Antibody drug conjugate: the “biological missile” for targeted cancer therapy

Signal Transduction and Targeted Therapy, Journal Year: 2022, Volume and Issue: 7(1)

Published: March 22, 2022

Antibody-drug conjugate (ADC) is typically composed of a monoclonal antibody (mAbs) covalently attached to cytotoxic drug via chemical linker. It combines both the advantages highly specific targeting ability and potent killing effect achieve accurate efficient elimination cancer cells, which has become one hotspots for research development anticancer drugs. Since first ADC, Mylotarg

Language: Английский

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An Insight into FDA Approved Antibody-Drug Conjugates for Cancer Therapy

Molecules, Journal Year: 2021, Volume and Issue: 26(19), P. 5847 - 5847

Published: Sept. 27, 2021

The large number of emerging antibody-drug conjugates (ADCs) for cancer therapy has resulted in a significant market 'boom', garnering worldwide attention. Despite ADCs presenting huge challenges to researchers, particularly regarding the identification suitable combination antibody, linker, and payload, as September 2021, 11 have been granted FDA approval, with eight these approved since 2017 alone. Optimism this therapeutic approach is clear, despite COVID-19 pandemic, 2020 was landmark year deals partnerships ADC arena, suggesting that there remains interest from Big Pharma. Herein we review enthusiasm by focusing on features those FDA, offer some thoughts where field headed.

Language: Английский

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Mechanisms of ADC Toxicity and Strategies to Increase ADC Tolerability

Cancers, Journal Year: 2023, Volume and Issue: 15(3), P. 713 - 713

Published: Jan. 24, 2023

Anti-cancer antibody-drug conjugates (ADCs) aim to expand the therapeutic index of traditional chemotherapy by employing targeting specificity monoclonal antibodies (mAbs) increase efficiency delivery potent cytotoxic agents malignant cells. In past three years, number ADCs approved Food and Drug Administration (FDA) has tripled. Although several have demonstrated sufficient efficacy safety warrant FDA approval, clinical use all leads substantial toxicity in treated patients, many failed during development due their unacceptable profiles. Analysis data that dose-limiting toxicities (DLTs) are often shared different deliver same payload, independent antigen is targeted and/or type cancer treated. DLTs commonly associated with cells tissues do not express (i.e., off-target toxicity), limit ADC dosage levels below those required for optimal anti-cancer effects. this manuscript, we review fundamental mechanisms contributing toxicity, summarize common treatment-related adverse events, discuss approaches mitigating toxicity.

Language: Английский

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Designing antibodies as therapeutics

Cell, Journal Year: 2022, Volume and Issue: 185(15), P. 2789 - 2805

Published: July 1, 2022

Language: Английский

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Targeting cancer with antibody-drug conjugates: Promises and challenges

mAbs, Journal Year: 2021, Volume and Issue: 13(1)

Published: Jan. 1, 2021

Antibody-drug conjugates (ADCs) are a rapidly expanding class of biotherapeutics that utilize antibodies to selectively deliver cytotoxic drugs the tumor site. As May 2021, U.S. Food and Drug Administration (FDA) has approved ten ADCs, namely Adcetris®, Kadcyla®, Besponsa®, Mylotarg®, Polivy®, Padcev®, Enhertu®, Trodelvy®, Blenrep®, Zynlonta™ as monotherapy or combinational therapy for breast cancer, urothelial myeloma, acute leukemia, lymphoma. In addition, over 80 investigational ADCs currently being evaluated in approximately 150 active clinical trials. Despite growing interest challenges remain expand their therapeutic index (with greater efficacy less toxicity). Recent advances manufacturing technology antibody, payload, linker combined with new bioconjugation platforms state-of-the-art analytical techniques helping shape future development ADCs. This review highlights current status marketed those under investigation focus on translational strategies improve product quality, safety, efficacy.

Language: Английский

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Antibody-Mediated Delivery of Chimeric BRD4 Degraders. Part 1: Exploration of Antibody Linker, Payload Loading, and Payload Molecular Properties

Journal of Medicinal Chemistry, Journal Year: 2021, Volume and Issue: 64(5), P. 2534 - 2575

Published: Feb. 17, 2021

The biological and medicinal impacts of proteolysis-targeting chimeras (PROTACs) related chimeric molecules that effect intracellular degradation target proteins via ubiquitin ligase-mediated ubiquitination continue to grow. However, these entities are relatively large compounds often possess molecular characteristics, which may compromise oral bioavailability, solubility, and/or in vivo pharmacokinetic properties. We therefore explored the conjugation such monoclonal antibodies using technologies originally developed for cytotoxic payloads so as provide alternate delivery options novel agents. In this report, we describe first phase our systematic development antibody–drug conjugates (ADCs) derived from bromodomain-containing protein 4 (BRD4)-targeting degrader entities. demonstrate antigen-dependent PC3-S1 prostate cancer cells along with on MYC transcription BRD4 levels. These experiments culminate identification one conjugate, exhibits antiproliferation effects LNCaP cells.

Language: Английский

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Degrader-antibody conjugates

Chemical Society Reviews, Journal Year: 2022, Volume and Issue: 51(10), P. 3886 - 3897

Published: Jan. 1, 2022

This review illustrates the design of antibody conjugates which employ chimeric protein degraders ( i.e. , PROTACs) as payloads and summarizes examples such entities that are currently known in scientific patent literature.

Language: Английский

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A comprehensive review of key factors affecting the efficacy of antibody drug conjugate

Biomedicine & Pharmacotherapy, Journal Year: 2023, Volume and Issue: 161, P. 114408 - 114408

Published: Feb. 24, 2023

Antibody Drug Conjugate (ADC) is an emerging technology to overcome the limitations of chemotherapy by selectively targeting cancer cells. ADC binds with antigen, specifically over expressed on surface cells, results decrease in bystander effect and increase therapeutic index. The potency ideal entirely depending several physicochemical factors such as site conjugation, molecular weight, linker length, Steric hinderance, half-life, conjugation method, binding energy so on. Inspite fact that there more than 100 ADCs are clinical trial only 14 approved FDA for use. However, design still challenging much be done. Here this review, we have discussed key components along their significant role or contribution towards efficacy ADC. Moreover, also explained about recent advancement method. Additionally, spotlit mode action ADC, challenges, future perspective regarding profound knowledge properties will help synthesis production different engineered ADCs. Therefore, contributes develop low safety concern high We hope review improve understanding encourage practicing research anticancer development.

Language: Английский

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

Chemical Reviews, Journal Year: 2023, Volume and Issue: 123(12), P. 7782 - 7853

Published: May 15, 2023

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

Language: Английский

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Exploration of the antibody–drug conjugate clinical landscape

mAbs, Journal Year: 2023, Volume and Issue: 15(1)

Published: Aug. 28, 2023

The antibody–drug conjugate (ADC) field has undergone a renaissance, with substantial recent developmental investment and subsequent drug approvals over the past 6 y. In November 2022, ElahereTM became latest ADC to be approved by US Food Drug Administration (FDA). To date, 260 ADCs have been tested in clinic against various oncology indications. Here, we review clinical landscape of that are currently FDA (11), agents trials but not yet (164), candidates discontinued following testing (92). These clinically further analyzed their targeting tumor antigen(s), linker, payload choices, highest stage achieved, highlighting limitations associated candidates. Lastly, discuss biologic engineering modifications preclinically demonstrated improve therapeutic index if incorporated may increase proportion molecules successfully transition regulatory approval.

Language: Английский

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