Abstract 334: proPBD-ADCs: optimization of therapeutic potential of ADCs based on capped PBD payload with attenuated potency
Abstract
Antibody-drug conjugates (ADCs) with pyrrolobenzodiazepine (PBD) dimer payloads have been explored preclinically and several PBD-based ADCs entered clinical trials. PBD dimers produce highly cytotoxic DNA crosslinks and thus have a mode-of-action differentiated from microtubule inhibitors, TOPO1 inhibitors and other DNA targeting warheads. In April 2021, the FDA approved the first PBD-based ADC, the CD19 targeting loncastuximab tesirine, for treatment of adult patients with relapsed or refractory large B-cell lymphoma, including DLBCL, after 2 or more lines of therapy. However, loncastuximab tesirine carries safety warnings - for example for effusion and edema, myelosuppression, and cutaneous reactions.
While PBD-based ADCs show efficacy in the clinic, they belong to a highly potent payload class with IC50 values on human cancer cell lines in the picomolar range. In fact, the ultrapotent character of the vast majority of PBD-based ADCs has highly limited the administration at clinically suitable dosing regimens. Therefore, increasing the therapeutic dose and at the same time improving the therapeutic windows of PBD-based ADCs will be key for the next generation of PBD-ADCs.
Although conjugation of linker-payload to the antibody is typically based on random conjugation to cysteine or lysine, we have shown that the native glycan of monoclonal antibodies is a privileged site for attachment of cytotoxic payloads1 (GlycoConnect® technology), while the therapeutic index is further…
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