Antibody–drug conjugates: in search of partners of choice

Fuentes-Antrás, Jesús; Genta, Sofia; Vijenthira, Abi; Siu, Lillian L.

doi:10.1016/j.trecan.2023.01.003

Cited by 80 publications

(84 citation statements)

References 93 publications

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“…Later in August 2022, the FDA approved T-Dxd as the first HER2-directed therapy for patients with HER2-low metastatic breast cancer and subsequently granted accelerated approval as the first drug for HER2 mutant non-small cell lung cancer (NSCLC) . Meanwhile, the success of checkpoint inhibitors has accelerated the development of immunostimulating antibody conjugates (ISACs), in which the classic cytotoxic drug was replaced with immunostimulant molecules including Toll-like receptor (TLR) activator and stimulator of interferon genes (STING) agonist . One successful example was presented by Ackerman et al, in which a new ISAC comprising a TLR7/8 dual agonist conjugated to anti -HER2 antibodies (Rituximab) was developed.…”

Section: How Are Antibodies Used?mentioning

confidence: 99%

“…200 Meanwhile, the success of checkpoint inhibitors has accelerated the development of immunostimulating antibody conjugates (ISACs), in which the classic cytotoxic drug was replaced with immunostimulant molecules including Toll-like receptor (TLR) activator and stimulator of interferon genes (STING) agonist. 201 One successful example was presented by Ackerman et al, in which a new ISAC comprising a TLR7/8 dual agonist conjugated to anti-HER2 antibodies (Rituximab) was developed. Systemic administration of this ISAC triggered a localized immune response in the tumor microenvironment (TME) for tumor clearance with immunological memory, eliminating toxicity associated with widespread immune activation after direct administration of TLR agonists.…”

Section: Antibody Conjugatesmentioning

confidence: 99%

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The Dawn of a New Era: Targeting the “Undruggables” with Antibody-Based Therapeutics

et al. 2023

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The high selectivity and affinity of antibodies toward their antigens have made them a highly valuable tool in disease therapy, diagnosis, and basic research. A plethora of chemical and genetic approaches have been devised to make antibodies accessible to more “undruggable” targets and equipped with new functions of illustrating or regulating biological processes more precisely. In this Review, in addition to introducing how naked antibodies and various antibody conjugates (such as antibody-drug conjugates, antibody-oligonucleotide conjugates, antibody-enzyme conjugates, etc.) work in therapeutic applications, special attention has been paid to how chemistry tools have helped to optimize the therapeutic outcome (i.e., with enhanced efficacy and reduced side effects) or facilitate the multifunctionalization of antibodies, with a focus on emerging fields such as targeted protein degradation, real-time live-cell imaging, catalytic labeling or decaging with spatiotemporal control as well as the engagement of antibodies inside cells. With advances in modern chemistry and biotechnology, well-designed antibodies and their derivatives via size miniaturization or multifunctionalization together with efficient delivery systems have emerged, which have gradually improved our understanding of important biological processes and paved the way to pursue novel targets for potential treatments of various diseases.

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Section: How Are Antibodies Used?mentioning

confidence: 99%

Section: Antibody Conjugatesmentioning

confidence: 99%

The Dawn of a New Era: Targeting the “Undruggables” with Antibody-Based Therapeutics

et al. 2023

View full text Add to dashboard Cite

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“…Beyond the identification of predictive biomarkers and signatures, it is equally relevant to expand the therapeutic armamentarium. In particular, leveraging new drug classes such as immune-oncology and antibody-drug conjugates would increase the likelihood of target-drug matching to advance precision medicine goals [135]. Most recently, trastuzumab deruxtecan-an antibody-drug conjugate composed of a humanized monoclonal antibody (trastuzumab) linked to a topoisomerase I inhibitor (deruxtecan)-was granted FDA approval for advanced HER2-low breast cancer treated with prior chemotherapy, as it showed both progression-free survival and overall survival benefit over physician's choice of chemotherapy [136].…”

Section: Trials In Precision Cancer Medicine: Future Perspectivesmentioning

confidence: 99%

Precision cancer medicine: Concepts, current practice, and future developments

Edsjö,

Holmquist,

Geoerger

et al. 2023

J Intern Med

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Precision cancer medicine is a multidisciplinary team effort that requires involvement and commitment of many stakeholders including the society at large. Building on the success of significant advances in precision therapy for oncological patients over the last two decades, future developments will be significantly shaped by improvements in scalable molecular diagnostics in which increasingly complex multilayered datasets require transformation into clinically useful information guiding patient management at fast turnaround times. Adaptive profiling strategies involving tissue‐ and liquid‐based testing that account for the immense plasticity of cancer during the patient's journey and also include early detection approaches are already finding their way into clinical routine and will become paramount. A second major driver is the development of smart clinical trials and trial concepts which, complemented by real‐world evidence, rapidly broaden the spectrum of therapeutic options. Tight coordination with regulatory agencies and health technology assessment bodies is crucial in this context. Multicentric networks operating nationally and internationally are key in implementing precision oncology in clinical practice and support developing and improving the ecosystem and framework needed to turn invocation into benefits for patients. The review provides an overview of the diagnostic tools, innovative clinical studies, and collaborative efforts needed to realize precision cancer medicine.

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“…Both nanoparticles and antibody-drug conjugates (ADCs) have shown promise in cell-specific targeting by using surface receptors on the cell type of interest to induce internalization and release of the drug into the cell. [8] Of these approaches, ADCs may provide a better therapeutic approach due to the mechanism of drug delivery. In general, when ADCs with noncleavable linkers bind to cell surface receptors, they are internalized into an early endosome, which eventually becomes a lysosome, leading to the degradation of the antibody and drug release into the cell.…”

mentioning

confidence: 99%

Activation of cholangiocyte mTORC1 drives alcohol-induced ductular reaction

Mackowiak

Gao

2023

Hepatology

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Activation of cholangiocyte mTORC1 drives alcoholinduced ductular reactionAlcohol consumption has increased over the COVID-19 pandemic, and this rise in alcohol consumption has led to increases in alcohol-associated liver disease and alcohol-associated hepatitis (AH) in particular. [1] The growing problem of AH has been exacerbated by the lack of suitable therapeutics to reverse AH, with many patients requiring liver transplants. The etiology of AH is complex, and current animal models of AH have not been able to replicate certain hallmarks of severe AH that correlate with prognosis, including ductular reaction (DR). This has greatly limited AH therapeutic development even though many targets and pathways have shown promise in preclinical models. In fact, several studies have shown that the mechanistic target of rapamycin complex 1 (mTORC1), a master regulator of cell growth, energy metabolism, and autophagy, is activated in AH, and inhibition of mTORC1 can reverse ethanol-induced liver injury. [2] However, the effect of mTORC1 on alcohol-associated DR and its associated liver injury remains unknown. Some of the questions surrounding mTORC1 in alcohol-associated liver disease are answered in this issue of HEPATOLOGY by Chao et al. [3] Chao and colleagues detected increased mTORC1 activation in chronic-plus-binge ethanol-fed mouse and human AH liver samples, and such elevated mTORC1 activation is associated with decreased protein levels of tuberous sclerosis complex 1 (TSC1), a negative regulator of mTORC1. These findings led the authors to characterize ethanol-induced liver injury in liverspecific Tsc1 knockout (L-Tsc1 KO) mice that exhibit constitutive mTORC1 activation. Alanine transaminase levels were not different between wild-type (WT) and L-Tsc1 KO mice subjected to the control diet, indicating that baseline liver injury may not be different. However, L-Tsc1 KO mice on the control diet exhibited increased liver size, DR, fibrosis, and immune cell infiltration compared with their WT

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Antibody–drug conjugates: in search of partners of choice

Cited by 80 publications

References 93 publications

The Dawn of a New Era: Targeting the “Undruggables” with Antibody-Based Therapeutics

The Dawn of a New Era: Targeting the “Undruggables” with Antibody-Based Therapeutics

Precision cancer medicine: Concepts, current practice, and future developments

Activation of cholangiocyte mTORC1 drives alcohol-induced ductular reaction

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