NBE-Therapeutics next-generation antibody-drug conjugates comprise a highly potent derivative of the anthracycline toxin PNU-159682, site-specifically conjugated to antibodies via NBE's proprietary SMAC-TechnologyTM. This results in ADCs with very stable peptide linkers connecting the highly potent payload to the antibody, which is only released upon binding to the cognate target in tumor cells and internalization and intracellular linker cleavage.
In addition to direct anti-tumor activity of the conjugates, NBE-Therapeutics ADCs have been found to induce a sustained and long-lasting anti-tumor immunity in tumor models with a fully functional adaptive immune system. This does not only result in the complete regression of tumors in syngeneic mouse tumor models, but after complete regression of the tumors in such models, the mice are entirely protected against tumor re-challenge with the same tumor cells.
In collaboration with immune-oncologists from the group of Prof. Zippelius group at the University Hospital Basel, it was shown that this anti-tumor immunity is established by the induction of an immunogenic cell death in ADC-targeted tumor cells. This in turn leads to an activation of tumor-antigen specific CD8 positive cytotoxic T cells and their increased infiltration into the tumor mass. Indeed, the anti-tumor immunity can be abrogated, if CD8 positive cytotoxic T cells are deleted in such mice by neutralizing anti-CD8 monoclonal antibodies.
In addition, this immune-oncology function of NBE-Therapeutics anthracycline-conjugated ADCs can be enhanced by combining ADC therapy with immune-modulating therapies, e.g. in combinations with immune-checkpoint inhibitor antibodies. In multiple syngeneic tumor models it was shown that immune-checkpoint inhibitor antibody therapy synergizes with NBE-Therapeutics' ADC therapy, such that even suboptimal doses of the ADC leads to complete regression of tumors in immuno-competent tumor models in vivo.
Due to this mode of action, NBE-Therapeutics ADCs have been termed immune-stimulatory ADCs, or iADCs.
It can reasonably be expected that some of the immune-oncology function of NBE-Therapeutics iADCs can be translated into the clinical setting, where existing immune-modulating therapies can further be improved or enhanced, in order to achieve sustained and durable anti-tumor responses.