Drug-conjugated bi-specific antibodies for the immune tolerance induction – DBAb-Tol

Immune tolerance remains the « Holy Grail » in transplantation because no more progress has been seen in long-term outcomes. Dendritic cells (DCs) are specialized cells in the pro and anti-inflammatory balance of the immune response. Moreover, subsets of DCs, identified in humans, appear to have their respective competences in immune response modulation. Cell therapy using dendritic cells has clearly demonstrated its limits considering the number of clinical trials with no patient benefit. An alternative strategy would be to develop in situ targeting subsets of this type of cells. Using genetic engineering, we designed scFv in tandem directed against different types of pathogen recognition receptors (PRRs) that target human dendritic cells. The double antigenic specificity of the bispecific antibody (bsAb) enhances the targeting of each DC subset. The linkage of the two PRRs on cell surface allows the induction of a pro-tolerant profile for the DCs (tolDCs) characterized by a specific phenotype and a high IL-10 secretion, and aiming to differentiate regulatory T cells. For 50 years, immunosuppressive drugs (IS) made the transplant possible by repressing the whole immune system. But the cost of this therapy is tremendous for patients, who become very sensitive to several types of infections and increase their risk of viro-induced cancers. Moreover, no increase of graft survival has been observed from the last 20 years. Both IS appear to be the most efficient drugs for the tolDC induction as demonstrated in both human and mouse models of transplants.
Our project is to develop an in situ DC subset targeting entity, using bsAb linked to immunosuppressive drugs to induce a tolerant status in humans. The aim of this designed molecule is to associate both effects of IS and of bsAb on DCs in a synergy to obtain a tolerogenic status. Two academic laboratories with expertise in immune tolerance, DCs and antibody design will be associated with a chemical company, McSAF (chemical tools for bio-conjugation and biodrugs), to elaborate immune-suppressive drug-conjugated bsAb against DCs. To be realistic about the objectives of this project, we plan to design only three different molecules directed towards inflammatory DCs, Langerhans cells and plasmacytoid DCs linked to IS. The project is divided in three work packages each aiming at an important step of the project.
Our first objective is to chemically modify both IS to obtain molecules allowing the bioconjugation to the bsAb. So, McSAF is able to develop different strategies for the activation of the drugs allowing their conjugations. The second objective is to produce modified bsAb able to be linked to the drugs. For that, we must first design specific links between scFv to allow drug conjugations and evaluate how these “new” bsAb are produced in CHO system. Next, we must produce our bsAb to be able to do all chemical modifications of bioconjugation. The conjugations with drugs will be an important step, as the achievement will essential for the next steps. Finally, we will evaluate the drug-conjugated antibody in ex vivo models on human cells. Several approaches will be used to determine the functionality of the bsAb on transfected HEK models and the tolerogenic effects on each specific DC subset.
The therapeutic conduction in grafts and immune diseases might be dramatically changed if these products could be evaluated on DCs and in vivo models. This project perfectly corresponds to the innovating biotherapies axis of both ANR and SNR objectives.