T-Cell Redirector INCA035784 Fights CALR-Mutated MPNs

Aaron T. Gerds, MD, hematologist-oncologist at Cleveland Clinic, discusses a new therapeutic approach for essential thrombocythemia, a less-common myeloproliferative neoplasm (MPNs).

Current MPN treatments, like JAK2 inhibitors, manage symptoms but do not eliminate the disease-causing cells. This research focuses on calreticulin (CALR) mutations (mutCALR), which are key drivers of MPNs and lead to the translocation of mutCALR to the cell surface, making it an ideal target.

The study aimed to develop INCA035784, a T-cell redirecting antibody designed to recognize and bind to mutant CALR on cancer cells and simultaneously activate T cells, thereby initiating the destruction of mutCALR-positive malignant cells.

Using advanced techniques like cryoelectron microscopy, the researchers determined that INCA035784 specifically binds to a conserved region on the N-domain of mutCALR. This unique binding ensures equipotent recognition of various CALR mutation types found in MPN patients. Crucially, INCA035784 does not bind to normal CALR and its efficacy is unaffected by soluble CALR. In laboratory experiments, INCA035784 demonstrated dose-dependent activation of T cells and effectively killed both engineered cells and patient-derived MPN cells carrying CALR mutations. Furthermore, INCA035784 showed a favorable safety profile, inducing minimal levels of cytokine release syndrome-associated cytokines compared to other T-cell engaging antibodies.

In conclusion, INCA035784 represents a significant advancement in targeting MPNs. Its ability to activate T cells specifically in the presence of mutCALR, its broad recognition of diverse mutCALR variants, and its low potential for cytokine induction position it as a highly promising therapeutic candidate for MPN patients who currently lack curative options.

REFERENCE:

Psaila B, Pandey V, Wang LC, et al. INCA035784, a novel, equipotent t cell-redirecting antibody for patients with myeloproliferative neoplasms carrying different types of calreticulin mutations. Presented at: 2025 EHA Congress; June 12-15, 2025; Milan, Italy. Abstract S212.