Antibodies for Siglec-15 and methods of use thereof
Inventors
Liu, Linda • Flies, Benjamin Dallas • Langermann, Solomon
Assignees
Publication Number
US-11390675-B2
Publication Date
2022-07-19
Expiration Date
2037-09-21
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Abstract
Siglec-15 binding molecules are provides. The molecules are typically an antibody or antigen binding fragment thereof that immunospecifically binds to Siglec-15. Siglec-15 ligand-binding molecules are also provided. The molecules are typically Siglec-15 polypeptide or fusion protein. Methods of using the molecules to reduce Siglec-15 mediated immunosuppression in a subject in need thereof are also provided.
Core Innovation
Siglec-15 binding molecules, particularly monoclonal antibodies or antigen-binding fragments thereof, are developed to specifically recognize and bind to Siglec-15. These antibodies are characterized at the molecular level by their complementarity determining regions (CDRs) and variable regions, conferring highly specific binding properties to the Siglec-15 epitope. The patent provides detailed sequence information for the light and heavy chain CDRs and variable regions of these antibodies, including both mouse-derived and humanized versions.
The invention addresses the need for tools and therapeutic strategies to modulate Siglec-15 and its downstream signaling. Siglec-15 has been implicated in immune suppression, particularly by enhancing TGF-β secretion from myeloid cells such as macrophages, thereby contributing to tumor progression and creating an immunosuppressive microenvironment. By blocking Siglec-15 interactions with its ligands or counter-receptors, these antibodies are capable of reducing Siglec-15-mediated immune suppression and can enhance immunological responses or reverse suppression in a subject in need thereof.
Additionally, the patent provides methods for using these Siglec-15 antibodies in pharmaceutical compositions for treating diseases and conditions associated with Siglec-15 function, including cancer, infections, inflammations, autoimmune diseases, as well as bone-related disorders by affecting osteoclast differentiation and bone resorption. The document further describes diagnostic and monitoring applications, leveraging the antibodies’ ability to detect Siglec-15 expression in tissues or peripheral samples.
Claims Coverage
There is one independent claim providing a key inventive feature centered on a specific Siglec-15 antibody characterized by its unique CDR sequences and variable regions.
Monoclonal antibody with defined Siglec-15 CDR sequences
A monoclonal antibody or antigen-binding fragment thereof that binds specifically to SIGLEC-15, wherein the antibody comprises these six CDR sequences: - Three heavy chain CDRs (HCDR1: SEQ ID NO:208, HCDR2: SEQ ID NO:374, HCDR3: SEQ ID NO:71) - Three light chain CDRs (LCDR1: SEQ ID NO:198, LCDR2: SEQ ID NO:202, LCDR3: SEQ ID NO:43). This structural definition confers unique specificity for SIGLEC-15. The antibody may include the heavy chain variable region with amino acid sequence SEQ ID NO:207 and the light chain variable region with sequence SEQ ID NO:201.
Pharmaceutical composition with the defined antibody
A pharmaceutical composition comprising the above-defined monoclonal antibody or antigen-binding fragment in combination with an excipient. This composition is intended for administration and therapeutic use, leveraging the antibody's specific SIGLEC-15 binding profile.
The inventive features are focused on a monoclonal antibody defined by precise heavy and light chain CDR sequences and variable regions conferring specificity to Siglec-15, as well as pharmaceutical compositions comprising this antibody.
Stated Advantages
The molecules can reduce or reverse Siglec-15-mediated immunosuppression, thereby increasing an immune response in a subject in need thereof.
Methods using these antibodies can inhibit or retard tumor growth, reduce tumor-mediated immune suppression, eliminate tumors, and deplete or block the activity of tumor-associated macrophages to alter their function.
Antagonistic Siglec-15 binding molecules can decrease TGF-β secretion by macrophages, reduce or reverse T cell suppression, and increase T cell proliferation.
Agonistic Siglec-15 binding molecules can decrease immune responses, increase or enhance T cell suppression, and increase TGF-β secretion by macrophages, which is beneficial for treating inflammation, autoimmune diseases, or in transplant recipients.
The antibodies can detect Siglec-15 expression in tissues or samples, enabling diagnosis, disease monitoring, and assessment of treatment responses.
Siglec-15 antagonists can reduce osteoclast differentiation, bone resorption, and increase bone formation, offering a selective therapeutic strategy for bone-related disorders.
Documented Applications
Treatment of cancer by administering Siglec-15 antibodies to retard tumor growth, inhibit tumor-mediated immune suppression, and target tumor-associated macrophages.
Treatment of infectious diseases (including acute and chronic infections) via administration of Siglec-15 antagonists to enhance immune responses.
Treatment of inflammatory and autoimmune disorders, as well as transplant rejection and graft-versus-host disease, using agonistic Siglec-15 antibodies to reduce or inhibit immune responses.
Reduction of osteoclast differentiation, bone resorption, and increase in bone formation by administration of Siglec-15 binding molecules to treat bone-related disorders.
Diagnostic and monitoring methods using Siglec-15 antibodies to detect and measure expression of Siglec-15 for disease diagnosis, monitoring progression, and evaluating treatment response.
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