Multispecific binders of TGFBeta-superfamily ligands and uses thereof
Inventors
Kumar, Ravindra • Sako, Dianne S. • Castonguay, Roselyne • Kuo, Tzu-Hsing
Assignees
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Publication Number
US-12103959-B2
Publication Date
2024-10-01
Expiration Date
Abstract
In certain aspects, the disclosure provides multispecific binders (e.g., ActRIIA:TβRII heteromultimers comprising an ActRIIA polypeptide and a TβRII polypeptide). The disclosure further provides that such multispecific binders (e.g., ActRIIA:TβRII heteromultimer) may be used to treat various disorders or conditions.
Core Innovation
The invention provides a heteromultimer comprising an ActRIIA fusion protein and a TβRII fusion protein. The ActRIIA fusion protein comprises an ActRIIA polypeptide defined by specific contiguous sequence regions within SEQ ID NO: 50, or by the sequences of SEQ ID NO: 51 or SEQ ID NO: 52. The TβRII fusion protein comprises a TβRII polypeptide defined by specific contiguous sequence regions within SEQ ID NO: 1 or SEQ ID NO: 2, or by the sequences of SEQ ID NO: 18 or SEQ ID NO: 27, or specified other SEQ ID NOs.
The heteromultimer binds to and/or inhibits one or more of GDF11, activin A, activin B, TGFβ1, and TGFβ3. The ActRIIA fusion protein and the TβRII fusion protein comprise a heterologous portion, and the disclosure describes soluble ActRIIA:TβRII heteromultimer formats with multispecific binding and antagonism across GDF11, activin family ligands, and TGFβ isoforms.
Dependent aspects further define the fusion architecture with linker domains between the receptor polypeptides and the heterologous portion, including (GGGGS)n linker variants and other specified linker sequences. The heterologous portion is described in narrowed embodiments as an immunoglobulin Fc domain with specified sequence identity and Kabat EU-numbered residue constraints, including engineered Fc-domain substitutions intended to favor heterodimer formation over homodimers.
Claims Coverage
The consolidated claim coverage centers on one independent ActRIIA:TβRII heteromultimer claim, with dependent refinements that define receptor sequence regions, linker domains, and the heterologous portion. Across the inputs, four inventive feature groupings are consistently supported: sequence-defined ActRIIA and TβRII fusion components, multispecific binding and/or inhibition of selected ligands, heterologous portion architecture, and Fc-domain narrowing with sequence identity and Kabat EU residue constraints.
Sequence-defined ActRIIA fusion protein extracellular domain boundaries
The ActRIIA fusion protein comprises an ActRIIA polypeptide defined by contiguous sequence regions within SEQ ID NO: 50, or by the sequences of SEQ ID NO: 51 or SEQ ID NO: 52.
Sequence-defined TβRII fusion protein extracellular domain boundaries
The TβRII fusion protein comprises a TβRII polypeptide defined by contiguous sequence regions within SEQ ID NO: 1 or SEQ ID NO: 2, or by the sequences of SEQ ID NO: 18 or SEQ ID NO: 27, or by specified other SEQ ID NOs.
Multispecific binding and/or inhibition of TGFβ-superfamily ligands
The heteromultimer binds to and/or inhibits one or more of GDF11, activin A, activin B, TGFβ1, and TGFβ3.
Heterologous portion in the ActRIIA and TβRII fusion proteins
The ActRIIA fusion protein and the TβRII fusion protein comprise a heterologous portion, in some embodiments defined by linker domains, interaction-pair members, or heterodimer-promoting amino acid modifications.
Defined heterologous portion as an immunoglobulin Fc domain
The heterologous portion is an immunoglobulin Fc domain in narrowed embodiments.
Immunoglobulin Fc domain identity and Kabat EU-position residue constraints
The immunoglobulin Fc domain comprises an amino acid sequence at least 75% identical to one of specified SEQ ID NO sequences and is characterized by particular residue types at specific Kabat EU-numbered positions.
Overall, the claims cover an ActRIIA:TβRII heteromultimer defined by SEQ ID NO-based ActRIIA and TβRII regions, with functional binding and/or inhibition of GDF11, activin A, activin B, TGFβ1, and TGFβ3. Dependent refinements further define linker architecture and narrow the heterologous portion to an immunoglobulin Fc domain with specified sequence identity and Kabat EU residue constraints.
Stated Advantages
Enables binding to and/or inhibition of one or more of GDF11, activin A, activin B, TGFβ1, and TGFβ3.
The TβRII fusions with a (GGGGS)4 linker show stronger affinity for TGFβ1/TGFβ3 than n<4, while n>4 retains similar inhibitory properties.
Engineered Fc-domain substitutions are intended to favor ActRIIA–TβRII heterodimer formation over homodimers.
The examples describe Fc engineering intended to facilitate purification of desired heteromeric species.
The results are described as showing distinct selectivity between TGFβs versus activin/GDFs and increased selectivity versus ActRIIA homodimer for BMP10 inhibition.
Documented Applications
Polynucleotides, cells, and pharmaceutical preparations.
Therapeutic uses across pulmonary, cancer, kidney, anemia, fibrotic/sclerotic indications, skeletal muscle disorders, and additional multispecific configurations involving TβRII with other binding elements.
Cell-based differential ligand inhibition in A549 reporter assays.
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