An avidity-driven, dual-targeting ADC with superior tumor selectivity for the treatment of solid tumors

Toxicities as consequence of antigen expression in healthy tissues (on-target) and instable conjugation technology (off-target)have hampered the application of highly potent pyrrolobenzodiazepine (PBD) payloads in ADCs. To address these safety liabilities, we have developed an AND-gate bispecific ADC (bsADC) which preferentially kills tumor cells expressing two tumor-associated antigens (TAAs), while sparing healthy cells expressing only one TAA. Our proprietary site-specific, click-based glycan-conjugation platform minimizes off-target toxicities by using a highly stable tumor-selective linker and a hydrophilic chemistry that reduces target-independent uptake. The beneficial safety profile and conjugation technology enables the use of a PBD dimer as cytotoxic payload. With our AND-gate approach, in vitro we show more potent binding to and killing of double target positive cells compared to single target positive or target negative cells. In vivo, our bsADC demonstrates promising efficacy, tolerability, and pharmacokinetics.

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