Combining antibody conjugates with cytotoxic and immune-stimulating payloads maximizes anti-cancer activity

Sep 22, 2026

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Antibody–drug conjugates (ADCs) are widely used for cancer therapy, yet durable responses can be limited by drug resistance and insufficient immune activation, especially in immunologically cold tumors. This study demonstrates that combining ADCs with immune-stimulating antibody conjugates (ISACs) improves efficacy versus either agent alone. Two non-competitive antibodies enhance tumor antigen internalization to deliver a toxic payload, while improved FcγR engagement enables STING agonist delivery to immune cells. Results show reduced tumor volume and tolerable side effects with limited weight loss.

LanguageEnglish

CategoryHealthcare

FormatPDF

Pages17

Reading Time43 min

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Introduction

ADCs and the need to overcome resistance

ADCs combined with checkpoint inhibitors

Cold tumors and innate immune activation via TLR/STING

Combining antibody conjugates with cytotoxic and immune-stimulating payloads maximizes anti-cancer activity Tiexin Wang 1,2 , Dong Jun Koo 1, Peter M. Tessier 1,2,3,4,5 and Greg M. Thurber 1,3,6 1 Department of Chemical Engineering, University of Michigan, Ann Arbor, USA 2 Biointerfaces Institute, University of Michigan, Ann Arbor, USA 3 Department of Biomedical Engineering, University of Michigan, Ann Arbor, USA 4 Department of Pharmaceutical Sciences, University of Michigan, Ann Arbor, USA 5 Program in Chemical Biology, University of Michigan, Ann Arbor, USA 6 Rogel Cancer Center, University of Michigan, Ann Arbor, USA Keywords ADC; antibody–drug conjugate; CEA; immune-stimulating antibody conjugate; ISAC; STING agonist Correspondence P. M. Tessier and G. M. Thurber, Department of Chemical Engineering, University of Michigan, Ann Arbor, MI 48109, USA Tel: +1 (734) 763-1486 and +1 (734) 764-8722 E-mail: [ptessier@umich.edu](ptessier@umich.edu); gthurber@ [umich.edu](umich.edu) (Received 28 July 2025, revised 24 October 2025, accepted 17 December 2025, available online 6 January 2026) doi:10 . 1002/1878-0261 .70198 Antibody–drug conjugates (ADCs) are rapidly expanding in the clinical treatment of cancers, and combinations with checkpoint inhibitors further enhance antitumor activity in patients sensitive to such immunotherapy. However, a method to improve treatment durability, including cases where immunologically cold tumors limit checkpoint inhibitor activity, is needed. Here, we demonstrate that mixtures of ADCs and immune-stimulating antibody conjugates (ISACs) enhance efﬁcacy compared to either agent alone. Our approach utilizes two non-competitive antibodies to increase the internalization of a tumor-associated antigen (carcinoembryonic antigen, CEA), facilitating the entry of the toxic payload (SN-38, a topoisomerase I inhibitor) into cancer cells. With improved FccR engagement, the designed ISAC better delivered the immunostimulatory agent (STING agonist) into immune cells. After treatment, the average tumor volume in the combination group was ~40% of the ADC group, and ~ 30% of the PBS group at day 14 . The side effects of combination therapy were tolerable, with an average weight loss of 7% or less after injections. We expect this approach can be readily extended to other ADCs to enhance their efﬁcacy, including for the treatment of immunologically cold tumors. 1. Introduction Antibody–drug conjugates (ADCs) are now well established as potent anti-cancer therapeutics due to their combination of speciﬁc targeting of tumor-associated antigens and intracellular delivery of toxic payloads. Blockbuster successes such as Kadcyla and Enhertu—both of which target HER2—highlight the great potential of this class of therapeutics. However, direct cancer cell killing alone using ADCs is often not sufﬁcient for durable responses due to the development of drug resistance [1] . Factors leading to drug resistance include insufﬁcient tumor penetration, receptor downregulation, heterogeneous antigen expression, and loss Abbreviations ADC, antibody–drug conjugates; ADCC, antibody-dependent cellular cytotoxicity; ADCP, antibody-dependent cellular phagocytosis; CEA, carcinoembryonic antigen; DAR, drug-to-antibody ratio; HER2, human epidermal growth factor receptor 2; HI FBS, fetal bovine serum, heat inactivated; ISAC, immune-stimulating antibody conjugate; PBS, phosphate-buffered saline; STING, stimulators of interferon genes; TLR, toll-like receptor; Trop2, trophoblast cell surface antigen 2 . 1220 Molecular Oncology 20 (2026) 1220–1236 ª 2026 The Author(s) . Molecular Oncology published by John Wiley & Sons Ltd on behalf of Federation of European Biochemical Societies. This is an open access article under the terms of the Creative Commons Attribution License, which permits use, distribution and reproduction in any medium, provided the original work is properly cited. T. Wang et al

FAQs

What problem does combining ADCs with immune-stimulating conjugates address?

The approach targets limited durability and resistance in ADC therapy and the reduced benefit of checkpoint inhibitors in immunologically cold tumors with few tumor-infiltrating lymphocytes.

How does the study’s design improve delivery to cancer cells and immune cells?

Two non-competitive antibodies increase internalization of a tumor-associated antigen (CEA) to facilitate toxic payload entry, while enhanced FcγR engagement helps the ISAC deliver the STING agonist into immune cells.

What treatment outcomes and safety observations are reported for the combination?

After treatment, the combination group shows average tumor volume around ~40% of the ADC group and ~30% of the PBS group at day 14. Side effects are described as tolerable, with average weight loss of 7% or less after injections.

Sep 22, 2026

Uploaded by Putri