HMGN partial peptide and cancer therapy using the same
Inventors
Matsushima, Kouji • Ueha, Satoshi • DESHIMARU, Shungo • Chen, Chang-Yu • Yokochi, Shoji • Ishiwata, Yoshiro • Shibayama, Shiro
Assignees
Tokyo University of Science • Ono Pharmaceutical Co Ltd • University of Tokyo NUC
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Publication Number
US-11919932-B2
Publication Date
2024-03-05
Expiration Date
Abstract
Disclosed are a novel therapeutic means effective and practical against cancer, and a novel substance useful as such a therapeutic means. Provided are novel peptides derived from a partial region of HMGN1, HMGN2, HMGN4 or HMGN5, and anti-cancer agents and anti-cancer effect enhancers containing the peptide as an active ingredient. The peptide of the present invention has an anti-tumor effect even independently, and exerts a remarkably excellent anti-tumor effect particularly when used in combination with an immune checkpoint regulator, or an anti-CD4 antibody or antigen-binding fragment thereof.
Core Innovation
The invention provides short HMGN-derived anti-tumor peptides consisting of partial regions of HMGN1, HMGN2, HMGN4, and HMGN5. The peptide sequences are defined by explicit sequence selection rules, including deletions at the N-terminus and/or C-terminus and limited amino-acid substitutions, and specific sequences are designated by SEQ ID NOs, including a minimal active HMGN1-derived core peptide (SEQ ID NO:18).
The described peptides exhibit anti-tumor activity as standalone anti-cancer agents. In addition, the peptides synergize with immune checkpoint regulators, including anti-PD-L1 antibodies, and with anti-CD4 antibodies, including cytotoxic anti-CD4 formats and antigen-binding fragments.
The document further characterizes the importance of sequence length and truncation boundaries for maintaining activity and synergy. It reports that full-length HMGN1 fragments/variants retain similar efficacy in Colon26 tumor-bearing mice, while over-truncations or certain deletions/substitutions abolish the synergy/anti-tumor effect.
Claims Coverage
The document includes two independent claims: one for a method of treating cancer and one for a method of enhancing the effect of an anti-cancer agent. Across the independent claims, the core inventive theme is administering an effective amount of an agent containing a peptide with an HMGN-derived amino-acid sequence selected from specified sequences and defined deletion/substitution rules.
Treating cancer with an HMGN-derived anti-cancer peptide sequence
Administering an effective amount of an anti-cancer agent containing an amino acid sequence of a peptide, wherein the peptide amino-acid sequence is selected from the sequences consisting of SEQ ID NO:3 or a sequence formed by specified N- and/or C-terminus deletions, including SEQ ID NO:12, and SEQ ID NO:15, or sequences formed by specified deletions and limited substitutions (SEQ ID NOs listed in sequences (1) to (5) and (7) to (9)).
Enhancing an anti-cancer agent effect using an HMGN-derived peptide sequence
Administering an effective amount of an agent containing an amino acid sequence of a peptide, wherein the peptide amino-acid sequence is selected from the sequences consisting of SEQ ID NO:3 or a sequence formed by specified N- and/or C-terminus deletions, including SEQ ID NO:12, and SEQ ID NO:15, or sequences formed by specified deletions and limited substitutions (SEQ ID NOs listed in sequences (1) to (5) and (7) to (9)).
The independent claim set is directed to (i) treating cancer by administering an effective amount of an agent comprising an HMGN-derived peptide with sequence definitions based on N-/C-terminus deletions and limited substitutions, and (ii) enhancing the effect of an anti-cancer agent by administering a peptide agent with the same defined sequence selection framework.
Stated Advantages
The peptides show anti-tumor activity alone.
The peptides synergize with immune checkpoint regulators, including anti-PD-L1.
The peptides synergize with anti-CD4 antibodies, including cytotoxic anti-CD4 formats.
The document reports practical chemical synthesis feasibility [procedural detail omitted for safety].
The peptides are stated to have favorable pharmacokinetic behavior, including a blood half-life similar to full-length HMGN1.
Documented Applications
Treatment of cancer in a patient in need of treatment of cancer, including solid cancer.
Enhancing the effect of an anti-cancer agent in a subject in need thereof.
Use with immune checkpoint regulators, including anti-PD-L1.
Use with anti-CD4 antibodies and antigen-binding fragments, including cytotoxic anti-CD4 formats.
Assessment in Colon26 tumor-bearing mice, including reported retention of similar efficacy for full-length HMGN1 fragments/variants and loss of synergy/anti-tumor effect for over-truncations or certain deletions/substitutions.
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