Abstract 2138: ALG01, a next-generation anti-PD-L1×TROP-2 bispecific antibody-drug conjugate (BiADC) with STAR technology, demonstrated excellent anti-tumor efficacy & safety in preclinical studies

The combination of anti-TROP2 ADCs with PD-(L)1 inhibitors represents a promising therapeutic strategy, merging targeted therapy with immunotherapy to improve treatment outcomes. Clinical trials are underway to explore its safety and efficacy in various cancer types. However, challenges remain, including accumulative toxicity, dosing difficulties, and tumor resistance. Bispecific ADCs (BiADCs), which target two antigens simultaneously, offer a promising advancement by enhancing tumor specificity, improving therapeutic efficacy, and reducing damage to healthy tissues. BiADCs are emerging as a pivotal innovation in oncology, particularly for difficult-to-treat cancers.Here, we present preclinical findings for ALG01, a novel anti-PD-L1×TROP2 BiADC with STAR (Smart TME (Tumor Microenvironment) Activated Release) technology and incorporated with targeted therapy and immunotherapy in one molecule, has shown remarkable anti-tumor activity and a favorable safety profile. ALG01 comprises a humanized PD-L1-targeting IgG1 fused with TROP2-targeting biparatopic VHHs at the C-terminal of the heavy chain, linked to exatecan via transglutaminase-mediated site-specific conjugation. In vitro studies demonstrated that ALG01 exhibits potent cytotoxicity against various TROP2 and/or PD-L1-positive cancer cell lines. Ex vivo, ALG01 was selectively and efficiently cleaved by proteases as designed within tumor tissues, compared to plasma and normal tissues (e.g., liver, spleen, lung), resulting in the release of anti-PD-L1 IgG1 and small-size anti-TROP2 VHH-drug conjugates. In vivo, ALG01 significantly regressed tumors in a TROP2-positive cell line-derived xenograft (CDX) model. Furthermore, in a MC38-PDL1-TROP2 syngeneic model, ALG01 treatment led to complete tumor eradication in 7 of 8 mice, showing significantly superior efficacy compared to reference anti-TROP2 ADC and its combination with reference anti-PD-L1 antibody.A rechallenge study further supported long-lasting ALG01's anti-tumor efficacy. After complete (8 of 8 mice) tumor eradication following a single dose of ALG01, mice were re-inoculated with tumor cells without additional treatment. Remarkably, the newly implanted tumors in 7 of 8 mice were once again fully eliminated, revealing a lasting immune activated memory effect. In toxicology studies, ALG01 was well tolerated in cynomolgus monkeys, with the highest non-severely toxic dose (HNSTD) observed at ≥45 mg/kg for DAR6 or ≥65 mg/kg for DAR4.These preclinical findings indicate that ALG01 offers a wide therapeutic window and may benefit patients with challenging-to-treat cancers. An IND application is planned for submission in 2025. Citation Format: Jun Xiang, Wenlong Gao. ALG01, a next-generation anti-PD-L1×TROP-2 bispecific antibody-drug conjugate (BiADC) with STAR technology, demonstrated excellent anti-tumor efficacy & safety in preclinical studies [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2025; Part 1 (Regular Abstracts); 2025 Apr 25-30; Chicago, IL. Philadelphia (PA): AACR; Cancer Res 2025;85(8_Suppl_1):Abstract nr 2138.