Anti-mutant calreticulin (calr) antibodies and uses thereof

  • The patent discloses antibodies specifically targeting mutant calreticulin (CALR) proteins implicated in myeloproliferative neoplasms and other cancers.

  • It emphasizes combined use of anti-mutant CALR antibodies with anticancer agents to achieve synergistic and enhanced tumor-killing effects.

  • Bispecific antibodies that bind mutant CALR and CD3 antigens boost immune targeting by recruiting T cells to cancer cells.

  • This targeted immunotherapy approach offers a promising, selective treatment strategy for CALR mutation-driven malignancies, improving therapeutic efficacy and patient outcomes.

  1. PDF
  2. https://patents.google.com/patent/WO2023107994A1/en?oq=WO2023107994A1

The patent focuses on innovative therapeutic approaches targeting mutant calreticulin (CALR) proteins, which are implicated in certain cancers, particularly Philadelphia-negative myeloproliferative neoplasms (MPNs). CALR is a chaperone protein primarily residing in the endoplasmic reticulum, and mutations in its gene—especially in exon 9—produce oncogenic forms that abnormally activate cellular receptors like the thrombopoietin receptor, driving disease progression.

The core invention described is a pharmaceutical composition comprising antibodies that specifically bind to mutant CALR proteins or their functional fragments. These antibodies may be monoclonal, chimeric, humanized, bispecific, or multi-specific, designed to recognize unique mutant sequences, including cleaved forms of mutant CALR that are prevalent in patient cells. The antibodies target epitopes formed by mutation-induced amino acid changes distinct from wild-type CALR, enabling selective recognition of cancerous cells.

Importantly, the patent emphasizes the synergistic use of these anti-mutant CALR antibodies in combination with various anticancer agents—such as alkylating agents, platinum compounds, antimetabolites, kinase inhibitors including JAK inhibitors, molecular targeting drugs, immunotherapeutics, and others. This combined treatment dramatically enhances antitumor efficacy compared to using either treatment alone, offering a promising strategy for improved cancer therapy.

One embodiment details bispecific antibodies that simultaneously bind mutant CALR and CD3 antigens, aiming to recruit T cells directly to mutant CALR-expressing cancer cells, boosting immune-mediated tumor destruction. This design addresses challenges with previous antibodies by enabling specific and potent targeting of both full-length and cleaved mutant proteins on cancer cell surfaces, enhancing therapeutic outcomes.

Overall, the patent presents a novel and effective approach to treating cancers associated with mutant CALR, especially MPNs, through precision-targeted immunotherapies combined with standard or innovative anticancer drugs. This approach holds potential to significantly improve patient prognosis by leveraging the distinct biology of mutant CALR and enhancing immune system engagement.