Compounds including a mutant KRAS sequence and a lipid and uses thereof
Inventors
DeMuth, Peter C. • Adams, Julian • STEINBUCK, MARTIN
Assignees
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Publication Number
US-12138301-B2
Publication Date
2024-11-12
Expiration Date
Abstract
The invention features a compound including a mutant KRAS sequence and a lipid, where the mutant KRAS sequence is conjugated to the lipid by a linker, and (i) the linker includes one or more polyethylene glycol blocks, (ii) the lipid is 1,2-distearoyl-sn-glycero-3-phosphoethanolamine (DSPE), and (iii) the mutant KRAS sequence comprises or consists of the amino acid sequence selected from the group consisting of SEQ ID NOs:1-7 and 22-30. The invention features a composition including one or more compounds of the invention and a pharmaceutically acceptable carrier. The invention also features a method of treating a cancer in a human patient, the method including administering the composition to the patient. Further, the invention features a kit comprising the compound.
Core Innovation
A compound is provided comprising a mutant KRAS sequence conjugated to a lipid by a linker, where the linker comprises one or more polyethylene glycol blocks and the lipid is 1,2-distearoyl-sn-glycero-3-phosphoethanolamine (DSPE). The mutant KRAS sequence consists of an amino acid sequence selected from specified KRAS SEQ ID variants. In the described compounds, the mutant KRAS sequence is conjugated to the linker through a cysteine-maleimide linkage.
Embodiments specify polyethylene glycol repeat-unit content for the linker, including one or more polyethylene glycol blocks with repeat units selected from a range of 2 to 50 and also specific embodiments including 48 repeat units. The document further describes compositions including pharmaceutically acceptable carrier and combinations of one or more lipid-conjugated mutant KRAS compounds, optionally together with a CpG-adjuvant oligonucleotide including a stated CpG nucleotide sequence identified as SEQ ID NO:8.
These compositions and kit embodiments are described for use in cancer treatment in humans, with stated focus on albumin binding and lymph-node delivery to enhance KRAS-specific immune responses. The document reports immune activation and T-cell responses with amphiphile-KRAS plus amphiphile-CpG versus soluble controls.
Claims Coverage
The document includes multiple independent compound claims defining the same core structural relationship: mutant KRAS conjugated to DSPE via a linker containing polyethylene glycol blocks, with conjugation through a cysteine-maleimide linkage. Independent features differ by the specific mutant KRAS amino-acid sequence (SEQ ID NO) recited in each independent claim.
Mutant KRAS-lipid conjugate with PEG linker and DSPE
A compound comprising a mutant KRAS sequence conjugated to DSPE by a linker comprising one or more polyethylene glycol blocks, wherein the mutant KRAS sequence consists of one of the amino acid sequences selected from the specified SEQ ID variants.
Mutant KRAS-lipid conjugate with cysteine-maleimide linkage
A compound comprising mutant KRAS sequence conjugated to DSPE by a linker comprising one or more polyethylene glycol blocks, wherein the mutant KRAS sequence is conjugated to the linker through a cysteine-maleimide linkage.
Across the independent claims provided, coverage centers on DSPE-conjugated mutant KRAS peptides linked through a polyethylene glycol-containing linker, with cysteine-maleimide conjugation, where each independent claim fixes the mutant KRAS amino-acid sequence to a specified SEQ ID variant. Dependent claims further constrain the polyethylene glycol repeat-unit content and connect these compounds to compositions and cancer-treatment use in humans, including optional use with a CpG adjuvant.
Stated Advantages
DSPE increases binding to endogenous albumin to enhance lymph-node delivery and KRAS-specific immune responses.
Documented Applications
Cancer treatment in humans by administering a composition comprising the lipid-conjugated mutant KRAS compound, with optional CpG adjuvant oligonucleotide.
The document references cancer contexts including pancreatic cancer, lung cancer, and colorectal cancer.
Use in immune activation and T-cell response measurements, including splenocyte activation and CD8+ T-cell response reporting such as ELISpot IFNγ and cytokine bead array results.
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