Antibody Drug Conjugates (ADCs) have recently made significant progress in the clinic with 11 FDA-approved agents including 6 for solid tumor indications. However, these agents continue to face challenges due to their unique design and need to tailor the properties for each specific target. One of the common features for successful ADCs in solid tumors is high antibody dosing to enable efficient tissue penetration of the ADC into the tumor. This overcomes the perivascular binding of ADCs that occurs with high expression targets and potent ADCs that have to be administered at low doses due to toxicity. This same effect can also be achieved by co-administering unconjugated antibody to partially block perivascular cells and improve tumoral distribution. However, high antibody doses can saturate tumors with low expression, thereby reducing ADC uptake and lowering efficacy. This presents an intrinsic challenge, since patients often display heterogeneous expression between and within tumors and metastases. To overcome this challenge, we designed High Avidity Low Affinity antibodies that partially compete with ADCs in high expression tumors to ensure efficient tissue penetration while not blocking uptake in low expression tumors to maximize response. We demonstrate how HALA antibodies automatically tune the amount of ADC binding in HER2 positive tumors to outperform ADC-only treatment in high expression tumors and ADC with antibody in low expression tumors. We also utilized Fc-engineered HALA antibodies to further enhance the immune response in an immunocompetent mouse model of cancer. This concept can be applied to any ADC target to auto-tune ADC delivery even between tumors in the same patient.
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