<i>In Vivo</i> Auto-tuning of Antibody–Drug Conjugate Delivery to Maximize Efficacy Using High-Avidity, Low-Affinity Antibodies

Antibody-drug conjugates (ADCs) have experienced a surge in clinical approvals in the past few years. Despite this success, a major limitation to ADC efficacy in solid tumors is poor tumor penetration, which leaves many cancer cells untargeted. Co-administration of unconjugated antibody can improve tumor penetration and increase efficacy when target receptor expression is high. However, it can also reduce efficacy in low-expression tumors where ADC delivery is limited by insufficient cellular uptake. This creates an intrinsic problem because many patients express different levels of target between and within tumors. Here, we show how unconjugated High-Avidity, Low-Affinity (HALA) antibodies can automatically tune the cellular ADC delivery to match the local expression level. Using HER2 ADCs as a model, the tumor distribution of trastuzumab emtansine and trastuzumab deruxtecan co-administered with the HALA antibody was improved in vivo, translating to equal or greater ADC efficacy across a range of HER2 expression levels. Furthermore, Fc-enhanced HALA antibodies elicited a strong response in an immunocompetent mouse model. These results demonstrate that HALA antibodies can expand treatment ranges beyond high-expression targets and leverage strong immune responses.