• effect of antibody-drug conjugates in breast cancer treatment
  • Artemis Azad Ara,1,*
    1. Department of Biology, Faculty of Basic Sciences, Mashhad Branch, Islamic Azad University, Mashhad, Iran


  • Introduction: Breast cancer (BC) continues to be an incurable condition and represents a significant contributor to cancer-related mortality among women globally. In addition to endocrine and targeted therapies, chemotherapy is frequently utilized as a treatment modality for this malignancy. Recently, a novel class of anticancer agents known as antibody-drug conjugates (ADCs) has emerged, enabling the targeted delivery of chemotherapeutic agents to solid tumors. ADCs are composed of three fundamental elements: an antibody that specifically binds to a target antigen, a cytotoxic payload, and a linker that connects the antibody to the payload. Trastuzumab emtansine (T-DM1) was the inaugural ADC to receive approval for use in breast cancer. Subsequently, two additional ADCs, trastuzumab deruxtecan (T-DXd) and sacituzumab govitecan (SG) have also obtained regulatory approval for breast cancer treatment. Both T-DXd and SG have exhibited bystander effects and remarkable tumor control in this context. Clinical trials indicate that T-DM1, T-DXd, and SG can be effective in the management of breast cancer; however, they may encounter certain challenges in their application.
  • Methods: This study was conducted through a comprehensive search of the PubMed, Web of Science, Scopus, and Google Scholar databases, utilizing scientific articles obtained from these sources.
  • Results: Antibodies, or immunoglobulins, are proteins synthesized by the humoral immune system in response to foreign antigens. T-DM1 is an antibody-drug conjugate (ADC) that combines the antibody trastuzumab with the microtubule inhibitor emtansine, utilizing a drug-to-antibody ratio (DAR) of 1:3.5. This conjugation occurs through a non-reducible thioether linker, which maintains stability in both systemic circulation and the tumor microenvironment. Due to the positive charge and membrane impermeability of emtansine upon its release into the cell, T-DM1 exhibits no bystander effect, meaning it does not impact adjacent non-target cells. The mechanism of action for T-DM1 is consistent with that of other ADCs; it first targets and binds to HER2 receptors on the surface of cancer cells. Subsequently, the complex is internalized via endocytosis, where it is transported to lysosomes for degradation. The active agent, DM1, is then released and binds to microtubules, disrupting their function, halting the cell cycle, and ultimately leading to cell death. T-DM1 is currently approved for use in both adjuvant and second-line metastatic settings for HER2-positive (HER2+) breast cancer. Deruxtecan, a derivative of exatecan mesylate, functions as a topoisomerase I inhibitor with approximately tenfold greater activity than 7-ethyl-10-hydroxycamptothecin (SN38), the active metabolite of irinotecan. The payload of T-DXd is linked via a tetrapeptide-based cleavable linker, which confers high stability in plasma. Deruxtecan's membrane permeability facilitates its diffusion from the target cell, allowing it to exert cytotoxic effects on neighboring cancer cells through a bystander effect. T-DXd is approved for use in second-line treatment and for patients previously treated with T-DM1 for metastatic HER2+ breast cancer. Clinical studies have demonstrated that T-DXd significantly outperforms T-DM1 in terms of progression-free survival, overall survival, and objective response rates. Sacituzumab govitecan (SG) is a humanized monoclonal antibody targeting trophoblastic cell-surface antigen-2 (TROP-2), a receptor identified in trophoblasts four decades ago. Sacituzumab is linked to the topoisomerase I inhibitor SN-38 via a hydrolysable linker. Similar to T-DXd, SG possesses a high DAR of 7.6:1 and also exhibits a bystander effect. It is approved for use in the third-line setting for metastatic triple-negative breast cancer (mTNBC) and in later lines of therapy for metastatic hormone receptor-positive (HR+) HER2-negative breast cancer. When comparing sacituzumab govitecan (SG) to trastuzumab deruxtecan (T-DXd) for the treatment of metastatic breast cancer, particularly in HER2-low and triple-negative subtypes, SG presents stronger clinical evidence of superiority in specific patient populations. While both agents demonstrate efficacy, SG may be favored in HER2-zero patients and in certain treatment sequences. The advent of these ADCs offers a more optimistic outlook for the future treatment of breast cancer.
  • Conclusion: The advent of ADCs in the treatment of breast cancer marks a significant advancement, as these therapies can now target specific cancer antigens beyond HER2. This development represents a move towards more personalized treatment approaches, although it may also present its own set of challenges. Ongoing efforts to develop next-generation ADCs are expected to enhance their precision, efficacy, and safety, thereby holding considerable promise for the future of breast cancer therapy.
  • Keywords: Breast Neoplasms, Immunoglobulins, Immunoconjugates, Ado-Trastuzumab Emtansine.