Developing an Organ on a Chip Model to Test the Therapeutic Efficacy of Adhirons in Breast Cancer

We hypothesise that fully humanised perfused and vascularised 3D breast cancer models can expedite and facilitate prioritisation of new antibody replacement reagents, Adhirons, for subsequent in vivo studies and that these have therapeutic potential. We will develop Adhirons to the therapeutic target HER2 comparing its efficacy to the current monoclonal antibody (mAb) therapeutic Trastuzumab. mAb production involves injection of 1-3 animals with immunogen. Thereafter they are bled repeatedly, often terminally and antibodies purified from their blood. In 2013 (UK), there were, respectively, nearly 1500 and >8000 procedures to produce mono- and polyclonal antibodies. Adhirons are direct antibody replacements which could completely eliminate the need for these procedures. Currently therapeutic mAbs can only be tested in animals as there are no in vitro systems with vasculature with sufficient retention times to test new therapeutics. We will use human cells (UK Breast Cancer Now Tissue Bank), to develop fully humanised, vascularised, Organ-on-a-Chip screening platforms, using SeedEZ™ 3D culture system and synthetic vasculature to model breast cancer molecular subtypes, validated against ‘gold standard’ human tissue. Ability of Adhirons to inhibit function will be tested in our screening platform. Market research shows appetite from pharma/CROs for robust in vitro models/platforms to test slow clearing drugs for both on-target efficacy/off-target safety testing. Currently this is met by PDX models. Crown Bioscience offers >2000 PDX models, Wuxi AppTec, Champions Oncology both offer 1000 PDX models; at least 4000 mice are used to maintain these models, before even considering those required for experiments. The breast cancer model we will develop will reduce the numbers of animals, providing informed decisions in which mouse avatar to test, reducing the number of “clinical trials in mice”. Ultimately this may lead to complete replacement.

• Further Funding: NC3Rs Infrastructure Grant, SEARCHbreast: A virtual resource to facilitate sharing breast cancer materials and knowledge to benefit the 3Rs, February 2014, £495,766
• Further Funding: NC3Rs Skills and Knowledge Transfer grant, Fully humanised 3D vascular perfused model for breast cancer modelling and therapeutic screening, October 2019, £75,912