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Review Open Access

Dual‑payload antibody‑drug conjugates in triple‑negative breast cancer: Preclinical advances and future perspectives (Review)

  • Authors:
    • Rahmah J. Syala
    • Esraa G. Younus
    • Mohammed N. Abed
    • Fawaz A. Alassaf
  • View Affiliations / Copyright

    Affiliations: Department of Pharmacology and Toxicology, College of Pharmacy, University of Mosul, Mosul, Nineveh Governorate 41002, Iraq, Department of Pharmaceutical Chemistry, College of Pharmacy, University of Mosul, Mosul, Nineveh Governorate 41002, Iraq, Department of Clinical Laboratory Sciences, College of Pharmacy, University of Mosul, Mosul, Nineveh Governorate 41002, Iraq
    Copyright: © Syala et al. This is an open access article distributed under the terms of Creative Commons Attribution License [CC BY 4.0].
  • Article Number: 106
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    Published online on: October 30, 2026
       https://doi.org/10.3892/wasj.2026.521
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Abstract

Triple‑negative breast cancer (TNBC), a highly aggressive and challenging subtype of breast cancer, is distinguished by the absence of certain receptors, which affects the utilization of current treatment options. While some TNBCs could initially respond to chemotherapy, this approach is associated with high rates of recurrence and resistance mechanisms. In an effort to increase the selectivity and therapeutic efficacy of chemotherapy, antibody‑drug conjugates (ADCs) have emerged to serve these purposes. However, tumor heterogeneity remains the major issue restricting their therapeutic effectiveness in TNBC, along with the emerging mechanisms of resistance associated with single‑payload ADCs. The search for novel strategies is urgent. Dual‑payload ADCs have been developed by incorporating two distinct payloads onto the same antibody to target a novel antigen overexpressed on TNBC, while also utilizing recent advances in the multi‑target approach (bispecific antibodies) and chemoimmunotherapy to combat tumor heterogeneity, relapse and multiple mechanisms of resistance associated with TNBC. The present review summarizes the currently available preclinical dual‑payload ADCs that target TROP2, CD276, EGFR and cMET, and future directions in an aim to provide a reference for researchers and facilitate further development. Notably, the most promising approach is TROP2‑directed dual‑payload ADCs, which could open new avenues in oncology.
View Figures

Figure 1

Schematic diagram illustrating the
fundamental design components of a dual-payload ADC. (1.) ADCs
consist of a mAb that targets a tumor-specific antigen and connects
to only one cytotoxic payload via a cleavable or non-cleavable
linker. (2.) Dual-payload ADCs: mAb carries two distinct payloads
through a linker. There are two distinct conjugation strategies for
dual-payload ADCs: (a.) Single-site dual-payload ADCs utilize one
reaction site to conjugate a multifunctional linker; (b.) multisite
dual-payload ADCs use two different conjugation sites on the mAb.
(3.) Bispecific dual-payload ADCs: These conjugate a bispecific mAb
that can bind two different antigens or epitopes, while carrying
more than one payload simultaneously. The figure was created using
BioRender. ADCs, antibody-drug conjugates; mAb, monoclonal
antibody.

Figure 2

Mechanisms of action of dual-payload
ADCs. Direct cytotoxicity: Following receptor-mediated endocytosis,
the ADC is trafficked to the lysosome, where lysosomal proteases
may cleave the linker or acid-mediated hydrolysis may occur,
thereby releasing the payloads to exert their cytotoxic effects. In
the event that the payload is sufficiently membrane-permeable, it
may diffuse into neighboring cells and induce a bystander killing
effect. In addition to direct cytotoxicity, immune-mediated
mechanisms may contribute to the antitumor activity of the
dual-payload ADCs. This has been investigated with CD276-directed
dual-chemoimmunotherapy ADCs, in which CD276 targeting combined
with an immunomodulatory payload, such as IMQ was associated with
enhanced immune-cell infiltration and activation of the tumor
microenvironment. The figure was created using BioRender. ADCs,
antibody-drug conjugates.
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Copy and paste a formatted citation
Spandidos Publications style
Syala RJ, Younus EG, Abed MN and Alassaf FA: Dual‑payload antibody‑drug conjugates in triple‑negative breast cancer: Preclinical advances and future perspectives (Review). World Acad Sci J 8: 106, 2026.
APA
Syala, R.J., Younus, E.G., Abed, M.N., & Alassaf, F.A. (2026). Dual‑payload antibody‑drug conjugates in triple‑negative breast cancer: Preclinical advances and future perspectives (Review). World Academy of Sciences Journal, 8, 106. https://doi.org/10.3892/wasj.2026.521
MLA
Syala, R. J., Younus, E. G., Abed, M. N., Alassaf, F. A."Dual‑payload antibody‑drug conjugates in triple‑negative breast cancer: Preclinical advances and future perspectives (Review)". World Academy of Sciences Journal 8.6 (2026): 106.
Chicago
Syala, R. J., Younus, E. G., Abed, M. N., Alassaf, F. A."Dual‑payload antibody‑drug conjugates in triple‑negative breast cancer: Preclinical advances and future perspectives (Review)". World Academy of Sciences Journal 8, no. 6 (2026): 106. https://doi.org/10.3892/wasj.2026.521
Copy and paste a formatted citation
x
Spandidos Publications style
Syala RJ, Younus EG, Abed MN and Alassaf FA: Dual‑payload antibody‑drug conjugates in triple‑negative breast cancer: Preclinical advances and future perspectives (Review). World Acad Sci J 8: 106, 2026.
APA
Syala, R.J., Younus, E.G., Abed, M.N., & Alassaf, F.A. (2026). Dual‑payload antibody‑drug conjugates in triple‑negative breast cancer: Preclinical advances and future perspectives (Review). World Academy of Sciences Journal, 8, 106. https://doi.org/10.3892/wasj.2026.521
MLA
Syala, R. J., Younus, E. G., Abed, M. N., Alassaf, F. A."Dual‑payload antibody‑drug conjugates in triple‑negative breast cancer: Preclinical advances and future perspectives (Review)". World Academy of Sciences Journal 8.6 (2026): 106.
Chicago
Syala, R. J., Younus, E. G., Abed, M. N., Alassaf, F. A."Dual‑payload antibody‑drug conjugates in triple‑negative breast cancer: Preclinical advances and future perspectives (Review)". World Academy of Sciences Journal 8, no. 6 (2026): 106. https://doi.org/10.3892/wasj.2026.521
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