Johnson & Johnson's Novel Drug Receives Clinical Trial Approval in China for Myeloproliferative Neoplasms

On March 31, China's National Medical Products Administration Center for Drug Evaluation (CDE) announced the approval of a clinical trial for Johnson & Johnson's (JNJ.US) new Class 1 drug, JNJ-88549968 injection, intended for the treatment of myeloproliferative neoplasms (MPNs). Public information indicates this is an investigational bispecific T-cell redirecting antibody targeting CALRmut×CD3. The approval signifies that clinical research for MPNs will soon commence.

Myeloproliferative neoplasms are clonal malignant hematopoietic stem cell disorders characterized by the overproduction of mature myeloid blood cells. Research shows that mutations in JAK2, the thrombopoietin receptor (MPL), and calreticulin (CALR) are phenotypic drivers in MPN pathogenesis. CALR mutations are the second most common mutations in MPNs. These mutations lead to a frameshift in the gene's final exon, resulting in the loss of the KDEL endoplasmic reticulum retention motif and the generation of a new, positively charged 36-amino acid C-terminal neoantigen. Due to the missing KDEL motif, the mutant CALR is not confined to the endoplasmic reticulum but is transported to the cell surface via interaction with MPL, leading to sustained MPL activation and exerting an oncogenic effect.

Immune therapies involving T cells, such as bispecific CD3 redirecting antibodies, are expected to demonstrate promising response rates clinically. JNJ-88549968 is a T-cell redirecting bispecific antibody targeting CALRmut, which functions by clearing the MPN clone. Its mechanism involves bridging CALRmut MPN cancer cells and T cells, inducing T-cell activation both in vitro and in vivo, and subsequently mediating T-cell cytotoxicity against CALRmut cancer cells.

Preclinical studies indicate that JNJ-88549968 recognizes a CALRmut epitope common to all known mutation types, showing selective binding to CALRmut cell lines with no significant binding to wild-type CALR cells. The product demonstrated selective T-cell activation against CALRmut in vitro and induced cytotoxicity in cell lines engineered with CALRmut. It also produced a concentration-dependent cytotoxic effect on patient-derived CALRmut CD34+ cells. JNJ-88549968-mediated cytotoxicity was observed against all tested CALRmut CD34+ cancer cells, regardless of the specific CALR mutation type. Researchers believe the product has the potential to be developed as a novel bispecific T-cell redirecting antibody for treating CALRmut MPNs.