Antibody-Drug Conjugates in Breast Cancer: What Is Beyond HER2?

Nicolò, Eleonora; Repetto, Matteo; Bielo, Luca Boscolo; Tarantino, Paolo; Curigliano, Giuseppe

doi:10.1097/ppo.0000000000000629

Cited by 7 publications

(4 citation statements)

References 75 publications

(154 reference statements)

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“…One prominent example is Trop-2, which serves as a target for sacituzumab govitecan (SG), the sole nonanti-HER2 ADC approved for BC. 10 This sheds new light on antitumor treatments and broadens the pool of patients who could potentially benefit from ADCs, particularly those in advanced stages. Following ADC binding to the target antigen on the cell surface, ADCs can interfere with crucial cellular metabolic processes in a manner that appears to depend on DNA insertion or the inhibition of microtubule formation to induce antigen positive tumor cells apoptosis.…”

Section: Introductionmentioning

confidence: 98%

“…Identifying new potential nondriver oncogene targets that may not be directly involved in breast cancer development and evolution is a popular research topic. One prominent example is Trop‐2, which serves as a target for sacituzumab govitecan (SG), the sole nonanti‐HER2 ADC approved for BC 10 . This sheds new light on antitumor treatments and broadens the pool of patients who could potentially benefit from ADCs, particularly those in advanced stages.…”

Section: Introductionmentioning

confidence: 99%

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Antibody–drug conjugates transform the outcome of individuals with low‐HER2‐expression advanced breast cancer

Qu,

Lu,

Liu

et al. 2024

Cancer

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Antibody–drug conjugates (ADCs)—a groundbreaking class of agents for targeted oncological therapies—consist of monoclonal antibodies with strong antigenic specificity coupled with highly active cytotoxic agents (also referred to as “payloads”). Over the past 2 decades, breast cancer research has evolved into a focal point for the research and development of ADCs, leading to several recent landmark publications. These advancements are ushering in a transformative era in breast cancer treatment and redefining conventional classifications by introducing a prospective subtype termed “HER2‐low.” The latest iterations of ADCs have demonstrated enhanced efficacy in disease management through the optimization of various factors, notably the incorporation of the bystander effect. These conjugates are no longer limited to the oncogenic driver human epidermal growth factor receptor 2 (HER2). Other antigens, including human epidermal growth factor receptor 3 (HER3), trophoblast cell surface antigen 2 (Trop‐2), zinc transporter ZIP6 (LIV‐1), and folate receptor α (FRα), have recently emerged as intriguing tumor cell surface nondriver gene targets for ADCs, each with one or more specific ADCs that showed encouraging results in the breast cancer field. This article reviews recent advances in the application of ADCs in the treatment of HER2‐low breast cancer. Additionally, this review explores the underlying factors contributing to the impact of target selection on ADC efficacy to provide new insights for optimizing the clinical application of ADCs in individuals with low HER2 expression in advanced breast cancer.

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Section: Introductionmentioning

confidence: 98%

Section: Introductionmentioning

confidence: 99%

Antibody–drug conjugates transform the outcome of individuals with low‐HER2‐expression advanced breast cancer

Qu,

Lu,

Liu

et al. 2024

Cancer

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“…Cancer is currently the second leading cause of death in the United States, with approximately 1.6 million new diagnoses and 600,000 deaths per year. , Conventional chemotherapeutic approaches aimed at inhibiting processes such as DNA replication and microtubule assembly have led to improvements in cancer-related mortality but are limited by the development of resistance and a lack of specificity toward tumor cells, resulting in unfavorable side effects. , Therefore, engineered targeted therapeutics such as antibody–drug conjugates (ADCs) have had a growing importance in cancer treatment in recent decades. − Composed of monoclonal antibodies functionalized with cytotoxic drugs, ADCs deliver their payloads by binding to cells expressing a target antigen and releasing therapeutic cargo after internalization. ,, This approach increases the specificity of drug delivery as antibodies that specifically bind to antigens overexpressed on cancer cells are utilized, thereby reducing off-target toxicity and allowing for administration of increasingly potent cytotoxic drugs. ,, To date, 14 ADCs have received FDA approval for the treatment of various hematological malignancies and solid tumors, and over 100 ADCs are currently undergoing clinical trials. ,− …”

Section: Introductionmentioning

confidence: 99%

Exploring the Sensitivity of Antibody–Drug Conjugate Efficacy to the Selection of Payload, Antibody, and Cell line

Rao,

Murali,

Amores

et al. 2024

Bioconjugate Chem.

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Antibody−drug conjugates (ADCs) make up a growing class of targeted therapeutics with important applications in cancer treatment. ADCs are highly modular in nature and thus can be engineered to target any cancer type, but their efficacy is strongly influenced by the specific choice of payload, antibody, and target cell. Considering the number of possible antibody−payload combinations, ADC development would benefit from an efficient method to narrow the number of ADC compositions to those with the highest and most universal potency prior to assessing pharmacokinetics and pharmacodynamics in animal models. To facilitate the identification of optimal ADC compositions, we describe the use of photoreactive antibody-binding domain-drug conjugates (known commercially as oYo-Link) to enable the site-specific labeling of off-the-shelf antibodies. This approach allows for the rapid generation of ADCs with a drug-to-antibody ratio of ∼2 with no subsequent purification required. As a demonstration of this approach, ADCs were generated with different combinations of tubulin-inhibitor drugs (DM1, DM4, VcMMAE, and VcMMAF) and anti-EGFR antibodies (cetuximab, panitumumab, anti-EGFR clone 425, and anti-EGFR clone 528) and were delivered to three EGFR-expressing cell lines (A431, A549, and MDA-MB-231). Real-time cytolysis assays indicated that the most effective antibody varied based on the choice of cell line: cetuximab was most potent against A431 cells, while 425 and 528 led to the greatest cytotoxicity against A549 and MDA-MB-231 cells. These results did not correlate with differences in measured anti-EGFR binding affinity as cetuximab had the highest affinity across all three cell lines, while 425 and 528 had the lowest affinities for all three cell lines. Panitumumab, which had the second-highest anti-EGFR affinity, exhibited the least effective cytolysis across A431, A549, and MDA-MB-231 cells. By demonstrating that ADC potency toward a given target is dependent on both the antibody and drug chosen, these findings can guide the selection of ADCs for further in vivo analysis.

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“…Trastuzumab emtansine in the HER2+ subtype [ 4 ], trastuzumab deruxtecan in the HER2+ [ 5 ] and HER2-low [ 6 ] subtypes, and sacituzumab govitecan in the triple-negative subtype (TN) [ 7 ] and recently the HR+/HER2- subtype [ 8 ]. Many others are under development, including our anti-nectin-4 ADC [ 9 , 10 ] and the ladiratuzumab vedotin anti-LIV1 ADC (SGN-LIV1A, Seagen; [ 11 , 12 ]).…”

Section: Introductionmentioning

confidence: 99%

Prognostic and Predictive Value of LIV1 Expression in Early Breast Cancer and by Molecular Subtype

et al. 2023

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Background: LIV1 is a transmembrane protein that may become a new therapeutic target through the development of antibody–drug conjugates (ADCs). Few studies are available regarding the assessment of LIV1 expression in clinical breast cancer (BC) samples. Methods: We analyzed LIV1 mRNA expression in 8982 primary BC. We searched for correlations between LIV1 expression and clinicopathological data, including disease-free survival (DFS), overall survival (OS), pathological complete response to chemotherapy (pCR), and potential vulnerability and actionability to anti-cancer drugs used or under development in BC. Analyses were performed in the whole population and each molecular subtype separately. Results: LIV1 expression was associated with good-prognosis features and with longer DFS and OS in multivariate analysis. However, patients with high LIV1 expression displayed a lower pCR rate than patients with low expression after anthracycline-based neoadjuvant chemotherapy, including in multivariate analysis adjusted on grade and molecular subtypes. LIV1-high tumors were associated with higher probabilities of sensitivity to hormone therapy and CDK4/6 inhibitors and lower probabilities of sensitivity to immune-checkpoint inhibitors and PARP inhibitors. These observations were different according to the molecular subtypes when analyzed separately. Conclusions: These results may provide novel insights into the clinical development and use of LIV1-targeted ADCs by identifying prognostic and predictive value of LIV1 expression in each molecular subtype and associated vulnerability to other systemic therapies.

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Antibody-Drug Conjugates in Breast Cancer: What Is Beyond HER2?

Cited by 7 publications

References 75 publications

Antibody–drug conjugates transform the outcome of individuals with low‐HER2‐expression advanced breast cancer

Antibody–drug conjugates transform the outcome of individuals with low‐HER2‐expression advanced breast cancer

Exploring the Sensitivity of Antibody–Drug Conjugate Efficacy to the Selection of Payload, Antibody, and Cell line

Prognostic and Predictive Value of LIV1 Expression in Early Breast Cancer and by Molecular Subtype

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