December 22, 2022: Monoclonal Antibody Shows Promise for Treating CALR-mutant MPNs in Preclinical Study

[PhysAssist]

A monoclonal antibody may be effective for treating CALR-mutant myeloproliferative neoplasms (MPNs), according to preclinical research presented at the 2022 ASH Annual Meeting.

The antibody, INCA033989, demonstrated activity in cells from MPN patients and a mouse model of essential thrombocythemia.

INCA033989 is fully human IgG1 antibody that selectively binds to mutant CALR, explained study presenter Edimara Reis, PhD, of Incyte Corporation in Wilmington, Delaware.

In experiments with Ba/F3 cells, Dr Reis and colleagues found that INCA033989 binds to mutant CALR and inhibits oncogenic signaling. The researchers also found that INCA033989 inhibited cell proliferation and induced death in mutant CALR cells. INCA033989 appeared to have no functional effect on Ba/F3 cells not expressing mutant CALR.

The researchers also tested INCA033989 in CD34+ cells isolated from patients with MPNs. The team found that INCA033989 inhibits STAT5 phosphorylation in CD34+ CALR mutant cells. INCA033989 also inhibited proliferation and differentiation of mutant CALR hematopoietic stem and progenitor cells.

In a mouse model of essential thrombocythemia, INCA033989 selectively decreased levels of mutant CALR-positive platelets, re-established normal megakaryopoiesis, and selectively targeted mutant CALR disease-initiating clones.

“These data collectively provide strong rationale for the clinical investigation of INCA033989 in myelofibrosis and essential thrombocytopenia patients with CALR mutations, and a phase 1 study is planned to initiate in 2023,” Dr Reis concluded.

Disclosures: This research was supported by Incyte Corporation. Some study authors declared relationships, including employment, with the company. Please see the original reference for a full list of disclosures.

Reference

Reis E, Buonpane R, Celik H, et al. Discovery of INCA033989, a monoclonal antibody that selectively antagonizes mutant calreticulin oncogenic function in myeloproliferative neoplasms (MPNs). Presented at ASH 2022. December 10-13, 2022. Abstract 6.

Source: ash.confex.com/ash/2022/web...

This also reminded me that I still haven't heard the results of my Next-Gen gene sequencing from my original Heme/Onc MD.

Best,

PA

[DJK12]

Thank you for posting that. At one point CALR seemed to be the Cinderella gene with not so much research interest in it, perhaps not surprisingly, as the more common Jak2. There was a posting earlier in the year about some positive results in Australia about other CALR research so 2022 has been a more hopeful year for us with this gene.

[PhysAssist in reply to DJK12]

De Nada!

I'm glad you found it helpful. It sucks enough to have a basic 'orphan disease', qand sucks even more to have an orphan amongst orphans. [orphan-squared]

Hopefully, all of the researchers will keeping pushing the envelope on all of the variants until we get both prevention [even if it's secondary [after the fact of disease identification], and cures.

Best,

PA

[EPguy in reply to DJK12]

CALR is getting more attention in the immune therapies lately. In simple form in my limited understanding, it's because CALR has the mutation exposed at the end of its gene (I think that's right) So it's easy to find and attack. Jak2 has its mutation more hidden within, so it requires other steps 1st to expose it before immune therapies can start.

There is work going on re this exposing of Jak2.

[DJK12 in reply to EPguy]

Hopefully the research into both will show benefits to each other. I recall initially being told ruxolitinib, having been developed for JAK2, rather depressingly was of no use to CALR. I was surprised a year of so later when the consultant said it had now been proven to help both and I amongst many have reaped the rewards of the JAK2 research.

[EmeraldA in reply to EPguy]

Thank you for posting that researchers are working on exposing the mutation inside the Jak2 gene. I did not know this and am so glad to hear this!

[EPguy in reply to EmeraldA]

There is a post somewhere discussing in more detail. But any therapy will most likely happen after the CALR version.

[EmeraldA in reply to EPguy]

Yes, I am watching to see what happens with CALR. It is exciting at the moment. There have been a number of positive developments albeit outside of blood cancer but still very interesting around T Cell and CRISP etc. Here's hoping 2023 is a good year for MPNs and research.