Fusion proteins containing insulin-like growth factor-1 and epidermal growth factor and variants thereof and uses thereof
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Publication Number
US-10967049-B2
Publication Date
2021-04-06
Expiration Date
Abstract
Fusion proteins comprising cytokines, particularly insulin-like growth factor-1 (IGF-1) and variants thereof, epidermal growth factor (EGF), and other ligands to the EGF receptor, are provided. The fusion proteins further comprise SEQ ID NO:1 or other segments having lysine, glutamic acid, or aspartic acid residues. Uses for the fusion proteins are also provided.
Core Innovation
The disclosure describes fusion polypeptide/cytokine constructs for cancer targeting in which a cytokine ligand is fused directly to the N-terminus of a cytokine and an anti-cancer chemotherapeutic agent is covalently attached to a fusion polypeptide. The fusion polypeptide includes either SEQ ID NO:1 or residues 2-18 of SEQ ID NO:1, with reactive residues enabling drug conjugation.
A particular targeting embodiment uses an IGF-1R ligand variant denoted 765IGF (SEQ ID NO:2) comprising an N-terminal purification/lysine leader (SEQ ID NO:1) and an R3-IGF region, with reduced binding to soluble IGF binding proteins to improve receptor targeting. The document further contrasts this with another variant (IGF132) and reports comparative measurements related to binding and conjugate performance.
The disclosure also provides embodiments in which the cytokine is a ligand to ErbB-1, including an EGF/ErbB-1 targeting fusion denoted 765EGF (SEQ ID NO:8). In this context, the document reports inhibition of tumor cell growth and in vivo xenograft tumor growth inhibition for conjugates that include chemotherapeutic agents and tumor-targeting fusion polypeptides.
Claims Coverage
The partial content identifies one independent claim, which includes a cancer treatment method in a mammal based on administering a compound that comprises an anti-cancer chemotherapeutic agent covalently attached to a fusion polypeptide fused to the N-terminus of a cytokine. The claim requires targeting via either ErbB-1 or IGF-1R that is overexpressed in the cancer cells, and includes inhibition of cancer cell growth. No additional independent claims are provided in the partial content.
Covalently attached chemotherapeutic agent on an N-terminal cytokine fusion for ErbB-1/IGF-1R targeting
A method of treating cancer in a mammal comprising administering a compound having an anti-cancer chemotherapeutic agent covalently attached to a fusion polypeptide that is fused directly to the N-terminus of a cytokine, wherein inhibition of growth of the cancer cells is achieved.
Fusion polypeptide includes SEQ ID NO:1 or residues 2-18 of SEQ ID NO:1
The method uses a fusion polypeptide that comprises either SEQ ID NO:1 or residues 2-18 of SEQ ID NO:1 fused directly to the N-terminus of a cytokine.
Cytokine is an ErbB-1 ligand or an IGF-1R ligand matched to overexpressed cancer cells
The cytokine is either a ligand to ErbB-1 with ErbB-1 overexpressed in the cancer cells, or a ligand to IGF-1R with IGF-1R overexpressed in the cancer cells.
Across the identified independent claim, the core coverage is a cancer treatment method using a covalent chemotherapeutic-agent conjugate attached to a fusion polypeptide that is N-terminally fused to a cytokine, with receptor-specific targeting based on ErbB-1 or IGF-1R overexpression to inhibit cancer cell growth.
Stated Advantages
Higher microbial expression yield.
Improved IGF-1R binding (lower Kd; greater displacement).
Higher methotrexate loading (approximately 88 MTX/IGF).
Increased storage stability versus another variant (IGF132).
In vitro inhibition of tumor cell growth using 765IGF-MTX.
Strong ErbB-1-cell proliferation inhibition.
In vivo xenograft tumor growth inhibition for 765EGF-bendamustine, including some cures.
Documented Applications
Treating cancer in a mammal by administering covalently attached anti-cancer chemotherapeutic agent conjugates fused to cytokines targeting ErbB-1 or IGF-1R overexpressed in cancer cells to inhibit growth.
Tumor cell growth inhibition in vitro using 765IGF-MTX.
ErbB-1-related inhibition of cell proliferation for EGF/ErbB-1 targeting fusion constructs (e.g., 765EGF-bendamustine).
In vivo xenograft tumor model testing for 765EGF-bendamustine showing marked tumor growth inhibition and some cures.
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