Fusion Therapeutics will present data on the effects of Fsn0503, a cathepsin S antibody on tumour invasion, metastasis and angiogenesis at the 5th International Conference on Tumour Microenvironment: Progression, Therapy and Prevention, Versailles, France 20-24th October 2009 & 6th General meeting of the International Proteolysis Society, Surfers Beach, Australia, 26th-28th October 2009

Antibody-mediated inhibition of Cathepsin S blocks tumour invasion, metastasis and angiogenesis

Roberta E. Burden^1,2, Julie A. Gormley², Thomas Jaquin², Donna M. Small^1,2, Derek J. Quinn¹, Shauna M Hegarty⁴, Claire Ward², Brian Walker¹, James A. Johnston^2,3, Shane A. Olwill², Christopher J. Scott^1,2.

¹School of Pharmacy, ³Centre for Infection and Immunity and ⁴Institute of Pathology, School of Medicine, Dentistry and Biomedical Sciences, Queen’s University Belfast, 97 Lisburn Road, Belfast, BT9 7BL, UK. ²Fusion Antibodies Ltd., Springbank Industrial Estate, Pembroke Loop Road, Belfast, BT17 0QL, UK.

Antibody-based therapeutics represent a major class of drugs which have contributed greatly to an improvement in treatment for patients suffering from many forms of cancer. The major characteristics which make antibodies attractive as therapeutics are their increased specificity, long half life and reduced toxicity. Traditionally antibodies have been developed against targets such as membrane receptors or ligands where they evoke an agonistic or antagonistic response. More recently some groups, including ours, have explored their application in targeting biomarkers present in the tumour microenvironment, which may originate from more than one tumour associated cell type.

Cathepsin S (CatS) is a lysosomal cysteine protease which has been implicated in tumour cell invasion and angiogenesis in a range of different tumour types. CatS is normally restricted to the lysosomes of professional antigen presenting cells, however in tumourigenesis, the protease is secreted into the tumour microenvironment where it is involved in extracellular matrix remodelling. We have developed an antibody which specifically targets and inhibits CatS and have demonstrated efficacy in a range of in vitro and in vivo tumourigenesis models. The CatS inhibitory antibody significantly impaired invasion of a range of tumour cell lines by the Boyden Matrigel invasion assay and also disrupts microtubule formation in the in vitro HUVEC and ex vivo rat aortic ring angiogenesis assays. Live-cell proteolysis assays have demonstrated that the perturbation of tumour invasion occurs as a result of the inhibitory antibody blocking CatS mediated collagen degradation. Furthermore, administration of the CatS antibody resulted in the inhibition of tumour growth, metastasis and neovascularisation in various xenograft tumour models.

In conclusion, this data highlights the potential of specifically targeting CatS within the tumour microenvironment and indicates that the CatS inhibitory antibody is an exciting experimental therapeutic which has great clinical potential.