Targeting TACC3 Induces Immunogenic Cell Death and Enhances T-DM1 Response in HER2-Positive Breast Cancer DOI Creative Commons
Mustafa Emre Gedik, Özge Saatci, Nathaniel Oberholtzer

и другие.

Cancer Research, Год журнала: 2024, Номер 84(9), С. 1475 - 1490

Опубликована: Фев. 6, 2024

Trastuzumab emtansine (T-DM1) was the first and one of most successful antibody-drug conjugates (ADC) approved for treating refractory HER2-positive breast cancer. Despite its initial clinical efficacy, resistance is unfortunately common, necessitating approaches to improve response. Here, we found that in sensitive cells, T-DM1 induced spindle assembly checkpoint (SAC)-dependent immunogenic cell death (ICD), an immune-priming form death. The payload mediated ICD by inducing eIF2α phosphorylation, surface exposure calreticulin, ATP HMGB1 release, secretion ICD-related cytokines, all which were lost resistance. Accordingly, gene signatures pretreatment samples correlated with response T-DM1-containing therapy, increased infiltration antitumor CD8+ T cells posttreatment better Transforming acidic coiled-coil containing 3 (TACC3) overexpressed T-DM1-resistant responsive patients had reduced TACC3 protein expression whereas nonresponders exhibited during treatment. Notably, genetic or pharmacologic inhibition restored T-DM1-induced SAC activation induction markers vitro. Finally, vivo elicited a vaccination assay potentiated efficacy dendritic maturation enhancing intratumoral cytotoxic cells. Together, these results illustrate key mechanism action targeting can restore T-DM1-mediated overcome

Язык: Английский

Optimizing the safety of antibody–drug conjugates for patients with solid tumours DOI Open Access
Paolo Tarantino, Biagio Ricciuti,

Shan M. Pradhan

и другие.

Nature Reviews Clinical Oncology, Год журнала: 2023, Номер 20(8), С. 558 - 576

Опубликована: Июнь 9, 2023

Язык: Английский

Процитировано

125
Antibody–drug conjugates: in search of partners of choice DOI Creative Commons
Jesús Fuentes‐Antrás, Sofia Genta, Abi Vijenthira

и другие.

Trends in cancer, Год журнала: 2023, Номер 9(4), С. 339 - 354

Опубликована: Фев. 4, 2023

Antibody-drug conjugates (ADCs) have become a credentialled class of anticancer drugs for both solid and hematological malignancies, with regulatory approvals mainly as single agents. Despite extensive preclinical clinical efforts to develop rational ADC-based combinations, date only limited number demonstrated survival improvements over standard care. The most appealing partners ADCs are those that offer additive or synergistic effects on tumor cells their microenvironment without unacceptable overlapping toxicities. Coadministration antiangiogenic compounds, HER2-targeting drugs, DNA-damage response agents immune checkpoint inhibitors (ICIs) represent active forerunners. Through the identification targets tumor-specific expression, improved conjugation technologies, novel linkers payloads offering superior therapeutic indices, next generation brings optimism combinatorial approaches.

Язык: Английский

Процитировано

123
The therapeutic window of antibody drug conjugates: A dogma in need of revision DOI Creative Commons
Raffaele Colombo,

Jamie R. Rich

Cancer Cell, Год журнала: 2022, Номер 40(11), С. 1255 - 1263

Опубликована: Окт. 13, 2022

Язык: Английский

Процитировано

102
Antibody–Drug Conjugates: A Review of Approved Drugs and Their Clinical Level of Evidence DOI Open Access
Pooja Gogia, Hamza Ashraf, S. Bhasin

и другие.

Cancers, Год журнала: 2023, Номер 15(15), С. 3886 - 3886

Опубликована: Июль 30, 2023

Antibody-drug conjugates (ADCs) are an innovative family of agents assembled through linking cytotoxic drugs (payloads) covalently to monoclonal antibodies (mAbs) be delivered tumor tissue that express their particular antigen, with the theoretical advantage augmented therapeutic ratio. As June 2023, eleven ADCs have been approved by Food and Drug Administration (FDA) on market. These added armamentarium acute myeloblastic lymphoblastic leukemias, various types lymphoma, breast, gastric or gastroesophageal junction, lung, urothelial, cervical, ovarian cancers. They proven deliver more potent effective anti-tumor activities than standard practice in a wide variety indications. In addition targeting antigen-expressing cells, bystander effects engineered extend killing low-antigen-expressing negative cells heterogenous milieu. Inevitably, myelosuppression is common side effect most due payload. Also, other unique specific antigen targeted for, such as cardiac toxicity Her-2 ADCs, hemorrhagic factor (TF) Tisotumab vedotin. Further exciting developments centered strategies improve tolerability efficacy window; well development novel payloads including (1) peptide-drug (PDCs), peptide replacing antibody, rendering greater penetration; (2) immune-stimulating antibody (ISACs), which upon conjugation cause influx pro-inflammatory cytokines activate dendritic harness T-cell response; (3) use radioactive isotopes payload enhance activity.

Язык: Английский

Процитировано

92
A comprehensive overview on antibody-drug conjugates: from the conceptualization to cancer therapy DOI Creative Commons
Federico Riccardi, Michele Dal Bo, Paolo Macor

и другие.

Frontiers in Pharmacology, Год журнала: 2023, Номер 14

Опубликована: Сен. 18, 2023

Antibody-Drug Conjugates (ADCs) represent an innovative class of potent anti-cancer compounds that are widely used in the treatment hematologic malignancies and solid tumors. Unlike conventional chemotherapeutic drug-based therapies, mainly associated with modest specificity therapeutic benefit, three key components form ADC (a monoclonal antibody bound to a cytotoxic drug via chemical linker moiety) achieve remarkable improvement terms targeted killing cancer cells and, while sparing healthy tissues, reduction systemic side effects caused by off-tumor toxicity. Based on their beneficial mechanism action, 15 ADCs have been approved date market approval Food Drug Administration (FDA), European Medicines Agency (EMA) and/or other international governmental agencies for use clinical oncology, hundreds undergoing evaluation preclinical phases. Here, our aim is provide comprehensive overview features revolving around strategy including structural targeting properties, role tumor microenvironment review providing discussion regarding toxicity profile, manifestations novel combination therapies. Finally, we briefly pathological contexts information manufacturing analytical characterization.

Язык: Английский

Процитировано

84
The promise and challenges of combination therapies with antibody-drug conjugates in solid tumors DOI Creative Commons
Qing Wei, Peijing Li, Teng Yang

и другие.

Journal of Hematology & Oncology, Год журнала: 2024, Номер 17(1)

Опубликована: Янв. 4, 2024

Antibody-drug conjugates (ADCs) represent an important class of cancer therapies that have revolutionized the treatment paradigm solid tumors. To date, many ongoing studies ADC combinations with a variety anticancer drugs, encompassing chemotherapy, molecularly targeted agents, and immunotherapy, are being rigorously conducted in both preclinical clinical trial settings. Nevertheless, combination therapy does not always guarantee synergistic or additive effect may entail overlapping toxicity risks. Therefore, understanding current status underlying mechanisms is urgently required. This comprehensive review analyzes existing evidence concerning ADCs other classes oncology medicines. Here, we discuss biological different strategies, provide prominent examples, assess their benefits challenges. Finally, future opportunities for practice.

Язык: Английский

Процитировано

64
The Evolving Landscape of Antibody–Drug Conjugates: In Depth Analysis of Recent Research Progress DOI Creative Commons
Janet M. Sasso,

Rumiana Tenchov,

Robert E. Bird

и другие.

Bioconjugate Chemistry, Год журнала: 2023, Номер 34(11), С. 1951 - 2000

Опубликована: Окт. 11, 2023

Antibody–drug conjugates (ADCs) are targeted immunoconjugate constructs that integrate the potency of cytotoxic drugs with selectivity monoclonal antibodies, minimizing damage to healthy cells and reducing systemic toxicity. Their design allows for higher doses drug be administered, potentially increasing efficacy. They currently among most promising classes in oncology, efforts expand their application nononcological indications combination therapies. Here we provide a detailed overview recent advances ADC research consider future directions challenges promoting this platform widespread therapeutic use. We examine data from CAS Content Collection, largest human-curated collection published scientific information, analyze publication landscape reveal exploration trends documents insights into area. also discuss evolution key concepts field, major technologies, development pipelines company focuses, disease targets, stages, investment trends. A comprehensive concept map has been created based on Collection. hope report can serve as useful resource understanding current state knowledge field ADCs remaining fulfill potential.

Язык: Английский

Процитировано

61
Antibody-Drug Conjugates in Lung Cancer: Recent Advances and Implementing Strategies DOI
Antonio Passaro, Pasi A. Jänne, Solange Peters

и другие.

Journal of Clinical Oncology, Год журнала: 2023, Номер 41(21), С. 3747 - 3761

Опубликована: Май 24, 2023

Antibody-drug conjugates (ADCs) are one of the fastest-growing oncology therapeutics, merging cytotoxic effect conjugated payload with high specific ability and selectivity monoclonal antibody targeted on a cancer cell membrane antigen. The main targets for ADC development antigens commonly expressed by lung cells, but not in normal tissues. They include human epidermal growth factor receptor 2, 3, trophoblast surface antigen c-MET, carcinoembryonic antigen-related adhesion molecule 5, B7-H3, each or more ADCs that showed encouraging results field, non-small-cell than small-cell histology. To date, multiple under evaluation, alone combination different molecules (eg, chemotherapy agents immune checkpoint inhibitors), optimal strategy selecting patients who may benefit from treatment is evolving, including an improvement biomarker understanding, involving markers resistance response to payload, besides target. In this review, we discuss available evidence future perspectives treatment, comprehensive discussion structure-based drug design, mechanism action, concepts. Data were summarized target antigen, biology, efficacy, safety, differing among according their pharmacokinetics pharmacodynamics properties.

Язык: Английский

Процитировано

57
A review of the clinical efficacy of FDA-approved antibody‒drug conjugates in human cancers DOI Creative Commons
Kaifeng Liu, Meijia Li, Yudong Li

и другие.

Molecular Cancer, Год журнала: 2024, Номер 23(1)

Опубликована: Март 23, 2024

Abstract While strategies such as chemotherapy and immunotherapy have become the first-line standard therapies for patients with advanced or metastatic cancer, acquired resistance is still inevitable in most cases. The introduction of antibody‒drug conjugates (ADCs) provides a novel alternative. ADCs are new class anticancer drugs comprising coupling antitumor mAbs cytotoxic drugs. Compared chemotherapeutic drugs, advantages good tolerance, accurate target recognition, small effects on noncancerous cells. occupy an increasingly important position therapeutic field. Currently, there 13 Food Drug Administration (FDA)‒approved more than 100 ADC at different stages clinical trials. This review briefly describes efficacy safety FDA-approved ADCs, discusses related problems challenges to provide reference work.

Язык: Английский

Процитировано

54
Disitamab vedotin (RC48) plus toripalimab for HER2-expressing advanced gastric or gastroesophageal junction and other solid tumours: a multicentre, open label, dose escalation and expansion phase 1 trial DOI Creative Commons
Yakun Wang,

Jifang Gong,

Airong Wang

и другие.

EClinicalMedicine, Год журнала: 2024, Номер 68, С. 102415 - 102415

Опубликована: Янв. 5, 2024

Although the antibody-drug conjugates (ADCs) have significantly improved survival outcomes of patients with human epidermal receptor 2 (HER2)-expressing gastric or gastroesophageal junction (G/GEJ) cancer, efficacy ADC used as a single agent is limited. Therefore, it necessary to investigate effective and safe combination regimens. Preclinical data indicated synergetic antitumour effect RC48 programmed cell death protein 1 (PD-1) inhibitors. We aimed evaluate safety plus toripalimab in HER2-expressing G/GEJ cancer other solid tumours.

Язык: Английский

Процитировано

32