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Signal Transduction and Targeted Therapy Mar 2022Antibody-drug conjugate (ADC) is typically composed of a monoclonal antibody (mAbs) covalently attached to a cytotoxic drug via a chemical linker. It combines both the... (Review)
Review
Antibody-drug conjugate (ADC) is typically composed of a monoclonal antibody (mAbs) covalently attached to a cytotoxic drug via a chemical linker. It combines both the advantages of highly specific targeting ability and highly potent killing effect to achieve accurate and efficient elimination of cancer cells, which has become one of the hotspots for the research and development of anticancer drugs. Since the first ADC, Mylotarg (gemtuzumab ozogamicin), was approved in 2000 by the US Food and Drug Administration (FDA), there have been 14 ADCs received market approval so far worldwide. Moreover, over 100 ADC candidates have been investigated in clinical stages at present. This kind of new anti-cancer drugs, known as "biological missiles", is leading a new era of targeted cancer therapy. Herein, we conducted a review of the history and general mechanism of action of ADCs, and then briefly discussed the molecular aspects of key components of ADCs and the mechanisms by which these key factors influence the activities of ADCs. Moreover, we also reviewed the approved ADCs and other promising candidates in phase-3 clinical trials and discuss the current challenges and future perspectives for the development of next generations, which provide insights for the research and development of novel cancer therapeutics using ADCs.
Topics: Antibodies, Monoclonal; Antineoplastic Agents; Humans; Immunoconjugates; Neoplasms; United States; United States Food and Drug Administration
PubMed: 35318309
DOI: 10.1038/s41392-022-00947-7 -
Molecules (Basel, Switzerland) May 2021Antibody-drug conjugates (ADCs) are a family of targeted therapeutic agents for the treatment of cancer. ADC development is a rapidly expanding field of research, with... (Review)
Review
Antibody-drug conjugates (ADCs) are a family of targeted therapeutic agents for the treatment of cancer. ADC development is a rapidly expanding field of research, with over 80 ADCs currently in clinical development and eleven ADCs (nine containing small-molecule payloads and two with biological toxins) approved for use by the FDA. Compared to traditional small-molecule approaches, ADCs offer enhanced targeting of cancer cells along with reduced toxic side effects, making them an attractive prospect in the field of oncology. To this end, this tutorial review aims to serve as a reference material for ADCs and give readers a comprehensive understanding of ADCs; it explores and explains each ADC component (monoclonal antibody, linker moiety and cytotoxic payload) individually, highlights several EMA- and FDA-approved ADCs by way of case studies and offers a brief future perspective on the field of ADC research.
Topics: Antineoplastic Agents; Clinical Trials as Topic; Drug Approval; Humans; Immunoconjugates; Neoplasms
PubMed: 34063364
DOI: 10.3390/molecules26102943 -
Molecular Cancer Therapeutics Dec 2021Trophoblast cell surface antigen 2 (TROP2) is highly expressed on various epithelial tumors and correlates with poor prognosis. We developed the novel TROP2-directed...
Trophoblast cell surface antigen 2 (TROP2) is highly expressed on various epithelial tumors and correlates with poor prognosis. We developed the novel TROP2-directed antibody-drug conjugate (ADC), datopotamab deruxtecan (Dato-DXd, DS-1062a), with a potent DNA topoisomerase I inhibitor (DXd), and evaluated its antitumor activity and safety profiles in preclinical models.The pharmacologic activity and mechanism of action of Dato-DXd were investigated in several human cancer cell lines and xenograft mouse models including patient-derived xenograft (PDX) models. Safety profiles were also assessed in rats and cynomolgus monkeys.Dato-DXd bound specifically to TROP2 and was internalized into tumor cells followed by intracellular trafficking to lysosome and DXd release, which induced DNA damage and apoptosis in TROP2-expressing tumor cells . Dato-DXd exhibited antitumor activity with DNA damage induced by the accumulated DXd in TROP2-expressing xenograft tumors, but neither isotype control IgG-ADC nor anti-TROP2 antibody had this effect. Dato-DXd also showed potent antitumor activity with tumor regression in several TROP2-expressing xenograft tumors including NSCLC PDX models. Safety profiles of Dato-DXd in rats and cynomolgus monkeys were acceptable.Dato-DXd demonstrated potent antitumor activity against TROP2-expressing tumors by efficient payload delivery into tumors and acceptable safety profiles in preclinical models. These results suggest Dato-DXd could be a valuable treatment option for patients with TROP2-expressing tumors in the clinical setting.
Topics: Animals; Antineoplastic Agents; Drug Delivery Systems; Humans; Immunoconjugates; Macaca fascicularis; Male; Mice; Mice, Nude; Rats
PubMed: 34413126
DOI: 10.1158/1535-7163.MCT-21-0206 -
Molecules (Basel, Switzerland) Oct 2020Antibody-drug conjugates (ADCs) are novel drugs that exploit the specificity of a monoclonal antibody (mAb) to reach target antigens expressed on cancer cells for the... (Review)
Review
Antibody-drug conjugates (ADCs) are novel drugs that exploit the specificity of a monoclonal antibody (mAb) to reach target antigens expressed on cancer cells for the delivery of a potent cytotoxic payload. ADCs provide a unique opportunity to deliver drugs to tumor cells while minimizing toxicity to normal tissue, achieving wider therapeutic windows and enhanced pharmacokinetic/pharmacodynamic properties. To date, nine ADCs have been approved by the FDA and more than 80 ADCs are under clinical development worldwide. In this paper, we provide an overview of the biology and chemistry of each component of ADC design. We briefly discuss the clinical experience with approved ADCs and the various pathways involved in ADC resistance. We conclude with perspectives about the future development of the next generations of ADCs, including the role of molecular imaging in drug development.
Topics: Antibodies, Monoclonal; Antineoplastic Agents; Cell Proliferation; Humans; Immunoconjugates; Neoplasms
PubMed: 33081383
DOI: 10.3390/molecules25204764 -
CA: a Cancer Journal For Clinicians Mar 2022As distinct cancer biomarkers have been discovered in recent years, a need to reclassify tumors by more than their histology has been proposed, and therapies are now... (Review)
Review
As distinct cancer biomarkers have been discovered in recent years, a need to reclassify tumors by more than their histology has been proposed, and therapies are now tailored to treat cancers based on specific molecular aberrations and immunologic markers. In fact, multiple histology-agnostic therapies are currently adopted in clinical practice for treating patients regardless of their tumor site of origin. In parallel with this new model for drug development, in the past few years, several novel antibody-drug conjugates (ADCs) have been approved to treat solid tumors, benefiting from engineering improvements in the conjugation process and the introduction of novel linkers and payloads. With the recognition that numerous surface targets are expressed across various cancer histologies, alongside the remarkable activity of modern ADCs, this drug class has been increasingly evaluated as suitable for a histology-agnostic expansion of indication. For illustration, the anti-HER2 ADC trastuzumab deruxtecan has demonstrated compelling activity in HER2-overexpressing breast, gastric, colorectal, and lung cancer. Examples of additional novel and potentially histology-agnostic ADC targets include trophoblast cell-surface antigen 2 (Trop-2) and nectin-4, among others. In the current review article, the authors summarize the current approvals of ADCs by the US Food and Drug Administration focusing on solid tumors and discuss the challenges and opportunities posed by the multihistological expansion of ADCs.
Topics: Antineoplastic Agents; Humans; Immunoconjugates; Lung Neoplasms
PubMed: 34767258
DOI: 10.3322/caac.21705 -
Pharmacology & Therapeutics Jan 2022Antibody-drug conjugates (ADCs) are cancer therapeutic agents comprised of an antibody, a linker and a small-molecule payload. ADCs use the specificity of the antibody... (Review)
Review
Antibody-drug conjugates (ADCs) are cancer therapeutic agents comprised of an antibody, a linker and a small-molecule payload. ADCs use the specificity of the antibody to target the toxic payload to tumor cells. After intravenous administration, ADCs enter circulation, distribute to tumor tissues and bind to the tumor surface antigen. The antigen then undergoes endocytosis to internalize the ADC into tumor cells, where it is transported to lysosomes to release the payload. The released toxic payloads can induce apoptosis through DNA damage or microtubule inhibition and can kill surrounding cancer cells through the bystander effect. The first ADC drug was approved by the United States Food and Drug Administration (FDA) in 2000, but the following decade saw no new approved ADC drugs. From 2011 to 2018, four ADC drugs were approved, while in 2019 and 2020 five more ADCs entered the market. This demonstrates an increasing trend for the clinical development of ADCs. This review summarizes the recent clinical research, with a specific focus on how the in vivo processing of ADCs influences their design. We aim to provide comprehensive information about current ADCs to facilitate future development.
Topics: Antineoplastic Agents; Humans; Immunoconjugates; Neoplasms; United States; United States Food and Drug Administration
PubMed: 34171334
DOI: 10.1016/j.pharmthera.2021.107917 -
Nature Reviews. Clinical Oncology Jun 2021Nine different antibody-drug conjugates (ADCs) are currently approved as cancer treatments, with dozens more in preclinical and clinical development. The primary goal of... (Review)
Review
Nine different antibody-drug conjugates (ADCs) are currently approved as cancer treatments, with dozens more in preclinical and clinical development. The primary goal of ADCs is to improve the therapeutic index of antineoplastic agents by restricting their systemic delivery to cells that express the target antigen of interest. Advances in synthetic biochemistry have ushered in a new generation of ADCs, which promise to improve upon the tissue specificity and cytotoxicity of their predecessors. Many of these drugs have impressive activity against treatment-refractory cancers, although hurdles impeding their broader use remain, including systemic toxicity, inadequate biomarkers for patient selection, acquired resistance and unknown benefit in combination with other cancer therapies. Emerging evidence indicates that the efficacy of a given ADC depends on the intricacies of how the antibody, linker and payload components interact with the tumour and its microenvironment, all of which have important clinical implications. In this Review, we discuss the current state of knowledge regarding the design, mechanism of action and clinical efficacy of ADCs as well as the apparent limitations of this treatment class. We then propose a path forward by highlighting several hypotheses and novel strategies to maximize the potential benefit that ADCs can provide to patients with cancer.
Topics: Animals; Antineoplastic Agents, Immunological; Drug Resistance, Neoplasm; Humans; Immunoconjugates; Neoplasms; Patient Selection
PubMed: 33558752
DOI: 10.1038/s41571-021-00470-8 -
Protein & Cell Jan 2018The antibody-drug conjugate (ADC), a humanized or human monoclonal antibody conjugated with highly cytotoxic small molecules (payloads) through chemical linkers, is a... (Review)
Review
The antibody-drug conjugate (ADC), a humanized or human monoclonal antibody conjugated with highly cytotoxic small molecules (payloads) through chemical linkers, is a novel therapeutic format and has great potential to make a paradigm shift in cancer chemotherapy. This new antibody-based molecular platform enables selective delivery of a potent cytotoxic payload to target cancer cells, resulting in improved efficacy, reduced systemic toxicity, and preferable pharmacokinetics (PK)/pharmacodynamics (PD) and biodistribution compared to traditional chemotherapy. Boosted by the successes of FDA-approved Adcetris and Kadcyla, this drug class has been rapidly growing along with about 60 ADCs currently in clinical trials. In this article, we briefly review molecular aspects of each component (the antibody, payload, and linker) of ADCs, and then mainly discuss traditional and new technologies of the conjugation and linker chemistries for successful construction of clinically effective ADCs. Current efforts in the conjugation and linker chemistries will provide greater insights into molecular design and strategies for clinically effective ADCs from medicinal chemistry and pharmacology standpoints. The development of site-specific conjugation methodologies for constructing homogeneous ADCs is an especially promising path to improving ADC design, which will open the way for novel cancer therapeutics.
Topics: Amino Acids; Animals; Antibodies, Monoclonal; Antigens; Genetic Engineering; Humans; Immunoconjugates
PubMed: 27743348
DOI: 10.1007/s13238-016-0323-0 -
The Lancet. Oncology Jun 2016Antibody-drug conjugates are monoclonal antibodies conjugated to cytotoxic agents. They use antibodies that are specific to tumour cell-surface proteins and, thus, have... (Review)
Review
Antibody-drug conjugates are monoclonal antibodies conjugated to cytotoxic agents. They use antibodies that are specific to tumour cell-surface proteins and, thus, have tumour specificity and potency not achievable with traditional drugs. Design of effective antibody-drug conjugates for cancer therapy requires selection of an appropriate target, a monoclonal antibody against the target, potent cytotoxic effector molecules, and conjugation of the monoclonal antibody to cytotoxic agents. Substantial advances in all these aspects in the past decade have resulted in regulatory approval of ado-trastuzumab emtansine and brentuximab vedotin for clinical use. Several promising antibody-drug conjugates are now in late-phase clinical testing. Ongoing efforts are focused on identifying better targets, more effective cytotoxic payloads, and further improvements in antibody-drug linker technology. Improved understanding of the mechanistic basis of antibody-drug conjugate activity will enable design of rational combination therapies with other agents, including immunotherapy.
Topics: Antibodies, Monoclonal; Humans; Immunoconjugates; Neoplasms
PubMed: 27299281
DOI: 10.1016/S1470-2045(16)30030-4 -
Trends in Cancer Apr 2023Antibody-drug conjugates (ADCs) have become a credentialled class of anticancer drugs for both solid and hematological malignancies, with regulatory approvals mainly as... (Review)
Review
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 and clinical efforts to develop rational ADC-based combinations, to date only a limited number have demonstrated survival improvements over standard of care. The most appealing partners for ADCs are those that offer additive or synergistic effects on tumor cells or their microenvironment without unacceptable overlapping toxicities. Coadministration with antiangiogenic compounds, HER2-targeting drugs, DNA-damage response agents and immune checkpoint inhibitors (ICIs) represent active forerunners. Through the identification of targets with tumor-specific expression, improved conjugation technologies, and novel linkers and payloads offering superior therapeutic indices, the next generation of ADCs brings optimism to combinatorial approaches.
Topics: Humans; Immunoconjugates; Antineoplastic Agents; Neoplasms; Tumor Microenvironment
PubMed: 36746689
DOI: 10.1016/j.trecan.2023.01.003