One of Faron’s key areas of focus is to develop a cancer treatment to support the hosts’ immune defences against tumours, as these are often suppressed in cancer patients. Our second most advanced drug development project, Clevegen®, revolves around Clever-1, an endothelial cell surface molecule involved in cancer growth and spread. The active pharmaceutical ingredient of Clevegen® is an anti-Clever-1 antibody.
Mechanism of action
All tumours are infiltrated by immune cells, for example macrophages, neutrophils, T-cells, dendritic cells, mast cells, myeloid derived suppressor cells and natural killer cells. Depending on the immune cells stimulated and activated, they can either have a protective effect for the host through suppression of tumour growth or deleterious effect by promoting tumour growth, invasion, metastasis and angiogenesis. Tumour associated macrophages (TAMs) have emerged as an essential constituent of the tumour environment, with influence over many aspects of cancer (proliferation and survival) as well as interaction with surrounding elements (angiogenesis, escape from antitumour specific immunity). When TAMs populate a tumour, one of the very significant influences they exert over it, is a strong increase in immune suppression. Clever-1-positive TAMs represent one major macrophage population involved in this elimination of host immune system activity against the tumour cells. Clevegen® is an anti-Clever-1 antibody which targets and eliminates Clever-1-positive TAM’s from cancer patients.
Clevegen® has two significant ways to intervene in the TAM role in tumour growth and spread: prevent TAM infiltration into a tumour and block TAM-to-Tumour cell interaction triggering TAM transformation into tumour supportive cell types.
BLOCKING TAM INFILTRATION INTO A TUMOUR
Tumour endothelial cells are Clever-1 positive and when anti-Clever-1 antibodies bind to the Clever-1 receptor, the infiltration of TAMs is prevented. Through blocking the infiltration of TAMs into the tumour, the ability of the tumour to suppress the hosts’ immune system is reduced.
BLOCKING TAM – TUMOUR CELL INTERACTION
Clevegen® prevents tumour cells – TAM interactions as shown on the picture. Through this action, the anti-Clever-1 antibody prevents further transformation of Clever-1 positive TAMs to tumour supportive phenotype.
CHANGE IN TUMOUR IMMUNITY
Anti-Clever-1 antibodies change the tumour immunity by lowering the presence of tumour supportive TAMs in the tumour. This will allow other immune cells to attack tumour cells and drive them to programmed cell death (apoptosis). In some tumours up to 50% of the tumour mass may contain TAMs and the only way to eliminate this dominance is remove them from tumours. It is these TAM cells that are the main target of the Clevegen® programme.