Agents that specifically bind 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-10323083-B2
Publication Date
2019-06-18
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
The invention discloses monoclonal antibodies and antibody fragments that specifically bind to matrilin-3, conjugates including these molecules linked to chondrogenic or anti-arthritis agents, and nucleic acid molecules encoding such antibodies or conjugates. Methods of treating or inhibiting cartilage disorders and of increasing chondrogenesis in cartilage tissue using these antibodies or conjugates are provided. These methods address treatment of growth plate disorders such as skeletal dysplasias and short stature, as well as articular cartilage disorders such as osteoarthritis.
The problem solved by this invention is the limited efficacy and systemic adverse effects of current therapies for skeletal cartilage disorders, such as the systemic administration of growth hormone which can lead to increased intracranial pressure, slipped capital femoral epiphysis, insulin resistance, and possibly type II diabetes mellitus. Existing paracrine growth factors have local action in the growth plate and are not readily usable for systemic administration. There is a need for therapeutic agents and treatment methods that specifically target growth plate cartilage, thereby improving efficacy and reducing adverse systemic effects.
The invention provides isolated monoclonal antibodies and antigen binding fragments specifically binding matrilin-3, which is primarily expressed in growth plate and articular cartilage extracellular matrix. These antibodies can include specific heavy and light chain variable regions and complementarity determining regions derived from identified clones (13, 22, 26). Conjugating such antibodies or antigen binding fragments to chondrogenic agents such as growth hormone, IGF-1, Indian Hedgehog, bone morphogenetic proteins, C-type natriuretic peptide, Wnt proteins, or steroids, allows targeting therapeutic payloads specifically to cartilage tissue. This targeting increases chondrogenesis and diminishes adverse effects on non-target tissues.
Claims Coverage
The patent includes multiple inventive features directed to monoclonal antibodies specifically binding matrilin-3, their structural characteristics, conjugation to effector molecules, and methods of using such conjugates to treat cartilage disorders.
Monoclonal antibodies specifically binding matrilin-3
An isolated monoclonal antibody comprising heavy and light chain variable regions including specific complementarity determining regions (CDRs) derived from SEQ ID NOs: 5 and 6 (clone 26) that specifically binds to matrilin-3.
Variants and framework characteristics of matrilin-3 antibodies
Monoclonal antibodies with heavy and light chain variable regions at least 80% identical to SEQ ID NOs: 5 and 6 and comprising respective CDR sequences, optionally comprising a human framework region and being IgG isotype.
Conjugation to detectable markers and effector molecules
Monoclonal antibodies conjugated to heterologous detectable markers (fluorescent, enzymatic, heavy metal, radioactive) or heterologous effector molecules, including chondrogenic agents such as growth hormone, insulin-like growth factor-1, Indian hedgehog, bone morphogenetic protein, C-type natriuretic protein, Wnt protein, biologically active fragments inducing chondrogenesis, or steroids.
Therapeutic methods using antibody conjugates
Methods of increasing chondrogenesis or targeting chondrogenic agents to cartilage tissue in a subject by administering therapeutically effective amounts of the antibody conjugated to a chondrogenic agent to form an immune complex. Methods are applicable to subjects with cartilage disorders including skeletal dysplasias (achondroplasia, hypochondroplasia, SHOX deficiency), osteoarthritis, or short stature of various etiologies.
Conjugates comprising antibodies linked to anti-arthritis agents
Monoclonal antibodies conjugated to anti-arthritis agents, such as parathyroid hormone or biologically active fragments thereof, and methods of targeting such conjugates to cartilage tissue in subjects with arthritis or cartilage disorders.
Compositions and kits
Pharmaceutical compositions comprising the described monoclonal antibodies, and kits comprising the antibodies and instructions for treating cartilage disorders.
The claims cover isolated monoclonal antibodies specifically binding matrilin-3 with defined structural features, their variants and isotypes, conjugation to various effector molecules including chondrogenic and anti-arthritis agents, methods of treatment of cartilage disorders including skeletal dysplasias and osteoarthritis using such conjugates, and related compositions and kits.
Stated Advantages
Targeted delivery of therapeutic agents specifically to growth plate cartilage increases efficacy and reduces adverse systemic effects associated with current treatments, such as growth hormone therapy.
Antibody fragments exhibit high affinity and specificity for matrilin-3 and cartilage tissue, enabling precise targeting of conjugated chondrogenic or anti-arthritis agents.
Coupling cartilage-binding antibodies to endocrine and paracrine signaling molecules allows creation of localized depots in cartilage, enhancing sustained therapeutic effect.
Documented Applications
Treating or inhibiting cartilage disorders including growth plate cartilage disorders (such as skeletal dysplasias including achondroplasia, hypochondroplasia, SHOX deficiency) and short stature.
Treating or inhibiting articular cartilage disorders, such as osteoarthritis.
Increasing chondrogenesis in cartilage tissue, including growth plate cartilage and articular cartilage.
Targeted drug delivery to growth plate or articular cartilage in subjects using antibody conjugates linked to chondrogenic or anti-arthritis agents.
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