An overview of antibody–drug conjugates in oncological practice

Antibody–drug conjugates (ADCs) are designed to manipulate the toxic efficacy of specific chemotherapeutic compounds, employing the high affinity of antibody-mediated delivery so as to drive them selectively to target cancer cells. These immunoconjugates encompass the general tendency towards precision medicine and avert the systemic toxicities of conventional chemotherapy, accomplishing an improved therapeutic index. Cumulative experience acquired from first-generation ADCs offers new perspectives to these promising therapeutic modalities for various hematological and solid cancers and propels their clinical development in a faster-than-ever pace, as indicated by the approval of four novel ADCs during the last year. This paper aims to provide an up-to-date overview of the eight ADCs approved by the US Food and Drug Administration and their current indications in oncological practice. Starting from their bio-pharmaceutical background, we track their clinical evolution, with an emphasis on the pivotal trials that led to their commercial release. Late-stage studies examining these eight ADCs in other-than-approved settings as well as the investigation of potential new candidates are also reviewed. In the close future, more data are expected to expand ADCs’ oncological utility and to further reshape their role in cancer therapeutics.

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Antibody-Drug Conjugates: The New Frontier of Chemotherapy

International Journal of Molecular Sciences ◽

10.3390/ijms21155510 ◽

2020 ◽

Vol 21 (15) ◽

pp. 5510 ◽

Cited By ~ 3

Author(s):

Sara Ponziani ◽

Giulia Di Vittorio ◽

Giuseppina Pitari ◽

Anna Maria Cimini ◽

Matteo Ardini ◽

...

Keyword(s):

First Generation ◽

Antitumor Agents ◽

Therapeutic Index ◽

European Medicines Agency ◽

Antibody Drug Conjugates ◽

Drug Conjugates ◽

Recent Developments ◽

Random Coupling ◽

Personalized Cancer ◽

Antibody Drug

In recent years, antibody-drug conjugates (ADCs) have become promising antitumor agents to be used as one of the tools in personalized cancer medicine. ADCs are comprised of a drug with cytotoxic activity cross-linked to a monoclonal antibody, targeting antigens expressed at higher levels on tumor cells than on normal cells. By providing a selective targeting mechanism for cytotoxic drugs, ADCs improve the therapeutic index in clinical practice. In this review, the chemistry of ADC linker conjugation together with strategies adopted to improve antibody tolerability (by reducing antigenicity) are examined, with particular attention to ADCs approved by the regulatory agencies (the U.S. Food and Drug Administration (FDA) and the European Medicines Agency (EMA)) for treating cancer patients. Recent developments in engineering Immunoglobulin (Ig) genes and antibody humanization have greatly reduced some of the problems of the first generation of ADCs, beset by problems, such as random coupling of the payload and immunogenicity of the antibody. ADC development and clinical use is a fast, evolving area, and will likely prove an important modality for the treatment of cancer in the near future.

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Antibody-drug conjugates for the treatment of lymphoma: clinical advances and latest progress

Journal of Hematology & Oncology ◽

10.1186/s13045-021-01097-z ◽

2021 ◽

Vol 14 (1) ◽

Author(s):

Yurou Chu ◽

Xiangxiang Zhou ◽

Xin Wang

Keyword(s):

Therapeutic Index ◽

Essential Elements ◽

Brentuximab Vedotin ◽

Efficacy And Safety ◽

Antibody Drug Conjugates ◽

Drug Conjugates ◽

Lymphoma Treatment ◽

Novel Targets ◽

Clinical Advances ◽

Antibody Drug

AbstractAntibody-drug conjugates (ADCs) are a promising class of immunotherapies with the potential to specifically target tumor cells and ameliorate the therapeutic index of cytotoxic drugs. ADCs comprise monoclonal antibodies, cytotoxic payloads with inherent antitumor activity, and specialized linkers connecting the two. In recent years, three ADCs, brentuximab vedotin, polatuzumab vedotin, and loncastuximab tesirine, have been approved and are already establishing their place in lymphoma treatment. As the efficacy and safety of ADCs have moved in synchrony with advances in their design, a plethora of novel ADCs have garnered growing interest as treatments. In this review, we provide an overview of the essential elements of ADC strategies in lymphoma and elucidate the up-to-date progress, current challenges, and novel targets of ADCs in this rapidly evolving field.

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Importance and Considerations of Antibody Engineering in Antibody-Drug Conjugates Development from a Clinical Pharmacologist’s Perspective

Antibodies ◽

10.3390/antib10030030 ◽

2021 ◽

Vol 10 (3) ◽

pp. 30

Author(s):

Andrew T. Lucas ◽

Amber Moody ◽

Allison N. Schorzman ◽

William C. Zamboni

Keyword(s):

Immune System ◽

Market Value ◽

Therapeutic Index ◽

Drug Carriers ◽

Antibody Engineering ◽

Antibody Drug Conjugates ◽

Success Stories ◽

Drug Conjugates ◽

Early Success ◽

Antibody Drug

Antibody-drug conjugates (ADCs) appear to be in a developmental boom, with five FDA approvals in the last two years and a projected market value of over $4 billion by 2024. Major advancements in the engineering of these novel cytotoxic drug carriers have provided a few early success stories. Although the use of these immunoconjugate agents are still in their infancy, valuable lessons in the engineering of these agents have been learned from both preclinical and clinical failures. It is essential to appreciate how the various mechanisms used to engineer changes in ADCs can alter the complex pharmacology of these agents and allow the ADCs to navigate the modern-day therapeutic challenges within oncology. This review provides a global overview of ADC characteristics which can be engineered to alter the interaction with the immune system, pharmacokinetic and pharmacodynamic profiles, and therapeutic index of ADCs. In addition, this review will highlight some of the engineering approaches being explored in the creation of the next generation of ADCs.

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Antibody–Drug Conjugates for the Treatment of Breast Cancer

Cancers ◽

10.3390/cancers13122898 ◽

2021 ◽

Vol 13 (12) ◽

pp. 2898

Author(s):

Chiara Corti ◽

Federica Giugliano ◽

Eleonora Nicolò ◽

Liliana Ascione ◽

Giuseppe Curigliano

Keyword(s):

Breast Cancer ◽

Bystander Effect ◽

Metastatic Breast ◽

Therapeutic Index ◽

Cytotoxic Agents ◽

Target Antigen ◽

Her2 Positive ◽

Antibody Drug Conjugates ◽

Drug Conjugates ◽

Antibody Drug

Metastatic breast cancer (BC) is currently an incurable disease. Besides endocrine therapy and targeted agents, chemotherapy is often used in the treatment of this disease. However, lack of tumor specificity and toxicity associated with dose exposure limit the manageability of cytotoxic agents. Antibody–drug conjugates (ADCs) are a relatively new class of anticancer drugs. By merging the selectivity of monoclonal antibodies with the cytotoxic properties of chemotherapy, they improve the therapeutic index of antineoplastic agents. Three core components characterize ADCs: the antibody, directed to a target antigen; the payload, typically a cytotoxic agent; a linker, connecting the antibody to the payload. The most studied target antigen is HER2 with some agents, such as trastuzumab deruxtecan, showing activity not only in HER2-positive, but also in HER2-low BC patients, possibly due to a bystander effect. This property to provide a cytotoxic impact also against off-target cancer cells may overcome the intratumoral heterogeneity of some target antigens. Other cancer-associated antigens represent a strategy for the development of ADCs against triple-negative BC, as shown by the recent approval of sacituzumab govitecan. In this review, we discuss the current landscape of ADC development for the treatment of BC, as well as the possible limitations of this treatment.

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Antibody-drug conjugates, immune-checkpoint inhibitors, and their combination in breast cancer therapeutics

Expert Opinion on Biological Therapy ◽

10.1080/14712598.2021.1936494 ◽

2021 ◽

Author(s):

Kamal S Saini ◽

Kevin Punie ◽

Chris Twelves ◽

Stefanella Bortini ◽

Evandro de Azambuja ◽

...

Keyword(s):

Breast Cancer ◽

Immune Checkpoint ◽

Immune Checkpoint Inhibitors ◽

Checkpoint Inhibitors ◽

Cancer Therapeutics ◽

Antibody Drug Conjugates ◽

Drug Conjugates ◽

Antibody Drug

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Application of Native Ion Exchange Mass Spectrometry to Intact and Subunit Analysis of Site-Specific Antibody–Drug Conjugates Produced by AJICAP First Generation Technology

Journal of the American Society for Mass Spectrometry ◽

10.1021/jasms.0c00129 ◽

2020 ◽

Vol 31 (8) ◽

pp. 1706-1712 ◽

Cited By ~ 2

Author(s):

Yutaka Matsuda ◽

Michal Kliman ◽

Brian A. Mendelsohn

Keyword(s):

Mass Spectrometry ◽

Ion Exchange ◽

Specific Antibody ◽

First Generation ◽

Site Specific ◽

Antibody Drug Conjugates ◽

Exchange Mass Spectrometry ◽

Drug Conjugates ◽

Generation Technology ◽

Antibody Drug

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The Pharmaceutical Industry in 2019. An Analysis of FDA Drug Approvals from the Perspective of Molecules

Molecules ◽

10.3390/molecules25030745 ◽

2020 ◽

Vol 25 (3) ◽

pp. 745 ◽

Cited By ~ 23

Author(s):

Beatriz G. de la Torre ◽

Fernando Albericio

Keyword(s):

Natural Products ◽

Pharmaceutical Industry ◽

Small Molecules ◽

Chemical Structure ◽

New Drugs ◽

Antibody Drug Conjugates ◽

Drug Conjugates ◽

The Us ◽

New Chemical Entities ◽

Antibody Drug

During 2019, the US Food and Drug Administration (FDA) approved 48 new drugs (38 New Chemical Entities and 10 Biologics). Although this figure is slightly lower than that registered in 2018 (59 divided between 42 New Chemical Entities and 17 Biologics), a year that broke a record with respect to new drugs approved by this agency, it builds on the trend initiated in 2017, when 46 drugs were approved. Of note, three antibody drug conjugates, three peptides, and two oligonucleotides were approved in 2019. This report analyzes the 48 new drugs of the class of 2019 from a strictly chemical perspective. The classification, which was carried out on the basis of chemical structure, includes the following: Biologics (antibody drug conjugates, antibodies, and proteins); TIDES (peptide and oligonucleotides); drug combinations; natural products; and small molecules.

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