MHC class II T-cell modulatory multimeric polypeptides for treating type 1 diabetes mellitus (T1D) and methods of use thereof

Inventors

Seidel, III, Ronald D. • Chaparro, Rodolfo J. • Ross, John F. • Low, Chee Meng

Assignees

Cue Biopharma Inc

Abstract

The present disclosure provides T-cell modulatory multimeric polypeptides (TMMPs) comprising a type 1 diabetes (T1D)-associated peptide epitope, MHC class II polypeptides, and PD-L1 polypeptides. A TMMP of the present disclosure is useful for modulating activity of a T cell. Thus, the present disclosure provides compositions and methods for modulating the activity of T cells, as well as compositions and methods for treating persons who have T1D.

Core Innovation

The disclosed invention relates to T-cell modulatory multimeric polypeptides (TMMPs) for treating type 1 diabetes (T1D). The TMMPs include a T1D-associated peptide epitope, MHC class II (HLA) alpha and beta polypeptides, and one or more immunomodulatory polypeptides. Immunomodulatory polypeptides include PD-L1, and other immunomodulatory polypeptides and variants are described.

The invention emphasizes TMMP design as disulfide-linked heterodimers, including configurations that use Ig Fc polypeptide scaffolds. Disulfide linkage is used to increase stability and/or expression compared to non-disulfide controls. Covalent linkage strategies are described for forming disulfide bonds between MHC chains, between Cys-containing linkers and MHC domains, or via Ig Fc-mediated linkage.

A modular component framework is described, including immunomodulatory polypeptide candidates and variant requirements, the selection of T1D peptide epitope examples, and arrangements that vary the position of the immunomodulatory polypeptide (MOD position 1–5). A large catalog of MHC class II alpha/beta chain types and Cys-substitution variants is described, including allelic forms and Cys-substitution variants relevant to T1D-associated HLA risk haplotypes such as DR3/DR4 and DQ2/DQ8.

The patent describes a T-cell modulatory multimeric polypeptide (TMMP) and nucleic acids and recombinant expression systems encoding TMMP/APP polypeptides. The disclosed TMMP is a homodimer of two heterodimers, wherein each heterodimer comprises a first polypeptide having the amino acid sequence set forth in SEQ ID NO: 185 and a second polypeptide having the amino acid sequence set forth in SEQ ID NO: 186.

Claims Coverage

The claim set includes two independent structural presentations of the TMMP architecture. In each, the TMMP is a homodimer of two heterodimers covalently linked through disulfide bonds formed between Ig Fc polypeptides in the second polypeptide of each heterodimer, with a dependent refinement to a pharmaceutical composition.

Overall, the claims cover a structurally defined TMMP formed as a homodimer of two heterodimers, with covalent disulfide linkage between heterodimers through Ig Fc polypeptides, and include a further refinement to formulation as a pharmaceutical composition.

Stated Advantages

Documented Applications