Abstract
Monoclonal antibodies and antibody fragments that specifically bind to matrilin-3, conjugates including these molecules, and nucleic acid molecules encoding the antibodies, antigen binding fragments and conjugates, are disclosed. Also disclosed are compositions including the disclosed antibodies, antigen binding fragments, conjugates, and nucleic acid molecules. Methods of treating or inhibiting a cartilage disorder in a subject, as well as methods of increasing chondrogenesis in cartilage tissue are further provided. The methods can be used, for example, for treating or inhibiting a growth plate disorder in a subject, such as a skeletal dysplasia or short stature.
Core Innovation
This invention discloses isolated monoclonal antibodies and antigen binding fragments that specifically bind to matrilin-3, a cartilage extracellular matrix protein, along with conjugates of these antibodies linked to chondrogenic or anti-arthritis agents. These antibodies and conjugates can be used to increase chondrogenesis in cartilage tissue, and to treat or inhibit cartilage disorders such as growth plate disorders and articular cartilage disorders.
The disclosed antibodies include heavy and light chain variable regions comprising complementarity determining regions (CDRs) derived from specific clones (clone 13, 22, or 26) with high affinity and specificity to matrilin-3. Conjugates formed by linking these antibodies or fragments to chondrogenic agents such as growth hormone, insulin-like growth factor-1 (IGF-1), Indian Hedgehog, bone morphogenetic proteins, C-type natriuretic peptide, Wnt proteins, or steroids can target therapeutic payloads specifically to cartilage tissue, inducing chondrogenesis with reduced adverse systemic effects compared to current therapies.
The problem addressed by this invention arises from the limitations and risks of current treatments for skeletal cartilage disorders, including growth plate disorders such as skeletal dysplasias and short stature. While recombinant growth hormone is used, its systemic administration has suboptimal efficacy and carries risks such as increased intracranial pressure, slipped capital femoral epiphysis, insulin resistance, and possibly diabetes mellitus. There is thus a need for therapies that specifically target cartilage to avoid systemic risks and improve therapeutic outcomes.
Claims Coverage
The patent claims cover a monoclonal antibody or antigen binding molecule specifically binding matrilin-3 and conjugates linked to chondrogenic or anti-arthritis agents, describing their structures, conjugation partners, and methods of use.
Monoclonal antibody or antigen binding molecule specifically binding matrilin-3
An isolated monoclonal antibody or antigen binding molecule comprising heavy and light chain variable regions with specific complementarity determining regions (CDRs) as set forth in SEQ ID NO: 3 and SEQ ID NO: 4 (clone 22), that specifically binds to matrilin-3.
Conjugate of antigen binding molecule linked to chondrogenic or anti-arthritis agent
A conjugate comprising the antigen binding molecule linked to a chondrogenic agent or an anti-arthritis agent, optionally including an Fc domain, with specified arrangements of chondrogenic agent, antibody or antigen binding molecule, and Fc domain.
Chondrogenic agent conjugate composition and variants
Conjugates wherein the chondrogenic agent is IGF-1, the antigen binding molecule is an scFv, and the Fc domain may be either dimerizing or a mutant non-dimerizing IgG Fc domain, including sequences set forth in SEQ ID NOs: 41-46 and 47-48.
Antibodies conjugated to detectable markers or effector molecules
Monoclonal antibodies or antigen binding molecules conjugated to heterologous detectable markers such as fluorescent, enzymatic, heavy metal, or radioactive markers, or to heterologous effector molecules including chondrogenic agents (growth hormone, IGF-1, Indian Hedgehog, bone morphogenetic protein, CNP, Wnt protein, or steroid) or anti-arthritis agents such as parathyroid hormone or fragments thereof.
Methods of increasing chondrogenesis and targeting effector molecules
Methods of increasing chondrogenesis in cartilage tissue by contacting it with a therapeutically effective amount of antibody or antigen binding molecule conjugated to a chondrogenic agent, and methods of targeting an effector molecule to cartilage tissue in a subject by administering an antibody or antigen binding molecule conjugated to the effector molecule, including treatment of arthritis and cartilage disorders such as skeletal dysplasias and short stature.
The claims comprehensively cover isolated antibodies and antigen binding molecules that specifically bind matrilin-3, their conjugates with chondrogenic or anti-arthritis agents, detectable markers, Fc fusion proteins, and methods for targeting and treating cartilage-related disorders by increasing chondrogenesis or addressing arthritis.
Stated Advantages
Targeting therapeutic agents specifically to growth plate and articular cartilage increases therapeutic efficacy while reducing systemic adverse effects.
The antibody fragments bind with high affinity and specificity to matrilin-3, enabling precise targeting of drugs or detectable markers to cartilage tissue.
Conjugation of chondrogenic agents to cartilage-binding antibodies allows local delivery, potentially improving treatment outcomes in growth plate disorders and osteoarthritis.
Documented Applications
Treatment or inhibition of cartilage disorders in subjects, including growth plate disorders such as skeletal dysplasias and short stature.
Increasing chondrogenesis in cartilage tissue to promote bone growth.
Treatment of arthritis, including rheumatoid arthritis and osteoarthritis, by targeting anti-arthritis agents to cartilage tissue.
Detection of matrilin-3 expression in biological samples or in vivo to identify cartilage tissue.
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