Variant ActRIIB proteins and uses thereof
Inventors
Kumar, Ravindra • Grinberg, Asya • Vogan, Erik M.
Assignees
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Publication Number
US-12240887-B2
Publication Date
2025-03-04
Expiration Date
Abstract
In certain aspects, the present invention provides compositions and methods for modulating (promoting or inhibiting) growth of red blood cells or a tissue, such as bone, cartilage, muscle, fat, and/or neuronal tissue. The present invention also provides methods of screening compounds that modulate activity of an ActRIIB protein and/or an ActRIIB ligand. The compositions and methods provided herein are useful in treating diseases associated with abnormal activity of an ActRIIB protein and/or an ActRIIB ligand.
Core Innovation
The invention relates to ActRIIB polypeptides defined by sequence identity to specified regions of SEQ ID NO: 2 and by the inclusion of a glutamic acid at a position corresponding to position 55 of SEQ ID NO: 2. The polypeptides are soluble extracellular domain variants described as homomultimers and heteromultimers, including homodimers and heterodimers, and include ActRIIB-Fc fusion polypeptides and variant ActRIIB-Fc homodimers.
These ActRIIB polypeptides maintain inhibition of activin A and GDF11 while demonstrating less potent inhibition of BMP9 compared to a wild type ActRIIB polypeptide. The disclosure also describes selective antagonism of activin B, GDF8, GDF11, and BMP6, together with altered binding kinetics and selective modulation of TGF-beta superfamily ligands.
The document further describes recombinant expression constructs and vectors for producing variant ActRIIB proteins, guided asymmetric Fc pairing, glycosylation, and engineered disulfide, electrostatic steering, knobs-into-holes, SEEDbody, and leucine zipper pairing strategies for selective chain association and heteromultimer formation. It also includes screening methods for compounds that modulate ActRIIB activity and ligand binding, and therapeutic-use concepts for modulating RBC growth, tissue growth, muscle growth, bone/cartilage growth, obesity/weight control, anemia/red blood cell production, and gene-therapy delivery context.
Claims Coverage
The independent claim coverage centers on three inventive features: sequence-identity-defined ActRIIB extracellular domain variants, a required glutamic acid at the residue corresponding to position 55 of SEQ ID NO: 2, and ligand-selective inhibitory activity with maintained inhibition of activin A and GDF11 and less potent BMP9 inhibition versus wild type ActRIIB.
Sequence identity-defined ActRIIB extracellular region variant
An ActRIIB polypeptide comprising an amino acid sequence at least 90% identical to amino acids 20-134 of SEQ ID NO: 2, at least 90% identical to amino acids 29-109 of SEQ ID NO: 2, or at least 90% identical to amino acids 25-131 of SEQ ID NO: 2.
Required glutamic acid at position corresponding to SEQ ID NO: 2 position 55
The ActRIIB polypeptide comprises a glutamic acid at the position corresponding to position 55 of SEQ ID NO: 2.
Maintained inhibition of activin A and GDF11 with less potent BMP9 inhibition versus wild type
The ActRIIB polypeptide maintains inhibition of activin A and GDF11 and demonstrates less potent inhibition of BMP9 compared to a wild type ActRIIB polypeptide.
Overall, the independent claims are directed to ActRIIB polypeptides defined by high sequence identity to specified regions of SEQ ID NO: 2, a glutamic acid at position 55, and selective ligand inhibition that preserves activin A and GDF11 inhibition while reducing BMP9 inhibition relative to wild type ActRIIB.
Stated Advantages
Selective antagonism that reduces antagonism of activin A, BMP9, and BMP10 while retaining antagonism of activin B, GDF8, GDF11, and BMP6.
Maintains inhibition of activin A and GDF11 while demonstrating less potent inhibition of BMP9 compared to a wild type ActRIIB polypeptide.
Therapeutic utility for the described selective antagonism pattern.
Documented Applications
Therapeutically useful selective antagonism of activin A, BMP9, and BMP10 while retaining antagonism of activin B, GDF8, GDF11, and BMP6.
Modulating RBC growth and tissue growth.
Screening compounds that modulate ActRIIB activity and ligand binding.
Muscle growth assays and therapeutic utility related to muscle growth.
Bone/cartilage growth assays and therapeutic utility related to bone/cartilage growth.
Obesity/weight control (adipogenesis) assays and therapeutic utility related to obesity/weight control.
Anemia/red blood cell production (RBC) assays and therapeutic utility related to anemia/red blood cell production.
Gene-therapy delivery context is explicitly described as part of therapeutic utility.
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