CRT OPPORTUNITY Biological Therapeutics - Target Validation ANTIBODY TARGET FOR THERAPEUTIC INHIBITION OF ADAM8 • ADAM8 is a tractable target with broad utility in oncology and inflammatory indications • Recent study validates ADAM8 as an antibody target in cancer

COMMERCIAL OPPORTUNITY A CRT is seeking a collaborative or licensing partner to develop an antibody against the validated target ADAM8 to inhibit activity for cancer therapy.

We identified an epitope on ADAM8 (MS2, CD156), where three amino acids are exposed on the outside of the domain (Fig 1A). This sequence forms a potential contact surface with several , influencing ADAM8 activity. This epitope was then mimicked by a cyclic peptide and use of this peptide resulted in decreased ADAM8 activity. We now seek collaboration with a partner wanting to develop an inhibitory antibody against the epitope for use in cancer therapy and other ADAM8-related diseases.

ADAM8 has been validated as a target by peptide inhibition, several knock-out and knock-down model systems and also by inhibition with commercial tool antibodies binding to the indicated epitope. Inhibition of ADAM8 by our peptide inhibitor BK-1361 comes with data that validates ADAM8 as a cancer target, plus identified targets potentially useful as PD markers. Additionally, there is the opportunity to develop a companion diagnostic. Figure 1: In vivo efficacy of inhibition of breast tumour formation with a commercial tool antibody against ADAM8 (MAb 1031). A) We demonstrated ADAM8 activity as being instrumental The epitope needed for activation of ADAM8. B) and C) show the inhibition of tumour formation and growth in a breast tumour model for tumour development in several indications including using MDA-MB-231 cells injected in the mammary fat pad of female pancreatic cancer [2] and glioma [3]. In addition there are mice (MFP model, data from reference 8). Additional in vitro data clear links with other inflammatory conditions (e.g. asthma) relating to assays testing the antibodies further, PD markers and where specific inhibition of ADAM8 may be beneficial. assays for drug development are available under CDA.

IN VIVO PROOF OF CONCEPT WITH BACKGROUND AND THERAPEUTIC COMMERCIAL INHIBITORY ANTIBODY RATIONALE

The peptide has validated the disintegrin domain as a region ADAM8 is a membrane-bound, -disintegrin to target and a recent study has demonstrated inhibition of originally described as being involved in inflammation. ADAM8 using an antibody [8]. This antibody recognises an More recently it has been linked to disease processes epitope within human ADAM8 which corresponds to the including inflammation, tissue remodelling, tumour cell metalloprotease and disintegrin-like domains, where the invasion and metastasis [1, 2]. identified epitope is located. The data showed a significant reduction in breast cancer tumour load (Fig 1B and C) and metastatic spread once mice are treated with an antibody directed against the extracellular domain of ADAM8. Read more overleaf CRT OPPORTUNITY Biological Therapeutics - Target Validation

In contrast to other ubiquitous ADAMs, only low levels of INTELLECTUAL PROPERTY ADAM8 expression are detected in distinct cell types including A patent application (WO 2009047523) has been filed cells of the central nervous system (CNS) and immune protecting the inhibitory peptide BK-1361 and the epitope system, lymphatic vessels, thymus and lung epithelial cells. to which the peptide is binding. Epitope claims also cover ADAM8 is non-essential under physiological conditions as other agents such as antibodies for binding and inhibition of evidenced by lack of phenotype in ADAM8-deficient mice ADAM8 activity. [10]. Its expression is up-regulated on most immune cells under inflammatory conditions including asthma, and in the CNS under neuroinflammatory conditions. Expression is ORIGINATING INSTITUTE dysregulated and associated with disease severity and poor The work was carried out at King’s College London, UK, and clinical outcome of patients with a number of cancer types Marburg University, Germany, under the direction of Prof Jörg including pancreatic [2], glioblastoma [3], prostate [4], lung [5], Bartsch. squamous cell carcinoma of head and neck [6], and renal [7].

Like most ADAM family members ADAM8 is involved in REFERENCES shedding of membrane proteins. Potential substrates 1. Wildeboer D. et al. 2006. J Neuropathol Exp Neurol. 65, identified, including TNF-R1, VE-cadherin, CD23, and p516 L-selectin, have been shown to modulate one or more 2. Valkovskaya N. et al. 2007. J Cell Mol Med. 11, p1162 of the following processes associated with cancer: cell 3. He S. et al. 2012. Med Oncol. 29, p2032 adhesion, migration, angiogenesis, and inflammation. ADAM8 4. Fritzsche F. et al. 2006. Virchows Arch. 449, p628 also serves adhesive functions, and binds and activates ß1 5. Ishikawa N. et al. 2004. Clin Cancer Res. 10, p8363 , a target implicated in mediating therapy resistance, 6. Zielinski V. et al. 2012. BMC Cancer 12, p76 particularly in breast cancer. 7. Roemer A. et al. 2004. J Urol. 172, p2162 8. Romagnoli M. et al. 2014. EMBO Mol Med. 6(2), p278-94 Growing evidence for an essential role of ADAM8 in 9. Dong F. et al. 2015 Neuro Oncol 17(11), p1474 malignancies and chemoresistance [9] makes an inhibitor of 10. Kelly K. et al. 2005 Dev Dyn 232(1), p221-31 ADAM8 highly attractive as a therapeutic.

THE TECHNOLOGY

Inhibition of ADAM traditionally suffers from a lack of selectivity. Industry has devoted considerable effort to generating specific small molecule metalloproteinase inhibitors but these have been largely unsuccessful due to high levels of homology between family members in their catalytic site. We now seek a partner to develop an antibody targeting the epitope with the 3 identified amino acids, resulting in a specific inhibition of ADAM8. Commercial tool antibodies were assessed for ADAM8 binding and tested for inhibition of ADAM8 activity; this information is available for interested parties (under CDA).

CONTACT

Irene Patzak, Business Development Manager [email protected] www.cancertechnology.com +44 (0)20 3469 8700