Tethered interleukin-15 and interleukin-21
Inventors
Hinrichs, Christian S. • Jin, Benjamin Y.
Assignees
US Department of Health and Human Services
Publication Number
US-12157762-B2
Publication Date
2024-12-03
Expiration Date
2039-02-07
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Abstract
Disclosed are nucleic acids and polypeptides which provide the co-expression of interleukin (IL)-21 and IL-15 by a host cell, each interleukin being bound to the cell membrane by a cell membrane anchor moiety. Also disclosed are related recombinant expression vectors, host cells, populations of cells, pharmaceutical compositions, and methods of treating or preventing cancer.
Core Innovation
The invention provides nucleic acids and polypeptides that enable the co-expression of interleukin (IL)-21 and IL-15 by a host cell, where each interleukin is bound to the cell membrane via a cell membrane anchor moiety. This co-expression involves linking IL-21 and IL-15 to the cell membrane through flexible linkers and specific anchor sequences, thereby delivering autocrine stimulation to the host cell. This configuration may involve a cleavable linker allowing for separate membrane-bound IL-21 and IL-15 polypeptides upon expression.
The problem addressed by the invention arises from the limitations of adoptive cell therapy for cancer treatment, notably the reduced persistence, survival, and anti-tumor activity of transferred T cells after adoptive transfer. Current approaches inadequately maintain these therapeutic effects, and there exists a need for improved methods and products to enhance the efficacy of adoptive cell therapy for treating or preventing cancer.
The invention aims to overcome these obstacles by providing nucleic acids and polypeptides encoding membrane-tethered IL-21 and IL-15, co-expressed on host cells such as T cells or natural killer cells. The tethering approach is proposed to reduce systemic toxicity and excessive cell growth seen with soluble cytokine administration, by confining IL-15 and IL-21 signaling to autocrine activation of the expressing cell. The co-expression of IL-21 and IL-15 simultaneously targets distinct intracellular signaling pathways, potentially enhancing anti-tumor efficacy and cell survival more effectively than expression of either cytokine alone.
Claims Coverage
The patent includes one independent claim covering a T cell expressing a membrane-bound IL-15 polypeptide with specific sequence and structural features.
Membrane-bound IL-15 expression on T cell surface
The T cell comprises a nucleic acid encoding a polypeptide with a signal sequence, a human IL-15 amino acid sequence, a linker, and a cell membrane anchor moiety, where the linker binds IL-15 to the anchor, and the anchor binds the polypeptide to the T cell membrane.
Signal sequence selection
The signal sequence is selected from a human granulocyte-macrophage colony-stimulating factor (GM-CSF) receptor signal sequence, a human prolactin signal sequence, or a human IgE signal sequence.
Cell membrane anchor moiety type
The cell membrane anchor moiety is selected from B7-1 transmembrane-intracellular amino acid sequence, B7-2 transmembrane-intracellular amino acid sequence, CD8α transmembrane-intracellular amino acid sequence, or their transmembrane variants.
IL-15 amino acid sequence identity
The human IL-15 amino acid sequence is at least 90% identical to SEQ ID NO: 3, comprising mature human IL-15.
Linker sequence specification
The linker sequence is a polypeptide of Formula III: X1mX2nX3pX4q, where m, p, q are 0 or 1, n is 20–65 residues of glycine and serine, and X1, X3, X4 are any naturally occurring amino acid residue.
Use of recombinant expression vectors
The nucleic acid is comprised in a recombinant expression vector, optionally a viral vector, including lentiviral, retroviral, alphaviral, vaccinial, adenoviral, adenoassociated, herpes viral, or fowl pox viral vectors.
Host T cell type
The T cell can be a tumor infiltrating lymphocyte (TIL).
Pharmaceutical composition inclusion
The T cell can be formulated together with a pharmaceutically acceptable carrier as a pharmaceutical composition.
The claims cover a T cell engineered to express a membrane-anchored human IL-15 polypeptide with defined signal sequences, cell membrane anchors, linkers, and amino acid sequence identity, optionally delivered via various recombinant viral vectors, and applications including tumor infiltrating lymphocytes and pharmaceutical compositions.
Stated Advantages
High expression levels of both membrane-bound IL-15 and IL-21 on host cells.
Enhanced function including increased anti-tumor efficacy compared to cells expressing antigen-specific receptor alone or with only one of IL-15 or IL-21.
Autocrine expression of IL-15 and IL-21 reduces or avoids undesirable excessive cell growth and systemic toxicity associated with soluble cytokines.
Co-expression of IL-15 and IL-21 provides balanced intracellular signaling through STAT proteins, potentially reducing adverse effects seen with IL-15 alone.
Documented Applications
Treatment or prevention of cancer in a mammal by administering engineered cells expressing tethered IL-21 and IL-15.
Use in adoptive cell therapy to enhance survival, persistence, and anti-tumor activity of transferred T cells.
Engineered cells comprising antigen-specific receptors for targeting various cancer types expressing specific cancer antigens, including HPV16 E7 and KK-LC-1.
Formulations as pharmaceutical compositions for parenteral administration including intravenous injection.
Enhancing immune responses to immunotherapies, including vaccines, by co-administration with the inventive materials.
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