In ovo approach for the assessment of efficacy and toxicity of drug candidates

INOVOTION has developed a new chick egg chorioallantoid membrane (CAM) assay to reduce animal use and attrition rates in anticancer drug development. The new approach requires only minute amounts of drug and combines efficacy and toxicity studies making the drug development process faster, more reliable and less expensive. INOVOTION are now seeking partners from industry or academia able to provide a diversity of novel reagents or compounds with preclinical/clinical data available to test in the model.

With support of funding from the Solutions scheme, INOVOTION will work with a large pharmaceutical company (Top 10) to assess the toxicity and efficacy of a novel class of antibody drug conjugates using a pyrrolobenzodiazepines (PBD) warhead. Data from the CAM model will be compared to existing in vivo mouse data provided by the pharmaceutical company to evaluate the effectiveness of the model as a cost-effective compound screening method.

Attrition is a major issue in anticancer drug development. Only 5% of agents that have anticancer activity in preclinical development are licensed after Phase III testing, making the drug development process enormously costly and inefficient (Kola and Landis, 2004). Poorly predictive preclinical oncology models are a major factor in this high failure rate. Current preclinical efficacy and toxicity testing strategies rely heavily on animals, specifically rodent xenograft models in which human cancer cells are implanted intraperitoneally in mice and left to grow into tumours. These are then treated with candidate drugs for several weeks or more to assess the drugs ability to inhibit tumour growth or invasion/metastasis. These models do not represent the primary tumours from which they are derived in terms of heterogeneity and drug resistance, leading to substantial limitations which affect their utility and validity in anticancer drug development (Ocana et al., 2010). These models also use considerable numbers of animals. The development of more predictive preclinical models will be critical to prevent further anticancer drug failures.

References

  • Kola I and Landis J, (2004). Can the pharmaceutical industry reduce attrition rates?. Nat Rev Drug Disc 3: 711-5. doi:10.1038/nrd1470.
  • Ocana A, Paniella A, Siu LL, et al. (2010). Preclinical development of molecular-targeted agents for cancer. Nat Rev Clin Oncol 8 (4): 200-9. doi:10.1038/nrclinonc.2010.194.

INOVOTION’s model uses tumour cells deposited as a homogeneous mass on the chorioallantoid membrane (CAM) of embryonated eggs. This allows tumour growth, invasion into the vasculature and possibly the embryo, and toxicity to be measured simultaneously in controlled conditions and in response to potential anticancer drugs. Measuring efficacy and toxicity of anticancer drug candidates in the same model is beneficial from a scientific perspective and may prove an attractive proposition for company internal decision making processes, reducing the number of compounds entering regulatory in vivo toxicology studies and subsequent animal use.

The initial assays are focused on improving lead optimisation of anticancer compounds; measuring quantitatively and simultaneously the impact on tumour growth and metastatic invasion as well as the toxicity of lead candidates. INOVOTION’s test results are equivalent to the current ‘gold standard’ mouse xenograft models but are much faster, more reliable, less expensive and need only minute amounts of drug (>1,000 times less than in mouse models). This demonstrates the potential of the in ovo model to significantly reduce animal use. INOVOTION’s proprietary tests are applicable to any preclinical anticancer drug discovery program and could be used more broadly for the early evaluation of the toxicity of any new drug candidate. With further development, INOVOTION hope to demonstrate how their model can also improve anticancer drug development beyond current mouse models. By extension, the model could also be useful to test the toxicity of a broad range of chemicals, including industrial or cosmetic.

INOVOTION have developed tests based on twelve human tumour cell lines, with a limited number of commercial drugs. To complete these validation studies and demonstrate the utility of the approach over current mouse models, INOVOTION would like to measure the activity and toxicity of a larger set of anticancer drugs, whether marketed or in development, and compare the results to those obtained with the mouse tests and available clinical data. Collaborators within industry or academia are sought to provide a diversity of novel reagents or compounds (i.e. small molecules, antibodies, nucleic acids) with preclinical/clinical data available to test in the model. INOVOTION and their partner would jointly publish the results of this further development/validation work, whilst keeping the nature of the molecules confidential. INOVOTION would also welcome input from their partners to improve the model according to the collaborators needs.

Many millions of mice are used annually in cancer drug development. In the UK, just under 500,000 mice were used in non-toxicology cancer research in 2012. Although the INOVOTION tests will not completely replace the use of mouse xenograft models in anticancer drug development, INOVOTION estimate from their initial validation work that they have the potential to reduce the above numbers by 20-30%, and perhaps more. As an example, many current customers are choosing to use only the INOVOTION assay for lead optimisation once they have observed the power of the approach, replacing up to 50 mice that would typically be used per compound, dependent on the number of rounds of lead optimisation.

Overview

With support of funding from the Solutions scheme, INOVOTION will work with a large pharmaceutical company (Top ten) to assess the toxicity and efficacy of a novel class of antibody drug conjugates using a pyrrolobenzodiazepines (PBD) warhead. Data from the CAM model will be compared to existing in vivo mouse data provided by the pharmaceutical company to evaluate the effectiveness of the model as a cost-effective compound screening method.

If successful, INOVOTION’s novel technology could dramatically reduce the use of rodents in cancer drug discovery, as more candidate molecules will be filtered out before progressing to testing in classical in vivo models.