Article
Chemistry, Multidisciplinary
Xiao-yi Zhu, Quan-xiao Li, Yu Kong, Ke-ke Huang, Gang Wang, Yun-ji Wang, Jun Lu, Guo-qiang Hua, Yan-ling Wu, Tian-lei Ying
Summary: Leveraging the specificity of antibody to deliver cytotoxic agent into tumor represents a promising approach in anticancer therapies. This study demonstrated the therapeutic potential of fully human single-domain antibodies (UdAbs) targeting CEACAM5, which effectively inhibited tumor growth in xenograft mice models.
ACTA PHARMACOLOGICA SINICA
(2023)
Article
Chemistry, Multidisciplinary
Liujuan Zhou, Fan Yang, Zhaoshuai Bai, Xiaohui Zhou, Zhihai Zhang, Zhihang Li, Junyuan Gong, Junqi Yu, Liqiang Pan, Chan Cao, James J. Chou
Summary: One challenge in improving clinical outcomes of antibody drug conjugates (ADCs) is overcoming cancer resistance to the antibody and/or drug components of ADCs. In this study, a self-assembled left-handed DNA (L-DNA) oligonucleotide was used to link combinatory single-domain antibodies and toxin payloads for tunable and adaptive delivery of ADCs. The newly constructed ADCs with L-DNA scaffold showed promising properties in vitro and in vivo. This suggests that the L-DNA based modular ADC (MADC) platform is a viable option for generating therapeutic ADCs and expanding the therapeutic window.
ANGEWANDTE CHEMIE-INTERNATIONAL EDITION
(2023)
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
Biochemistry & Molecular Biology
Ksenia A. Sapozhnikova, Evgeny L. Gulyak, Vsevolod A. Misyurin, Maria A. Simonova, Ekaterina V. Ryabukhina, Anastasiya V. Alexeeva, Nataliya A. Tikhonova, Natalia A. Lyzhko, Galina P. Popova, Andrey V. Misyurin, Alexey V. Ustinov, Vladimir A. Korshun, Vera A. Alferova, Dmitry Yu. Ryazantsev, Vladimir A. Brylev
Summary: Fluorescent antibodies are essential in molecular biology and diagnostics. This study introduces a methodology for synthesizing site-specific antibody-dye conjugates with a high degree of labeling, which was demonstrated to successfully detect PRAME protein on cell surfaces using flow cytometry.
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
Biochemistry & Molecular Biology
Seetharamsing Balamkundu, Chuan-Fa Liu
Summary: Antibody-drug conjugates (ADCs) are a powerful therapeutic modality for cancer treatment, and the success of ADCs depends on the development of linker systems that allow for targeted release of drugs. Currently, there is a focus on improving the stability of ADC linkers in human plasma while maintaining lysosomal cleavability. This review provides an overview of recent advances in the design and structure-activity relationship studies of various peptide/peptidomimetic linkers in this field.
Article
Chemistry, Medicinal
Thomas J. Tucker, Mark W. Embrey, Candice Alleyne, Rupesh P. Amin, Alan Bass, Bhavana Bhatt, Elisabetta Bianchi, Danila Branca, Tjerk Bueters, Nicole Buist, Sookhee N. Ha, Mike Hafey, Huaibing He, John Higgins, Douglas G. Johns, Angela D. Kerekes, Kenneth A. Koeplinger, Jeffrey T. Kuethe, Nianyu Li, BethAnn Murphy, Peter Orth, Scott Salowe, Aurash Shahripour, Rodger Tracy, Weixun Wang, Chengwei Wu, Yusheng Xiong, Hratch J. Zokian, Harold B. Wood, Abbas Walji
Summary: The study has successfully designed highly potent orally bioavailable macrocyclic peptide PCSK9 inhibitors, demonstrating promising therapeutic effects in animal experiments, potentially as a future development of once-daily oral lipid-lowering agents.
JOURNAL OF MEDICINAL CHEMISTRY
(2021)
Article
Microbiology
Kimberly K. Kajihara, Homer Pantua, Hilda Hernandez-Barry, Meredith Hazen, Kiran Deshmukh, Nancy Chiang, Rachana Ohri, Erick R. Castellanos, Lynn Martin, Marissa L. Matsumoto, Jian Payandeh, Kelly M. Storek, Kellen Schneider, Peter A. Smith, Michael F. T. Koehler, Siao Ping Tsai, Richard Vandlen, Kelly M. Loyet, Gerald Nakamura, Thomas Pillow, Dhaya Seshasayee, Sharookh B. Kapadia, Wouter L. W. Hazenbos
Summary: This study demonstrates that an anti-P. aeruginosa AAC can locally concentrate antibiotic and kill P. aeruginosa inside phagocytes, providing additional therapeutic options for antibiotics that are moderately active or have an unfavorable pharmacokinetics or toxicity profile. This approach may provide new therapeutic options for antibiotics that are dose limited.
Article
Chemistry, Medicinal
Xiaotong Chen, Fangcen Liu, Xiaoxiao Yu, Lin Li, Jiayao Yan, Xinjie Chen, Qin Liu, Baorui Liu
Summary: Gastric cancer is a global health problem and its treatment is limited by off-target side effects. Peptide-drug conjugates (PDCs) offer a targeted drug delivery strategy to overcome drug resistance and improve antitumor effects. In this study, we proposed KK-LC-1 as a potential target for PDC design and reported the first KK-LC-1-targeting PDC product 1131-MMAE. 1131-MMAE efficiently entered KK-LC-1 positive gastric cancer cells, released the drug, and arrested the cell cycle. As a monotherapy, 1131-MMAE significantly delayed tumor growth with reduced toxicity. Furthermore, we demonstrated that 1131-MMAE was a potent radiosensitizer, enhancing the radiation response of KK-LC-1 positive tumor cells.
EUROPEAN JOURNAL OF MEDICINAL CHEMISTRY
(2022)
Article
Oncology
Yuqi Yang, Shuhang Wang, Peiwen Ma, Yale Jiang, Keman Cheng, Yue Yu, Ning Jiang, Huilei Miao, Qiyu Tang, Funan Liu, Yan Zha, Ning Li
Summary: Drug conjugates are substances that combine a tumor-homing carrier and a cytotoxic agent through a linker, designed to deliver a highly toxic drug directly to cancer cells to enhance treatment efficacy and reduce side effects. They have the potential to revolutionize current cancer treatment strategies. Besides antibody-drug conjugates, other types of drug conjugates have emerged that overcome limitations of antibodies.
Article
Pharmacology & Pharmacy
Simon Frachet, Aurore Danigo, Mathilde Duchesne, Laurence Richard, Franck Sturtz, Laurent Magy, Claire Demiot
Summary: Antibody-drug conjugates (ADCs) are anticancer drugs consisting of a monoclonal antibody and a potent cytotoxic agent called MMAE. This study developed a mouse model of MMAE-induced peripheral neuropathy by injecting MMAE into mice for seven weeks. The results showed that MMAE caused sensory nerve damage and allodynia in the mice. This model can be used to screen neuroprotective strategies for peripheral neuropathies caused by MMAE-ADCs.
TOXICOLOGY AND APPLIED PHARMACOLOGY
(2023)
Article
Chemistry, Analytical
Chendi Zhu, Hai Han, Zhiwei Chen, Yuan Shen, Qiaoxuan Zhang, Cai Bao, Jia-Huan Qu, Qiqin Wang, Zhengjin Jiang
Summary: In this study, a novel affinity matrix material was developed for the selective enrichment and analysis of therapeutic antibodies. The material demonstrated high porosity, good affinity, and specificity, as well as low non-specific adsorption. It successfully enriched and analyzed antibody-drug conjugates from cell culture media, showing great potential for biopharmaceutical analysis.
ANALYTICA CHIMICA ACTA
(2023)
Article
Chemistry, Medicinal
Courtney P. Jackson, Siteng Fang, Samantha R. Benjamin, Tchilabalo Alayi, Yetrib Hathout, Sarah M. Gillen, Jillian P. Handel, Brittany M. Brems, Justin M. Howe, L. Nathan Tumey
Summary: The use of esters in antibody-drug conjugates (ADCs) has been avoided due to the nature of human esterases. Cellular uptake results in selective but inefficient cleavage of esters by cytosolic esterases. Little cleavage of ester-containing linkers occurs in lysosomes. However, ADCs with ester-linked payloads are active in immune-suppressive assays. The cleavage of ester linkage in plasma depends on the site of attachment.
BIOORGANIC & MEDICINAL CHEMISTRY LETTERS
(2022)
Article
Chemistry, Multidisciplinary
Wen Yin, Tianqi Xu, Haozhong Ding, Jie Zhang, Vitalina Bodenko, Maria S. Tretyakova, V. Mikhail Belousov, Yongsheng Liu, Maryam Oroujeni, Anna Orlova, Vladimir Tolmachev, Torbjorn Graslund, Anzhelika Vorobyeva
Summary: Treatment with antibody drug conjugates targeting receptors over-expressed on cancer cells is well established for clinical use. Resistance often occurs, motivating the development of novel drugs. In this study, the impact of the cytotoxic payload on binding properties, cytotoxicity, and biodistribution was investigated.
JOURNAL OF CONTROLLED RELEASE
(2023)
Article
Biochemistry & Molecular Biology
Yuka Tanaka, Maho Murata, Che-Hung Shen, Masutaka Furue, Takamichi Ito
Summary: The study found that high expression of NECTIN4 is associated with disease-free survival in melanoma, and in BRAFi-resistant melanoma cells, both NECTIN4 and the PI3K/Akt pathway are upregulated. Inhibiting NECTIN4 can increase the sensitivity of BRAFi-resistant cells to BRAFi, offering a novel treatment strategy for melanoma.
INTERNATIONAL JOURNAL OF MOLECULAR SCIENCES
(2021)