Background Activation of professional antigen-presenting cells shows promise for overcoming limitations in PD1-based immunotherapy. Toll-like receptor 7/8 agonists have gained attention as potential partners for immune checkpoint inhibitors due to their potent APC activation. GQ1007 is a novel HER2 targeting immune agonist conjugate (AIAC) that was developed based on GeneQuantum’s highly stable linker and enzymatic conjugation technologies. Through the fine tuning of TLR7/8 agonist potency and immune activation, here we report the unique attributes of GQ1007, demonstrating a favorable balance between efficacy and safety.
Methods We assessed in vitro immune activation and ADCP through PBMC/monocyte and tumor cell co-culture experiments. Non-specific release of proinflammatory cytokines was measured using a human whole blood assay, monitoring secretion of 13 different cytokines/chemokines. In vivo antitumor activity was evaluated in diverse mouse models. Serum cytokines secretion and TIL were analyzed in syngeneic model to understand the MOA. Ex vivo linker stability was determined using a sensitive LC-MS/MS method. The safety of GQ1007 was assessed in a toxicology study using cynomolgus monkeys.
Results GQ1007 selectively increased TNF-α secretion when co-cultured with HER2-positive cells, correlating with HER2 expression levels (figure 1). Treatment with GQ1007 enhanced phagocytosis specifically in HER2-positive cells, with no increase observed in HER2-negative cells (figure 2). GQ1007 demonstrated potent antitumor response in diverse HER2-expressing animal models (figure 3A). Combination therapy with GQ1007 and anti-mPD-1 showed improved efficacy compared to monotherapy (figure 3B). Tumor rechallenge experiments revealed immunological memory and epitope spreading in mice (figure 4). In vivo experiments demonstrated rapid tumor cell death, accompanied by infiltration of APCs and CD8+ T cells, and transient induction of key proinflammatory mediators (figures 5 and 6). Notably, compared to other clinical stage benchmark test articles, GQ1007 showed minimal cytokine induction in a whole blood assay, indicating a favorable safety profile (figure 7). No release of free agonist was observed in human plasma after 96 hours of incubation at 37°C, confirming the stability of GQ1007 (figure 8). The excellent safety profile of GQ1007 was further supported by the results of the GLP monkey toxicology study (table 1).
Conclusions GQ1007 demonstrates potent antitumor activities and robust tumor-specific immune activation. Importantly, our data strongly indicate a high potential for a favorable safety profile for GQ1007, highlighting its suitability for clinical exploration as a monotherapy or as a combination treatment with the existing ICI therapies. In conclusion, GQ1007 holds a great promise as a novel and effective treatment option for advanced HER2-expressing patients.
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