Antibody–Drug Conjugates—Evolution and Perspectives

International Journal of Molecular Sciences, Journal Year: 2024, Volume and Issue: 25(13), P. 6969 - 6969

Published: June 26, 2024

Antineoplastic therapy is one of the main research themes this century. Modern approaches have been implemented to target and heighten effect cytostatic drugs on tumors diminish their general/unspecific toxicity. In context, antibody-drug conjugates (ADCs) represent a promising successful strategy. The aim review was assess different aspects regarding ADCs. They were presented from chemical pharmacological perspective like structure, conjugation development particularities alongside effects, clinical trials, safety issues perspectives challenges for future use these discussed. Representative examples include but are not limited following structural components ADCs: monoclonal antibodies (trastuzumab, brentuximab), linkers (pH-sensitive, reduction-sensitive, peptide-based, phosphate-based, others), payloads (doxorubicin, emtansine, ravtansine, calicheamicin). Regarding pharmacotherapy success, high effectiveness expectation associated with ADC treatment supported by large number ongoing trials. Major such as strategies first discussed, advantages disadvantages, efficacy, offering retrospective insight subject. second part prospective, focusing various plans overcome previously identified difficulties.

Language: Английский

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Antibody-Drug Conjugates in Urothelial Cancer: From Scientific Rationale to Clinical Development

Cancers, Journal Year: 2024, Volume and Issue: 16(13), P. 2420 - 2420

Published: June 30, 2024

Antibody-drug conjugates (ADCs) have been a significant advancement in cancer therapy, particularly for urothelial (UC). These innovative treatments, originally developed hematological malignancies, use target-specific monoclonal antibodies linked to potent cytotoxic agents. This rational drug design efficiently delivers cell-killing agents cells expressing specific surface proteins, which are abundant UC owing their high antigen expression. is an ideal candidate ADC as it enhances on-target efficacy while mitigating systemic toxicity. In recent years, considerable progress has made understanding the biology and mechanisms of tumor progression UC. However, despite introduction immune checkpoint inhibitors, advanced characterized by rapid poor survival rates. Targeted therapies that include anti-nectin 4 enfortumab vedotin fibroblast growth factor receptor inhibitor erdafitinib. Enfortumab shown prospective studies patients with UC, alone combination pembrolizumab. The anti-Trop-2 sacituzumab govitecan also demonstrated effectiveness single-armed studies. review highlights mechanism action ADCs, application mono- therapies, primary resistance, future perspectives clinical treatment. ADCs proven be increasingly vital component therapeutic landscape carcinoma, filling gap treatment this progressive disease.

Language: Английский

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Epidermal Growth Factor Receptor Targeting in Colorectal Carcinoma: Antibodies and Patient-Derived Organoids as a Smart Model to Study Therapy Resistance

International Journal of Molecular Sciences, Journal Year: 2024, Volume and Issue: 25(13), P. 7131 - 7131

Published: June 28, 2024

Colorectal cancer (CRC) is the second leading cause of cancer-related death worldwide. Therefore, need for new therapeutic strategies still a challenge. Surgery and chemotherapy represent first-line interventions; nevertheless, prognosis metastatic CRC (mCRC) patients remains unacceptable. An important step towards targeted therapy came from inhibition epidermal growth factor receptor (EGFR) pathway, by anti-EGFR antibody, Cetuximab, or specific tyrosine kinase inhibitors (TKI). mouse-human chimeric monoclonal antibody (mAb), binds to extracellular domain EGFR thus impairing EGFR-mediated signaling reducing cell proliferation. TKI can affect biochemical pathway at different steps along cascade. Apart other mAbs have been developed, such as Panitumumab. Both antibodies approved treatment KRAS-NRAS wild type mCRC, alone in combination with chemotherapy. These display strong differences activating host immune system against CRC, due their immunoglobulin isotypes. Although are efficient, drug resistance occurs high frequency. Resistant tumor populations either already be present before develop later adaptations genomic mutations pathway. Numerous efforts made improve efficacy find agents that able block downstream cascade molecules. Indeed, we examined importance analyzing antibody-drug conjugates (ADC) developed overcome and/or stimulate host's immunity growth. Also, patient-derived organoid cultures useful feasible vitro model study behavior response. Organoids reflect genetic heterogeneity found tissue origin, representing unique tool personalized medicine. Thus, CRC-derived smart studying microenvironment preclinical assay drugs.

Language: Английский

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Economics of Antibody Drug Conjugates (ADCs): Innovation, Investment and Market Dynamics

Current Oncology Reports, Journal Year: 2024, Volume and Issue: 26(10), P. 1224 - 1235

Published: July 22, 2024

Language: Английский

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Single-Domain Antibodies as Antibody–Drug Conjugates: From Promise to Practice—A Systematic Review

Cancers, Journal Year: 2024, Volume and Issue: 16(15), P. 2681 - 2681

Published: July 27, 2024

Background: Antibody–drug conjugates (ADCs) represent potent cancer therapies that deliver highly toxic drugs to tumor cells precisely, thus allowing for targeted treatment and significantly reducing off-target effects. Despite their effectiveness, ADCs can face limitations due acquired resistance potential side Objectives: This study focuses on advances in various ADC components improve both the efficacy safety of these agents, includes analysis several novel formats. work assesses whether unique features VHHs—such as small size, enhanced tissue penetration, stability, cost-effectiveness—make them a viable alternative conventional antibodies reviews current status development. Methods: Following PRISMA guidelines, this focused VHHs ADCs, examining advancements prospects from 1 January 2014 30 June 2024. Searches were conducted PubMed, Cochrane Library, ScienceDirect LILACS using specific terms related single-domain antibodies. Retrieved articles rigorously evaluated, excluding duplicates non-qualifying studies. The selected peer-reviewed analyzed quality synthesized highlight advancements, methods, payloads, future directions research. Results: offer significant advantages drug conjugation over smaller size structure, which enhance penetration enable access previously inaccessible epitopes. Their superior solubility, manufacturability facilitate cost-effective production expand range targetable antigens. Additionally, some naturally cross blood–brain barrier or be easily modified favor making promising targeting brain tumors metastases. Although no VHH–drug (nADC nanoADC) are currently clinical arena, preclinical studies have explored methods linkers. Conclusions: While transforming treatment, mechanisms associated toxicities challenge traditional views bioavailability vary with different types. Severe toxicities, often linked compound instability, effects, nonspecific blood cell interactions, need better understanding. Conversely, rapid distribution, clearance could advantageous, potentially toxicity by minimizing prolonged exposure. These attributes make strong candidates next generation enhancing safety.

Language: Английский

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Targeting uPAR with an antibody-drug conjugate suppresses tumor growth and reshapes the immune landscape in pancreatic cancer models

Science Advances, Journal Year: 2025, Volume and Issue: 11(3)

Published: Jan. 17, 2025

Antibody-drug conjugates (ADCs) hold promise to advance targeted therapy of pancreatic ductal adenocarcinoma (PDAC), where the desmoplastic tumor stroma challenges effective treatment. Here, we explored urokinase plasminogen activator receptor (uPAR) as a candidate ADC target in PDAC, harnessing its massive tumoral and stromal expression this stroma-dense tumor. We generated site-specific offering high-affinity, cross-species reactivity, efficient internalization anti-uPAR monoclonal antibody, FL1, carrying potent anthracycline derivative (PNU-158692). In vitro, FL1-PNU exhibited specific cytotoxicity against uPAR-expressing PDAC cell lines, immune cells, bystander killing uPAR-negative cells. vivo, induced remission or sustained regression extended survival xenograft models. syngeneic orthotopic models, antitumor effect promoted immunomodulation by enhancing infiltrating effectors decreasing immunosuppressive This study lays grounds for further exploring putative clinical candidate, potentially providing promising therapeutic avenue monotherapy combinatorial regimens.

Language: Английский

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Challenges and opportunities in single-domain antibody-based tumor immunotherapy

Biochimica et Biophysica Acta (BBA) - Reviews on Cancer, Journal Year: 2025, Volume and Issue: unknown, P. 189284 - 189284

Published: Feb. 1, 2025

Language: Английский

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Prospects for the Use of Antibody-Drug Conjugates in Cancer Therapy

Russian Journal of Bioorganic Chemistry, Journal Year: 2025, Volume and Issue: 51(2), P. 556 - 573

Published: April 1, 2025

Language: Английский

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Antibody–Drug Conjugates (ADCs): current and future biopharmaceuticals

Journal of Hematology & Oncology, Journal Year: 2025, Volume and Issue: 18(1)

Published: April 30, 2025

Language: Английский

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Evaluating the Potential of Cyclodextrins in Reducing Aggregation of Antibody–Drug Conjugates with Different Payloads

Journal of Pharmaceutical Sciences, Journal Year: 2024, Volume and Issue: 113(8), P. 2443 - 2453

Published: April 27, 2024

Cyclodextrins (CDs) are versatile agents used to solubilize small drugs and stabilize proteins. This dual functionality may be particularly beneficial for antibody–drug conjugates (ADCs), as CDs "mask" the hydrophobicity of drug payloads. In this study, we explored effect on physical stability ADCs composed same antibody but with different payloads (maytansinoid, auristatin, fluorophore payloads). The aggregation was evaluated under shaking stress conditions elevated temperatures using size-exclusion chromatography, turbidity, backgrounded membrane imaging. Our results showed that hydroxypropyl-(HP)-CDs effectively stabilized all during stress, increasing stabilization in order HPαCD < HPγCD HPβCD at concentrations 7.5 mM (near) complete 75 mM. Native without surface activity also certain ADCs, although less than HP-CDs agitation stress. During quiescent incubation, HP-CD effects were most ADCs. However, an ADC a payload rapidly aggregated after conjugation, substantially reduced aggregate levels, line fluorescence data supporting CD–ADC interactions. contrast, sulfobutylether-β-CD (SBEβCD) increased rates conditions. conclusion, study highlights potential appropriate CD formulations improve

Language: Английский

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