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Antibody drug conjugation

Katsuya Nagaoka, Xuewei Bai, Kosuke Ogawa, Xiaoqun Dong, Songhua Zhang, Yanmei Zhou, Rolf I Carlson, Zhi-Gang Jiang, Steve Fuller, Michael S Lebowitz, Hossein Ghanbari, Jack R Wands
Pancreatic ductal adenocarcinoma (PDAC) is an extremely aggressive malignancy with very limited treatment options. Antibody drug conjugates (ADCs) are promising cytotoxic agents capable of highly selective delivery. Aspartate-β-hydroxylase (ASPH) is a type II transmembrane protein highly expressed in PDACs (97.1%) but not normal pancreas. We investigated anti-tumor effects of an ADC guided by a human monoclonal antibody (SNS-622) against ASPH in human PDAC cell lines and derived subcutaneous (s.c.) xenograft as well as a patient-derived xenograft (PDX) murine model with spontaneous pulmonary metastasis...
February 12, 2019: Cancer Letters
Ross W Boyle, Jordon Sandland
This review aims to highlight key aspects of tetrapyrrole-based antibody-drug-conjugates (ADCs) and the significant developments in the field since 2010. Many new conjugation methods have been developed and employed in the past decade and, associated with this, there has been a rising interest in theranostic conjugates. We have investigated the physicochemical properties that tetrapyrroles need to possess in order to be viable photosensitizers for conjugation to antibodies. Differences in conjugation strategies are discussed, and structure-activity relationships of tetrapyrrole-antibody conjugates are reported, where available...
February 15, 2019: Bioconjugate Chemistry
Anna Bång-Rudenstam, Myriam Cerezo-Magaña, Mattias Belting
Although the overall mortality in cancer is steadily decreasing, major groups of patients still respond poorly to available treatments. The key clinical challenge discussed here relates to the inherent capacity of cancer cells to metabolically adapt to hypoxic and acidic stress, resulting in treatment resistance and a pro-metastatic behavior. Hence, a detailed understanding of stress adaptive responses is critical for the design of more rational therapeutic strategies for cancer. We will focus on the emerging role of extracellular vesicles (EVs) and lipoprotein particles in cancer cell metabolic stress adaptation and how these pathways may constitute potential Achilles' heels of the cancer cell machinery and alternative treatment targets of metastasis...
February 15, 2019: Cancer Metastasis Reviews
Ibrahim Aldoss, Stephen J Forman, Vinod Pullarkat
Acute lymphoblastic leukemia (ALL) in older adults presents a real challenge as a result of adverse disease biology and comorbidities that preclude delivering curative regimens. Conventional chemotherapy approaches have generally yielded unsatisfactory results in older patients with ALL as a result of excessive induction mortality, chemotherapy resistance of the leukemia, and the need to omit or dose reduce key drugs during the course of therapy because of adverse effects. Philadelphia chromosome-positive ALL represents about a quarter of newly diagnosed older adults, and the striking single-agent activity and excellent safety profile of tyrosine kinase inhibitors has allowed incorporation of these agents into therapy, significantly improving the outcome of older adults with Philadelphia chromosome-positive ALL...
February 2019: Journal of Oncology Practice
Galina Nifontova, Fernanda Ramos-Gomes, Maria Baryshnikova, Frauke Alves, Igor Nabiev, Alyona Sukhanova
Imaging agents and drug carriers are commonly targeted toward cancer cell through functionalization with specific recognition molecules. Quantum dots (QDs) are fluorescent semiconductor nanocrystals whose extraordinary brightness and photostability make them attractive for direct fluorescent labeling of biomolecules or optical encoding of the membranes and cells. Here, we analyse the cytotoxicity of QD-encoded microcapsules, validate an approach to the activation of the microcapsule's surface for further functionalization with monoclonal antibody Trastuzumab, a humanized monoclonal antibody targeting the extracellular domain of the human epidermal growth factor receptor 2 (HER2) and already in clinical use for the treatment of HER2 positive breast cancer...
2019: Frontiers in Chemistry
Johann S de Bono, Nicole Concin, David S Hong, Fiona C Thistlethwaite, Jean-Pascal Machiels, Hendrik-Tobias Arkenau, Ruth Plummer, Robert Hugh Jones, Dorte Nielsen, Kristian Windfeld, Srinivas Ghatta, Brian M Slomovitz, James F Spicer, Jeffrey Yachnin, Joo Ern Ang, Paul Morten Mau-Sørensen, Martin David Forster, Dearbhaile Collins, Emma Dean, Reshma A Rangwala, Ulrik Lassen
BACKGROUND: Tisotumab vedotin is a first-in-human antibody-drug conjugate directed against tissue factor, which is expressed across multiple solid tumour types and is associated with poor clinical outcomes. We aimed to establish the safety, tolerability, pharmacokinetic profile, and antitumour activity of tisotumab vedotin in a mixed population of patients with locally advanced or metastatic (or both) solid tumours known to express tissue factor. METHODS: InnovaTV 201 is a phase 1-2, open-label, dose-escalation and dose-expansion study done at 21 centres in the USA and Europe...
February 7, 2019: Lancet Oncology
Rong Wang, Liang Li, Aijun Duan, Yi Li, Xiujun Liu, Qingfang Miao, Jianhua Gong, Yongsu Zhen
Combining antibody-drug conjugates (ADCs) with targeted small-molecule inhibitors can enhance antitumor effects beyond those attainable with monotherapy. In this study, we investigated the therapeutic combination of a CD30-targeting ADC (anti-CD30-lidamycin [LDM]) with a small-molecule inhibitor (crizotinib) of nucleophosmin-anaplastic lymphoma kinase NPM-ALK in CD30+ /ALK+ anaplastic large cell lymphoma (ALCL). In vitro, anti-CD30-LDM showed strong synergistic antiproliferative activity when combined with crizotinib...
February 8, 2019: Cancer Letters
Mona M Al-Shehri, Adel S El-Azab, Manal A El-Gendy, Mohammed A Hamidaddin, Ibrahim A Darwish
Crizotinib (CZT) is a potent drug used for treatment of non-small cell lung cancer (NSCLC); however, its circulating concentration variability has been associated with acquired resistance and toxicity, restricting the success of cancer treatment. As such, the development of an assay that monitors CZT plasma concentrations in patients is a valuable tool in cancer treatment. In this study, a hapten of CZT was synthesized by introducing the acetohydrazide moiety as a spacer into the chemical structure of CZT. The chemical structure of the CZT acetohydrazide (hapten) was confirmed by mass, 1H-, and 13C-NMR spectrometric techniques...
2019: PloS One
Delong Liu, Juanjuan Zhao, Yongping Song, Xiaofeng Luo, Ting Yang
The relapse rate remains high after chemotherapy for adult patients with acute lymphoblastic leukemia (ALL). With better molecular diagnosis and classification as well as better assessment for minimal residual disease, major progress in the treatment for refractory and/or relapsed ALL is being made. In addition to the tyrosine kinase inhibitors (TKIs) for Philadelphia chromosome-positive ALL, immunotherapeutic agents, blinatumomab, inotuzumab ozogamicin (INO), and chimeric antigen receptor (CAR) T cells, are changing the treatment paradigm for ALL...
February 8, 2019: Journal of Hematology & Oncology
Aditya V Gandhi, Theodore W Randolph, John F Carpenter
The impact of drug conjugation on intra- and intermolecular interactions of trastuzumab (TmAb) was determined by comparing the conformational and colloidal stabilities of TmAb and trastuzumab emtansine (T-DM1). In low ionic strength formulations, drug conjugation to native lysine residues of TmAb significantly reduced the repulsive electrostatic interactions between T-DM1 molecules. When these electrostatic interactions were screened in solutions with high ionic strength, intermolecular interactions between T-DM1 molecules were found to be more attractive than those between TmAb molecules...
February 5, 2019: Journal of Pharmaceutical Sciences
Stuart W Hicks, Chiara Tarantelli, Alan Wilhem, Eugenio Gaudio, Min Li, Alberto J Arribas, Filippo Spriano, Roberta Bordone, Luciano Cascione, Katharine C Lai, Qifeng Qiu, Monica Taborelli, Davide Rossi, Georg Stüssi, Emanuele Zucca, Anastasios Stathis, Callum M Sloss, Francesco Bertoni
Antibody-drug conjugates (ADCs) are a novel way to deliver potent cytotoxic compounds to cells expressing a specific antigen. Four ADCs targeting CD19, including SAR3419 (coltuximab ravtansine), have entered clinical development. Here, we present huB4-DGN462, a novel ADC based on the SAR3419 anti-CD19 antibody linked via sulfo-SPDB to the potent DNA-alkylating agent DGN462. huB4-DGN462 had improved in vitro anti-proliferative and cytotoxic activity compared to SAR3419 across multiple B-cell lymphoma and human acute lymphoblastic leukemia cell lines...
February 7, 2019: Haematologica
Deaglan McHugh, Mario Eisenberger, Elisabeth I Heath, Justine Bruce, Daniel C Danila, Dana E Rathkopf, Jarett Feldman, Susan F Slovin, Banmeet Anand, Rong Chu, Jacqueline Lackey, Leonard Reyno, Emmanuel S Antonarakis, Michael J Morris
Background Antibody drug conjugates (ADC) offer the potential of maximizing efficacy while minimizing systemic toxicity. ASG-5ME, an SLC44A4-targeting antibody carrying monomethyl auristatin E (MMAE), a microtubule-disrupting agent, was investigated in men with metastatic castration resistant prostate cancer. Methods The primary objective of this phase I study was to determine maximum tolerated dose (MTD) and recommended phase II dose. Secondary objectives were safety, antitumor activity, pharmacokinetic properties, immunogenicity, and the detection of SLC44A4 on circulating tumor cells...
February 6, 2019: Investigational New Drugs
Nathan Simon, Antonella Antignani, Stephen M Hewitt, Massimo Gadina, Christine Alewine, David FitzGerald
The routes by which antibody-based therapeutics reach malignant cells are poorly defined. Tofacitinib, an FDA-approved JAK inhibitor, reduced tumor-associated inflammatory cells and allowed increased delivery of antibody-based agents to malignant cells. Alone, tofacitinib exhibited no antitumor activity, but combinations with immunotoxins or an antibody drug conjugate resulted in increased anti-tumor responses. Quantification using flow cytometry revealed that antibody-based agents accumulated in malignant cells at higher percentages following tofacitinib treatment...
February 5, 2019: JCI Insight
Richard Harrop, Eric O'Neill, Peter L Stern
Cancer stem cells (CSCs) can act as the cellular drivers of tumors harnessing stem cell properties that contribute to tumorigenesis either as founder elements or by the gain of stem cell traits by the malignant cells. Thus, CSCs can self-renew and generate the cellular heterogeneity of tumors including a hierarchical organization similar to the normal tissue. While the principle tumor growth contribution is often from the non-CSC components, it is the ability of small numbers of CSCs to avoid the effects of therapeutic strategies that can contribute to recurrence after treatment...
2019: Therapeutic advances in vaccines and immunotherapy
Grerk Sutamtewagul, Brian K Link
Follicular lymphoma (FL) is a common B-cell malignancy characterized by relatively indolent growth and incurability with an expected lifetime course of serial intermittent treatment courses. Many patients with FL have lives shortened by the disease and despite a relatively favorable prognosis relative to other incurable systemic malignancies, optimal management of FL has not been achieved. This review focuses on identifying both patients for whom novel therapies might be most beneficial as well as systematically reviewing novel strategies at various levels of investigation...
2019: Therapeutic Advances in Hematology
A Keith Stewart, Amrita Y Krishnan, Seema Singhal, Ralph V Boccia, Manish R Patel, Ruben Niesvizky, Asher A Chanan-Khan, Sikander Ailawadhi, Jochen Brumm, Kirsten E Mundt, Kyu Hong, Jacqueline McBride, Quyen Shon-Nguyen, Yuanyuan Xiao, Vanitha Ramakrishnan, Andrew G Polson, Divya Samineni, Douglas Leipold, Eric W Humke, James Scott McClellan, Jesus G Berdeja
FcRH5 is a cell surface marker enriched on malignant plasma cells when compared to other hematologic malignancies and normal tissues. DFRF4539A is an anti-FcRH5 antibody-drug conjugated to monomethyl auristatin E (MMAE), a potent anti-mitotic agent. This phase I study assessed safety, tolerability, maximum tolerated dose (MTD), anti-tumor activity, and pharmacokinetics of DFRF4539A in patients with relapsed/refractory multiple myeloma. DFRF4539A was administered at 0.3-2.4 mg/kg every 3 weeks or 0.8-1.1 mg/kg weekly as a single-agent by intravenous infusion to 39 patients...
February 4, 2019: Blood Cancer Journal
Maria Pia Savoca, Elisa Tonoli, Adeola G Atobatele, Elisabetta A M Verderio
The biocatalytic activity of transglutaminases (TGs) leads to the synthesis of new covalent isopeptide bonds (crosslinks) between peptide-bound glutamine and lysine residues, but also the transamidation of primary amines to glutamine residues, which ultimately can result into protein polymerisation. Operating with a cysteine/histidine/aspartic acid (Cys/His/Asp) catalytic triad, TGs induce the post-translational modification of proteins at both physiological and pathological conditions (e.g., accumulation of matrices in tissue fibrosis)...
October 31, 2018: Micromachines
Kyoji Tsuchikama
Antibody-drug conjugates (ADCs), monoclonal antibodies conjugated with highly potent drugs (payloads) through chemical linkers, are an emerging class of therapeutic agents for cancer chemotherapy. Their clinical success has been demonstrated by the 4 ADCs already approved by the U.S. Food and Drug Administration (FDA), and more than 60 promising ADCs now in clinical trials. Further advancement of this novel molecular platform could potentially revolutionize current strategies and regimens for treating cancers...
2019: Yakugaku Zasshi: Journal of the Pharmaceutical Society of Japan
Zhoukang Zhuang, Chengzhou Jiang, Fan Zhang, Rong Huang, Liwei Yi, Yong Huang, Xiaohui Yan, Yanwen Duan, Xiangcheng Zhu
Tiancimycins (TNMs) are a group of ten-membered anthraquinone-fused enediynes newly discovered from Streptomyces sp. CB03234. Among them TNM-A and TNM-D have exhibited excellent antitumor performances and could be exploited as very promising warheads for the development of anticancer antibody-drug conjugates (ADC). However, their low titers, especially TNM-D, have severely limited following progress. Therefore, the streptomycin-induced ribosome engineering was adopted in this work for strain improvement of CB03234, and a TNMs high producer Streptomyces sp...
February 3, 2019: Biotechnology and Bioengineering
Alain Beck, Valentina D'Atri, Anthony Ehkirch, Szabolcs Fekete, Oscar Hernandez-Alba, Rabah Gahoual, Emmanuel Leize-Wagner, Yannis François, Davy Guillarme, Sarah Cianférani
The development and optimization of antibody drug conjugates (ADCs) rely on improving their analytical and bioanalytical characterization, by assessing critical quality attributes (CQAs). Among the CQAs, the glycoprofile, drug load distribution (DLD), the amount of unconjugated antibody (D0), the average drug-to-antibody ratio (DAR), the drug conjugation sites and the residual drug-linker and related product proportions (SMDs) in addition to high and low molecular weight species (H/LMWS), and charge variants are the most important ones...
February 1, 2019: Expert Review of Proteomics
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