A platform for engineering bi-specific antibody constructs

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Global trends in the pharmaceutical sector indicate that monoclonal antibodies (mAb) will be among the blockbuster drugs of the future, and their worldwide sales are forecast to reach 125 B$ by 2020. However, mAb therapies can be very expensive (upwards to $60,000 per year per patient), which can be prohibitive to their use - almost irrespectively of their efficacy in treating disease. There is thus an immediate need to reduce the cost of mAb therapies. Over the past six years, our group has contributed to this goal by e.g., improving the efficiency of key manufacturing steps and overcoming viscosity challenges that prevent injection (less costly to administer than infusion). To pursue these developments, our program over the next five years will capitalize on our expertise on this topic to develop a platform to facilitate and accelerate the R&D process for bispecific antibodies (bsAb), an emerging variant of mAb that has shown promise in cancer treatment. Facilitating the R&D process will lead to more potent and more affordable bsAb therapies for Canadians. Unlike conventional mAb, which have one target, bsAb can bind two different targets. This can be exploited to bring together cancer cells and cancer-killing cells of the patient's own immune system. However, while bsAb have the potential to revolutionize cancer treatment, it is currently unknown what the `optimal structure' of a bsAb should be. This research program proposes to use `DNA nanotechnology' to rapidly study the effect of bsAb structural parameters on T-cell engagement and antibody-dependent cellular cytotoxicity. DNA nanotechnology is well known for exploiting the precise base-pairing between custom DNA strands in order to assemble 3D nanostructures of incredible complexity. These structures are ideal for precisely positioning the two different target-binding portions of antibodies in space. Our program will therefore use bioconjugate, supramolecular, and dynamic chemistry to develop and consolidate a platform technology to facilitate the development of future bsAb for a variety of diseases.