Molecular guide system peptides and uses thereof
Inventors
Brown, Kathlynn C. • Collins, Nathan • Li, Shunzi “Susan” • Allred, Curtis • Chung, Keen • McGuire, Michael
Assignees
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Publication Number
US-12441774-B2
Publication Date
2025-10-14
Expiration Date
Abstract
Disclosed are compositions comprising an antibody conjugated to one or more molecular guidance system (MGS) peptides. Disclosed are methods of treating a subject in need thereof comprising administering to the subject in need thereof an effective amount of an antibody conjugated to one or more MGS peptides, wherein the antibody targets an intracellular target involved in the disease process. Disclosed are methods of targeting an intracellular target comprising administering an antibody conjugated to one or more MGS peptides, wherein the antibody targets an intracellular target.
Core Innovation
The invention relates to antibody conjugates with molecular guidance system (MGS) peptides for intracellular targeting. The antibody is conjugated to an MGS peptide either directly or via a linker, including linker-mediated conjugation formats and fusion protein conjugation formats. The MGS peptide is selected from a group of specified MGS peptide sequences and chemically modified variants, including PEGylated forms.
The MGS peptides are configured to deliver antibodies to intracellular and subcellular compartments, including lysosome, Golgi apparatus, endoplasmic reticulum, cytoplasm, and nucleus. The described conjugates include MGS peptide sequence examples and optimized variants, including PEG11 optimized MGS peptides and acylated N-terminus forms. The described conjugate formats include specific sequence-defined MGS peptides and PEG-conjugated variants.
The invention further describes a platform used to identify MGS peptides (FOX-Three) and positions subcellular precision delivery as improving therapeutic efficacy. The narrative examples described in the partial content include increased cellular uptake and tumor retention, reduced off-target uptake, and reduced tumor growth with no gross toxicities reported in mouse studies, including targeting of Ras pathway-related processes.
Claims Coverage
The partial content identifies two independent claims covering (i) compositions of an antibody conjugated to a specified set of MGS peptides (including selected PEG/acylated variants) and (ii) an MGS peptide itself selected from a defined group of specific sequences (including PEG-conjugated forms). Across the independent claims, the inventive features center on the defined conjugation relationship (antibody–MGS peptide) and the restricted, sequence-defined selection set of MGS peptides, including chemically modified variants.
Antibody conjugated to selected MGS peptides
A composition comprising an antibody conjugated to a molecular guidance system (MGS) peptide, directly or via a linker, wherein the MGS peptide is selected from the group consisting of YAAWPASGAWT (SEQ ID NO: 6), D-Leu-RGDLATLRQL (SEQ ID NO: 8), LQWRRNFGVWARYRL (SEQ ID NO: 31), KQYATPRVFWT (SEQ ID NO: 33), and chemically modified/PEGylated acylated variants including CH3CO-YAAWPASGAWT-PEG11-C-NH2 (SEQ ID NO: 71), CH3CO-LQWRRNFGVWARYRL-PEG11-C-NH2 (SEQ ID NO: 72), CH3CO-RGDLATLRQL-PEG11-YC-NH2 (SEQ ID NO: 73), CH3CO-D-Leu-RGDLATLRQL-PEG11-YC-NH2 (SEQ ID NO: 74), CH3CO-FHAVPQSFYT (SEQ ID NO: 80), CH3CO-D-Leu-RGDLATLRQL-PEG11-YC-NH2 (SEQ ID NO: 81), CH3CO-YAAWPASGAWT (SEQ ID NO: 82), CH3CO-KQYATPRVFWT (SEQ ID NO: 84), and CH3CO-LQWRRNFGVWARYRL (SEQ ID NO: 85).
Selected MGS peptide sequence set
A molecular guidance system (MGS) peptide selected from the group consisting of D-Leu-RGDLATLRQL (SEQ ID NO: 8), LQWRRNFGVWARYRL (SEQ ID NO: 31), CH3CO-YAAWPASGAWT-PEG11-C-NH2 (SEQ ID NO: 71), CH3CO-LQWRRNFGVWARYRL-PEG11-C-NH2 (SEQ ID NO: 72), and CH3CO-LQWRRNFGVWARYRL (SEQ ID NO: 85).
Together, the independent claims require strict selection from defined MGS peptide sequence sets and, for the composition claim, the conjugation of the antibody to the selected MGS peptide either directly or via a linker, with explicitly recited PEGylated/acylated variants.
Stated Advantages
Subcellular precision delivery improves therapeutic efficacy.
Increased cellular uptake and tumor retention are reported in the narrative examples.
Reduced off-target uptake is reported in the narrative examples.
Reduced tumor growth and no gross toxicities are reported in mouse studies in the narrative examples.
Documented Applications
Therapeutic targeting applications involving diseases including infectious disease/bioterrorism, cancer, diabetes, neurological/neurodegenerative diseases, and genetically inherited diseases, as described in the partial content.
Targeting Ras/KRAS signaling and Ras pathway-related processes using antibody conjugates with MGS peptides, as described in the partial content.
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