FAP靶向ADC性能的机制驱动因素

Cancer-associated fibroblasts (CAFs), the main stromal cell population within the tumor microenvironment (TME), play a pivotal role in cancer progression, metastasis, and immune evasion. To target this compartment, two antibody-drug conjugates (ADCs), OMTX705 and OMTX105, were developed against fibroblast activation protein (FAP) expressed on CAFs. Both share the same human IgG1 antibody backbone (OMTX005) but differ in linker-payload chemistry: OMTX705 carries the cytolysin A1B1, whereas OMTX105 includes monomethyl auristatin E (MMAE). Despite similar drug-antibody ratios (DAR ≈ 4), their distinct vc-PABA-derived linkers confer differential stability and intracellular processing characteristics.We performed a comprehensive characterization of their mechanisms of action, including internalization, intracellular trafficking, and bystander cytotoxicity, in vitro and in vivo, as well as plasma stability and maximum tolerated dose (MTD) analyses to assess their pharmacological and safety profiles. Both ADCs displayed potent antitumor effects but differed markedly in their intracellular fate and pharmacodynamic properties. OMTX105 demonstrated faster processing and stronger bystander killing, leading to higher antitumor activity in murine xenografts; however, its effective dose was close to the MTD in rat, limiting its therapeutic window. In contrast, OMTX705 exhibited slower intracellular processing, resulting in a sustained and controlled payload release. This translated into a longer-lasting effect in vivo, with CAFs acting as a drug reservoir prolonging cytotoxic activity in neighboring tumor cells, while maintaining a superior safety profile.Remarkably, both ADCs exhibited in humanized xenograft mice a shared immunomodulatory activity, promoting infiltration of CD4⁺ and CD8⁺ T lymphocytes within the TME-particularly CD8⁺ cells in treated tumors-suggesting that FAP-targeted ADCs facilitate immune cell recruitment compared to control. This was confirmed in clinical samples from patients treated with OMTX705, currently under clinical development. In these patients, CAF disruption, much lower FAP expression and higher CD8⁺ and CD4 + cell infiltration was detected in tumor areas co-localizing with the OMTX705 payload signal, providing evidence that OMTX705 enhances local immune activation and supports an antitumor immune response.Overall, these findings reveal both cytotoxic and immunomodulatory functions for FAP-targeted ADCs within the TME and provide molecular mechanistic insights into their bystander effect, emphasizing how differences in linker-payload chemistry critically determine efficacy, durability of response, immune engagement, and tolerability. This study highlights OMTX705 potential as a safer FAP-targeted ADC with long-lasting effect and underlines the importance of biology-driven linker-payload engineering for next-generation stroma-directed ADC anticancer therapies.