Antibody–Drug Conjugates: An Emerging Concept in Cancer Therapy

Chari, Ravi V. J.; Miller, Michael L.; Widdison, Wayne C.

doi:10.1002/anie.201307628

Cited by 930Monoclonal and Polyclonal Antibodies ResearchToxin Mechanisms and ImmunotoxinsRadiopharmaceutical Chemistry and Applications

Antibody–Drug Conjugates: An Emerging Concept in Cancer Therapy

Chari, Ravi V. J., Miller, Michael L., Widdison, Wayne C.·2014·Angewandte Chemie International Edition

DOI 10.1002/anie.201307628

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Abstract

Traditional cancer chemotherapy is often accompanied by systemic toxicity to the patient. Monoclonal antibodies against antigens on cancer cells offer an alternative tumor‐selective treatment approach. However, most monoclonal antibodies are not sufficiently potent to be therapeutically active on their own. Antibody–drug conjugates (ADCs) use antibodies to deliver a potent cytotoxic compound selectively to tumor cells, thus improving the therapeutic index of chemotherapeutic agents. The recent approval of two ADCs, brentuximab vedotin and ado‐trastuzumab emtansine, for cancer treatment has spurred tremendous research interest in this field. This Review touches upon the early efforts in the field, and describes how the lessons learned from the first‐generation ADCs have led to improvements in every aspect of this technology, i.e., the antibody, the cytotoxic compound, and the linker connecting them, leading to the current successes. The design of ADCs currently in clinical development, and results from mechanistic studies and preclinical and clinical evaluation are discussed. Emerging technologies that seek to further advance this exciting area of research are also discussed.

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ADCs bind to cell surface receptors that are upregulated by mutant RAS.
“They bind to cell surface receptors that are upregulated by mutant RAS and exhibit potent antitumor activity, demonstrating their efficacy in targeting undruggable proteins outside the cell.645–649”
From Recent advances in targeting the “undruggable” proteins: from drug discovery to clinical trials (2023) · cites this paper as [645]
ADCs demonstrate efficacy in targeting undruggable proteins outside the cell.
“They bind to cell surface receptors that are upregulated by mutant RAS and exhibit potent antitumor activity, demonstrating their efficacy in targeting undruggable proteins outside the cell.645–649”
From Recent advances in targeting the “undruggable” proteins: from drug discovery to clinical trials (2023) · cites this paper as [645]
ADCs exhibit potent antitumor activity.
“They bind to cell surface receptors that are upregulated by mutant RAS and exhibit potent antitumor activity, demonstrating their efficacy in targeting undruggable proteins outside the cell.645–649”
From Recent advances in targeting the “undruggable” proteins: from drug discovery to clinical trials (2023) · cites this paper as [645]

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A BRIEF HISTORY OF CANCER CHEMOTHERAPY
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Self-citation
Abstract B126: Potent antigen-specific anti-tumor activity observed with antibody-drug conjugates (ADCs) made using a new class of DNA-crosslinking agents
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Self-citation
Abstract 4331: Advantages of polyacetal polymer-based antibody drug conjugates employing cysteine bioconjugation.
Yurkovetskiy, A., Bodyak, N. D., Yin, M., et al. (2013) · Cancer Research · doi:10.1158/1538-7445.am2013-4331 · Cited by 4 · see citing works
Abstract 4329: Novel HER2 targeting antibody-drug conjugates based on DNA-interacting duocarmycin and an unique linker technology with great potential in breast cancer and NSCLC.
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Strategies and challenges for the next generation of antibody–drug conjugates
Beck, A., Goetsch, L., Dumontet, C., & Corvaïa, N. (2017) · Nature Reviews Drug Discovery · doi:10.1038/nrd.2016.268 · Cited by 2,271 · see citing works
Recent advances in targeting the “undruggable” proteins: from drug discovery to clinical trials
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Antibody–Drug Conjugates (ADCs) for Personalized Treatment of Solid Tumors: A Review
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Antibody Conjugation of a Chimeric BET Degrader Enables <i>in vivo</i> Activity
Pillow, T. H., Adhikari, P., Blake, R. A., Chen, J., Del Rosario, G., Deshmukh, G., Figueroa, I., Gascoigne, K. E., Kamath, A. V., Kaufman, S., et al. (2020) · ChemMedChem · doi:10.1002/cmdc.201900497 · Cited by 216 · see citing works
Antibody-Mediated Delivery of Chimeric BRD4 Degraders. Part 2: Improvement of In Vitro Antiproliferation Activity and In Vivo Antitumor Efficacy
Dragovich, P. S., Pillow, T. H., Blake, R. A., Sadowsky, J. D., Adaligil, E., Adhikari, P., Chen, J., Corr, N., dela Cruz-Chuh, J., Del Rosario, G., et al. (2021) · Journal of Medicinal Chemistry · doi:10.1021/acs.jmedchem.0c01846 · Cited by 174 · see citing works
Antibody-Mediated Delivery of Chimeric BRD4 Degraders. Part 1: Exploration of Antibody Linker, Payload Loading, and Payload Molecular Properties
Dragovich, P. S., Pillow, T. H., Blake, R. A., Sadowsky, J. D., Adaligil, E., Adhikari, P., Bhakta, S., Blaquiere, N., Chen, J., dela Cruz-Chuh, J., et al. (2021) · Journal of Medicinal Chemistry · doi:10.1021/acs.jmedchem.0c01845 · Cited by 152 · see citing works
Targeted clearance of senescent cells using an antibody-drug conjugate against a specific membrane marker
Poblocka, M., Bassey, A. L., Smith, V. M., Falcicchio, M., Manso, A. S., Althubiti, M., Sheng, X., Kyle, A., Barber, R., Frigerio, M., et al. (2021) · Scientific Reports · doi:10.1038/s41598-021-99852-2 · Cited by 137 · see citing works
Antibody-mediated delivery of chimeric protein degraders which target estrogen receptor alpha (ERα)
Dragovich, P. S., Adhikari, P., Blake, R. A., Blaquiere, N., Chen, J., Cheng, Y.-X., den Besten, W., Han, J., Hartman, S. J., He, J., et al. (2020) · Bioorganic & Medicinal Chemistry Letters · doi:10.1016/j.bmcl.2019.126907 · Cited by 120 · see citing works
A non-internalizing antibody-drug conjugate based on an anthracycline payload displays potent therapeutic activity in vivo
Dal Corso, A., Gébleux, R., Murer, P., Soltermann, A., & Neri, D. (2017) · Journal of Controlled Release · doi:10.1016/j.jconrel.2017.08.040 · Cited by 75 · see citing works
Importance and Considerations of Antibody Engineering in Antibody-Drug Conjugates Development from a Clinical Pharmacologist’s Perspective
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Middle-Down Multi-Attribute Analysis of Antibody-Drug Conjugates with Electron Transfer Dissociation
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Authors: Chari, R. V. J., Miller, M. L., & Widdison, W. C.
Affiliations: ImmunoGen (United States) (US)
Corresponding author: Chari, Ravi V. J.
ORCID: Chari, Ravi V. J.
Miller, Michael L.
Widdison, Wayne C.
Venue: Angewandte Chemie International Edition
Publisher: Wiley
Published: 2014-02-20
Volume: 53
Issue: 15
Pages: 3796-3827
ISSN: 1433-7851 (ISSN-L)
1521-3773
DOI: 10.1002/anie.201307628
OpenAlex: W2165168809
Cited by: 930
References: 150
Citations by year: 2026: 38 · 2025: 45 · 2024: 47 · 2023: 68 · 2022: 44 · 2021: 78 · 2020: 82 · 2019: 112 · 2018: 96 · 2017: 97 · 2016: 113 · 2015: 74 · 2014: 36
FWCI: 16.59
Type: journal article
Language: en
Open access: closed
Licence: onlinelibrary.wiley.com/termsAndConditions#vor (vor)
Locations: Angewandte Chemie International Edition (publishedVersion)
PubMed (publishedVersion)
Topics: Health Sciences › Medicine › Radiology, Nuclear Medicine and Imaging › Monoclonal and Polyclonal Antibodies Research
Life Sciences › Immunology and Microbiology › Immunology › Toxin Mechanisms and Immunotoxins
Health Sciences › Medicine › Radiology, Nuclear Medicine and Imaging › Radiopharmaceutical Chemistry and Applications
Keywords: antibody-drug conjugates, targeted cancer therapy, monoclonal antibodies, cytotoxic payloads, chemical linkers, brentuximab vedotin, trastuzumab emtansine, therapeutic index, ADC design
MeSH terms: Antibodies, Monoclonal, Antineoplastic Agents, Humans, Neoplasms

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Antibody–Drug Conjugates: An Emerging Concept in Cancer Therapy

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