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HEIndividual fellowship2022–2024

MirrorBody · Discovery, total chemical synthesis, and validation of “mirror-image” D-Nanobodies

Horizon Europe — Marie Skłodowska-Curie Actions

Duration
2022-08-01 → 2024-07-31
EU contribution
€195,915
Participants
1
Scheme
HORIZON-TMA-MSCA-PF-EF

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Results in brief

Discovery, total chemical synthesis, and validation of “mirror-image” D-Nanobodies

Therapeutic proteins are the most rapidly growing class of drugs, and antibody-based biologics represent their vast majority. Antibodies are excellent tools for target binding and for disrupting protein-protein interactions in terms of potency and specificity, but they have limitations such as poor tissue and cellular penetration and complex manufacturing. Small nature-derived and engineered proteins can retain antibody binding affinity and specificity; and thanks to their reduced size can overcome penetration issues and can be accessed by chemical synthesis, making them extremely versatile to introduce tailored modifications, but a key limitation that is linked to all therapeutic proteins is their immunogenicity. Immunogenicity of therapeutic proteins involves their tendency to trigger an unwanted immune response against themselves, for example by producing antibodies that bind to the proteins and reduce or eliminate their therapeutic effects, but also leading to potentially life-threatening complications. In this scenario D-proteins, completely composed of D-amino acids, have the unique advantage of having an extremely low immunogenic potential. Although these properties have been known for almost 60 years, currently there are very few examples of antibody-like D-proteins in the literature, the main bottleneck being the lack of efficient discovery processes. The overall objective of this project is to explore the potential of a novel, multidisciplinary approach for the discovery of D-proteins as for molecular targeting that could lead to a novel generation of biomedical tools.

Data: CORDIS, © European Union

Project objective

The central role of molecularly-targeted therapeutics and imaging probes in translational research entails the development of an ever-growing arsenal of “chemical biologics” endowed with optimal in vivo properties. In this regard, mAbs and their derivatives (e.g. ADCs) still suffer from unsettled drawbacks involving difficulties in production and characterization, leading to heterogeneous conjugates in terms of size, potency and toxicity. Chemical modifications on mAbs are highly unreliable due to their complex structure: a central problem in this discipline, where heterogeneous drug-to-antibody ratio (DAR) and conjugation site represent significative limitations. Immunogenicity is a major drawback which affects humanized, as well as fully-human mAbs, and is exacerbated by long half-lives. Cases of unwanted activation of the immune system reportedly degenerated to life-threatening conditions such as acute anaphylaxis, serum sickness and cytokine release syndrome. Their bulky size (≈150 kDa) hinders their extravasation, impairing their efficiency to enter tumors. Nanobodies (Nbs) are the smallest naturally-derived antibody fragments (≈13-14 kDa) that retain antigen-binding affinities in the same range of mAbs (nM to pM affinity range) while having extremely reduced half-lives ( ≈ 15 min.) when not bound to their target, thanks to a fast renal excretion. MirrorBody intends to push the boundaries of targeted “chemical biologics” via an interdisciplinary approach that exploits both immunology and synthetic chemistry techniques for the generation of synthetic D-nanobodies that bind natural L-targets with high affinity. Such unprecedented synthetic D-Nbs will be endowed with improved biocompatibility, and will enable “plug-and-play” approaches for the controlled conjugation of diverse moieties.

Original text from CORDIS.

Participants

  • CENTRE NATIONAL DE LA RECHERCHE SCIENTIFIQUE CNRS · ParisCoordinatorFrance

Links

Data: CORDIS, © European Union