Review
Biotechnology & Applied Microbiology
John A. Hartley
Summary: Reviewing the clinical efficacy and safety data from almost forty clinical trials of PBD dimer-containing ADCs highlights the complexities and challenges of ADC early clinical development. It enables some conclusions to be made about reasons for failure and suggests strategies to optimize the future clinical development of this promising class of ADCs in a rapidly expanding field.
EXPERT OPINION ON BIOLOGICAL THERAPY
(2021)
Article
Chemistry, Medicinal
Joshua D. Thomas, Aleksandr Yurkovetskiy, Mao Yin, Natalya D. Bodyak, Dmitry R. Gumerov, Shuyi Tang, Eoin Kelleher, Brian D. Jones, Marina Protopopova, LiuLiang Qin, Alex Uttard, Damon R. Demady, Timothy B. Lowinger
Summary: Pyrrolobenzodiazepine (PBD) polyamide hybrids can serve as effective antibody drug conjugate (ADC) payloads and suppress tumor growth.
BIOORGANIC & MEDICINAL CHEMISTRY LETTERS
(2022)
Article
Pharmacology & Pharmacy
Kai H. Liao, Jason H. Williams, Santhosh Palani, Donghua Yin, Xu Meng
Summary: This study describes the use of three joint disposition metrics (JDMs) for integrated pharmacokinetic (PK) analysis of antibody-drug conjugates (ADCs). These JDMs offer an effective approach for comparing ADCs in terms of favorable PK characteristics by comparing the ratio of appropriate PK parameters of ADC components, and their utility is demonstrated in both clinical candidates and FDA-approved ADCs.
Article
Chemistry, Applied
Dane Holte, Meera Rao, Alexander Huters, Justin Simanis, Jean-Christophe Califano, Aaron Kempema, Jean-Noel Levy
Summary: SG3259 is a fully synthetic small molecule with high potency but poor solubility, currently being developed as a warhead for antibody-drug conjugates. The synthesis route is complex and requires a large amount of drug for research and clinical trials.
ORGANIC PROCESS RESEARCH & DEVELOPMENT
(2021)
Article
Chemistry, Analytical
Florian Fussl, Conor S. Barry, Kathryn M. Pugh, K. Phin Chooi, Balakumar Vijayakrishnan, Gyoung-Dong Kang, Christina von Bulow, Philip W. Howard, Jonathan Bones
Summary: ADCs are a promising class of oncology treatments combining monoclonal antibodies' specificity with small molecule compounds' cytotoxic properties. Monitoring the structure and quality of these toxic molecules is crucial, and SEC-MS method provides a reliable and efficient way to characterize ADCs.
JOURNAL OF PHARMACEUTICAL AND BIOMEDICAL ANALYSIS
(2021)
Review
Chemistry, Medicinal
Ivan Cheng-Sanchez, Federico Moya-Utrera, Cristina Porras-Alcala, Juan M. Lopez-Romero, Francisco Sarabia
Summary: Antibody-drug conjugates (ADCs) are an important class of therapeutics for cancer treatment, combining the selective targeting properties of antibodies with the cytotoxicity of payload drugs to reduce off-target toxicities in patients, resulting in high specificity and potency.
Article
Chemistry, Multidisciplinary
Katja E. Grier, Anders H. Hansen, Christina S. Haxvig, Xin Li, Oliver Krigslund, Niels Behrendt, Lars H. Engelholm, Fabio Rossi, Bebiana C. Sousa, Grant J. Harradence, Nicolas Camper, Katrine M. Qvortrup
Summary: This study describes the targeted release of alcohol-containing payloads in antibody-drug conjugates (ADCs) using a sulfatase-sensitive linker. The linker exhibits efficient sulfatase-mediated release and high stability in human and mouse plasma. In vitro evaluation demonstrates potent antigen-dependent toxicity towards breast cancer cell lines.
CHEMICAL COMMUNICATIONS
(2023)
Article
Biochemistry & Molecular Biology
Qiyu Li, Wenjing Li, Keyuan Xu, Yutong Xing, Haobo Shi, Zhe Jing, Shuang Li, Zhangyong Hong
Summary: This study proposed a novel design strategy for miniaturized ADCs by site-specific coupling drug molecules and small ligand proteins via a bifunctional poly(ethylene glycol) (PEG) chain, significantly prolonging the circulation half-life while reducing the cytotoxicity of the conjugates. The results indicated that prolonging the half-life is very helpful in improving the therapeutic capacity of miniaturized ADCs.
INTERNATIONAL JOURNAL OF MOLECULAR SCIENCES
(2021)
Article
Chemistry, Applied
Stefan G. Koenig, Remy Angelaud, Christopher M. Crittenden, Kenji Kurita, David J. Russell, Jean-Francois Marcoux, Thomas Matt, Francis Gosselin
Summary: In this study, the synthetic strategies for two distinct but related linker-toxins were reconfigured to establish an efficient and unified supply chain. The streamlined approach avoided challenging desymmetrization efforts and reduced the need for multiple chromatographic purifications, resulting in robust synthetic processes for both compounds 1 and 2.
ORGANIC PROCESS RESEARCH & DEVELOPMENT
(2022)
Article
Biochemistry & Molecular Biology
Keyuan Xu, Jiani Han, Liu Yang, Li Cao, Shuang Li, Zhangyong Hong
Summary: Traditional antibody-drug conjugates are limited by the large molecular weight of the antibody molecules, resulting in low permeability into solid tumors. A new cleavable ADC design with improved tumor tissue permeability and a long circulation half-life was proposed by fusing the small ADC with the Fc domain of the antibody for extended circulation and inserting a digestion sequence between them. The experimental results showed significantly enhanced tumor treatment ability of the designed molecule compared to conventional ADCs.
INTERNATIONAL JOURNAL OF MOLECULAR SCIENCES
(2023)
Review
Oncology
Mo Wu, Wei Huang, Nan Yang, Yanyong Liu
Summary: Chemotherapy is criticized for its non-selective toxicity and drug resistance. Combination therapy, such as drug conjugates, has been developed to improve clinical efficacy. Compared to antibody-drug conjugates, peptide-drug conjugates have advantages but also face limitations in development.
EXPERIMENTAL HEMATOLOGY & ONCOLOGY
(2022)
Article
Medicine, Research & Experimental
Tashbib Khan, Nicholas J. Lyons, Madeline Gough, Kayden K. X. Kwah, Tahleesa J. Cuda, Cameron E. Snell, Brian W. Tse, Kamil A. Sokolowski, Lesley A. Pearce, Timothy E. Adams, Stephen E. Rose, Simon Puttick, Marina Pajic, Mark N. Adams, Yaowu He, John D. Hooper, Thomas Kryza
Summary: This study evaluated the rationale of targeting CDCP1 with ADCs and demonstrated the efficacy of CDCP1-directed ADCs against multiple malignant tumors. CDCP1 expression was found to be elevated in the majority of cancers and restricted in normal tissues. CDCP1-directed ADCs exhibited robust anti-tumor effects both in vitro and in pre-clinical cancer models.
Article
Pharmacology & Pharmacy
Eun-Jeong Jeon, Ju-Hee Han, Youjin Seo, Eun Mi Koh, Kang-Hyun Han, Kyunghwa Hwang, Kyung Jin Jung
Summary: Antibody-drug conjugates (ADCs) are a promising cancer treatment that selectively bind target antigens without the side effects of traditional chemotherapies. This study optimized methods for quantifying a specific ADC, T-DM1, in rats. Four analytical methods were optimized and used to analyze samples in order to evaluate the quantification, pharmacokinetics, and immunogenicity of T-DM1. This research establishes a systematic bioanalysis of ADCs with validated assays, providing a foundation for future investigations on the efficacy and safety of ADC development.
Review
Biochemistry & Molecular Biology
Cynthia Mark, Jin Sun Lee, Xiaojiang Cui, Yuan Yuan
Summary: Antibody drug conjugates (ADCs) combine monoclonal antibodies with cytotoxic drugs for selective delivery to cancer cells, optimizing treatment effectiveness. ADC research has significantly impacted breast cancer management, providing valuable options. However, important questions remain, such as drug sequencing and overcoming resistance mechanisms.
INTERNATIONAL JOURNAL OF MOLECULAR SCIENCES
(2023)
Article
Chemistry, Multidisciplinary
Anne Tvilum, Mikkel Johansen, Laerke N. Glud, Diana M. Ivarsen, Amanda B. Khamas, Sheiliza Carmali, Snehit Satish Mhatre, Ane B. Sogaard, Emma Faddy, Lisanne de Vor, Suzan H. M. Rooijakkers, Lars Ostergaard, Nis P. Jorgensen, Rikke L. Meyer, Alexander N. Zelikin
Summary: In this study, antibody-drug conjugates (ADCs) containing mitomycin C, an anti-neoplastic drug with antimicrobial properties, were engineered to target bacteria in biofilms. The ADCs released the drug without entering the bacterial cells, likely through interaction with thiols on the bacterial cell surface. The targeted ADCs showed superior antimicrobial effects compared to non-specific counterparts in vitro, in biofilms, and in an in vivo osteomyelitis model. These findings have significant translational potential for the development of ADCs as a treatment for bacterial biofilm infections.
Editorial Material
Veterinary Sciences
Erin Straley, Shameen Afif-Rider
Editorial Material
Medicine, Legal
Claire Kent, Brett Coupland, Claire Barnard, Jason Schofield, Shameen Afif-Rider
REGULATORY TOXICOLOGY AND PHARMACOLOGY
(2021)
Article
Chemistry, Analytical
Florian Fussl, Conor S. Barry, Kathryn M. Pugh, K. Phin Chooi, Balakumar Vijayakrishnan, Gyoung-Dong Kang, Christina von Bulow, Philip W. Howard, Jonathan Bones
Summary: ADCs are a promising class of oncology treatments combining monoclonal antibodies' specificity with small molecule compounds' cytotoxic properties. Monitoring the structure and quality of these toxic molecules is crucial, and SEC-MS method provides a reliable and efficient way to characterize ADCs.
JOURNAL OF PHARMACEUTICAL AND BIOMEDICAL ANALYSIS
(2021)
Article
Oncology
Arnaud C. Tiberghien, Balakumar Vijayakrishnan, Arman Esfandiari, Mahammad Ahmed, Raul Pardo, John Bingham, Lauren Adams, Kathleen Santos, Gyoung-Dong Kang, Kathryn M. Pugh, Shameen Afif-Rider, Kapil Vashisht, Kemal Haque, Ravinder Tammali, Edward Rosfjord, Adriana Savoca, John A. Hartley, Philip W. Howard
Summary: Antibody-drug conjugates (ADC) delivering pyrrolobenzo-diazepine (PBD) DNA cross-linkers have shown promising results in clinical trials for lymphomas. A comparison study found that a novel PBD mono-imine showed stronger antitumor activity than a conventional PBD bis-imine in mice. Furthermore, the study also revealed differences in toxicologic profiles between the two ADCs, suggesting potential implications for tolerability and therapeutic index.
MOLECULAR CANCER THERAPEUTICS
(2023)
Article
Oncology
Mary Jane Masson Hinrichs, Pauline M. Ryan, Bo Zheng, Shameen Afif-Rider, Xiang Qing Yu, Michele Gunsior, Haihong Zhong, Jay Harper, Binyam Bezabeh, Kapil Vashisht, Marlon Rebelatto, Molly Reed, Patricia C. Ryan, Shannon Breen, Neki Patel, Cui Chen, Luke Masterson, Arnaud Tiberghien, Phillip W. Howard, Nazzareno Dimasi, Rakesh Dixit
CLINICAL CANCER RESEARCH
(2017)