Interleukin-4 receptor-binding fusion proteins and uses thereof
Inventors
Merchant, Fahar • Puri, Raj K. • Joshi, Bharatkumar H.
Assignees
Medicenna Therapeutics Inc • United States, REPRESENTED BY SECRETARY Departnemt Of Health And Human Services AS • US Department of Health and Human Services
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Publication Number
US-11084856-B2
Publication Date
2021-08-10
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 (IL-4) receptor binding protein moiety joined to a pro-apoptotic Bcl-2 family member protein moiety. More specifically, these fusion proteins comprise an IL-4 receptor binding protein, such as IL-4 or IL-13 or variants thereof, fused to pro-apoptotic proteins of the Bcl-2 family, including those with a BH3 domain like Bad, Bik/Nbk, Bid, Bim/Bod, Hrk, Bak, or Bax. The fusion may include circularly permuted versions of IL-4 and may use linkers such as GS or ubiquitin variants for joining the moieties.
The problem being solved is the limitation in existing therapeutic agents that induce apoptosis for treatment of diseases such as neurodegenerative diseases and cancers. Current chemotherapeutic agents are often toxic to normal cells and apoptosis inhibitory molecules have low membrane permeability. Additionally, targeted immunotoxins have limitations in specificity and toxicity. The fusion proteins of the invention aim to selectively induce apoptosis in IL-4 receptor expressing cells by combining IL-4 receptor binding specificity with a pro-apoptotic effector.
Claims Coverage
The patent includes seven independent claims covering methods of inducing cell death and treating cancer or hyperproliferative disorders using specific fusion proteins or nucleic acid compositions.
Fusion protein comprising IL-4 receptor binding protein and pro-apoptotic Bcl-2 family polypeptide
The fusion protein includes an IL-4 receptor binding protein and a pro-apoptotic Bcl-2 family polypeptide with the amino acid sequence as set forth in any one of SEQ ID NOs: 24-27.
Nucleic acid composition encoding the fusion protein
The nucleic acid composition comprises a nucleic acid sequence encoding the fusion protein of SEQ ID NOs: 24-27, with sequences set forth in SEQ ID NOs: 35-38.
Method of inducing cell death by contacting IL-4 receptor expressing cells with the fusion protein or nucleic acid
Contacting a target cell expressing IL-4R with either the fusion protein (SEQ ID NOs: 24-27) or a nucleic acid encoding the fusion protein (SEQ ID NOs: 35-38) to induce cell death.
Method of treating IL-4 receptor expressing cancer by administering fusion protein or nucleic acid
Administrating to a subject in need a fusion protein comprising IL-4 receptor binding protein and a pro-apoptotic Bcl-2 family polypeptide (SEQ ID NOs: 24-27) or nucleic acid encoding the same (SEQ ID NOs: 35-38) to treat IL-4 receptor expressing cancer.
Method of treating cancer by contacting neoplastic IL-4R expressing cells with fusion protein or nucleic acid
Contacting neoplastic cells that express IL-4R with the fusion protein comprising an IL-4 receptor binding protein and pro-apoptotic Bcl-2 family polypeptide (SEQ ID NOs: 24-27) or nucleic acid encoding it (SEQ ID NOs: 35-38).
Method of treating cancer by contacting non-malignant IL-4R expressing cells in tumor microenvironment
Contacting a non-malignant cell expressing IL-4R in a tumor microenvironment of a subject with the fusion protein (SEQ ID NOs: 24-27) or nucleic acid encoding it (SEQ ID NOs: 35-38) to treat cancer.
Method of treating IL-4 receptor expressing hyperproliferative or differentiative disorders
Administering to a subject a fusion protein comprising an IL-4 receptor binding protein and a pro-apoptotic Bcl-2 family polypeptide (SEQ ID NOs: 24-27) or nucleic acid encoding the fusion protein (SEQ ID NOs: 35-38) to treat hyperproliferative or differentiative disorders.
The claims cover methods of inducing cell death and treating cancer or hyperproliferative disorders by administrating specifically sequenced fusion proteins consisting of an IL-4 receptor binding protein joined to a pro-apoptotic Bcl-2 family polypeptide or nucleic acids encoding these fusion proteins.
Stated Advantages
The fusion proteins provide selective targeting and killing of IL-4 receptor expressing cells, offering increased specificity relative to existing therapies.
They demonstrate efficacy in inhibiting cell survival and proliferation and enhancing apoptosis of tumor cells expressing IL-4 receptor.
The fusion proteins can be administered at substantially lower doses compared to immunotoxins or native IL-4R binding proteins, potentially reducing toxicity.
The fusion proteins are composed mainly of human sequences, reducing antigenicity and immunogenicity risks.
Documented Applications
Treatment of cancers expressing IL-4 receptor, including CNS cancers such as gliomas and other solid tumors.
Therapeutic use for hyperproliferative disorders like pulmonary fibrosis, cardiac fibrosis, hyperplasia, inflammatory conditions, and autoimmune diseases such as Graves disease.
Use in targeting both malignant neoplastic IL-4R-expressing cells and non-malignant IL-4R-expressing cells in the tumor microenvironment for improved cancer therapies.
Induction of apoptosis in IL-4 receptor expressing cells for conditions requiring inhibition of cell survival, proliferation or enhancement of cell death.
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