Compositions and methods for assaying proteins and nucleic acids
Inventors
Hornburg, Daniel • Figa, Michael • Zhao, Xiaoyan • Siddiqui, Asim S. • Ma, Philip • Kim, Sangtae • Farokhzad, Omid C. • DONOVAN, Margaret • Blume, John E. • Platt, Theodore • Goldberg, Martin • HARRIS, Damian
Assignees
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Publication Number
US-12276668-B2
Publication Date
2025-04-15
Expiration Date
Abstract
Disclosed herein are compositions and methods for assaying for proteins and nucleic acids, in parallel.
Core Innovation
The invention is a method for analyzing a biological sample from a subject by assaying the biological sample using mass spectrometry to identify proteins and obtain proteomic information comprising signals assignable to a first plurality of proteins or protein fragments in the biological sample. In parallel, nucleic acid molecules from the biological sample are analyzed by obtaining sequences of the nucleic acid molecules to identify genotypic information comprising signals assignable to a second plurality of proteins or protein fragments associated with the nucleic acid molecules.
The method identifies a peptide variant of the subject based on the proteomic information and the genotypic information, wherein the peptide variant is not otherwise identifiable in the mass-spectrometry proteomic information alone. The identifying uses predicted protein sequences constructed from the genotypic information, where a signal of the genotypic information overlaps with a signal of the proteomic information, and wherein the plurality of predicted protein sequences comprise a sequence of the peptide variant.
The described approach integrates proteomic signals and sequencing-derived genotypic information by using overlapping signals to connect mass-spectrometry observations to predicted protein sequences derived from nucleic-acid sequences. The document further describes protein-nucleic-acid analysis workflows in which biomolecule corona-forming sensor particles support multiplexing heterogeneous particle panels and downstream processing for mass spectrometry and nucleic-acid sequencing, enabling detection and characterization of peptide and genomic variants and biological states.
Claims Coverage
The document includes one independent claim. It contains a core inventive combination of mass-spectrometry proteomic analysis, nucleic-acid sequence-based genotypic analysis, and peptide-variant identification using predicted protein sequences constructed from genotypic information with overlapping signals, where the peptide variant is not otherwise identifiable from the proteomic assay alone.
Mass spectrometry proteomic information for proteins or fragments
Assaying the biological sample using mass spectrometry to identify proteins and obtain proteomic information comprising signals assignable to a first plurality of proteins or protein fragments in the biological sample.
Nucleic-acid sequence genotypic information associated with protein fragments
Analyzing nucleic acid molecules by obtaining sequences of the nucleic acid molecules to identify genotypic information, where the genotypic information comprises signals assignable to a second plurality of proteins or protein fragments associated with the nucleic acid molecules.
Peptide variant identification using predicted protein sequences from genotypic overlap
Identifying a peptide variant based on the proteomic information and the genotypic information, where the peptide variant is not otherwise identifiable in the proteomic information, and where identification is based at least in part on a plurality of predicted protein sequences constructed from the genotypic information; a signal of the genotypic information overlaps with a signal of the proteomic information; and the plurality of predicted protein sequences comprise a sequence of the peptide variant.
Overall, the independent claim covers a combined proteomic-and-genotypic analysis in which peptide variants are identified by linking overlapping signals from mass-spectrometry proteomic information and nucleic-acid sequence genotypic information, using predicted protein sequences constructed from the genotypic information.
Stated Advantages
Enables identification of a peptide variant that is not otherwise identifiable in the proteomic information alone.
Allows compression of proteomic dynamic range enabling detection across multiple orders of magnitude.
Supports multi-sample and parallel protein–nucleic-acid proteogenomic analysis.
Documented Applications
Disease-state biomolecule fingerprinting, including cancer diagnosis and staging.
Proteogenomic analysis that includes parallel protein and nucleic acid analysis with genomic/transcriptomic information integration for peptide-variant detection and variant frequencies.
Integration with machine learning for classification and analysis, including PCA, PLS-DA, random forest, SVM, and clustering.
Identification of peptide and genomic variants and characterization of biological states, including cancer [procedural detail omitted for safety].
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