Australian researchers have developed a novel therapeutic approach to target myelofibrosis with a monoclonal antibody that they say may have the potential to extend lifespan while also significantly improving quality of life.
A team from the South Australian Health and Medical Research Institute (SAHMRI) and the University of South Australia made an accidental discovery when generating antibodies using a peptide fragment called ‘neoepitope’ that is only present within the cancer and not on any normal tissues.
On further testing they found it was effective against the calreticulin (CALR) somatic mutation associated with myelofibrosis that would normally be considered undruggable.
According to their paper, CALR is recurrently mutated in myelofibrosis via a frameshift that removes an endoplasmic reticulum retention signal, creating a neoepitope potentially targetable by immunotherapeutic approaches.
In animal models the team developed a specific monoclonal IgG2α antibody, 4D7, that selectively binds to cells co-expressing mutant CALR and thrombopoietin receptor (TpoR) and blocks JAK-STAT signalling.
They showed it also blocks TPO-independent proliferation and megakaryocyte differentiation of mutant CALR myelofibrosis progenitors by disrupting the binding of CALR dimers to TpoR.
4D7 had no effect on normal progenitor cells and shows activity against ruxolitinib-resistant cells without haematological toxicity
“Importantly, 4D7 inhibited proliferation of patient samples with both insertion and deletion CALR mutations but not JAK2 V617F and prolonged survival in xenografted bone marrow models of mutant CALR-dependent myeloproliferation,” they reported.
Dr Daniel Thomas, leader of the Myeloid Metabolism Lab at SAHMRI was a co-investigator in the study published in Embo Reports, in collaboration with Professor Angel Lopez and Dr Denis Tvorogov at the Centre for Cancer Biology, SA Pathology and UniSA. Dr Thomas says it was a stroke of luck that led to the extraordinary find.
“We were actually trying to make a tool to study myelofibrosis. We didn’t realise the antibody we made would have therapeutic properties,” he said.
“Our drug blocked the growth of cancer cells in a very aggressive live model of the disease, significantly increasing survival rate without noticeable negative side effects,” he added.
The team are now progressing towards human trials of the antibody, which they say may offer a better therapeutic option for patients with myelofibrosis compared to current treatment, ruxolitinib.
“We estimate there are at least 12,000 Australians living with cancer or having had cancer that express a recurrent neoepitope similar to what is found in myelofibrosis, that could be curable with an immunotherapeutic approach,” said Dr Thomas.
“This discovery brings us a fresh perspective. We need to build cell therapies and antibody therapies against these fragments as fast as possible.”
Co-lead author and biochemist Dr Denis Tvorogov said the finding was exciting because many other cancers have similar peptide fragments that we could also target by harnessing antibodies.
“These fragments are created by the insertion or deletion mutations within the cancer. We’ve found they not only drive cancer growth but also vulnerable for targeting without side effects,” he said.