TAA x TNFR Bispecific Trimerbody
LeadArtis has generated Bispecific Trimerbodies (BMTs) exploiting the expression of two cell surface antigens, one being a costimulatory TNFR on the T cells and the other being a TAA on the tumor cells. The anti-TAA antibody allows effective location of the BMT into the tumor deposits, providing an efficient interaction and activation of the TNFR expressed primarily on the surface of activated tumor infiltrating T lymphocytes.
We have focused on a specific TAA and costimulatory TNFRs since their function is clinically validated in numerous prevalent cancer types. Recent clinical results using conventional mAbs reveal durable clinical responses in a small subset of patients with metastatic cancers underscoring clinically validated mechanisms of action. In addition, preclinical results in cancer in vivo models show synergy when combining specific individual anti-TNFR and anti-TAA mAbs (IgG type).
• Selective location within the tumor of the BMT and costimulation through the TNFR will be restricted exclusively to the tumor infiltrating lymphocytes. The tumor targeting would be mediated by the anti TAA domains and favored by the BMT molecular architecture, valence and size. The estimated half-life of a BMT ensures sufficient access to the tumor; additionally, the small size and absence of the Fc region will allow a more efficient extravasation through the irregular tumor vasculature. Finally, the multivalence (three anti-TAA domains) would establish efficient and durable interactions (enhanced avidity) with tumor cells expressing different TAA levels on the membrane thus reducing any potential selection for variants with low TAA levels (tumor escape).
• More efficient crosslinking / activation of the TNFR due to: (i) BMT molecular adaptation to the trimeric structure of the TNFR, and (ii) BMT interaction with the TAA expressed on the surface of tumor cells (additional crosslinking). Once bound to the tumor cells, the BMTs act as «recruitment points» capable of providing effective crosslinking tumor-specific.
• The BMT would avoid the adverse effects associated with the interaction of the Fc fragment with cell surface receptors, such as observed in a significant proportion of patients treated with certain conventional anti-TNFR mAbs which in some cases requires discontinuation due to severe liver inflammation; the BMT lacks the Fc region and therefore will not have this toxicity limitation.
Importantly, based on the BMT modularity, the tumor-specific domain could be easily replaced by another binding domain in order to retarget the BMT to newly identified TAAs as they are discovered, thereby fostering a regular BMT pipeline.