scholarly journals Antibody-Drug Conjugates: The New Frontier of Chemotherapy

2020 ◽  
Vol 21 (15) ◽  
pp. 5510 ◽  
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.

scholarly journals An overview of antibody–drug conjugates in oncological practice

2020 ◽  
Vol 12 ◽  
pp. 175883592096299
Author(s):  
Charalampos Theocharopoulos ◽  
Panagiotis-Petros Lialios ◽  
Helen Gogas ◽  
Dimitrios C. Ziogas
Keyword(s):  
First Generation ◽  
Cancer Therapeutics ◽  
Therapeutic Index ◽  
General Tendency ◽  
Antibody Drug Conjugates ◽  
Therapeutic Modalities ◽  
Drug Conjugates ◽  
The Us ◽  
Oncological Practice ◽  
Antibody Drug

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.

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

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.

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

Antibodies ◽  
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.

scholarly journals Antibody–Drug Conjugates for the Treatment of Breast Cancer

Cancers ◽  
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.

scholarly journals Correction: Verkade, J.M.M.; et al. A Polar Sulfamide Spacer Significantly Enhances the Manufacturability, Stability, and Therapeutic Index of Antibody–Drug Conjugates. Antibodies 2018, 7, 12

Antibodies ◽  
2018 ◽  
Vol 7 (3) ◽  
pp. 34 ◽  
Author(s):  
Jorge Verkade ◽  
Marloes Wijdeven ◽  
Remon van Geel ◽  
Brian Janssen ◽  
Sander van Berkel ◽  
...  
Keyword(s):  
Conflict Of Interest ◽  
Therapeutic Index ◽  
Antibody Drug Conjugates ◽  
Drug Conjugates ◽  
Interest Section ◽  
Published Paper ◽  
Antibody Drug

The conflict of interest section of the published paper [1] has been updated as follows[...]

scholarly journals Challenges and opportunities to develop enediyne natural products as payloads for antibody-drug conjugates

2021 ◽  
Vol 4 (1) ◽  
pp. 1-15
Author(s):  
Ajeeth Adhikari ◽  
Ben Shen ◽  
Christoph Rader
Keyword(s):  
Natural Products ◽  
First Generation ◽  
Gemtuzumab Ozogamicin ◽  
Antibody Drug Conjugates ◽  
Clinical Utilization ◽  
Drug Conjugates ◽  
Dna Damaging Agents ◽  
Challenges And Opportunities ◽  
Antibody Drug

Abstract Calicheamicin, the payload of the antibody-drug-conjugates (ADCs) gemtuzumab ozogamicin (Mylotarg®) and inotuzumab ozogamicin (Besponsa®), belongs to the class of enediyne natural products. Since the isolation and structural determination of the neocarzinostatin chromophore in 1985, the enediynes have attracted considerable attention for their value as DNA damaging agents in cancer chemotherapy. Due to their non-discriminatory cytotoxicity towards both cancer and healthy cells, the clinical utilization of enediyne natural products relies on conjugation to an appropriate delivery system, such as an antibody. Here, we review the current landscape of enediynes as payloads of first-generation and next-generation ADCs.

scholarly journals Advances and Limitations of Antibody Drug Conjugates for Cancer

Biomedicines ◽  
2021 ◽  
Vol 9 (8) ◽  
pp. 872
Author(s):  
Candice Maria Mckertish ◽  
Veysel Kayser
Keyword(s):  
Therapeutic Index ◽  
Narrow Therapeutic Index ◽  
Antibody Drug Conjugates ◽  
Drug Conjugates ◽  
The Stability ◽  
Drug Antibody Ratio ◽  
Chemotherapy Agents ◽  
The Impact ◽  
Antibody Ratio ◽  
Antibody Drug

The popularity of antibody drug conjugates (ADCs) has increased in recent years, mainly due to their unrivalled efficacy and specificity over chemotherapy agents. The success of the ADC is partly based on the stability and successful cleavage of selective linkers for the delivery of the payload. The current research focuses on overcoming intrinsic shortcomings that impact the successful development of ADCs. This review summarizes marketed and recently approved ADCs, compares the features of various linker designs and payloads commonly used for ADC conjugation, and outlines cancer specific ADCs that are currently in late-stage clinical trials for the treatment of cancer. In addition, it addresses the issues surrounding drug resistance and strategies to overcome resistance, the impact of a narrow therapeutic index on treatment outcomes, the impact of drug–antibody ratio (DAR) and hydrophobicity on ADC clearance and protein aggregation.

Sign in / Sign up

Export Citation Format

Share Document