Isogenica Ltd., a leader in the use of synthetic biology and in vitro display for the discovery and optimisation of novel biotherapeutics, today announced the publication in Nature Communications of a promising new strategy for treatment of Wnt-hypersensitive tumours using VHH-mediated targeting of LRP5 and LRP6 (Fenderico et al., 2019).

Under a collaboration between Isogenica and scientists at the Oncode Institute and University Medical Center Utrecht, led by Professor Madelon Maurice, Isogenica’s fully synthetic, highly diverse LlamdA™ library was screened for Wnt pathway inhibitors using CIS Display, the company’s in vitro library selection system.

Inappropriate activation of Wnt/b-catenin signalling is a frequent occurrence during the onset and progression of human cancer, including colorectal cancer.  More than 1.2 million patients are diagnosed with colorectal cancer every year, and more than 600,000 die from the disease (Brenner et al., 2014).

This research uncovered the first example of monovalent single domain antibodies (VHHs) blocking both LRP5- and LRP6-mediated Wnt3/3a-dependent b-catenin signalling.  Being monovalent, these VHHs do not trigger receptor agonism that hampered the development of conventional monoclonal antibodies to LRP6 (Gong et al., 2010, Ettenberg et al., 2010).

Treatment with anti-LRP5/6 VHHs was shown to impair the growth of Wnt-hypersensitive intestinal tumor organoids by blocking cellular responses to Wnt3, as well as simultaneously promoting terminal differentiation of cancer stem cells.  Driving tumor stem cell differentiation has recently been heralded as a promising strategy for eradication of human colorectal cancer (Jin et al., 2017).

Dr. Guy Hermans, CSO of Isogenica Ltd., commented “LlamdA™ library derived VHH antibodies block both LRP5 and LRP6 driven Wnt signalling in stem cells without activating the receptors that bivalent conventional antibodies do. This re-opens the perspective for development of VHH-driven biotherapeutics for Wnt/b-catenin sensitive tumours. Our collaborative effort exemplifies both the added value of the VHH format over conventional monoclonal antibodies, as well as the benefit of using a synthetic VHH library such as LlamdA™ to discover antibody fragments to challenging targets and epitopes”.

Isogenica is developing LlamdA™ (single domain VHH) and Alexandria™ (human Fab) therapeutic antibodies from its proprietary fully synthetic antibody libraries and leveraging its CIS Display and Colibra™ technologies to accelerate the discovery and development process.  Over the last four years Isogenica has entered into eight significant partnerships, leveraging its libraries, technologies and expertise to build a broad pipeline of programs that are now advancing into pre-clinical and early clinical development with our partners.

For more information, visit http://www.isogenica.com.

Summary of main messages:

• LRP5 and LRP6 are well validated targets in colorectal cancer
• This study for the first time describes VHHs blocking both LRP5 and LRP6-mediated Wnt pathways, without triggering dimerization and unwanted agonism
• This inhibition leads to a dual mode of action, wherein tumour growth is inhibited and cancer stem cells are depleted through forced terminal differentiation
• The latter is currently considered a promising novel way of addressing tumour metastasis and recurrence

Contact:
Dr. Adam Collier, Director of Business Development
T: +44 1799 533 680
E: adam.collier@isogenica.com

References:
Fenderico et al., Nat Commun. 10, Article number: 365 (2019).
Gong et al., PLoS ONE 5, e12682 (2010).
Ettenberg et al., PNAS 107, 15473–15478 (2010).
Jin et al., Tumour Biol. 39 (10) 1010428317729933 (2017).
Brenner et al., The Lancet 38 (9927) 1490-1502, (2014).