Composition for overcoming resistance to EGFR-targeting agent
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Publication Number
US-11548915-B2
Publication Date
2023-01-10
Expiration Date
Abstract
The present invention relates to methods of overcoming the resistance to an EGFR (Epidermal Growth Factor Receptor)-targeting antibody through a peptide that binds specifically to neuropilin-1 (NRP1). Moreover, the present invention relates to a fusion antibody in which a peptide that binds specifically to NRP1 is fused to an EGFR-targeting antibody, and to a composition of overcoming the resistance to an EGFR-targeting antibody alone by co-administration of the EGFR-targeting antibody and an NRP1-binding peptide-fused Fc. In addition, the fusion antibody according to the present invention, in which the NRP1-specific binding peptide is fused to an EGFR-targeting antibody, overcomes the resistance to the EGFR-targeting antibody alone in pancreatic cancer. Furthermore, the fusion antibody, in which the NRP1-specific binding peptide is fused to the EGFR-targeting antibody, also overcomes resistance to the EGFR-targeting antibody alone even in lung cancer. Thus, the NRP1-specific binding-fused EGFR-targeting antibody according to the present invention may be highly effective in the treatment of various tumors resistant to EGFR-targeting antibody alone.
Core Innovation
The disclosed invention relates to an EGFR-targeting antibody resistance-overcoming composition for cancer treatment. The composition comprises one or more neuropilin-1 (NRP1)-specific binding peptide(s) selected from SEQ ID NOS: 1 to 3, and includes embodiments in which the NRP1-binding peptide is fused to an EGFR-targeting antibody or an antibody fragment.
The problem addressed is cancer resistance to EGFR-targeting antibody treatment. The disclosure describes NRP1-mediated signaling as being associated with resistance, including integrin β1/FAK/Src/Akt signaling in pancreatic cancer and NRP1–integrin α3–KRAS signaling in lung cancer, and characterizes the approach as overcoming EGFR-antibody resistance in NRP1-expressing settings.
The disclosed compositions are described as reducing proliferation and inducing apoptosis in NRP1-expressing EGFR-antibody-resistant cells. They are further described as increasing endocytosis of NRP1 and active integrins, reducing adhesion to fibronectin, and inhibiting tumor growth in mouse xenografts, accompanied by reduced phosphorylation of resistance markers.
The peptides and fusion constructs are described with SEQ ID NOs for NRP1-binding peptides (TPP11, TPP1, TPP8) and linker motifs including (GGGGS)n linker described with SEQ ID NO: 16. Antibody fragment formats are described as Fc, Fab, scFv, VH, and VL for EGFR antibody-related embodiments, and examples include cetuximab (Ctx)-TPP11 and panitumumab (Pnm)-TPP11.
Claims Coverage
The document provides two independent claims (clm-00001 and clm-00012), covering a cancer-treatment composition containing NRP1-specific binding peptides selected from SEQ ID NOS: 1 to 3 and a co-administration composition including an NRP1-binding peptide fused to either an Fc antibody fragment or an EGFR-targeting antibody. Across these independent claims, the core inventive features are NRP1-specific peptide selection (SEQ ID NOS: 1–3) and fusion to an Fc antibody fragment or an EGFR-targeting antibody.
Cancer-treatment composition comprising NRP1-specific binding peptides selected from SEQ ID NOS: 1 to 3
A composition for treatment of cancer comprising one or more neuropilin-1 (NRP1)-specific binding peptide(s) selected from the group consisting of SEQ ID NOS: 1 to 3.
Co-administration composition with NRP1-binding peptide fused to Fc or EGFR-targeting antibody
A composition for co-administration with a cancer treatment, comprising a neuropilin-1 (NRP1)-binding peptide comprising an amino acid sequence selected from the group consisting of SEQ ID NOS: 1 to 3, wherein the NRP1-binding peptide is fused to an Fc antibody fragment or an EGFR-targeting antibody.
Overall, the claim coverage is centered on compositions that include NRP1-specific binding peptides defined as SEQ ID NOS: 1 to 3, with a key structural feature in the second independent claim that fuses the NRP1-binding peptide to an Fc antibody fragment or an EGFR-targeting antibody for co-administration.
Stated Advantages
Overcomes EGFR-antibody resistance in NRP1-expressing EGFR-antibody-resistant cells, as described by reduced proliferation and induced apoptosis.
Increases endocytosis of NRP1 and active integrins.
Reduces adhesion to fibronectin.
Inhibits tumor growth in mouse xenografts with reduced phosphorylation of resistance markers.
No activity is reported in NRP1-negative cells.
No activity is reported in colorectal cancer models driven by KRAS/BRAF mutations.
Documented Applications
Treatment of cancer using a composition comprising NRP1-specific binding peptides selected from SEQ ID NOS: 1 to 3.
Co-administration with a cancer treatment, where the NRP1-binding peptide is fused to an Fc antibody fragment or an EGFR-targeting antibody.
Pancreatic cancer and lung cancer indications are described for embodiments involving resistance associated with integrin β1/FAK/Src/Akt signaling (pancreatic) and NRP1–integrin α3–KRAS signaling (lung).
Mouse xenograft inhibition is described, alongside reported reductions in phosphorylation of resistance markers.
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