Targeting CALR Mutations in Myeloproliferative Neoplasms: The Development of JNJ-88549968 as a Promising T-Cell Redirecting Therapy

Myeloproliferative neoplasms (MPNs) are a group of blood malignancies that originate from the stem cells and are marked by an overproduction of myeloid blood cells. The progression of MPNs to secondary acute myeloid leukemia (sAML) is a leading cause of mortality, and this transition is typically driven by clones with specific mutations. Current treatments are not curative and only address symptoms, highlighting a need for new therapeutic strategies that can halt the progression to sAML.

The JAK2, MPL, and CALR genes are known to be key in MPN development, with CALR mutations being the second most common. These mutations result in a frameshift that leads to the loss of the KDEL motif, which is crucial for protein retention in the endoplasmic reticulum (ER). Without this motif, the mutated CALR proteins are trafficked to the cell surface, where they can cause continuous MPL receptor activation and promote cancerous growth.

A new bispecific antibody, JNJ-88549968, has been developed to target these CALR mutations. It functions by bridging the gap between the mutated cells and T cells, triggering an immune response that leads to the destruction of the cancer cells. The antibody is designed to recognize all known types of CALR mutations and has been shown to selectively bind to cells with these mutations without affecting normal CALR cells.

In vitro studies have shown that JNJ-88549968 can activate T cells and induce cytotoxicity against CALR-mutated cell lines. Furthermore, in an autologous setting using cells from MPN patients, the antibody demonstrated a concentration-dependent cytotoxic effect on patient-derived cells. Importantly, this cytotoxicity was observed regardless of the specific type of CALR mutation.

In vivo studies in mice with CALR-positive leukemia also showed promising results, with JNJ-88549968 treatment significantly extending the lifespan of the mice compared to controls. Additionally, soluble CALRmut protein present in patient plasma did not interfere with the antibody's activity in vitro.

In conclusion, JNJ-88549968 represents a first-of-its-kind approach to treating MPNs with CALR mutations, and it is currently progressing towards clinical trials for patients with this condition.