Avacta Therapeutics has presented groundbreaking preclinical data on its dual payload pre|CISION® technology, designated AVA6207, at the 2025 AACR-NCI-EORTC International Conference on Molecular Targets and Cancer Therapeutics held in Boston, Massachusetts. This pioneering approach aims to simultaneously deliver two distinct therapeutic agents directly to the tumor microenvironment (TME) via a unique fibroblast activation protein (FAP)-mediated cleavage mechanism.
As the first organization to develop dual payload peptide drug conjugates (PDCs), Avacta is addressing significant challenges in oncology by overcoming the resistance mechanisms that tumors develop against single-agent therapies, thereby enhancing therapeutic efficacy through targeted combination treatment.
The company”s dual payload pipeline consists of two primary strategies: the combination of microtubule inhibition with topoisomerase I inhibition (MMAE combined with exatecan) and DNA damage response (DDR) agents (including ATR or PARP inhibitors) paired with exatecan, which amplifies the cytotoxic effects of the latter.
Dr. Christina Coughlin, CEO of Avacta, remarked, “The introduction of the first dual payload peptide drug conjugate represents a substantial advancement in cancer treatment, significantly broadening the capabilities of our pre|CISION® platform by integrating combination therapy within a single small molecule.” She emphasized the promising results observed with their exatecan-DDR inhibitor combinations, which could greatly enhance treatment outcomes for patients with resistant tumors.
The pre|CISION® platform has shown promising clinical data, particularly with faridoxorubicin (AVA6000, FAP-Dox), which achieved a remarkable tumor-to-plasma concentration ratio and significantly reduced off-target toxicities, even at doses up to four times higher than conventional doxorubicin.
Key preclinical findings highlight the robust FAP-selective delivery and strong anti-tumor activity of the dual payload technology. The mechanism for dual payload release was validated through biological and biochemical analyses, confirming that both therapeutic agents are released simultaneously from a single cleavage event. Adjustments to the self-immolative linkers enabled the fine-tuning of payload release kinetics, allowing for optimized therapeutic profiles tailored to various combinations.
Furthermore, dual payload compounds exhibited potent cytotoxic effects comparable to those of free agents when FAP was present, while showing minimal activity without FAP, confirming their excellent tumor selectivity in both two-dimensional and three-dimensional tumor models. Biomarker modulation specific to each payload was observed only in FAP-positive environments, with significant reductions in DNA repair markers and cell cycle arrest patterns corroborating the operational mechanisms of both therapies.
The dual approach also demonstrated enhanced synergistic effects against known resistance pathways, indicating a four- to five-fold increase in tumor cell death compared to exatecan alone. This validates the potential of the technology to overcome DDR-mediated resistance.
In studies involving tumor-fibroblast co-culture, the FAP-positive cancer-associated fibroblasts facilitated payload release, leading to concentrated therapeutic effects in the TME and effective eradication of FAP-negative tumor cells, supporting the bystander mechanism of action.
The findings from this research on dual payload cancer therapies mark a novel direction in oncology, with the pre|CISION® platform poised to offer substantial advantages over traditional antibody drug conjugates (ADCs), including targeted payload release, reduced toxicity, enhanced tumor penetration, and a broad market potential.
The poster presentation titled “Discovery and characterization of novel pre|CISION® technology compounds delivering complementary dual payloads to the tumor microenvironment following FAP cleavage” is accessible on the Avacta website. The team will provide further insights into the published data during a presentation via Investor Meet Company following the conference.
For additional information regarding Avacta, interested parties are encouraged to reach out through their official channels.
