scholarly journals Current state of clinical development of TROP2-directed antibody–drug conjugates for triple-negative breast cancer

2021 ◽  
Author(s):  
Maximilian Marhold
Keyword(s):  
Breast Cancer ◽  
Triple Negative ◽  
Short Review ◽  
Clinical Development ◽  
Breast Cancers ◽  
Antibody Drug Conjugates ◽  
Drug Conjugates ◽  
Current State ◽  
Epithelial Cell Marker ◽  
Antibody Drug

SummaryAntibody–drug conjugates (ADCs) against numerous molecular targets are currently being developed for the treatment of breast cancer (BCa). While the first ADC directed against Her2, namely trastuzumab–emtansine, was approved several years ago, targeting of TROP‑2, an epithelial cell marker overexpressed in approximately 80% of triple-negative breast cancers (TNBC) has gained interest through positive clinical data reported for the compound sacituzumab–govitecan (SG) resulting from the phase 3 ASCENT trial. This short review summarizes the data that led to approval of SG and to take a closer look at the state of clinical development of other ADCs targeting TROP‑2 in TNBC.

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.

scholarly journals Novel antibody–drug conjugates for triple negative breast cancer

2020 ◽  
Vol 12 ◽  
pp. 175883592091598 ◽  
Author(s):  
Aiko Nagayama ◽  
Neelima Vidula ◽  
Leif Ellisen ◽  
Aditya Bardia
Keyword(s):  
Breast Cancer ◽  
Triple Negative Breast Cancer ◽  
Triple Negative ◽  
Metastatic Breast ◽  
Clinical Development ◽  
Antibody Drug Conjugate ◽  
Drug Conjugates ◽  
Anti Cancer ◽  
Late Stages ◽  
Antibody Drug

Triple negative breast cancer (TNBC) is a heterogenous subtype of breast cancer often associated with an aggressive phenotype and poor prognosis. Antibody–drug conjugate (ADC), comprising of a monoclonal antibody linked to a cytotoxic payload by a linker, is gaining increasing traction as an anti-cancer therapeutic. Emerging ADC drugs such as sacituzumab govitecan (IMMU-132) and trastuzumab deruxtecan (DS-8201a) are in late stages of clinical development for patients with metastatic breast cancer, including TNBC. In this article, we review and discuss the development and clinical application of ADCs in patients with advanced TNBC.

scholarly journals Navitoclax enhances the effectiveness of EGFR-targeted antibody-drug conjugates in PDX models of EGFR-expressing triple-negative breast cancer

2020 ◽  
Vol 22 (1) ◽  
Author(s):  
Jason J. Zoeller ◽  
Aleksandr Vagodny ◽  
Veerle W. Daniels ◽  
Krishan Taneja ◽  
Benjamin Y. Tan ◽  
...  
Keyword(s):  
Breast Cancer ◽  
Tumor Growth ◽  
Triple Negative Breast Cancer ◽  
Triple Negative ◽  
Negative Patient ◽  
Apoptotic Signaling ◽  
Antibody Drug Conjugates ◽  
Drug Conjugates ◽  
Pdx Models ◽  
Antibody Drug

Abstract Background Targeted therapies for triple-negative breast cancer (TNBC) are limited; however, the epidermal growth factor receptor (EGFR) represents a potential target, as the majority of TNBC express EGFR. The purpose of these studies was to evaluate the effectiveness of two EGFR-targeted antibody-drug conjugates (ADC: ABT-414; ABBV-321) in combination with navitoclax, an antagonist of the anti-apoptotic BCL-2 and BCL-XL proteins, in order to assess the translational relevance of these combinations for TNBC. Methods The pre-clinical efficacy of combined treatments was evaluated in multiple patient-derived xenograft (PDX) models of TNBC. Microscopy-based dynamic BH3 profiling (DBP) was used to assess mitochondrial apoptotic signaling induced by navitoclax and/or ADC treatments, and the expression of EGFR and BCL-2/XL was analyzed in 46 triple-negative patient tumors. Results Treatment with navitoclax plus ABT-414 caused a significant reduction in tumor growth in five of seven PDXs and significant tumor regression in the highest EGFR-expressing PDX. Navitoclax plus ABBV-321, an EGFR-targeted ADC that displays more effective wild-type EGFR-targeting, elicited more significant tumor growth inhibition and regressions in the two highest EGFR-expressing models evaluated. The level of mitochondrial apoptotic signaling induced by single or combined drug treatments, as measured by DBP, correlated with the treatment responses observed in vivo. Lastly, the majority of triple-negative patient tumors were found to express EGFR and co-express BCL-XL and/or BCL-2. Conclusions The dramatic tumor regressions achieved using combined agents in pre-clinical TNBC models underscore the abilities of BCL-2/XL antagonists to enhance the effectiveness of EGFR-targeted ADCs and highlight the clinical potential for usage of such targeted ADCs to alleviate toxicities associated with combinations of BCL-2/XL inhibitors and systemic chemotherapies.

scholarly journals Clinical Development of New Antibody–Drug Conjugates in Breast Cancer: To Infinity and Beyond

BioDrugs ◽  
2021 ◽  
Vol 35 (2) ◽  
pp. 159-174
Author(s):  
Romualdo Barroso-Sousa ◽  
Sara M. Tolaney
Keyword(s):  
Breast Cancer ◽  
Clinical Development ◽  
Antibody Drug Conjugates ◽  
Drug Conjugates ◽  
Antibody Drug

scholarly journals Antibody-Drug Conjugates Used in Breast Cancers

2021 ◽  
Vol 2021 ◽  
pp. 1-7
Author(s):  
Aram J. Abbas ◽  
Marah F. Ibrahim ◽  
Maher S. Saifo
Keyword(s):  
Breast Cancer ◽  
Targeted Delivery ◽  
Cytotoxic Drugs ◽  
Breast Cancers ◽  
Receptor Targeting ◽  
Broad Application ◽  
Antibody Drug Conjugates ◽  
Drug Conjugates ◽  
Antibody Drug

The prognosis of breast cancer has radically changed in recent years and continues to improve due to the broad application of effective therapies. New targeting strategies including targeted delivery of cytotoxic drugs via receptor-targeting agents have been developed. We summarize recent publications and developments of novel antibody-drug conjugates (ADCs) used to control breast cancer.

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