Fusion protein comprising IL-2 protein and CD80 protein, and use thereof
Inventors
Assignees
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Publication Number
US-11492384-B2
Publication Date
2022-11-08
Expiration Date
Abstract
Provided is a fusion protein comprising IL-2 protein and CD80 protein. A fusion protein comprising CD80 fragment, immunoglobulin Fe, and an IL-2 variant can activate immune cells, such as natural killer cells, and at the same time, can control immune cell regulatory activity of regulatory T cells. Therefore, a pharmaceutical composition comprising the fusion protein as an active ingredient is very industrially useful in that such pharmaceutical composition can increase immune activity in the body, and thus can be effectively used against infectious diseases as well as cancer.
Core Innovation
The invention relates to a CD80–Fc–IL-2 fusion protein that includes a CD80 protein, an Fc domain, and an IL-2 protein arranged in a defined structural formula. The fusion protein is presented in two structural forms in which the order of the CD80 and IL-2 portions relative to the Fc domain can be swapped, while maintaining peptide linkers between the N′-proximal portion and the Fc domain and between the Fc domain and the C′-proximal portion.
X is the CD80 protein and Y is the IL-2 protein, and the fusion protein uses peptide linkers and an Fc domain positioned between the CD80 and IL-2 portions according to structural formula (I) or (II). The document further defines embodiments that use CD80 fragments as well as IL-2 variants defined by specified amino-acid substitution combinations, and Fc domain sequences defined in terms of specific amino-acid sequences identified by SEQ ID NOs.
The document describes functional characterization of the fusion protein constructs, including binding affinity and kinetics to CTLA-4, PD-L1, PD-1, and IL-2Rα/β, and immune activation readouts such as IFN-γ secretion as well as effects on T cell and NK proliferation and effects on regulatory T cells. The disclosure also describes in vivo antitumor efficacy in multiple mouse tumor models and nonclinical monkey toxicity findings with immune/cytokine assessments.
Claims Coverage
The independent claim defines the core fusion-protein architecture and includes two alternative structural arrangements, with peptide linkers and optional linker-position presence. Dependent claims further specify particular CD80/IL-2 forms, Fc domain sequences, sequence-identity constraints, and a fusion-protein dimer construct.
Defined fusion-protein structural formula with CD80–Fc–IL-2 order swap
A fusion protein having structural formula (I) or (II) in which X is a CD80 protein and Y is an IL-2 protein, with the arrangement N′-X-[linker (1)]-Fc domain-[linker (2)]-Y-C′ (I) or N′-Y-[linker (1)]-Fc domain-[linker (2)]-X-C′ (II), where N′ is the N-terminus, C′ is the C-terminus, and linkers (1) and (2) are peptide linkers.
Peptide linkers and optional linker-position presence
The fusion protein includes peptide linkers (1) and (2) between the N′-proximal portion and the Fc domain and between the Fc domain and the C′-proximal portion, with positions n and m each independently 0 or 1.
CD80 fragment specified by amino-acid interval
The fusion protein uses a CD80 fragment comprising amino acids 35 through 242 of SEQ ID NO: 11.
IL-2 variant defined by specified multi-substitution combinations
The IL-2 variant includes one of specified amino-acid substitution combination sets in the amino acid sequence of SEQ ID NO: 10: R38A/F42A, R38A/F42A/Y45A, R38A/F42A/E61R, or R38A/F42A/L72G.
Fc domain fixed to a specific amino-acid sequence
The fusion protein has an Fc domain containing the amino acid sequence of SEQ ID NO: 4.
Sequence identity constraint relative to specified reference sequences
The fusion protein has at least 90% sequence identity to the amino acid sequence of SEQ ID NO: 9, 26, 28, or 30.
Fusion-protein dimer formed by attachment of two claim-1 fusion proteins
A fusion protein dimer is provided in which two fusion proteins as defined are attached to each other.
Overall claim coverage centers on a CD80–Fc–IL-2 fusion protein with a defined structural formula that allows swapping the CD80 and IL-2 order, together with peptide linkers and optional linker-position presence. Dependent refinements specify CD80 fragment boundaries, IL-2 variant substitution sets, an Fc domain sequence, a >=90% sequence-identity constraint to specified references, and an attached dimer construct.
Stated Advantages
Activates immune cells including natural killer (NK) cells and CD8+ T cells.
Regulates regulatory T cells (Treg cells).
Provides in vivo antitumor efficacy in multiple mouse tumor models.
Nonclinical monkey toxicity findings and immune/cytokine assessments suggest tolerability.
Documented Applications
Treating cancer.
Treating infectious diseases.
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