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-10093708-B2
Publication Date
2018-10-09
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 receptor binding protein moiety joined to a pro-apoptotic Bcl-2 family member protein moiety.
Core Innovation
The invention relates to fusion proteins that include an interleukin-4 receptor binding protein moiety joined to a pro-apoptotic Bcl-2 family member protein moiety. Specifically, the fusion proteins can comprise IL-4 or IL-13 proteins (including native, variant, or circularly permuted forms) fused to pro-apoptotic Bcl-2 family polypeptides containing BH3 domains, such as Bad, Bik/Nbk, Bid, Bim/Bod, Hrk, Bak, or Bax.
The problem addressed by the invention is the need for targeted therapeutic agents that induce apoptosis selectively in cells expressing IL-4 receptors (IL-4R), particularly to overcome limitations of existing chemotherapeutic agents that are toxic to normal cells. The background describes the biological role of IL-4 and its receptors, the regulation of apoptosis by Bcl-2 family proteins, and the challenges in clinical application of apoptotic inhibitors and immunotoxins. The invention aims to provide fusion proteins capable of inhibiting cell survival or proliferation, or enhancing apoptosis in IL-4R-expressing cells, with potential uses in cancer and other hyperproliferative disorders.
Claims Coverage
The claims comprise one independent claim directed to a fusion protein, and other independent claims directed to nucleic acid molecules, vectors, and host cells encoding or comprising the fusion protein. Five independent inventive features are identified.
Fusion protein comprising IL-4 receptor binding and pro-apoptotic Bcl-2 family polypeptides
A fusion protein that includes an interleukin-4 (IL-4) receptor binding protein and a pro-apoptotic Bcl-2 family polypeptide, comprising the amino acid sequence of any one of SEQ ID NOs: 24 to 27.
Pharmaceutical composition containing the fusion protein
A pharmaceutical composition comprising the fusion protein described above.
Nucleic acid molecules encoding the fusion protein
Nucleic acid molecules comprising the nucleic acid sequences of SEQ ID NOs: 35 to 38, encoding the fusion proteins.
Vectors comprising the nucleic acid molecules
Vectors that include the nucleic acid molecules encoding the fusion proteins as described.
Host cells comprising the vectors
Isolated or cultured host cells that contain the vectors encoding the fusion proteins.
The claims cover fusion proteins composed of IL-4 receptor binding moieties fused to pro-apoptotic Bcl-2 family polypeptides with defined sequences, pharmaceutical compositions containing these proteins, nucleic acid molecules encoding them, vectors bearing these nucleic acids, and host cells containing these vectors, providing a comprehensive scope for the engineered fusion proteins and their production.
Stated Advantages
The fusion proteins can selectively inhibit cell survival and proliferation or enhance apoptosis in IL-4R-expressing target cells.
They overcome limitations of existing chemotherapeutic agents by potentially reducing toxicity to normal cells via targeted delivery.
Fusion proteins containing human sequences may be less antigenic than immunotoxins, allowing administration at lower doses.
The fusion proteins demonstrate specific activity that can be effectively blocked by excess IL-4, indicating targeted receptor-mediated effects.
CpIL-4BAD fusion protein shows in vitro and in vivo efficacy in killing tumor cells and regressing tumors, prolonging survival in animal models.
Documented Applications
Treatment of cancers including gastric carcinoma, lymphoma, melanoma, leukemia, non-Hodgkin lymphoma, pancreatic cancer, colorectal cancer, thyroid cancer, liver cancer, ovarian cancer, prostate cancer, breast cancer, non-small cell lung cancer, head and neck cancers, and gliomas.
Treatment of hyperproliferative and differentiative disorders such as pulmonary fibrosis, benign prostatic hyperplasia, cardiac fibrosis, liver fibrosis, inflammatory conditions (prostatitis, vernal keratoconjunctivitis, atherosclerosis, idiopathic pulmonary pneumonia), and autoimmune conditions such as Graves disease.
Inducing apoptosis or cell death in cells expressing IL-4 receptors to inhibit survival and proliferation, including neoplastic and non-malignant cells in tumor microenvironments.
Combination therapies with anti-cancer therapeutics and sensitizing agents in cancer treatment to improve efficacy and overcome drug resistance.
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