Binders of TGFβ-superfamily ligands and uses thereof
Inventors
Kumar, Ravindra • Sako, Dianne S. • Castonguay, Roselyne • Kuo, Tzu-Hsing
Assignees
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Publication Number
US-12168683-B2
Publication Date
2024-12-17
Expiration Date
Abstract
In certain aspects, the disclosure provides multispecific binders (e.g., ActRIIB:TβRII heteromultimers comprising an ActRIIB polypeptide and a TβRII polypeptide). In some embodiments, the disclosure provides for novel binders comprising a TβRII polypeptide and a heterologous portion. The disclosure further provides that such multispecific binders (e.g., ActRIIB:TβRII heteromultimer) may be used to treat various disorders or conditions.
Core Innovation
The invention relates to a heteromultimer comprising an ActRIIB fusion protein and a TRII fusion protein. The heteromultimer binds to and/or inhibits one or more TGF-superfamily ligands, including GDF11, GDF8, activin A, activin B, BMP10, TGF1, TGF2, and TGF3, and each fusion protein further comprises a heterologous portion.
The ActRIIB fusion protein comprises an ActRIIB polypeptide defined by at least 98% identity to specified SEQ ID sequences or selected start and end position ranges, and the TRII fusion protein comprises a TRII polypeptide defined by at least 98% identity to specified SEQ ID sequences or selected start and end position ranges. The constructs are described in Fc-containing formats with sequence-defined receptor polypeptides.
The document describes heteromultimer and heterodimer architectures designed for asymmetric heteromer formation, including Fc engineering for interface-defined assembly. The receptor ectodomains are fused to heterologous Fc domains, and the constructs include Fc domain design features and mutations, together with electrostatic steering, knobs-into-holes, SEEDbody, and leucine zipper pairing.
Claims Coverage
The consolidated claim coverage centers on an ActRIIB:TRII heteromultimer with sequence-defined ActRIIB and TRII fusion proteins, each including a heterologous portion. The independent claim content identifies three core inventive features: the ActRIIB fusion protein, the TRII fusion protein, and binding to and/or inhibition of specified ligands.
Heteromultimer with actriib fusion and Trii fusion
A heteromultimer comprising an ActRIIB fusion protein and a TRII fusion protein, wherein the heteromultimer binds to and/or inhibits one or more of GDF11, GDF8, activin A, activin B, BMP10, TGF1, TGF2, and TGF3, and wherein the ActRIIB fusion protein and the TRII fusion protein further comprise a heterologous portion.
Actriib fusion protein defined by high-identity sequence regions
An ActRIIB fusion protein comprising an ActRIIB polypeptide that is at least 98% identical to specified SEQ ID sequences or selected start and end position ranges.
Trii fusion protein defined by high-identity sequence regions
A TRII fusion protein comprising a TRII polypeptide that is at least 98% identical to specified SEQ ID sequences or selected start and end position ranges.
Immunoglobulin Fc domain as the heterologous portion
The heteromultimer includes a heterologous portion that is an immunoglobulin Fc domain.
Fc domain sequence defined by high identity and Kabat EU-positioned residues
The immunoglobulin Fc domain has an amino acid sequence that is at least 98% identical to specified SEQ ID sequences and is characterized by Kabat EU-positioned residues.
Overall, the claims coverage centers on a heteromultimer defined by ActRIIB and TRII fusion polypeptides specified by at-least-98% identity to SEQ IDs or defined start and end position ranges, with binding and/or inhibition of a specified panel of ligands. Dependent features specify that the heterologous portion is an immunoglobulin Fc domain and further constrain Fc sequence identity and Kabat EU-positioned residues.
Stated Advantages
Enables binding and/or inhibition of one or more ligands selected from GDF11, GDF8, activin A, activin B, BMP10, TGF1, TGF2, and TGF3.
Antagonizes a broad Smad2/3 ligand set while showing reduced BMP9 signaling inhibition versus ActRIIB homodimers.
Documented Applications
Screening assays for identifying agonists and antagonists of ActRIIB/TRII signaling using ActRIIB:TRII heteromultimers.
Therapeutic use across tissue growth disorders.
Therapeutic use for muscular disorders, including muscular dystrophy, muscle wasting/fibrosis, DMD/BMD, ALS, CMT, cachexia, and sarcopenia.
Therapeutic use for pulmonary hypertension, interstitial lung disease, idiopathic pulmonary fibrosis, and fibrotic conditions.
Therapeutic use for cancer and tumors.
Therapeutic use for dysplasia.
Therapeutic use for anemia-related conditions, including ineffective erythropoiesis, thalassemia, MDS, myelofibrosis, and sickle cell disease.
Therapeutic use for kidney diseases, including CKD, CKD-MBD, Alport syndrome, PKD, and renal fibrosis.
Pharmaceutical compositions and gene therapy delivery concepts described for use with the ActRIIB:TRII heteromultimers.
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