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2562 Background: Anti-PD-L1 antibodies are well-established as potent immune effectors in solid tumors expressing PD-L1 and demonstrate binding to these tumor cells within the TME. By contrast, due to the ubiquitous expression of CD47 on normal cells and tissues, anti-CD47 therapeutic agents with an active antibody Fc can lead to serious dose-limiting toxicities and profound biodistribution problems. To overcome these issues, we have generated LB101, a next-generation conditionally activated PD-L1xCD47 bispecific mAb with two anti-CD47 domains blocked by two further anti-PD-L1 domains, linked by two proprietary IgG-derived hinges, which inhibit CD47 interactions in the periphery, but are degraded in the PD-L1+ TME, thereby activating CD47 blockade to induce antibody-dependent cellular phagocytosis (ADCP). Methods: An IgG1-based, conditionally activated bispecific molecule was examined in binding, phagocytosis, PD-L1 blocking and flow cytometry assays. Efficacy analyses were performed in an hPD-L1+ syngeneic model in hPD-L1+/hPD1+ C57BL/6 mice, and preliminary safety and exposure analyses were completed in monkey. Results: In its intact locked form, LB101 exhibited anti-PD-L1 assay potency similar to atezolizumab. CD47 binding was only observed for LB101 after unlocking by hinge linker cleavage, leading to strongly enhanced ADCP by human CD14+ cells. In monkey, plasma stability of the locked construct was established with a PK profile mimicking that of a typical PD-L1 mAb. In the MC38 mouse model, systemically administered LB101 monotherapy delivered at equimolar dose to atezolizumab, led to no anemia, weight-loss, or overt toxicity. Monotherapy LB101 exhibited greatly improved efficacy and durability of response (14/16 tumors eradicated) over isotype control IgG (0/16) and atezolizumab (1/16). The CD47 naked parent IgG1 mAb was not tolerated in mouse, with 100% lethality above 2mg/kg. In rechallenge experiments, all naïve mice established tumors rapidly while none of the mice from groups with prior LB101-induced regressions exhibited tumor growth. Conclusions: Single agent LB101 immunotherapy delivered systemically in a difficult to treat syngeneic mouse model resulted in PD-L1 directed, local tumor-specific CD47 effector engagement leading to significant tumor regressions as compared to atezolizumab without overt toxicity. Future developments will focus on developing LB101 as a single agent therapeutic and exploring the potential of LockBody technology in improving the therapeutic index of other anti-cancer biological effectors through conditional activation within the TME.

e17783 Background: Measuring progress in cancer treatment research is complicated by the reality that various stakeholders judge achievements differently, because they have diverse priorities and v...