Dual Antibodies Beat Single for Type 1 CALR-Mutant Myelofibrosis

Dual monoclonal antibody therapy targeting distinct epitopes on the mutant calreticulin protein is more effective than single-agent therapy in models of type 1 mutant CALR myelofibrosis, according to a study published in Blood. Results suggest that type 2 mutations require distinct immunotherapy-based approaches, underscoring the need for an ultra-precision medicine approach tailored to the specific CALR mutation class.

The study used primary patient-derived megakaryocyte progenitors from individuals with CALR-mutant myelofibrosis.

Key Efficacy Results

The central finding was the superior activity of a 2-antibody combination against the type 1 mutant CALR neoantigen. Dual targeting was significantly more effective than single agent treatment in eradicating primary megakaryocyte progenitors in vitro and led to improved survival in xenograft models. The dual-antibody approach was superior in blocking constitutive STAT5 and ERK phosphorylation and prevented accumulation of JAK2 phosphorylation, overcoming ruxolitinib (Jakafi) resistance.

In contrast, cells harboring type 2 mutations showed increased CALR dimerization and were partially resistant to antibody targeting. Type 2 mutations could be impacted by a ruxolitinib triple combination.

Implications for Patient Management and Next Research Steps

These findings demonstrate that an approach tailored to either type 1 or type 2 mutation classes will be required for maximal efficacy and complete blockade of JAK/STAT signaling. For type 1 mutations, the most promising strategy is dual targeting with 2 monoclonal antibodies. For type 2 mutations, the path involves alternative combinations, such as a ruxolitinib triple therapy.

This research defines distinct therapeutic strategies for the 2 major classes of CALR mutations in myelofibrosis, with implications for future patient management and clinical trial design.

REFERENCE

Thompson-Peach CAL, Thomas D, Dottore M, et al. Ultraprecision therapy for type 1 vs type 2 calr+ mpn by dual epitope targeting that restores ruxolitinib sensitivity. Blood. 2026 Published online January 2, 2026. doi: 10.1182/blood.2024027897