Modular in vivo antibody–ADC click to reverse drug resistance in tumours

Researchers have introduced a novel strategy called “antibody, ADC click” that could potentially overcome drug resistance in tumors by enabling modular in vivo assembly of antibody-drug conjugates (ADCs). This innovative approach utilizes bioorthogonal click chemistry to form functional antibody, ADC constructs without requiring extensive antibody reengineering. The technique allows for the combination of targeting and reaction components, facilitating the creation of tailored therapeutic agents that can engage multiple tumor targets or distinct domains of the same receptor. The concept builds upon existing advancements in antibody combinations and multispecific antibody formats, aiming to address the limitations of traditional ADCs. Current FDA-approved ADCs often depend on high, uniform antigen expression and efficient internalization, which can hinder their effectiveness in heterogeneous or resistant tumors. By leveraging the inverse electron demand Diels, Alder cycloaddition between trans-cyclooctene (TCO) and tetrazine, the new strategy introduces a modular system where an antibody, TCO is administered followed by a non-targeted small-molecule tetrazine. This enables the in vivo formation of functional antibody, ADC constructs that can target either the same receptor or different tumor antigens. To illustrate the potential of this approach, researchers focused on two well-characterized receptors: human epidermal growth factor receptor 2 (HER2) and epidermal growth factor receptor 1 (EGFR). Both are widely expressed across various tumor types and have been individually targeted by ADCs or monoclonal antibodies. However, EGFR is known to play a role in developing resistance, particularly by forming heterodimers with HER2, thereby reducing the effectiveness of HER2-targeted ADCs. In cases where HER2 expression is low or uneven, EGFR can act as a secondary target to enhance the uptake and internalization of HER2-directed ADCs through in vivo bioorthogonal assembly. The study demonstrated that the antibody, ADC click strategy could effectively deliver HER2-directed ADCs, such as trastuzumab deruxtecan (T-DXd) and trastuzumab emtansine (T-DM1), to both EGFR-high and EGFR-low cancer cells, regardless of varying levels of HER2 expression. The process relies on the specific chemical interaction between the antibody and ADC components, while the targeted binding and subsequent trafficking determine the efficiency of uptake and therapeutic outcome. This modular design offers flexibility in applying the strategy to other receptors and ADC combinations, especially in tumors that do not respond adequately to current treatments. Further optimization of the antibody, ADC click method involves refining the parameters that govern its efficacy, such as the timing and sequence of administration, the choice of click chemistries, and the compatibility of the selected antibodies and ADCs. Researchers are exploring how these factors influence the stability, specificity, and overall performance of the assembled constructs. Additionally, they are investigating whether this approach can be extended beyond HER2 and EGFR to other receptor pairs commonly found in resistant or heterogeneous cancers. This breakthrough represents a significant step forward in the field of targeted cancer therapy, offering a promising solution to the challenges posed by tumor heterogeneity and resistance. As the research continues, the goal is to translate this laboratory innovation into clinical applications, ultimately improving outcomes for patients who have limited options due to inadequate responses to existing ADC therapies.