Lymphoma has rituximab. Myeloma has daratumumab. Myeloproliferative neoplasms (MPN) have … let’s see, let me think now, oh — they have nothing. Absolutely no “-mAb” of any kind.
Monoclonal antibodies (mAb) have entered the modern therapeutics chat in a big way, at times even dominating the forum, in all hematology spaces covering classical to malignant. Both researchers and clinicians in the field of MPN have, in fact, longed for the day they might have access to bona fide targeted therapies for these lifelong, often excessively burdensome chronic malignancies, but alas, to date — muted silence.
While the top driver mutation in MPN, JAK2 V617F, has garnered a lot of screentime and served as the focus of targeted JAK inhibitor therapy, the second most frequent drivers — calreticulin (CALR) mutations — have barely even had a speaking role despite being present in up to 30 percent of MPN patients. Now, all that is about to change. Sunday’s Plenary abstract “Discovery of INCA033989, a Monoclonal Antibody That Selectively Antagonizes Mutant Calreticulin Oncogenic Function in MPN,” presented by Dr. Edimara Reis, had many of us MPN aficionados quietly cheering from our seats like fiercely proud parents. It was happening. We were finally getting our very own mAb. And even more, it was going to be directed at CALR, representing a long-awaited opportunity for this driver to step into the limelight.
Before going any further, in order to better appreciate the pathophysiological mechanisms underlying CALR-mutated MPN, and by extension, how radical and exceptional targeted therapy with this new mAb might be, let’s lay down a short summary of the plot twists that turn “good” CALR, well … bad. Calreticulin is a little like Walter White — modest, totally lawful chaperone protein by day, but when things go awry (aka, a nasty frameshift mutation causing loss of the KDEL endoplasmic reticulum retention motif), we witness its transformation into a molecular kingpin as it commandeers an otherwise innocent accessory, the thrombopoietin receptor (TPO-R), to drive JAK-STAT signaling in a most reckless fashion. Popcorn anyone?
Dr. Reis and her team built on the premise that selectively targeting MPN cells harboring mutant CALR would offer the considerable benefit of eradicating only neoplastic cells while conserving normal hematopoiesis. They discovered and characterized INCA033989, a high-affinity human IgG1 that selectively binds mutant CALR, abrogating TPO-R–induced signaling and subsequent downstream JAK-STAT pathway activation. The drug was first shown to bind mutant CALR on the surface of Ba/F3 cells, blocking TPO-R dimerization and ensuing cellular proliferation. The kicker? INCA033989 had no functional effect on Ba/F3 cells expressing wild-type CALR. Importantly, when tested in MPN patient-derived CD34+ cells, INCA033989 was shown to block mutant CALR-induced JAK-STAT pathway activation in a dose-dependent fashion, an effect not observed in either JAK2-mutated MPN or non-MPN subjects, highlighting the selectivity of the drug. Finally, INCA033989 was tested in vivo in a mouse model of MPN. Herein, it demonstrated prevention of thrombocytosis development in line with effective reduction of exclusively CALR+ platelets and restriction of CALR+ megakaryocyte accretion in bone marrow. Moreover, proof that INCA033989 was targeting disease-initiating CALR+ stem cells was provided by absence of disease development following secondary transplants. Bad CALR can reform for good, it would seem.
In discussing her work, Dr. Reis expressed how it represented “an important research milestone in myelofibrosis and essential thrombocythemia.” She explained, “this is a drug that has been developed specially with these diseases and patients in mind.” Furthermore, she anticipates far-reaching impact of INCA033989 on clinical practice. “INCA033989 has the potential to alter the course of the disease and reduce mutant CALR allele burden,” she stated. She emphasized one of the unique features of the drug: “The inhibitory activity observed in CALR mutated CD34 hematopoietic stem cells (HSC) is not observed in normal CD34 HSCs that do not have CALR mutations (signifying) … that INCA033989 is not expected to have the clinical adverse effects associated with broad inhibition of the JAK/STAT pathway in nonmutated cells.” The next steps? “We are planning to initiate clinical trials for INCA033989 next year,” Dr. Reis offered.
A brief “reader discretion is advised” note is in order here. The majority of the authors of this plenary, including Dr. Reis, are affiliated with Incyte Corporation, the company that developed INCA033989. Notwithstanding, this work was subject to as rigorous a peer-review process as all other submissions and required the same critical disclosures to ensure transparency. Attendees can balance these various considerations and ultimately forge their own informed opinions and interpretations of study results.
Ultimately, the very concept of this study and its preliminary findings remain cautiously encouraging. This also typifies a turning point in the narrative of MPN therapy. Will INCA033989 be the precedent-setting, first of many future mAbs for use in MPN? Will the high selectivity of the drug have a favorable impact on drug tolerance and rates/patterns of discontinuation? … on long-term outcomes? As we wishfully await the next season — or perhaps the spin-off to find out, let’s stay tuned, keep focus, and if you’re so inclined (as I am) — root for the protagonist.
Dr. Szuber indicated no relevant conflicts of interest.
