University of Manchester
Project Term: November 1, 2023 - October 31, 2026
We are aiming to bring a new treatment option to patients with chronic myelomonocytic leukemia (CMML) by utilising CCL2-drug conjugates that specifically target and eliminate cancerous cells. Our leading conjugate shows potent and selective efficacy in killing CMML cells. The proposed work will help us understand how this drug works, which patients are most likely to benefit and how it can be combined with current treatments to achieve the greatest patient benefit.
Our research aims to bring both a new drug delivery method and a promising targeted therapy to improve outcomes for patients with chronic myelomonocytic leukemia (CMML). CMML is a type of blood cancer with few effective treatments and most patients have poor prognosis. To address this problem we have come up with a new approach using drugs that specifically attach to and eliminate the key cells responsible for the disease, more efficiently and accurately.
Our idea is to attach drugs to a manufactured protein (called CCL2) that in the body is naturally taken up by monocytes and other blood cells only – meaning we can deliver potent drugs just to the CMML cells we want to hit, whilst leaving healthy cells unharmed. CCL2 enters cells by first binding to a protein called CCR2, which is present in much higher levels on the surface of CMML (than healthy) blood cells.
We have already done extensive work, with promising results. Our lead drug candidate, CCL2-MM145, effectively kills cancer cells and has worked well against all CMML patient samples tested. We believe the drug part works by binding to a protein called Survivin: a protein which normally prevents cell death and is also made in excessively high amounts by CMML cells. However, we have reason to believe this drug may be working in other ways too: for example, inducing cells to make harmful reactive oxygen species (ROS) and activating cell death through other proteins. In our proposed project we aim to speed up the development of CCL2-MM145 and bring it to CMML patients in clinical trials. We will conduct various studies to understand how it works in CMML cells, determine what factors make these cells sensitive or resistant to the drug, and establish exactly what beneficial (and any harmful) effects the drug might have. This will help us decide which patients are most likely to benefit from this treatment, and how it should best be used in clinical trials. We will also investigate how CCL2-MM145 might work together with other existing or emerging drugs by conducting drug combination tests in samples from CMML patients and in animal models of this disease.
Our research will make use of our large collection of CMML samples, including those generously donated by patients in our CMML clinic. Our team has extensive experience in developing new drugs, understanding CMML biology, and conducting clinical trials.