Clinical genomic and quantitative IHC–driven target identification to enable precision, tumor-selective activation of SynchroLINK T2X antibody-drug conjugates.

Abstract

e15043 Background: Conventional antibody–drug conjugates (ADCs) rely on single-step payload release and are often limited by off-tumor toxicity and variable therapeutic index. SynchroLINK T2X ADCs are designed for precision, tumor-selective activation through sequential intracellular processes. We sought to identify tumor-specific biological features supporting this activation paradigm using integrative genomic analysis and quantitative immunohistochemistry (IHC) to inform patient selection and target prioritization. Methods: Large-scale transcriptomic datasets from human tumors and matched normal tissues were analyzed to identify cancer-enriched expression patterns of genes associated with intracellular ADC processing and activation. Candidate targets were prioritized based on differential tumor-to-normal expression and pathway coherence. Quantitative IHC was performed on tumor tissue microarrays using analytically validated monoclonal antibodies. Digital image analysis with cytoplasmic-specific algorithms was used to generate H-scores, enabling objective assessment of protein abundance and spatial distribution across tumor types. Results: Genomic analyses revealed distinct tumor-enriched expression profiles for multiple biological components implicated in sequential ADC activation, with limited expression in corresponding normal tissues. Co-expression analyses demonstrated coordinated upregulation of these features across several solid tumor indications. Quantitative IHC confirmed robust, cytoplasmically localized protein expression in tumors, with significantly lower expression in adjacent normal tissues. Digital H-score distributions supported clear tumor-normal separation and revealed inter-tumoral heterogeneity consistent with a precision-based activation model. Integration of genomic and IHC data enabled identification of tumor subsets predicted to support efficient, sequential activation of SynchroLINK T2X ADCs. Conclusions: Integrative genomic and quantitative IHC analyses identify tumor-specific biological features that support precision, tumor-selective activation of SynchroLINK T2X ADCs. These findings provide a translational framework for patient selection and support a novel activation paradigm with potential to improve the therapeutic index of ADC-based cancer therapies.