Anti-ALK2 antibodies and uses thereof
Inventors
Hunter, Jeffrey William • Chandler, Julian • BOUCHARD, Keith • Marozsan, Andre • Bento, Patricia • Kukreja, Anjli
Assignees
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Publication Number
US-12428484-B2
Publication Date
2025-09-30
Expiration Date
Abstract
Provided herein are antibodies that bind to activin receptor-like kinase 2 (ALK2) and are useful for treating bone disorders, such as those involving reduced bone mineral density and bone mineralization defects, and promoting bone growth. Also provided are polynucleotides encoding the antibodies, vectors comprising the polynucleotides, and cells that produce the antibodies.
Core Innovation
The disclosure relates to an isolated antibody that binds to activin receptor-like kinase 2 (ALK2). The antibody is defined by specific heavy chain and light chain CDR1, CDR2, and CDR3 sequences set out as particular SEQ ID NOs, with multiple defined heavy-chain/light-chain CDR set groupings.
The disclosed ALK2-targeting antibodies are evaluated in an ALK2 signaling context using a BRE-luciferase BMP9 signaling assay, including comparison with a parent antibody identified as JAB0481. Affinity-matured anti-ALK2 monoclonal antibody variants show improved potency versus the parent mAb, and binding kinetics to the ALK2 extracellular domain are characterized using Biacore with reduced off-rate.
The materials also describe binding specificity and humanization of the anti-ALK2 antibody based on JAB0481. In vivo efficacy is reported in an osteopenia mouse model, and the antibodies are associated with stimulation of bone mineralization and increased bone mineral density.
Claims Coverage
The provided claim coverage centers on one independent claim directed to an isolated ALK2-binding antibody defined by specified heavy-chain and light-chain CDR sequences. The partial claim set also includes alternative CDR-set groupings and related antibody formats and constructs, for a total of six inventive features.
Isolated ALK2-binding antibody defined by heavy and light chain CDR sequences
An isolated antibody that binds to activin receptor-like kinase 2 (ALK2) comprising heavy chain CDR1, CDR2, and CDR3 sequences and light chain CDR1, CDR2, and CDR3 sequences, where the CDR sequences are defined by specific SEQ ID NOs.
Multiple defined CDR set groupings for ALK2 binding
The antibody comprises one of multiple enumerated combinations of heavy-chain CDR1/CDR2/CDR3 sequences and corresponding light-chain CDR1/CDR2/CDR3 sequences, each combination being specified by sets of SEQ ID NOs.
Monoclonal ALK2-binding antibody with variable-region sequence-identity constraints
An isolated monoclonal antibody or antigen-binding portion that binds ALK2 and includes heavy- and light-chain sequences with at least 90% identity to specified SEQ ID NO pairs.
ALK2-binding antibody formats including effectorless Fc and multiple antibody types
The antibody is defined as one or more of IgG1, IgG2, IgG3, and/or IgG4 antibody or variant, containing an effectorless Fc region, including an IgG2/IgG4 hybrid Fc region, and/or being a full-length antibody or an antigen-binding fragment, including chimeric, human, or humanized antibodies, and/or having a second binding specificity.
Immunoconjugate linking an ALK2-binding antibody to an agent
An immunoconjugate comprising linking the isolated antibody or antigen-binding portion to an agent.
Carrier-containing composition comprising an ALK2-binding antibody
A composition comprising the isolated antibody or antigen-binding portion together with a carrier.
Coverage is centered on isolated ALK2-binding antibodies defined by particular heavy-chain and light-chain CDR1, CDR2, and CDR3 sequences, with alternative enumerated CDR-set groupings, sequence-identity constraints, antibody format selections including effectorless Fc and IgG subclasses, and related immunoconjugate and carrier-containing composition claims.
Stated Advantages
Affinity-matured anti-ALK2 mAb variants show markedly improved potency in a BRE-luciferase BMP9 signaling assay versus the parent JAB0481.
Affinity-matured antibodies show complete inhibition of BMP9-mediated ALK2 signaling at the highest tested conditions where JAB0481 does not fully inhibit at the reported condition.
Affinity-matured antibodies exhibit improved binding affinities to the ALK2 extracellular domain in Biacore characterization, associated with reduced off-rate.
Increases bone mineral density.
Stimulates bone mineralization.
Increases cortical thickness.
Inhibits BMP ligand/SMAD signaling.
No adverse disruption of bone morphology or growth is stated in the disclosure provided.
Specificity is evaluated for binding to baculovirus particles using BVP risk scores.
Documented Applications
Use in a BRE-luciferase BMP9 signaling assay to evaluate ALK2 signaling inhibition by affinity-matured anti-ALK2 monoclonal antibody variants compared with a parent antibody.
Assessment of antibody specificity by ELISA binding to baculovirus particles with BVP risk score evaluation.
Binding-kinetics characterization of ALK2 extracellular domain (ECD) interaction using Biacore.
Humanization of the anti-ALK2 antibody based on JAB0481.
Binding to human tissue.
In vivo efficacy in an osteopenia mouse model, including use of JAB0505 and measurement using μCT bone metrics in OVX C57Bl/6J mice.
Therapeutic and/or prophylactic use for bone disorders, including osteoporosis or osteopenia and fractures, is described.
Use in an ALK2 detection assay is described.
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