Bystander effect of antibody–drug conjugates: fact or fiction?

Giugliano, Federica; Corti, Chiara; Tarantino, Paolo; Michelini, Flavia; Curigliano, Giuseppe

doi:10.1007/s11912-022-01266-4

Cited by 67 publications

(51 citation statements)

References 37 publications

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“…Some payloads exert a bystander effect, where the free drug is released unintentionally from the target tumor cell across the cell membrane following internalization and degradation of the ADC, to kill adjacent tumor cells, including those cells that may not express the target antigen on its cell surface. This feature of certain ADCs is often debated and some pharmacological characteristics, such as a hydrophobic payload or a cleavable linker, appear to play a major role in this phenomen 5 . When the cytotoxic payload released is permeable or transmembrane, it can also induce the ‘bystander effect’, which can enhance the efficacy of ADC.…”

Section: Mechanism Of Actionmentioning

confidence: 99%

“…In addition, the bystander effect of ADCs may also alter the tumor microenvironment, which in turn may further enhance the killing effect of ADCs 6 . Moreover, regarding the bystander effect, some chemical properties of the payloads, e.g., lipophilic, hydrophobic, and uncharged payloads are important for the membrane permeability of ADCs, allowing for the distribution from the ADC-targeted tumor cells to non-targeted tumor cells 5 . As described above, the linker type, such as the conjugation to the lysine residue, can also result in attenuated bystander effect, as charged residues can promote drug staying within the targeted tumor cell 5 .…”

Section: Mechanism Of Actionmentioning

confidence: 99%

“…Moreover, regarding the bystander effect, some chemical properties of the payloads, e.g., lipophilic, hydrophobic, and uncharged payloads are important for the membrane permeability of ADCs, allowing for the distribution from the ADC-targeted tumor cells to non-targeted tumor cells 5 . As described above, the linker type, such as the conjugation to the lysine residue, can also result in attenuated bystander effect, as charged residues can promote drug staying within the targeted tumor cell 5 . Important considerations in the design of an ADC include target cell selection, the nature of antigen, structure, and stability of the antibody, the linker chemistry, and the cytotoxic payload.…”

Section: Mechanism Of Actionmentioning

confidence: 99%

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Antibody-drug conjugates in lung cancer: dawn of a new era?

et al. 2023

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Antibody-drug conjugates (ADCs) are one of fastest growing classes of oncology drugs in modern drug development. By harnessing the powers of both cytotoxic chemotherapy and targeted therapy, ADCs are unique in offering the potential to deliver highly potent cytotoxic agents to cancer cells which express a pre-defined cell surface target. In lung cancer, the treatment paradigm has shifted dramatically in recent years, and now ADCs are now joining the list as potential options for lung cancer patients. Since 2020, the first ADC for NSCLC patients has been FDA-approved (trastuzumab deruxtecan) and two ADCs have been granted FDA Breakthrough Therapy Designation, currently under evaluation (patritumab deruxtecan, telisotuzumab vedotin). Furthermore, several early-phase trials are assessing various novel ADCs, either as monotherapy or in combinations with advanced lung cancer, and more selective and potent ADCs are expected to become therapeutic options in clinic soon. In this review, we discuss the structure and mechanism of action of ADCs, including insights from pre-clinical work; we summarize the ADCs’ recent progress in lung cancer, describe toxicity profiles of ADCs, and explore strategies designed to enhance ADC potency and overcome resistance. In addition, we discuss novel ADC strategies of interest in lung cancer, including non-cytotoxic payloads, such as immunomodulatory and anti-apoptotic agents.

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Section: Mechanism Of Actionmentioning

confidence: 99%

Section: Mechanism Of Actionmentioning

confidence: 99%

Section: Mechanism Of Actionmentioning

confidence: 99%

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Antibody-drug conjugates in lung cancer: dawn of a new era?

et al. 2023

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“…Linker chemistry can play a central role in activity and controlling bystander effects. , This is because with noncleavable linkers, the drug-linker motif remains attached to at least the amino acid it was conjugated to. The resulting amino acid-linker-drug catabolites are typically too polar to exhibit bystander activity and can exhibit reduced potency compared to the corresponding ADC with a cleavable linker.…”

Section: Linker Propertiesmentioning

confidence: 99%

Structure–Activity Relationships of Antibody-Drug Conjugates: A Systematic Review of Chemistry on the Trastuzumab Scaffold

et al. 2022

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Antibody-drug conjugates (ADCs) are a rapidly growing class of cancer therapeutics that seek to overcome the low therapeutic index of conventional cytotoxic agents. However, realizing this goal has been a significant challenge. ADCs comprise several independently modifiable components, including the antibody, payload, linker, and bioconjugation method. Many approaches have been developed to improve the physical properties, potency, and selectivity of ADCs. The anti-HER-2 antibody trastuzumab, first approved in 1998, has emerged as an exceptional targeting agent for ADCs, as well as a broadly used platform for testing new technologies. The extensive work in this area enables the comparison of various linker strategies, payloads, drug-to-antibody ratios (DAR), and mode of attachment. In this review, these conjugates, ranging from the first clinically approved trastuzumab ADC, ado-trastuzumab emtansine (Kadcyla), to the latest variants are described with the goal of providing a broad overview, as well as enabling the comparison of existing and emerging conjugate technologies.

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“…This is how the payload moves from ADC-targeted cells to untargeted cells. This effect is modulated by the type of linker used and by the pharmacological characteristics of the released payload, which must contain nonpolar and charge-neutral properties allowing it to cross cell membranes 17,18 …”

Section: Mechanism Of Action and Structure Of Adcsmentioning

confidence: 99%

Antibody-Drug Conjugates and Tissue-Agnostic Drug Development

2022

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Antibody-drug conjugates (ADCs) deliver effective medications to tumor cells that express specific antigens, maximizing efficacy and reducing adverse effects. Because ado-trastuzumab emtansine was approved in 2013, 5 ADCs received US Food and Drug Administration approval for solid tumor treatment. Technical advancements in the development of each component of ADCs allowed novel monoclonal antibodies, linkers, and payloads to increase drug transport to malignant cells and drug activity even in cancers with heterogeneous antigen expression. In addition, several ADCs are in development using new molecular targets expressed across a broad range of histologies to allow the use of ADC biomarker-driven therapy irrespective of the primary tumor site. This suggests that the future efficacy of ADCs in multiple histologies may be similar to other classes of drugs that are considered histology-agnostic therapies nowadays. This review focuses on novel ADCs for the treatment of solid tumors, including topics such as their structure and mechanism of action, the latest indications of already US Food and Drug Administration-approved ADCs, and the outlook for new promising ADCs under development for the treatment of tumors of various histologies.

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Bystander effect of antibody–drug conjugates: fact or fiction?

Cited by 67 publications

References 37 publications

Antibody-drug conjugates in lung cancer: dawn of a new era?

Antibody-drug conjugates in lung cancer: dawn of a new era?

Structure–Activity Relationships of Antibody-Drug Conjugates: A Systematic Review of Chemistry on the Trastuzumab Scaffold

Antibody-Drug Conjugates and Tissue-Agnostic Drug Development

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