scholarly journals Breast Cancer Treatment and Antibody Drug Conjugates: Beyond T-DM1

2021 ◽  
Vol 9 (8) ◽  
Author(s):  
Mony Ung ◽  
Jean Lacaze ◽  
Eleonora Maio ◽  
Florence Dalenc
Keyword(s):  
Breast Cancer ◽  
Anticancer Agents ◽  
Bystander Effect ◽  
Cytotoxic Agents ◽  
Clinical Activity ◽  
Trastuzumab Emtansine ◽  
Her2 Positive ◽  
Antibody Drug Conjugates ◽  
Drug Conjugates ◽  
Antibody Drug

Antibody–drug conjugates (ADCs) are a new class of anticancer agents that combine cytotoxic agents attached by a linker to a monoclonal antibody. These engineered drugs can selectively deliver a cytotoxic payload to targeted cancer cells and the local microenvironment (bystander effect), thereby increasing activity and reducing off-target toxicity. The association of ADCs with other anti-cancer therapies is therefore promising. Trastuzumab-emtansine was the first approved ADC in breast cancer (BC), specifically for the management of human epidermal growth factor receptor 2 (HER2)-positive advanced breast cancer. New ADCs are in development in BC. Some have shown meaningful clinical benefit and have been recently approved, such as trastuzumab deruxtecan in HER2-positive trastuzumab emtansine (T-DM1) pretreated BC and Trop-2 guided sacituzumab govitecan in triple-negative BC. Trastuzumab deruxtecan also has potential clinical activity in HER2-low BC thanks to a bystander effect. In this article, we review the ADCs under development in advanced BC.

scholarly journals Antibody–Drug Conjugates for the Treatment of Breast Cancer

Cancers ◽  
2021 ◽  
Vol 13 (12) ◽  
pp. 2898
Author(s):  
Chiara Corti ◽  
Federica Giugliano ◽  
Eleonora Nicolò ◽  
Liliana Ascione ◽  
Giuseppe Curigliano
Keyword(s):  
Breast Cancer ◽  
Bystander Effect ◽  
Metastatic Breast ◽  
Therapeutic Index ◽  
Cytotoxic Agents ◽  
Target Antigen ◽  
Her2 Positive ◽  
Antibody Drug Conjugates ◽  
Drug Conjugates ◽  
Antibody Drug

Metastatic breast cancer (BC) is currently an incurable disease. Besides endocrine therapy and targeted agents, chemotherapy is often used in the treatment of this disease. However, lack of tumor specificity and toxicity associated with dose exposure limit the manageability of cytotoxic agents. Antibody–drug conjugates (ADCs) are a relatively new class of anticancer drugs. By merging the selectivity of monoclonal antibodies with the cytotoxic properties of chemotherapy, they improve the therapeutic index of antineoplastic agents. Three core components characterize ADCs: the antibody, directed to a target antigen; the payload, typically a cytotoxic agent; a linker, connecting the antibody to the payload. The most studied target antigen is HER2 with some agents, such as trastuzumab deruxtecan, showing activity not only in HER2-positive, but also in HER2-low BC patients, possibly due to a bystander effect. This property to provide a cytotoxic impact also against off-target cancer cells may overcome the intratumoral heterogeneity of some target antigens. Other cancer-associated antigens represent a strategy for the development of ADCs against triple-negative BC, as shown by the recent approval of sacituzumab govitecan. In this review, we discuss the current landscape of ADC development for the treatment of BC, as well as the possible limitations of this treatment.

Antibody-Drug-Conjugates for Breast Cancer

2021 ◽  
Author(s):  
Frederik Marmé
Keyword(s):  
Breast Cancer ◽  
Bystander Effect ◽  
Systemic Exposure ◽  
Clinical Development ◽  
Therapeutic Window ◽  
Target Cells ◽  
Magic Bullet ◽  
Antibody Drug Conjugates ◽  
Drug Conjugates ◽  
Antibody Drug

Background Despite the advances that have been made to improve conventional chemotherapies, their use is limited by a narrow therapeutic window based on off-target toxicities. Antibody-drug-conjugates (ADCs) are composed of an antibody and a toxic payload covalently coupled by a chemical linker. They constitute an elegant means to tackle the limitations of conventional chemotherapeutics by selectively delivering a highly toxic payload directly to target cells and thereby increasing efficacy of the delivered cytotoxic but at the same time limiting systemic exposure and toxicities. As such they appear inspired by Paul Ehrlich´s concept of a “magic bullet”, which he envisioned as drugs that go directly to their target to attack pathogens but remain harmless in healthy tissues. Summary The concept of conjugating drugs to antibodies via chemical linkers is not new. As early as in the 1960s researchers started to investigate such ADCs in animal models and first clinical trials based on mouse antibodies began in the 1980s. Although the concept appears relatively straightforward, ADCs are highly complex molecules, and it took several decades of research and development until the first ADC became approved by the FDA in 2000 and the second followed not until 11 years later. The development of an effective ADC is highly demanding, and each individual component of an ADC must be optimized: the target, the antibody, the linker and its conjugation chemistry as well as the cytotoxic payload. Today there are 9 approved ADCs overall and 3 for breast cancer. So, the pace of development seems to pick up with over 100 candidates in various stages of clinical development. Many ADCs of the newest generation are optimized to elicit a so-called bystander effect, to increase efficacy and tackle heterogneous antigen expression. This approach requires a balancing of efficacy and systemic toxicity. Hence, ADCs based on their complex biology cause relevant toxicities, which are characteristic for each specific compound and may include hematologic toxicities, elevated transaminases, gastrointestinal events, pneumonitis but also ocular toxicities as well as others many physicians may initially not be very familiar with. Management of the side effects will be key to the successful clinical use of these potent drugs. Key Messages This review focusses on the clinical experience with ADCs approved in breast cancer as well as promising candidates in late-stage clinical development. We will discuss the mode of action, biology, and composition of ADCs and how each of these crucial components influences their properties and efficacy.

Antibody-drug conjugates: Principles and clinical results in breast cancer treatment

2018 ◽  
Vol 39 (4) ◽  
pp. 490-495
Author(s):  
Nguyen Phuong Loan ◽  
Duong Hong Quan
Keyword(s):  
Breast Cancer ◽  
Cancer Treatment ◽  
Safety Data ◽  
Clinical Results ◽  
Breast Cancer Treatment ◽  
Surface Proteins ◽  
Cytotoxic Agents ◽  
Antibody Drug Conjugates ◽  
Drug Conjugates ◽  
Antibody Drug

Antibody-drug conjugates (ADCs) are consisted of the combination of highly specific monoclonal antibodies (mAbs) with conventional cytotoxic agents to particular cancer types. The use of mAbs that are specific to tumor cell-surface proteins allows highly selective accumulation of cytotoxic agents as ADCs at the tumor tissue, that is not achievable with conventional cytotoxic agents alone. Designing of effective ADCs for cancer treatment requires identification of an appropriate target, a mAb against the target, potent cytotoxic agents and conjugation of the mAb to cytotoxic agents. Until now, three ADCs including Gemtuzumab ozogamicin, Brentuximab and trastuzumab emtansine have received an FDA approval so far. These three ADCs have shown improved efficacy and safety data compared with standard chemotherapy for the treatment of patients of acute myeloid leukemia, advanced lymphoma and breast cancer, respectively. Moreover, several promising ADCs are now in the latter-phase of clinical testing. Thus, with special focusing on these new anti-cancer drugs, this review briefly describes the principles of ADCs including their structure and mechanism of action, and summarizes their clinical performance in breast cancer. Citation: Nguyen Phuong Loan, Duong Hong Quan, 2017. Antibody-drug conjugates: Principles and clinical results in breast cancer treatment. Tap chi Sinh hoc, 39(4): 489-493. DOI: 10.15625/0866-7160/v39n4.9327.*Corresponding author: [email protected] 15 March 2017, accepted 12 December 2017

scholarly journals The Evolution of Antibody-Drug Conjugates: A Positive Inflexion Point

2020 ◽  
pp. 127-134 ◽  
Author(s):  
Anthony W. Tolcher
Keyword(s):  
Breast Cancer ◽  
B Cell Lymphoma ◽  
Cytotoxic Chemotherapy ◽  
Cytotoxic Agents ◽  
Full Potential ◽  
Antibody Drug Conjugates ◽  
Drug Conjugates ◽  
Her2 Breast Cancer ◽  
The Many ◽  
Antibody Drug

In 2019, an important inflection point occurred when the U.S. Food and Drug Administration approved three new antibody-drug conjugates (ADCs) for the treatment of malignancies, including urothelial cancer (enfortumab vedotin-ejfv), diffuse large B-cell lymphoma (polatuzumab vedotin-piiq), and HER2 breast cancer (fam-trastuzumab deruxtecan-nxki), and expanded the indication for ado-trastuzumab emtansine to early breast cancer. This near doubling in the number of approved ADCs within 1 year validates the ADC platform and represents a successful evolution over the past 30 years. ADCs were born in an era when systemic therapy for cancer was largely cytotoxic chemotherapy. Many of the investigational cytotoxic agents were determined to be too toxic for oral and intravenous use. The agents were especially potent, with inhibitory concentrations that inhibited 50% of cells in the nanomolar and picomolar range but had poor therapeutic indexes when administered systemically. Now, over the last 30 years, we have seen an evolution of the many aspects of this complex platform with better antigen target selection, more sophisticated chemistry for the linkers, a growing diversity of payloads from cytotoxic chemotherapy to targeted therapies and immunostimulants, and, with the recent series of regulatory approvals, a buoyed sense of optimism for the technology. Nonetheless, we have not fully realized the full potential of this platform. In this review, the many components of ADCs will be discussed, the difficulties encountered will be highlighted, the innovative strategies that are being used to improve them will be assessed, and the direction that the field is going will be considered.

scholarly journals RAB5A expression is a predictive biomarker for trastuzumab emtansine in breast cancer

2021 ◽  
Vol 12 (1) ◽  
Author(s):  
Olav Engebraaten ◽  
Christina Yau ◽  
Kristian Berg ◽  
Elin Borgen ◽  
Øystein Garred ◽  
...  
Keyword(s):  
Breast Cancer ◽  
Drug Transport ◽  
Predictive Biomarkers ◽  
Predictive Biomarker ◽  
Cytotoxic Agents ◽  
Trastuzumab Emtansine ◽  
Targeted Therapeutics ◽  
Breast Cancer Patients ◽  
Her2 Positive ◽  
Drug Conjugates

AbstractHER2 is a predictive biomarker for HER2-targeted therapeutics. For antibody–drug conjugates (ADCs; e.g., trastuzumab emtansine (T-DM1)), HER2 is utilized as a transport gate for cytotoxic agents into the cell. ADC biomarkers may therefore be more complex, also reflecting the intracellular drug transport. Here we report on a positive correlation between the early endosome marker RAB5A and T-DM1 sensitivity in five HER2-positive cell lines. Correlation between RAB5A expression and T-DM1 sensitivity is confirmed in breast cancer patients treated with trastuzumab emtansine/pertuzumab in the I-SPY2 trial (NCT01042379), but not in the trastuzumab/paclitaxel control arm. The clinical correlation is further verified in patients from the KAMILLA trial (NCT01702571). In conclusion, our results suggest RAB5A as a predictive biomarker for T-DM1 response and outline proteins involved in endocytic trafficking as predictive biomarkers for ADCs.

scholarly journals The Resurgence of Antibody Drug Conjugates in Cancer Therapeutics: Novel Targets and Payloads

2020 ◽  
pp. e58-e74
Author(s):  
Valentina Boni ◽  
Manish R. Sharma ◽  
Amita Patnaik
Keyword(s):  
Breast Cancer ◽  
Target Selection ◽  
Antigen Specificity ◽  
Her2 Positive ◽  
Antibody Drug Conjugates ◽  
Her2 Positive Breast Cancer ◽  
Drug Conjugates ◽  
Metastatic Urothelial Cancer ◽  
Antibody Drug ◽  
Positive Breast Cancer

Antibody drug conjugates (ADCs) are an emerging class of therapeutics that consist of a cytotoxic agent linked covalently to an antibody, which is directed toward a specific cell surface target expressed by tumor cells and/or the microenvironment. ADCs leverage the specificity of the antibody such that it functions as a carrier to deliver the cytotoxic payload into the tumor. Four parameters are considered critical for this class of complex engineered therapeutics: target selection, antibody, cytotoxic payload, as well as conjugation and linker technology. The development of this class of drugs has proven more complex than expected. Several challenges have arisen, including a lack of true tumor antigen specificity, early release of the cytotoxic payload into the bloodstream due to linker instability, and low potency of the payload, resulting in either greater toxicity or lack of improved efficacy compared with unconjugated cytotoxics. The approval of trastuzumab emtansine in 2013 for HER2-positive breast cancer served as a proof of concept that ADCs have therapeutic application in solid tumors. Two novel ADCs have recently been approved: trastuzumab deruxtecan for HER2-positive breast cancer and enfortumab vedotin for locally advanced or metastatic urothelial cancer. Trastuzumab deruxtecan is distinguished by a unique biochemical structure with a novel cytotoxic payload, deruxtecan—a highly potent, topoisomerase I inhibitor. Enfortumab vedotin is directed toward nectin-4 and represents an example of successful and strategic target selection. This review focuses on the concepts underlying the choice of suitable targets and novel payloads, discusses specific examples of ADCs in preclinical and clinical development, and provides future directions related to this unique class of therapeutics.

scholarly journals Antibody-drug conjugates in HER2-positive breast cancer

2021 ◽  
Vol Publish Ahead of Print ◽  
Author(s):  
Lixi Li ◽  
Di Zhang ◽  
Binliang Liu ◽  
Dan Lv ◽  
Jingtong Zhai ◽  
...  
Keyword(s):  
Breast Cancer ◽  
Her2 Positive ◽  
Antibody Drug Conjugates ◽  
Her2 Positive Breast Cancer ◽  
Drug Conjugates ◽  
Antibody Drug ◽  
Positive Breast Cancer

scholarly journals Treating Prostate Cancer by Antibody–Drug Conjugates

2021 ◽  
Vol 22 (4) ◽  
pp. 1551
Author(s):  
Matteo Rosellini ◽  
Matteo Santoni ◽  
Veronica Mollica ◽  
Alessandro Rizzo ◽  
Alessia Cimadamore ◽  
...  
Keyword(s):  
Prostate Cancer ◽  
Parp Inhibitors ◽  
Cytotoxic Agents ◽  
Clinical Activity ◽  
Castration Resistant Prostate Cancer ◽  
Male Population ◽  
Antibody Drug Conjugates ◽  
Drug Conjugates ◽  
Castration Resistant ◽  
Antibody Drug

Prostate cancer is the most frequent malignancy in the worldwide male population; it is also one of the most common among all the leading cancer-related death causes. In the last two decades, the therapeutic scenario of metastatic castration-resistant prostate cancer has been enriched by the use of chemotherapy and androgen receptor signaling inhibitors (ARSI) and, more recently, by immunotherapy and poly(ADP–ribose) polymerase (PARP) inhibitors. At the same time, several trials have shown the survival benefits related to the administration of novel ARSIs among patients with non-castration-resistant metastatic disease along with nonmetastatic castration-resistant cancer too. Consequently, the therapeutic course of this malignancy has been radically expanded, ensuring survival benefits never seen before. Among the more recently emerging agents, the so-called “antibody–drug conjugates” (ADCs) are noteworthy because of their clinical practice changing outcomes obtained in the management of other malignancies (including breast cancer). The ADCs are novel compounds consisting of cytotoxic agents (also known as the payload) linked to specific antibodies able to recognize antigens expressed over cancer cells’ surfaces. As for prostate cancer, researchers are focusing on STEAP1, TROP2, PSMA, CD46 and B7-H3 as optimal antigens which may be targeted by ADCs. In this paper, we review the pivotal trials that have currently changed the therapeutic approach to prostate cancer, both in the nonmetastatic castration-resistant and metastatic settings. Therefore, we focus on recently published and ongoing trials designed to investigate the clinical activity of ADCs against prostate malignancy, characterizing these agents. Lastly, we briefly discuss some ADCs-related issues with corresponding strategies to overwhelm them, along with future perspectives for these promising novel compounds.

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