Article
Biochemical Research Methods
Matthew Giese, Paul D. Davis, Robert H. Woodman, Greg Hermanson, Alex Pokora, Melissa Vermillion
Summary: Protease-activated prodrugs selectively activate cytotoxins in tumors while minimizing toxicity to normal tissues by leveraging increased protease activity in the tumor microenvironment and tight regulation in healthy tissues. Modulating cathepsin-mediated release of cytotoxic payload through steric shielding provided by appropriately designed hydrophilic linkers and conjugated carriers offers a potential strategy for balancing off-target and tumor-targeted payload release. Structural variables of linker architectures can be manipulated to effectively shield enzymatically labile trigger-payloads from enzymes with readily accessible binding sites.
BIOCONJUGATE CHEMISTRY
(2021)
Article
Pharmacology & Pharmacy
Dian Su, Donglu Zhang
Summary: The design of linkers plays a crucial role in modulating the stability and payload release efficiency of ADCs, thus impacting their pharmacokinetics, efficacy, and toxicity. Integrated strategies can help achieve a balance in linker design to optimize desired efficacy.
FRONTIERS IN PHARMACOLOGY
(2021)
Article
Chemistry, Analytical
Shujuan Wang, Fengzhu Wang, Ling Wang, Zhihao Liu, Meiling Liu, Shenjun Li, Ying Wang, Xiaohan Sun, Jing Jiang
Summary: Antibody-drug conjugates (ADCs) are crucial in oncology as their efficacy and toxicity depend on drug concentration in the body, which can be quantitatively assessed using physiologically-based pharmacokinetic (P.K.) models. Sophisticated bioanalysis is required to characterize the entire drug, with multiple strategies used to accurately quantify total antibody (TAb), ADC, antibody-conjugate payload (ac-payload), and free-payload. In this study, a high throughput capture LC-MS/MS method was described and validated to detect ac-payload concentrations in cynomolgus monkey serum, allowing determination of the Drug to Antibody Ratio (DAR). The method demonstrated good linearity, selectivity, benchtop stability, and accuracy for assessing average DAR changes in P.K. studies.
JOURNAL OF PHARMACEUTICAL AND BIOMEDICAL ANALYSIS
(2023)
Article
Chemistry, Applied
Yuichi Nakahara, Brian A. Mendelsohn, Yutaka Matsuda
Summary: Continuous flow reactors allow chemical reactions to occur within shielded pipes and tubes. This study reports the first continuous flow process-mediated ADC synthesis and discusses the optimized mixer type, reaction time, and mixer diameter. The results demonstrate that reliable and robust processes for ADCs can be developed using continuous flow chemistry.
ORGANIC PROCESS RESEARCH & DEVELOPMENT
(2022)
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)
Review
Chemistry, Medicinal
Ahmad Hussain, Armin Grimm, Wenjie Sheng, Chaoyu Zhang, Marwah Al-Rawe, Karen Braeutigam, Mobarak Abu Mraheil, Felix Zeppernick, Ivo Meinhold-Heerlein
Summary: Antibodies have revolutionized cancer treatment with their unique ability to recognize specific antigens and various therapeutic mechanisms. Modification techniques have allowed for the development of new antibody-conjugate-based diagnostic and therapeutic agents, but overcoming the heterogeneity generated by bioconjugation approaches remains a challenge. This review highlights enzyme-based site-specific conjugation methods to improve antibody properties.
Review
Pharmacology & Pharmacy
Zheng Su, Dian Xiao, Fei Xie, Lianqi Liu, Yanming Wang, Shiyong Fan, Xinbo Zhou, Song Li
Summary: ADCs are gradually revolutionizing clinical cancer therapy, and the linker molecule plays a crucial role in determining their efficacy and safety. An ideal linker should release the cytotoxic payload specifically in the tumor to avoid off-target toxicity. Recent research progress in novel linkers for ADCs has been significant, aiming to improve therapeutic outcomes and minimize adverse effects.
ACTA PHARMACEUTICA SINICA B
(2021)
Article
Chemistry, Multidisciplinary
Eugen Merkul, Joey A. Muns, Niels J. Sijbrandi, Hendrik-Jan Houthoff, Bart Nijmeijer, Gerro van Rheenen, Jan Reedijk, Guus A. M. S. van Dongen
Summary: The Pt-II linker Lx has shown potential in ADCs with conjugation efficiency improved from <15% to 75-90%, thanks to the addition of NaI. By utilizing the iodide effect, researchers were able to develop a general and scalable conjugation procedure for the production of Lx-ADCs with an excellent conjugation efficiency of 89% at a 5g scale.
ANGEWANDTE CHEMIE-INTERNATIONAL EDITION
(2021)
Article
Biotechnology & Applied Microbiology
Ana L. de Faria e Silva, Alan G. Ryder
Summary: ADCs are promising anticancer therapeutics, and the control of critical quality attributes during the manufacturing process is essential. The use of pEEM spectroscopy allows for rapid and accurate assessment of ADC CQAs, providing important guidance for the manufacturing process.
BIOTECHNOLOGY AND BIOENGINEERING
(2022)
Review
Biotechnology & Applied Microbiology
Tomohiro Fujii, Yutaka Matsuda
Summary: This review explores unconventional strategies for designing conjugates with novel mechanisms of action and provides examples of promising approaches. It discusses representative examples of novel format payloads, their classification, attributes, and appropriate conjugation techniques in detail.
EXPERT OPINION ON BIOLOGICAL THERAPY
(2023)
Article
Chemistry, Medicinal
Xinyue Hu, Hailun Jiang, Weiqi Bai, Xiujun Liu, Qingfang Miao, Linlin Wang, Jie Jin, Along Cui, Rui Liu, Zhuorong Li
Summary: ADCs, composed of a monoclonal antibody and warhead, are a successful strategy for treating solid tumors. Novel linker-MMAE conjugates showed increased activity for some ADCs and potential for treating other types of cancer.
EUROPEAN JOURNAL OF MEDICINAL CHEMISTRY
(2021)
Review
Chemistry, Medicinal
Yutaka Matsuda, Brian A. Mendelsohn
Summary: ADCs are biopharmaceuticals made by linking small molecules to antibodies that target specific cells, resulting in heterogeneous drug-antibody ratios. The lack of a standardized method to measure the DAR for ADCs is a challenging issue that affects the quality and regulatory perspective of these drugs. The review explores various DAR determination methods and discusses the future landscape of bioconjugate DAR analysis.
CHEMICAL & PHARMACEUTICAL BULLETIN
(2021)
Article
Multidisciplinary Sciences
Nicholas C. C. Nicolaides, J. Bradford Kline, Luigi Grasso
Summary: Subsets of tumor-produced proteins can bind to antibodies and suppress their immune activities. These proteins, called humoral immuno-oncology (HIO) factors, can affect the efficacy of antibody-drug conjugates (ADCs) by reducing internalization. The study evaluated the efficacy of a HIO-refractory ADC and a HIO-bound ADC and found that a specific HIO factor had a negative effect on internalization and tumor cell killing. However, the HIO-refractory ADC showed robust killing of tumor cells in vitro and in vivo. The findings suggest that HIO-refractory antibodies in ADC format can improve therapeutic efficacy and warrant further clinical trials.
Article
Chemistry, Medicinal
Peter S. Dragovich, Thomas H. Pillow, Robert A. Blake, Jack D. Sadowsky, Emel Adaligil, Pragya Adhikari, Sunil Bhakta, Nicole Blaquiere, Jinhua Chen, Josefa Dela Cruz-Chuh, Karen E. Gascoigne, Steven J. Hartman, Mingtao He, Susan Kaufman, Tracy Kleinheinz, Katherine R. Kozak, Liang Liu, Liling Liu, Qi Liu, Ying Lu, Fanwei Meng, Melinda M. Mulvihill, Aimee O'Donohue, Rebecca K. Rowntree, Leanna R. Staben, Steven T. Staben, John Wai, Jian Wang, BinQing Wei, Catherine Wilson, Jianfeng Xin, Zijin Xu, Hui Yao, Donglu Zhang, Hongyan Zhang, Hao Zhou, Xiaoyu Zhu
Summary: This study explores the use of antibody-drug conjugates as delivery vehicles to improve the bioavailability and anticancer activity of proteolysis-targeting chimeras. Results demonstrate that these conjugates can have antigen-dependent effects on prostate cancer cells.
JOURNAL OF MEDICINAL CHEMISTRY
(2021)
Article
Chemistry, Multidisciplinary
Seol Hwa Shin, Yun-Hee Park, Seok Soon Park, Eun Jin Ju, Jin Park, Eun Jeong Ko, Dong Jun Bae, Sang-Yeob Kim, Chul-Woong Chung, Ho Young Song, Se Jin Jang, Seong-Yun Jeong, Si Yeol Song, Eun Kyung Choi
Summary: LCB-ADC exhibits higher cytotoxicity compared to T-DM1 and effectively inhibits tumor growth in animal models with HER2 high expression. Furthermore, LCB-ADC demonstrates good efficacy in suppressing tumor growth in HER2-positive gastric cancer PDX model and T-DM1-resistant models.
