Presentation

Building on antibody expertise, many different bispecific formats have been engineered to allow the additional neutralization of an escaping pathway or the recruitment of effectors, but often at the expense of the overall physico-chemical properties of the biologic itself compared to the actual state of the art for monoclonal antibodies. Nanofitin-Antibody fusion is proposed as a novel multispecific platform, whereby additional targeting specificities are provided by the fusion of Nanofitins to existing antibodies without altering their initial physico-chemical properties.
Nanofitin is a small (7 kDa) single chain, hyperstable, cysteine-free, and highly soluble alternative scaffold that can be custom-engineered for a defined targeting specificity. Nanofitins are easily assembled with each other or with third-party molecules such as antibodies by simple, rapid and proven methods to design an ideal targeted molecule. With the strong rational behind the targeting of multiple disease pathways, the trend is moving smoothly from the design of bispecific to multi-specific antibodies, which could be easily adapted with Nanofitins. Thanks to their small size, Nanofitins can be plugged on an antibody at different locations, either as a single module or as an assembly, while still providing a minimal hindrance on the antibody that retain its functionality. Resulting Nanofitin-Antibody fusions benefit from the high stability and solubility of the Nanofitin scaffold, providing to the Nanofitin-based multi-specific platform a developablility advantage.

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Affilogic is developing a new anti-cancer therapeutic approach. Different multispecific assemblies of Nanofitins are developed with a variation of the modules that compose them. In order to potentiate the anti-tumor response, the choice of Nanofitin modules to assemble focuses on those with activities involved in cancer synergistic signaling pathways. In the development of multispecific anti-tumor proteins, Nanofitins provide several advantages. Indeed, thanks to their good tolerance to engineering modifications as well as the non-involvement of their N- and C-terminal ends in the binding, their multimerizations with other molecules / proteins / toxins / antibodies and Nanofitins are facilitated and used in order to do multi-targeting and/or increase avidity. Moreover the robustness of these proteins limits the possibilities of their deactivation in the presence of an aggressive tumor environment. In addition, the absence of cysteines and post-translational modifications allows the production in prokaryotic system of several Nanofitins grouped in a single molecule, which will bring an attractive cost in the multimers development. Finally, their low molecular weight promotes their diffusion within the tumor mass and gives them a short plasma half-life allowing the elimination in a few minutes of unbound proteins which is interesting for reducing side effects.

This project was partially sponsored from January 2018 to December 2020 by a grant from the European Regional Development Fund (ERDF / FEDER) via the Region Pays de Loire.

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