Catalytic Cleavage of Disulfide Bonds in Small Molecules and Linkers of Antibody–Drug Conjugates

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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Perspectives on the development of antibody-drug conjugates targeting ROR1 for hematological and solid cancers

Antibody Therapeutics ◽

10.1093/abt/tbab023 ◽

2021 ◽

Author(s):

Haiyong Peng

Keyword(s):

Cancer Therapy ◽

Small Molecules ◽

Pharmaceutical Companies ◽

Antibody Drug Conjugates ◽

Drug Conjugates ◽

Solid Malignancies ◽

Selective Delivery ◽

And Performance ◽

Antibody Drug ◽

Made In

Abstract Antibody–drug conjugates (ADCs) are targeted therapeutics generated by conjugation of cytotoxic small molecules to monoclonal antibodies (mAbs) via chemical linkers. Due to their selective delivery of toxic payloads to antigen-positive cancer cells, ADCs demonstrate wider therapeutic indexes compared to conventional chemotherapy. After decades of intensive research and development, significant advances have been made in the field, leading to a total of ten FDA-approved ADCs to treat cancer patients. Currently, ~ 80 ADCs targeting different antigens are under clinical evaluation for treatment of either hematological or solid malignancies. Notably, 3 ADCs targeting the same oncofetal protein, ROR1, have attracted considerable attention when they were acquired or licensed successively in the fourth quarter of 2020 by 3 major pharmaceutical companies. Apparently, ROR1 has emerged as an attractive target for cancer therapy. Since all the components of ADCs, including the antibody, linker, and payload, as well as the conjugation method, play critical roles in ADC’s efficacy and performance, their choice and combination will determine how far they can be advanced. This review summarizes the design and development of current anti-ROR1 ADCs and highlights an emerging trend to target ROR1 for cancer therapy.

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The Pharmaceutical Industry in 2020. An Analysis of FDA Drug Approvals from the Perspective of Molecules

Molecules ◽

10.3390/molecules26030627 ◽

2021 ◽

Vol 26 (3) ◽

pp. 627 ◽

Cited By ~ 1

Author(s):

Beatriz G. de la Torre ◽

Fernando Albericio

Keyword(s):

Pharmaceutical Industry ◽

Small Molecules ◽

New Drugs ◽

Biologic Drugs ◽

Antibody Drug Conjugates ◽

Aromatic Heterocycles ◽

Drug Conjugates ◽

New Chemical Entities ◽

Pharmaceutical Agents ◽

Antibody Drug

Although the pharmaceutical industry will remember 2020 as the year of COVID-19, it is important to highlight that this year has been the second-best—together with 1996—in terms of the number of drugs accepted by the US Food and Drug Administration (FDA). Each of these two years witnessed the authorization of 53 drugs—a number surpassed only in 2018 with 59 pharmaceutical agents. The 53 approvals in 2020 are divided between 40 new chemical entities and 13 biologic drugs (biologics). Of note, ten monoclonal antibodies, two antibody–drug conjugates, three peptides, and two oligonucleotides have been approved in 2020. Close inspection of the so-called small molecules reveals the significant presence of fluorine atoms and/or nitrogen aromatic heterocycles. This report analyzes the 53 new drugs of the 2020 harvest from a strictly chemical perspective, as it did for those authorized in the previous four years. On the basis of chemical structure alone, the drugs that received approval in 2020 are classified as the following: biologics (antibodies, antibody-drug conjugates, and proteins); TIDES (peptide and oligonucleotides); natural products; fluorine-containing molecules; nitrogen aromatic heterocycles; and other small molecules.

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Next generation maleimides enable the controlled assembly of antibody–drug conjugates via native disulfide bond bridging

Organic & Biomolecular Chemistry ◽

10.1039/c4ob01550a ◽

2014 ◽

Vol 12 (37) ◽

pp. 7261-7269 ◽

Cited By ~ 93

Author(s):

Felix F. Schumacher ◽

João P. M. Nunes ◽

Antoine Maruani ◽

Vijay Chudasama ◽

Mark E. B. Smith ◽

...

Keyword(s):

Disulfide Bond ◽

Disulfide Bonds ◽

Next Generation ◽

Antibody Drug Conjugates ◽

Controlled Assembly ◽

Drug Conjugates ◽

Antibody Drug

Highly homogeneous ADCs are generated by the efficient bridging of interchain disulfide bonds in trastuzumab, using next generation maleimides.

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ASCO-GU 2019: Metastasierte Urothelkarzinome

Onkologische Welt ◽

10.1055/a-0869-6415 ◽

2019 ◽

Vol 10 (03) ◽

pp. 140-141

Author(s):

Alexander Kretzschmar

Keyword(s):

San Francisco ◽

Antibody Drug Conjugates ◽

Drug Conjugates ◽

Chapel Hill ◽

Antibody Drug

Die Therapielandschaft des metastasierten Urothelkarzinoms hat sich seit der Zulassung der ersten Immun-Checkpoint-Inhibitoren verändert. Die neuen Therapien sind deutlich effektiver, allerdings erreichen die Responseraten der neuen Therapien nur bis zu etwa 30 %, beklagte Prof. Matthew Milowsky, Chapel Hill/USA, auf einer Oral Abstract Session auf dem ASCO-GU. In San Francisco gaben erste Vorträge und Poster bereits einen Einblick, wovon diejenigen Patienten profitieren könnten, die auf die etablierten Chemotherapien und die neuen Immuntherapien nicht ansprechen. Manche Onkologen sprechen bereits von der „Post-Checkpoint-Ära”. Als Kandidaten werden vor allem Antikörper-Wirkstoff-Konjugate (antibody-drug conjugates; ADC) gehandelt – und zwar nicht nur zur Therapie des metastasierten Blasenkarzinoms.

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