Interleukin-4 receptor-binding fusion proteins and uses thereof
Inventors
Assignees
Medicenna Therapeutics Inc • US Department of Health and Human Services
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Publication Number
US-10106592-B2
Publication Date
2018-10-23
Expiration Date
2034-09-24
Abstract
The present invention relates to interleukin-4 receptor-binding fusion proteins. More specifically, the invention provides, in part, fusion proteins that include an interleukin-4 or interleukin-13 protein moiety joined to an anti-apoptotic Bcl-2 family member protein moiety.
Core Innovation
The invention provides fusion proteins that include an interleukin-4 receptor-binding protein moiety, such as interleukin-4 or interleukin-13, joined to an anti-apoptotic Bcl-2 family member protein moiety. These fusion proteins are designed to enhance cell survival, inhibit cell death or apoptosis, protect against cell death, increase cell activation, or promote cell maturation of target cells expressing an IL-4 receptor. Variants include circularly permuted IL-4 or IL-13 proteins and mutants selective for binding to either Type I or Type II IL-4 receptors.
The fusion proteins may include linkers, such as the amino acid sequence Gly-Ser or ubiquitin or ubiquitin variants, to connect the IL-4 receptor-binding moiety with the anti-apoptotic Bcl-2 family polypeptide. The Bcl-2 family polypeptides used are anti-apoptotic members like Bcl-xL, Bcl-w, or Bcl-2, or fragments thereof, capable of enhancing cell survival or inhibiting apoptosis.
The background problem is that apoptosis is involved in many diseases including neurodegenerative diseases and cancer, with aberrant regulation leading to excessive cell death or hyperproliferation. Therapeutic agents targeting apoptosis, such as caspase inhibitors, have shown limited clinical success due to low membrane permeability or toxicity. Existing immunotoxins aiming to kill cancer cells have limitations. Thus, there is a need for fusion proteins that can deliver anti-apoptotic effects selectively to IL-4 receptor-expressing cells to overcome these issues.
Claims Coverage
The independent claims focus on fusion proteins with specific compositions and nucleic acid molecules encoding them, providing main inventive features related to sequence-specific fusion proteins and compositions.
Fusion protein comprising IL-4 receptor-binding protein and anti-apoptotic Bcl-2 family polypeptide
A fusion protein including an interleukin-4 receptor binding protein moiety and an anti-apoptotic Bcl-2 family polypeptide, where the fusion comprises the amino acid sequence of any one of SEQ ID NOs:18 and 20-24.
Pharmaceutical and nucleic acid compositions comprising the fusion protein
Compositions including the fusion protein and pharmaceutical compositions thereof, as well as nucleic acid molecules comprising sequences encoding the fusion protein (SEQ ID NOs: 30 or 31), vectors containing these nucleic acids, and host cells harboring these vectors.
The independent claims cover fusion proteins defined by specific amino acid sequences combining IL-4 receptor-binding and anti-apoptotic Bcl-2 family domains, as well as pharmaceutical compositions, encoding nucleic acids, vectors, and host cells, providing molecules useful for enhancing cell survival and related therapeutic applications.
Stated Advantages
Fusion proteins, such as cpIL-4-Ub-BclxL, increase neural cell survival more effectively than recombinant IL-4 alone after insults like GSNO or STS.
Fusion proteins generate higher yields of human dendritic cells without altering phenotype or gene expression, useful for immunotherapy.
Fusion proteins allow targeted enhancement of cell survival, proliferation, and inhibition of apoptosis, potentially at lower doses than immunotoxins or native cytokines.
Documented Applications
Treatment or prophylaxis of diseases involving cells expressing IL-4 receptor that require enhanced survival, proliferation, activation, or maturation, such as neurological disorders, autoimmune disorders, and cell transplantation.
Therapeutic use in neurodegenerative diseases, CNS disorders, autoimmune diseases, inflammatory disorders, skin disorders including psoriasis, and cancer immunotherapy.
Use as vaccine adjuvants, notably for cancer or infectious diseases, and for ex vivo expansion of dendritic cells or engineered T cells for adoptive and chimeric antigen receptor (CAR) therapies.
Ex vivo methods including culturing and expansion of immune cells with fusion proteins to reduce apoptosis and enhance efficacy of therapeutic vaccines.
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