Abstract 1863: Evaluation of BDB101, a first-in-class TLR7/8 dual agonist conjugated to an anti-PD-L1 mAb, in cancer treatment

Abstract

Abstract Background Responses to antiPDL1 checkpoint inhibitors (CPIs) in many tumors are governed by the PDL1 expression on tumor and immune cells in the tumor microenvironment (TME). Increasing PDL1 expression on cells may enhance the response to CPIs. Tolllike receptor (TLR) agonists have shown to induce PDL1 expression in the TME and may enhance the antitumor effects of CPIs. The effective dose of TLR agonist administered to patients is limited by systemic toxicities. To overcome this limitation, one approach is to conjugate the TLR agonist to an antibody. This allows for delivery and release of higher doses of the TLR agonist in the TME while limiting systemic exposure.BDB001 is an intravenously (IV) delivered TLR7/8 dual agonist that activates both the innate and adaptive immune system. In clinical trials, BDB001 has been well tolerated and shown promising antitumor responses in monotherapy and in combination with antiPDL1 therapy (Patel M. et al, SITC 2020 and SITC 2021). To further enhance the antitumor effect and allow for increased concentration of the TLR7/8 dual agonist in the TME, we developed BDB101, a proprietary firstinclass TLR7/8 dual agonist - antiPDL1 monoclonal antibody (mAb) conjugate using our TollLike receptor Agonist Conjugate (TLAC) platform. Here we report on the preclinical and nonhuman primate (NHP) evaluation of BDB101. Methods BDB101 utilizes a cleavable linker, allowing for the TLR7/8 dual agonist payload to be released in the TME and enabling a bystander effect. BDB101 was assessed for in vitro TLR7/8 dual agonist activity and PDL1 binding, and in vivo antitumor efficacy in immune competent mouse models. The pharmacokinetic and pharmacodynamic effects of BDB101 was evaluated in NHP. Results The conjugated TLR7/8 dual agonist did not change the PDL1 binding specificity of the antibody, and the uncleaved conjugate did not activate TLR7 or TLR8. In the C26 mouse model, a BDB101 mouse surrogate showed a significantly more robust antitumor effect compared to the TLR7/8 dual agonist or the antiPDL1 mAb alone. In NHP, a single IV infusion of BDB101 showed no significant differences in PK parameters between BDB101 and the total antiPDL1 mAb. BDB101 demonstrated remarkable in vitro stability in human plasma for up to 21 days. In NHP, BDB101 was also very stable with minimal release of free TLR7/8 dual agonist payload. Pharmacodynamic studies in NHP were consistent with PK behavior. Conclusions BDB101 exhibits robust preclinical efficacy and prolonged stability in NHP. The low rate of free TLR7/8 dual agonist payload released into the systemic circulation from the conjugated form of BDB101, should minimize the risk of systemic TLR7/8 dual agonist exposure, while maintaining the ability to deliver the payload to the TME. These results indicate that BDB101 will likely have a good in vivo therapeutic window and strongly support the clinical development of BDB101. Citation Format: Jing Yang, Robert H. Andtbacka, Walter Lau, Lixin Li. Evaluation of BDB101, a first-in-class TLR7/8 dual agonist conjugated to an anti-PD-L1 mAb, in cancer treatment [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2023; Part 1 (Regular and Invited Abstracts); 2023 Apr 14-19; Orlando, FL. Philadelphia (PA): AACR; Cancer Res 2023;83(7_Suppl):Abstract nr 1863.