Antibody-Drug Conjugates for Breast Cancer

Abstract

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 for the Treatment of HER2-Positive Breast Cancer

“…Ideally, the target antigen should be tumor specific and preferentially expressed in tumor tissues but lowly expressed in non-tumorigenic tissues. Moreover, the target antigen must be easily accessible to antibody binding to facilitate effective internalization and delivery of the active cytotoxic drug into the tumor cell [ 115 , 116 ]. Currently, two antigens are approved for targeting breast cancer with ADCs, HER2 and TROP2.…”

“…The compatibility and specificity of the antibody is critical for the activity of an ADC. The mechanism of action of ADCs relies on the internalization of antibody-bound antigens for the delivery of cytotoxic agents [ 115 , 116 ]. Hence, the antibody must have a high affinity to the target antigen to achieve maximum effect while reducing cross-reactivity that may reduce efficacy of the cytotoxic component of the ADC [ 122 ].…”

An Update on the General Features of Breast Cancer in Male Patients—A Literature Review

“…In a study presented by Marme [ 125 ], it was shown that there are currently nine approved ADCs, including three for breast cancer. With over 100 candidates in various stages of clinical development, the rate of development appears to be quickening.…”

Current and New Novel Combination Treatments for Metastatic Triple-Negative Breast Cancer

“…However, more than 60 ADCs are at different stages of development for use in breast cancer patients, including several trials for TNBC, with molecular targets such as TROP-2, LIV-1, HER2, HER3 and ROR2, amongst others. The selected agents included in this review are trastuzumab deruxtecan (T-DXd) (NCT04556773), ladiratuzumab vedotin (SGN-LIV1a) (NCT03310957), vic-trastuzumab duocarmazine (SYD985) (NCT04602117), anti-B7-H3-ADC (MGC018) (NCT03729596), CAB-ROR-ADC (BA3021) (NCT03504488), datopotamab deruxtecan (DS-1062) (NCT05374512) and tusamitamab Ravtansine (SAR408701) (NCT04659603) [ 22 ] ( Table 2 ).…”

“…However, more than 60 ADCs are at different stages of development for use in breast cancer patients, including several trials for TNBC, with molecular targets such as TROP-2, LIV-1, HER2, HER3 and ROR2, amongst others. The selected agents included in this review are trastuzumab deruxtecan (T-DXd) (NCT04556773), ladiratuzumab vedotin (SGN-LIV1a) (NCT03310957), vic-trastuzumab duocarmazine (SYD985) (NCT04602117), anti-B7-H3-ADC (MGC018) (NCT03729596), CAB-ROR-ADC (BA3021) (NCT03504488), datopotamab deruxtecan (DS-1062) (NCT05374512) and tusamitamab Ravtansine (SAR408701) (NCT04659603) [22] (Table 2). Abbreviations: Progression-free survival (PFS), overall survival (OS), response rate (RR), percentage of participants with adverse events (AEs), serious adverse events (SAEs), overall response rate (ORR), duration of response (DOR), clinical benefit rate (CBR), disease control rate (DCR), maximum tolerated dose (MTD), recommended phase II dose (RP2D), best overall response (OR), event-free survival (EFS), time-to-treatment failure (TTF), time to objective response (TTOR) and time to response (TTR).…”