By A/Prof David Ross, Royal Adelaide Hospital and Flinders Medical Centre, Adelaide.
Targeting CALR
The calreticulin gene (CALR) is the second commonest MPN-associated driver mutation, occurring in around 25-30% of people with ET and MF. Calreticulin mutations result in the production of an abnormal CALR protein that is present on the surface of some types of blood cells bound to the thrombopoietin (TPO) receptor. TPO is the main growth factor for platelets and megakaryocytes (large platelet-producing cells that are normally found only in the bone marrow). The TPO receptor is mostly present only on these cells and in blood and marrow stem cells.
Two points make CALR an ideal candidate for immune-based treatments. Firstly, mutant CALR protein appears on the cell surface, so it is accessible to antibody binding. Secondly, the mutant CALR protein has a different structure from its normal counterpart, which means that antibodies can be designed specifically to bind only the mutant protein and have no effect on cells with normal CALR (which means that this approach won’t work for people with other MPN driver mutations, such as JAK2 or MPL).
Initial results with a CALR antibody
At this year’s EHA congress in June we heard the latest results using the Incyte INCA33989 antibody (called ‘989’ for short) in both ET and MF with very encouraging responses in both diseases. To date, more than 200 people from around the world have taken part in the Phase 1 trial. In ET, the platelet count was reduced by 50% or more in 85% of people treated and in most of the responders the platelet count returned to normal. In MF the spleen volume was reduced by an average of around 30% after 6 months of treatment and some patients also had an improvement in anaemia. In both diseases, these changes in test results were accompanied by a reduced symptom burden.
Excitingly, the 989 trials also reported a reduction in the level of the CALR mutation in the blood. This suggests that suppressing the MPN cells has enabled some recovery of normal marrow. We think this means that we are turning back the clock to a less advanced stage of the disease, and we hope that this will lead to improved progression-free survival in the longer term.
It is very rare for any treatment to work equally well for every patient, and CALR antibodies are no exception. One of the factors that is emerging as a key determinant of response is the mutation type. CALR mutations all affect the same region of the protein, but mutations occur at variable starting points and consequently result in different protein changes. More than 100 different mutations have now been reported: the two most common are imaginatively called Type 1 and Type 2. These two types account for around 80% of cases of CALR MPN. All the other mutations are uncommon, each individually occurring in 1-2% or less. It turns out that patients with Type 1 CALR on average have better responses than other mutation types. Some patients with Type 2 and other mutation types still respond to 989, but may require higher doses or respond less well.
One of the most impressive aspects of the reported results with 989 was the safety and tolerability of the treatment. Serious treatment-related side effects were rare. The most frequent serious side effects were low blood counts. Low blood counts are an expected effect of suppressing the abnormal CALR-mutated blood cells. As long as the healthy cells are unaffected, the blood counts should improve over time, as we are already seeing with anaemia responses.
The 989 antibody is given as a short intravenous infusion once every two weeks. This requires venous access and hospital attendance, so it is not very convenient, especially for country patients who may live a long way from the nearest hospital that can deliver the treatment.
Future directions
There is room for improvement both in response and convenience, so several companies are developing alternative antibodies. Possible ways to improve convenience include the development of subcutaneous injections (injecting the antibody into the fat under the skin, which could potentially be done by a patient or carer at home) and the development of long-acting antibodies that can be given less frequently. Antibodies cannot be taken by mouth as they would be digested and destroyed in the stomach.
Damora is a company that is developing a long-acting CALR antibody (DMR-001) and will begin its first clinical trial in Australia later in 2026. In this Phase 1 trial, DMR-001 will be given by subcutaneous injection once every 4 weeks. Apart from the convenience, the long-acting antibody might be more effective due to a more sustained effect on the abnormal cells.
Other ways to improve response are also being explored. CALR antibodies can be divided into three types. The first type, like 989, binds to CALR and may result in CALR being removed from the surface of the MPN cell so that it no longer helps the cell to grow. The second type activates the immune system after binding to CALR so that the immune system may see the MPN cell as abnormal and kill it. This is similar to how natural antibodies fight infection. The third type has one domain to bind CALR and another domain to bind a T cell, an important part of the immune response. So-called ‘bispecific’ antibodies strongly activate the immune response against the target cells and have been used very successfully in other blood cancers. However, ramping up activation of the immune system can also lead to an increased risk of immune-related side effects. It remains to be seen whether immune activation can improve responses with an acceptable safety profile. Bispecific antibodies for CALR MPN are currently being tested internationally by Incyte (using antibody 784, including Australian sites) and Johnson & Johnson.
A different approach to try to improve the effectiveness of CALR antibody treatment was tested in original research done in Adelaide University and published in the prestigious journal, Blood. The researchers made antibodies that bind to different locations in mutant CALR protein and showed that using both antibodies together improved responses both in Type 1 and especially in Type 2 CALR cells. A new company, Calytrix Bio, is developing a new type of CALR antibody based on that research. The Phase 1 Calytrix antibody clinical trial is expected to open in Australia in the first half of 2027.
CALR antibody clinical trials in Australia
| Antibody | Trial | Status in Australia |
| Incyte 989 | Phase 1 in MF/ET
Mutant-specific antibody |
Completed enrolment with patients in Adelaide, Brisbane, Melbourne |
| Phase 3 in MF/ET | Coming soon | |
| Incyte 784 | Phase 1 in MF/ET
Bispecific antibody |
Open in Adelaide, Melbourne, Sydney |
| Damora DMR-001 | Phase 1 in MF/ET
Long-acting antibody |
Opening later in 2026 in Adelaide, Brisbane, Melbourne, Newcastle, Perth, Sunshine Coast, and Sydney |
| Calytrix Bio | Phase 1 in MF/ET
Antibody |
Coming soon |
If you would like to know more about the current studies, you can check MPN AA list of clinical trials, the ClinTrial Refer website or clinicaltrials.gov. If you have a CALR mutation and you are interested in participating in one of these studies, please ask your specialist whether this might be an option for you.
About the author
Dr David Ross is a clinician–researcher specialising in chronic myeloid leukaemia (CML) and myeloproliferative neoplasms (MPNs), with expertise spanning laboratory diagnosis, clinical management, clinical trials and disease biology. He works as a clinical haematologist in the Royal Adelaide Hospital and Flinders Medical Centre and as a molecular haematologist in SA Pathology.
David was chair of the CML/MPN working party of the Australasian Leukaemia and Lymphoma Group for 6 years and leads the Collaborative Australian Myeloproliferative Registry (CAMPR). He is the lead clinician for MPN in South Australia and principal investigator in multiple clinical trials for CML and MPN. He has co-authored >150 scientific journal articles and is regularly invited to speak at national and international meetings. He has also presented at several MPN AA educational events.
Dr Ross has received research funding from Novartis and honoraria for consultancy or advisory board participation from BMS, Calytrix, Damora, GSK, Incyte, Jubilant, Merck, Novartis, Prelude, and Takeda.
