Development of peptide-drug conjugates for the treatment of Chronic Myelomonocytic Leukaemia (CMML)
Lead Research Organisation:
University of Manchester
Department Name: School of Health Sciences
Abstract
Chronic Myelomonocytic Leukaemia (CMML) is a type of blood cancer for which is no generally effective treatment. For the majority of people diagnosed with CMML the prognosis is dismal, with 50% of patients dying within 15-20 months of diagnosis.
Chemotherapy approaches in CMML frequently fail due to a lack of selectivity for the cancerous cells relative to the rest of the patient's body, or lack of activity against the cancerous cells in the bone marrow that cause the disease to recur.
We are seeking to address this shortfall by developing a new class of drug that selectively targets and kills the cancerous cells through the patient's body, with little or no impact on healthy cell types. We will achieve this by attaching a highly toxic compound to a protein that is taken up only by the type of cells that have become cancerous in patients with CMML.
We have demonstrated that a prototype of these drugs can selectively target and kill CMML cells in a test tube and that this activity and selectivity is maintained in animal experiments, which are needed to model the complex requirements of treating a patient with CMML.
In this project we will conduct further studies to make as sure as possible that these compounds will be useful for treating CMML, whist also developing these prototypes to ensure they have all the required properties for testing in patients. If successful this will give us all the information we need to take one of these drugs into final toxicity tests and then clinical trials in CMML patients.
Chemotherapy approaches in CMML frequently fail due to a lack of selectivity for the cancerous cells relative to the rest of the patient's body, or lack of activity against the cancerous cells in the bone marrow that cause the disease to recur.
We are seeking to address this shortfall by developing a new class of drug that selectively targets and kills the cancerous cells through the patient's body, with little or no impact on healthy cell types. We will achieve this by attaching a highly toxic compound to a protein that is taken up only by the type of cells that have become cancerous in patients with CMML.
We have demonstrated that a prototype of these drugs can selectively target and kill CMML cells in a test tube and that this activity and selectivity is maintained in animal experiments, which are needed to model the complex requirements of treating a patient with CMML.
In this project we will conduct further studies to make as sure as possible that these compounds will be useful for treating CMML, whist also developing these prototypes to ensure they have all the required properties for testing in patients. If successful this will give us all the information we need to take one of these drugs into final toxicity tests and then clinical trials in CMML patients.
Technical Summary
Chronic Myelomonocytic Leukaemia (CMML) is an orphan disease defined by myeloid dysplasia, myeloproliferation and malignant expansion of classical monocytes. There is no generally effective treatment, so for the majority of patients prognosis is dismal, with median survival of 15-20 months.
Chemotherapeutic approaches in CMML (and other leukaemias) frequently fail due to a lack of specificity, or insufficient activity against disease initiating/sustaining progenitor cells in the bone marrow niche.
We are seeking to address this unmet need by developing a new class of CCL2-drug conjugates that mobilise CMML progenitor cells and selectively kill CMML cells throughout the disease clone.
C-C chemokine receptor type 2 (CCR2) is a chemokine receptor that is expressed almost exclusively on cells of monocytoid lineage, including the expanded classical monocyte population characteristic of CMML and the progenitors that propagate the disease, as well as blasts of monocytoid lineage from other myeloid malignancies. CCL2, the ligand for CCR2, mediates mobilisation of monocytoid cells from the bone marrow and chemotaxis of mature monocytes.
We have demonstrated that; 1) active uptake of CCL2 by CCR2+ cells can be exploited to selectively deliver a small molecule payload to the cytoplasm, 2) CCR2 is highly expressed on the most relevant populations/stages of CMML, 3) conjugation of a novel cytotoxic payload to CCL2 results in a targeted agent that exhibits cell-cycle independent cytotoxicity after 48-96 hours (CC50 1-10 nM), 4) CCL2 conjugates rapidly and comprehensively target all CCR2+ cell populations in vivo, resulting in a 50% reduction in circulating CCR2+ cells 48 hours after a single administration.
The overall objective is to de-risk critical aspects of the programme by; 1) further building the platform of evidence for our approach and identifying a clinical candidate and 2) conducting a package of pre-clinical studies to de-risk further translation of this agent.
Chemotherapeutic approaches in CMML (and other leukaemias) frequently fail due to a lack of specificity, or insufficient activity against disease initiating/sustaining progenitor cells in the bone marrow niche.
We are seeking to address this unmet need by developing a new class of CCL2-drug conjugates that mobilise CMML progenitor cells and selectively kill CMML cells throughout the disease clone.
C-C chemokine receptor type 2 (CCR2) is a chemokine receptor that is expressed almost exclusively on cells of monocytoid lineage, including the expanded classical monocyte population characteristic of CMML and the progenitors that propagate the disease, as well as blasts of monocytoid lineage from other myeloid malignancies. CCL2, the ligand for CCR2, mediates mobilisation of monocytoid cells from the bone marrow and chemotaxis of mature monocytes.
We have demonstrated that; 1) active uptake of CCL2 by CCR2+ cells can be exploited to selectively deliver a small molecule payload to the cytoplasm, 2) CCR2 is highly expressed on the most relevant populations/stages of CMML, 3) conjugation of a novel cytotoxic payload to CCL2 results in a targeted agent that exhibits cell-cycle independent cytotoxicity after 48-96 hours (CC50 1-10 nM), 4) CCL2 conjugates rapidly and comprehensively target all CCR2+ cell populations in vivo, resulting in a 50% reduction in circulating CCR2+ cells 48 hours after a single administration.
The overall objective is to de-risk critical aspects of the programme by; 1) further building the platform of evidence for our approach and identifying a clinical candidate and 2) conducting a package of pre-clinical studies to de-risk further translation of this agent.
