Epitope selection for combination therapy using antibody-drug conjugates and immune immune-stimulating antibody conjugates
5 affiliations
- 1Department of Chemical Engineering, University of Michigan
- 2Biointerfaces Institute, University of Michigan
- 3Department of Biomedical Engineering, University of Michigan
- 4Department of Pharmaceutical Sciences, University of Michigan
- 5Rogel Cancer Center, University of Michigan
Abstract
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.
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BibTeX
@article{kwon2026epitope,
title = {{Epitope selection for combination therapy using antibody-drug conjugates and immune immune-stimulating antibody conjugates}},
author = {Hyeyoung Kwon and Anna Kopp and Tiexin Wang and Andrew Philippart and Dong Jun Koo and Haolong Huang and Troyee Naha and Peter M. Tessier and Greg M. Thurber},
journal = {Frontiers in Immunology},
year = {2026},
month = oct,
doi = {10.3389/fimmu.2026.1960790},
url = {https://www.frontiersin.org/articles/10.3389/fimmu.2026.1960790/full},
note = {CC BY 4.0},
}
RIS
TY - JOUR
TI - Epitope selection for combination therapy using antibody-drug conjugates and immune immune-stimulating antibody conjugates
AU - Hyeyoung Kwon
AU - Anna Kopp
AU - Tiexin Wang
AU - Andrew Philippart
AU - Dong Jun Koo
AU - Haolong Huang
AU - Troyee Naha
AU - Peter M. Tessier
AU - Greg M. Thurber
PY - 2026
DA - 2026/10/08
JO - Frontiers in Immunology
DO - 10.3389/fimmu.2026.1960790
UR - https://www.frontiersin.org/articles/10.3389/fimmu.2026.1960790/full
AB - 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.
SN - 1664-3224
ER -