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-11680093-B2
Publication Date
2023-06-20
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 provides monoclonal antibodies and antigen binding fragments that specifically bind to matrilin-3, along with conjugates containing these molecules, nucleic acid molecules encoding them, and compositions including these components. These antibodies and fragments target growth plate cartilage and can be conjugated to chondrogenic agents to increase chondrogenesis in cartilage tissue, thus treating or inhibiting cartilage disorders such as skeletal dysplasias and short stature.
The problem addressed is the limited efficacy and systemic risks of current treatments for skeletal cartilage disorders, including recombinant growth hormone therapy, which carries risks such as increased intracranial pressure, slipped capital femoral epiphysis, insulin resistance, and possibly type II diabetes mellitus. Thus, there is a need for therapeutic agents and methods that avoid these systemic risks while effectively targeting cartilage tissue.
The disclosed monoclonal antibodies and antigen binding fragments specifically bind matrilin-3 in the extracellular matrix of growth plate cartilage. Conjugates linking these antibodies or fragments to chondrogenic agents, such as growth hormone or insulin-like growth factor-1 (IGF-1), enable targeted delivery to growth plate cartilage, promoting chondrogenesis while reducing adverse systemic effects. Methods of treating cartilage disorders by administering therapeutically effective amounts of these antibodies, fragments, or conjugates to subjects are provided, with the capability to increase height or treat cartilage disorders.
Claims Coverage
The patent includes multiple independent claims directed at monoclonal antibodies that specifically bind matrilin-3, antigen binding molecules including such antibodies or fragments, and conjugates of these molecules linked to chondrogenic or anti-arthritis agents. The claims cover antibody structures, conjugates, and methods of increasing chondrogenesis or targeting effector molecules to cartilage.
Monoclonal antibody specifically binding matrilin-3
An isolated monoclonal antibody or antigen binding molecule containing heavy and light chain variable regions defined by specific complementarity determining regions (CDRs) amino acid sequences (SEQ ID NOs: 1 and 2) from clone 13, which specifically binds to matrilin-3.
Antigen binding molecule fragments and conjugates linked to chondrogenic or anti-arthritis agents
The antibody or antigen binding molecule can be an Fv, Fab, F(ab')2, scFv or scFv2, and can be conjugated to a chondrogenic agent or anti-arthritis agent, optionally including an Fc domain, with specific arrangements of chondrogenic agent, antibody fragment, and Fc domain, including dimeric or mutant monomeric Fc domains that affect dimerization under physiological conditions.
Chondrogenic agents include IGF-1 and related conjugates
Conjugates comprising the antigen binding molecule and chondrogenic agents such as IGF-1, with the antigen binding molecule as an scFv and an Fc domain (wildtype or mutant), with defined amino acid sequences, retaining binding affinity and specificity to matrilin-3.
Conjugation to detectable markers or effectors to target cartilage tissue
The antibody or antigen binding molecule can be conjugated to detectable markers (fluorescent, enzymatic, heavy metal, radioactive) or effector molecules (such as growth hormone, IGF-1, Indian Hedgehog, bone morphogenetic protein, C-type natriuretic protein, Wnt protein, steroids), enabling therapeutic or diagnostic targeting to cartilage tissue, for increasing chondrogenesis or treating arthritis.
Methods of increasing chondrogenesis and treating cartilage disorders
Methods comprising administering therapeutically effective amounts of the conjugates or antibodies to cartilage tissue or subjects to increase chondrogenesis and treat cartilage disorders including skeletal dysplasias, osteoarthritis, or short stature.
The claims cover isolated monoclonal antibodies specifically binding matrilin-3 with defined variable region sequences, antigen binding fragments and their conjugates linked to chondrogenic or anti-arthritis agents including IGF-1, Fc domain fusions, as well as methods employing these molecules for targeted treatment of cartilage disorders by increasing chondrogenesis or delivering effector molecules to cartilage tissue.
Stated Advantages
The antibodies and conjugates specifically target growth plate cartilage, enabling localized therapy that increases chondrogenesis while diminishing adverse systemic effects observed with current systemic therapies such as growth hormone.
Conjugation of chondrogenic agents to cartilage-binding antibodies enhances therapeutic efficacy and reduces off-target activity, potentially lowering risks such as malignancy and diabetes mellitus.
Targeting paracrine factors and endocrine agents to growth plate cartilage provides novel therapeutic opportunities for skeletal dysplasias, short stature, and joint diseases like osteoarthritis, which are not addressed effectively by current systemic treatments.
Documented Applications
Treating or inhibiting cartilage disorders including growth plate cartilage disorders such as skeletal dysplasias, achondroplasia, short stature, and articular cartilage disorders such as osteoarthritis by administering antibodies or conjugates that specifically bind matrilin-3.
Increasing chondrogenesis in cartilage tissue in vivo or in vitro by contacting cartilage tissue with therapeutically effective amounts of monoclonal antibodies or antigen binding fragments conjugated to chondrogenic agents.
Targeting effector molecules, including chondrogenic agents or anti-arthritis agents, to cartilage tissue in subjects having arthritis or other cartilage disorders.
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