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

Molecules ◽  
2020 ◽  
Vol 25 (3) ◽  
pp. 745 ◽  
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.

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 DNA damaging agent-based antibody-drug conjugates for cancer therapy

2018 ◽  
Vol 1 (2) ◽  
pp. 43-53 ◽  
Author(s):  
Ying Fu ◽  
Mitchell Ho
Keyword(s):  
Cancer Therapy ◽  
Cancer Therapeutics ◽  
Future Directions ◽  
Agent Based ◽  
Antibody Drug Conjugates ◽  
Microtubule Inhibitors ◽  
Drug Conjugates ◽  
Dna Damaging Agents ◽  
Further Development ◽  
Antibody Drug

ABSTRACT Currently, four antibody-drug conjugates (ADCs) are approved by the Food and Drug Administration or the European Medicine Agency to treat cancer patients. More than 60 ADCs are in clinical development for cancer therapy. More than 60% of ADCs in clinical trials employ microtubule inhibitors as their payloads. A better understanding of payloads other than microtubule inhibitors, especially DNA-damaging agents, is important for further development of ADCs. In this review, we highlight an emerging trend of using DNA-damaging agents as payloads for ADCs. This review summarizes recent advances in our understanding gained from ongoing clinical studies; it will help to define the utility of DNA-damaging payloads for ADCs as cancer therapeutics. Future directions of the development of ADCs are also discussed, focusing on targeting drug resistance and combination treatment with immunotherapy.

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 MALDI-MS: a Rapid and Reliable Method for Drug-to-Antibody Ratio Determination of Antibody-Drug Conjugates

2019 ◽  
Vol 23 (6) ◽  
pp. 395-403
Author(s):  
Mehri Abedi ◽  
Reza Ahangari Cohan ◽  
Fereidoun Mahboudi ◽  
Mehdi Shafiee Ardestani ◽  
Fatemeh Davami ◽  
...  
Keyword(s):  
Reliable Method ◽  
Maldi Ms ◽  
Antibody Drug Conjugates ◽  
Drug Conjugates ◽  
Ratio Determination ◽  
Antibody Ratio ◽  
Antibody Drug
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