T-cell modulatory multimeric polypeptides and methods of use thereof
Inventors
Seidel, III, Ronald D. • Chaparro, Rodolfo J.
Assignees
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Publication Number
US-12152061-B2
Publication Date
2024-11-26
Expiration Date
Abstract
The present disclosure provides variant immunomodulatory polypeptides, and fusion polypeptides comprising the variant immunomodulatory peptides. The present disclosure provides T-cell modulatory multimeric polypeptides, and compositions comprising same, where the T-cell modulatory multimeric polypeptides comprise a variant immunomodulatory polypeptide of the present disclosure. The present disclosure provides nucleic acids comprising nucleotide sequences encoding the T-cell modulatory multimeric polypeptides, and host cells comprising the nucleic acids. The present disclosure provides methods of modulating the activity of a T cell; the methods comprise contacting the T cell with a T-cell modulatory multimeric polypeptide of the present disclosure.
Core Innovation
The invention provides synTac (T-cell modulatory multimeric) fusion and multimeric polypeptides that function as surrogate APCs. The polypeptides couple TCR-targeting epitopes presented by MHC class I, including HLA class I/b2-microglobulin or MHC class I heavy chain, with an immunomodulatory domain including a variant IL-2. The architecture is configured to present an epitope to a T cell receptor as multimeric heterodimer assemblies.
The multimeric design includes engineered cysteine residues and disulfide bond design between b2M and the MHC class I heavy chain, together with Ig Fc polypeptide association. The assemblies further join two heterodimers through one or more disulfide bonds that join the Ig Fc polypeptide of one heterodimer to the Ig Fc polypeptide of the other heterodimer, forming a homodimer of two heterodimers.
The immunomodulatory activity is implemented using variant IL-2 polypeptides with reduced IL-2R affinity, described as variant IL-2 amino acid sequences with specified substitutions and combinations. The partial content also states sequence identity thresholds, BLAST-based identity determination, peptide linker arrangements, and positional amino-acid constraints at defined IL-2 positions.
Claims Coverage
The independent claims cover two heterodimer-based pharmaceutical compositions, each built into a homodimer of two heterodimers. Across the claims, the inventive features include epitope presentation by a virus-associated peptide/b2M and MHC class I heavy chain, disulfide-linked Fc association, and a second polypeptide containing two linked variant IL-2 copies with specified sequence-identity and positional constraints.
Homodimer of two heterodimers with disulfide-linked b2M-MHC epitope module and two linked variant IL-2 copies
A pharmaceutical composition comprising a homodimer of two heterodimers, wherein each heterodimer comprises a first polypeptide with a virus-associated peptide other than a peptide associated with a human papilloma virus and a b2-microglobulin (b2M) polypeptide; and a second polypeptide comprising two copies of a variant IL-2 polypeptide linked by a peptide linker, an MHC Class I heavy chain polypeptide, and an Ig Fc polypeptide, with a disulfide bond covalently linking a Cys residue in the b2M polypeptide to a Cys residue in the MHC class I heavy chain polypeptide; wherein each heterodimer presents an epitope to a T cell receptor; wherein the two heterodimers are joined by one or more disulfide bonds joining the Ig Fc polypeptide of one heterodimer to the Ig Fc polypeptide of the other heterodimer; wherein the MHC Class I heavy chain is HLA-A, HLA-B, or HLA-E; and wherein percent sequence identity is determinable by BLAST.
IgG1 Fc, defined b2M and HLA-A heavy chain, and restricted variant IL-2 position-16 amino acid identities with BLAST-based identity measurement
A pharmaceutical composition wherein each heterodimer comprises an IgG1 Fc polypeptide with at least about 95% amino acid sequence identity to SEQ ID NO:57; wherein the b2M polypeptide comprises at least 95% amino acid sequence identity to amino acids 21 to 119 of SEQ ID NO:95; wherein the MHC Class I heavy chain polypeptide is an HLA-A heavy chain polypeptide; and wherein amino acid 16 in each variant IL-2 polypeptide is Ala, Glu, Thr, or Asp, with percent sequence identity determinable by sequence alignment performed using BLAST.
The independent claims define a disulfide-connected heterodimer/Fc-associated homodimer configuration that presents an epitope to a T cell receptor using MHC class I and b2M, coupled to a variant IL-2 component carried as two linked copies with defined sequence identity and position constraints. The second independent claim further tightens Fc, b2M, and HLA-A identity constraints and restricts the allowable amino acid at variant IL-2 position 16.
Stated Advantages
Selective modulation of T cells in a patient.
Documented Applications
Selective modulation of T cells in a patient by administering the pharmaceutical composition.
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