Antibodies that bind to cleaved form of mutant calreticulin, and diagnostic, preventive, or therapeutic agent for myeloproliferative neoplasm

Inventors

ARAKI, Marito • KIHARA, Yoshihiko • KOMATSU, Norio

Assignees

Juntendo Educational Foundation • Meiji Seika Pharma Co Ltd

Abstract

A diagnostic, preventive, or therapeutic agent may be used for a myeloproliferative neoplasm. An antibody or a functional fragment thereof that binds to a cleaved mutant CALR protein, may include an antigen-recognition site in (a) a polypeptide chain having an amino acid sequence set forth in SEQ ID NO: 1 or (b) a polypeptide chain having an amino acid sequence having deletion, substitution, or addition of one to several amino acids in SEQ ID NO: 1; and a diagnostic, preventive, or therapeutic agent for a myeloproliferative neoplasm containing the antibody.

Core Innovation

Many oncogenic mutant CALR proteins are cleaved, so full-length neo-antigen epitopes may be lost and detection by prior antibodies may be impaired. This causes a technical problem in detecting cleaved mutant CALR proteins, including in the context of myeloproliferative neoplasms (MPN). The invention addresses the cleaved nature of mutant CALR by focusing antigen binding on epitopes present after cleavage.

The invention generates and provides an antibody or a functional fragment thereof that binds to a cleaved mutant CALR polypeptide. The antibody binding specificity is defined by an antigen-recognition site specified by an amino acid sequence set forth in SEQ ID NO:1 or a close variant, and the antibody includes immunoglobulin variable regions characterized by CDR1, CDR2, and CDR3 sequences defined by SEQ ID NOs.

Embodiments include antibodies and functional fragments with VH and VL chain CDR1/2/3 amino acid sequences selected from defined SEQ ID options, including specific CDR sequence-defined antibodies such as B3, C6, and G1. The disclosed approach detects cleavage-type mutant CALR in cultured cells and patient blood or platelets, improves cell-surface detection sensitivity, and supports identification of therapeutic efficacy and screening based on binding to the SEQ ID NO:1 cleaved-mutant epitope polypeptide.

Claims Coverage

The claim coverage centers on antibodies or functional fragments that bind a cleaved mutant CALR polypeptide, with sequence-defined antigen-recognition and VH/VL CDR determinants. The document also includes method and composition coverage tied to detection, therapeutic agent identification, and MPN diagnosis or treatment.

Overall, the claim coverage focuses on antibodies or functional fragments that bind a cleaved mutant CALR polypeptide via a SEQ ID NO:1-defined antigen-recognition site and specified VH/VL CDR1/2/3 determinants. The covered uses include detecting mutant CALR through antibody–polypeptide complex formation, identifying therapeutic agents by complex formation indicative of therapeutic effect on MPN, and therapeutic or diagnostic compositions for MPN.

Stated Advantages

Documented Applications