JNJ-88549968

Report on JNJ-88549968: A Novel CALRmut-Targeting T-Cell Redirecting Bispecific Antibody for Myeloproliferative Neoplasms

I. Executive Summary

JNJ-88549968 is an investigational, first-in-class, T-cell redirecting bispecific antibody developed by Janssen Research & Development, LLC, a Johnson & Johnson company.[1] This therapeutic agent is engineered to dually target the mutated form of the calreticulin protein (CALRmut), a neoantigen specifically expressed on the surface of myeloproliferative neoplasm (MPN) cells, and the CD3 antigen present on T-lymphocytes.[1] The core mechanism of JNJ-88549968 involves forming a bridge between these two cell types, thereby inducing T-cell activation and subsequent T-cell-mediated cytotoxic destruction of the CALRmut-expressing cancer cells.[1]

The primary therapeutic focus for JNJ-88549968 encompasses CALR-mutated MPNs, with essential thrombocythemia (ET) and myelofibrosis (MF) being lead indications.[1] Currently, JNJ-88549968 is advancing through Phase 1 clinical development, with the first-in-human trial, identified as NCT06150157, actively enrolling patients.[2]

Preclinical investigations have provided substantial evidence supporting the drug's mode of action. These studies have demonstrated the antibody's high selectivity for CALRmut-expressing cells and its potent anti-tumor activity in both in vitro and in vivo models.[1] The development of JNJ-88549968 is driven by the significant unmet medical need for curative or disease-modifying therapies for patients with CALR-mutated MPNs, as current treatments are often palliative and do not target the underlying genetic driver of the disease.[1] JNJ-88549968 represents a promising targeted immunotherapy that leverages the specificity of CALR mutations as neoantigens, offering the potential to overcome the limitations of existing MPN therapies by selectively eliminating the malignant clone.