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Life sciences · Journal article
Frontiers in Immunology · October 8, 2026
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Introduction With an increase in FDA-approved antibody-drug conjugates (ADCs), recent work has focused on potential combination therapies to maximize efficacy, including those with immune-stimulating antibody conjugates (ISACs). When combining antibody therapies against the same target, competitive antibodies can improve tumor tissue distribution and efficacy, while mixtures of non-competitive antibodies can crosslink receptors and increase cellular internalization but reduce tissue penetration. Methods Given these trade-offs, we investigated the impact of combination therapy using competitive and non-competitive antibodies on two cytotoxic ADCs – trastuzumab emtansine (T-DM1) and trastuzumab deruxtecan (TDXd) – in combination with trastuzumab (competitive) or pertuzumab (noncompetitive) antibodies with or without a moderate-potency Toll-Like Receptor 7 (TLR7) agonist payload to enable high ISAC dosing. Results Competitive trastuzumab antibodies achieved more homogeneous tumor distribution, while non-competitive pertuzumab reduced tissue penetration. However, HER2 receptor downregulation with pertuzumab enhanced HER2 signaling blockade and was associated with increased payload delivery to cancer cells. The combination of a trastuzumab-ISAC to increase tissue penetration and pertuzumab to enhance cellular internalization of the T-DXd resulted in maximum efficacy. Both combinations of T-DXd with a TLR7 ISAC resulted in maximum complete responses. Discussion These findings highlight the importance of epitope selection in combination therapy and demonstrate that strategies to increase both tumor tissue penetration and ADC internalization while delivering multiple payloads result in the greatest efficacy of ADC and ISAC combination treatments. The rational design of antibody combinations with competitive and non-competitive epitopes can achieve these aims to maximize tumor growth inhibition and complete responses at tolerable doses.