Vector co-expressing vaccine and costimulatory molecules
Inventors
Schreiber, Taylor • Fromm, George
Assignees
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Publication Number
US-10046047-B2
Publication Date
2018-08-14
Expiration Date
Abstract
Compositions and methods for co-expressing a secretable vaccine protein (such as gp96-Ig) and T-cell co-stimulatory molecules from a single vector, among others, are provided herein. Materials and methods for using gp96-Ig vaccination and T-cell co-stimulation to treat a clinical condition (e.g., cancer) in a subject also are provided.
Core Innovation
The invention relates to a single expression vector strategy that comprises a first nucleotide sequence encoding a secretable gp96-Ig fusion protein and a second nucleotide sequence encoding a T cell costimulatory fusion protein comprising OX40L-Ig. The approach is directed to co-expression of the gp96-Ig fusion and the OX40L-Ig costimulatory fusion from the same vector to enhance antigen-specific T cell responses.
The problem addressed is the need to enhance activation of antigen-specific T cells in a subject for treating cancers. The described vector design and co-expression approach are presented as improving activation and proliferation or expansion of antigen-specific CD8+ T cells, including tumor regression and or survival improvements in mouse models.
The document further describes embodiments and refinements relating to secretable gp96-Ig fusion proteins, including optional gp96 KDEL deletion, selectable Ig-Fc tags from human immunoglobulin classes or subclasses, and delivery formats such as incorporation into virus or virus-like particles and incorporation into human tumor cells for engineered tumor-cell vaccines. It also includes combination with checkpoint blockade, including PD-1/PD-L1 and CTLA-4, to enhance therapeutic effects.
Claims Coverage
The independent claim defines an expression vector having two nucleotide sequences encoding, respectively, a secretable gp96-Ig fusion protein and a T cell costimulatory fusion protein comprising OX40L-Ig, with the stated function of enhancing activation of antigen-specific T cells upon administration. The provided claim set indicates dependent refinements rather than additional independent claim structures in the excerpt.
Single vector encoding secretable gp96-Ig and OX40L-Ig
An expression vector comprising a first nucleotide sequence encoding a secretable gp96-Ig fusion protein, and a second nucleotide sequence encoding a T cell costimulatory fusion protein comprising OX40L-Ig, wherein the OX40L-Ig fusion protein comprises SEQ ID NO:11 and enhances activation of antigen-specific T cells when administered to a subject.
gp96 truncation without a C-terminal KDEL sequence
The gp96-Ig fusion protein comprises first 799 amino acids of SEQ ID NO:2 and does not include a C-terminal KDEL sequence (SEQ ID NO:3).
Ig tag as a human IgG CH2-CH3 domain
The Ig tag in the gp96-Ig expression vector is a CH2-CH3 domain from human IgG.
Human IgG1 Ig tag
The expression vector includes human IgG1.
Virus or virus-like particle incorporation
The expression vector is incorporated into a virus or virus-like particle.
Engineered tumor cells from established cancer lineages
The incorporated human tumor cells are from established cancer cell lines including a panel of cancer types.
Across the provided claims, the core inventive concept is an expression vector co-encoding a secretable gp96-Ig fusion and an OX40L-Ig costimulatory fusion (SEQ ID NO:11) to enhance activation of antigen-specific T cells. Dependent features narrow gp96 design, define Ig-tag domains or subclasses, and specify delivery contexts such as virus or virus-like particle incorporation or incorporation into human tumor cells from established cancer cell lineages.
Stated Advantages
Enhances activation of antigen-specific T cells when administered to a subject.
Co-expression from an expression vector supports enhanced antigen-specific CD8+ T cell activation, proliferation, or expansion as described in the provided content.
Synergistic anti-tumor effects, including tumor regression and survival improvements in mouse models as described in the provided content.
Improved antigen-specific CD8 expansion is described as superior to separate agonist antibody co-administration in the provided content.
Documented Applications
Treating cancers by administering an expression vector encoding secretable gp96-Ig and OX40L-Ig that enhances activation of antigen-specific T cells.
Treating infections is mentioned in the provided content.
Engineered tumor-cell vaccination is described, including incorporation of the vector into human tumor cells as off-the-shelf irradiated or live-attenuated sources as stated in the provided content.
Combination with checkpoint blockade, including PD-1/PD-L1 and CTLA-4, is described as part of therapeutic use as stated in the provided content.
Mouse model evaluation is described in the provided content, including CT26 colorectal carcinoma and B16.F10-ova melanoma models for anti-tumor effects and antigen cross-presentation.
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