Development of therapeutic antibodies against cachexia

Abstract

We have discovered a receptor that causes cancer cachexia a complication of cancer that affects up to 80% of patients with solid tumours and is responsible for around 25% of cancer deaths. We have produced monoclonal antibodies that block this condition, giving the prospect of a treatment. The signal for cachexia originates in the tumor leading to a search for the soluble factor released into the blood stream. We are in the process of humanizing the antibody in preparation for clinical trials.With the discovery that Fn14 in tumor cells and not in peripheral tissues, causes cachexia, and that the ligand of Fn14 is not required for the action of Fn14, we are seeking to discover the soluble factor released by the tumor responsible for the cachectic state in peripheral tissues. Further, the finding that the ligand TWEAK is not required for this process raises the question of the intracellular signalling components in the tumor cell. We aim to determine these details before we commence clinical trials. In collaboration with Andrew Scott and his team at the ONJCRI, we have recently completed the humanisation of the mouse anti-cachectic antibody and are in the process of producing a stable cell line which produces this antibody.This work will be prelude to pharmacokinetic and toxicological studies and testing in multiple preclinical models of cachexia. The work is funded by the Victorian Cancer Agency and involves a team of collaborators consisiting of clinical oncologist, Professor Andrew Scott at the ONJCRI, Amelia Johnston, Hamsa Puthalakath, Megan Maher from LIMS and John Silke from the Walter and Eliza Hall Institute and Ulf Eriksson from the Karolinska Institute in Stockholm, Sweden.