Community Research and Development Information Service - CORDIS


BisProt Report Summary

Project ID: 336041
Funded under: FP7-IDEAS-ERC
Country: Israel

Mid-Term Report Summary - BISPROT (Developing Multispecific Biological Agents that Target Tumor Neovasculature for Cancer Imaging and Therapy)

Many cancer diagnostics and medications work solely to target capillary vessels and prevent cancer cells from creating new capillaries, chocking off their much-needed blood and nutrient supply to halt the growth of tumors and slow down cancer spread. In our ERC funded study, we are creating a new type of engineered proteins that will be significantly more effective at preventing blood vessel formation (angiogenesis) and cancer spread (metastasis) by targeting not one, but two of the chemical receptors that control these processes.
Since activation of my ERC grant two and a half years ago, we were able to engineer protein-based platforms, namely tendamistat and N-TIMP2, with potential to bind with high affinity to MT1-MMP and integrin – two highly important chemical receptors expressed on the primary tumor and its vasculature. To achieve this goal, we adopted several state of the art mutagenesis approaches to introduce diversity into exposed loops within the tendamistat and N-TIMP2 protein scaffolds, and utilized different library screening methods to obtain protein variants that bind to the desired MT1-MMP and integrin receptors. In these approaches, the protein scaffold loops were mutated in a randomized manner to create combinatorial libraries that were displayed on the yeast cell surface for high-throughput screening against cancer chemical receptors that were produced recombinantly in bacterial and mammalian cells.
We then screened our libraries against the recombinant soluble MT1-MMP and integrin receptors and selected for protein variants with high affinity towards these desired targets. We were also able to produce these high affinity protein variants as soluble drugs and verify their high stability and correct folding. These variants were able to bind soluble and cancer cell expressing MT1-MMP and integrin receptors with high affinity and specificity, and most importantly, with extremely high antagonistic potency. These bi-specific cancer-targeting drugs are expected to show high potency in inhibiting cancer progression and spread and to be used for cancer diagnostics.

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