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Antibody-Drug Conjugate

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https://www.readbyqxmd.com/read/27913998/immunotherapy-for-breast-cancer-past-present-and-future
#1
Alison Spellman, Shou-Ching Tang
Immunotherapy has shown promise in many solid tumors including melanoma and non-small cell lung cancer with an evolving role in breast cancer. Immunotherapy encompasses a wide range of therapies including immune checkpoint inhibition, monoclonal antibodies, bispecific antibodies, vaccinations, antibody-drug conjugates, and identifying other emerging interventions targeting the tumor microenvironment. Increasing efficacy of these treatments in breast cancer patients requires identification of better biomarkers to guide patient selection; recognizing when to initiate these therapies in multi-modality treatment plans; establishing novel assays to monitor immune-mediated responses; and creating combined systemic therapy options incorporating conventional treatments such as chemotherapy and endocrine therapy...
December 2, 2016: Cancer Metastasis Reviews
https://www.readbyqxmd.com/read/27913499/novel-agents-and-strategies-in-transplant-eligible-patients-with-relapsed-and-refractory-hodgkin-lymphoma
#2
Craig Moskowitz
The majority of patients with Hodgkin lymphoma are cured with frontline therapy; however, 10% to 15% with early-stage disease and 20% to 30% with advanced stage require second-line therapy that includes a potentially curative transplant, of which an additional 50% to 55% are cured. Those with multiply relapsed disease traditionally would receive novel agents on a clinical trial or combination chemotherapy as a potential bridge to an allogeneic stem cell transplant. This treatment paradigm has changed with the availability of brentuximab vedotin, an antibody drug conjugate used pre- and post-ASCT, as well as for palliation...
December 2, 2016: Hematology—the Education Program of the American Society of Hematology
https://www.readbyqxmd.com/read/27907066/b-cell-based-seamless-engineering-of-antibody-fc-domains
#3
Koji Hashimoto, Kohei Kurosawa, Akiho Murayama, Hidetaka Seo, Kunihiro Ohta
Engineering of monoclonal antibodies (mAbs) enables us to obtain mAbs with additional functions. In particular, modifications in antibody's Fc (fragment, crystallizable) region can provide multiple benefits such as added toxicity by drug conjugation, higher affinity to Fc receptors on immunocytes, or the addition of functional modules. However, the generation of recombinant antibodies requires multiple laborious bioengineering steps. We previously developed a technology that enables rapid in vitro screening and isolation of specific mAb-expressing cells from the libraries constructed with chicken B-cell line DT40 (referred to as the 'ADLib system')...
2016: PloS One
https://www.readbyqxmd.com/read/27903969/targeting-tissue-factor-as-a-novel-therapeutic-oncotarget-for-eradication-of-cancer-stem-cells-isolated-from-tumor-cell-lines-tumor-xenografts-and-patients-of-breast-lung-and-ovarian-cancer
#4
Zhiwei Hu, Jie Xu, Jijun Cheng, Elizabeth McMichael, Lianbo Yu, William E Carson Iii
Targeting cancer stem cell (CSC) represents a promising therapeutic approach as it can potentially fight cancer at its root. The challenge is to identify a surface therapeutic oncotarget on CSC. Tissue factor (TF) is known as a common yet specific surface target for cancer cells and tumor neovasculature in several solid cancers. However, it is unknown if TF is expressed by CSCs. Here we demonstrate that TF is constitutively expressed on CD133 positive (CD133+) or CD24-CD44+ CSCs isolated from human cancer cell lines, tumor xenografts from mice and breast tumor tissues from patients...
November 26, 2016: Oncotarget
https://www.readbyqxmd.com/read/27902473/rituximab-conjugated-doxorubicin-loaded-microbubbles-as-a-theranostic-modality-in-b-cell-lymphoma
#5
Shoubing Zhou, Xiu Zhang, Cailian Wang
This study evaluated rituximab-conjugated, doxorubicin-loaded microbubbles (RDMs) in combination with ultrasound as molecular imaging agents for early diagnosis of B cell lymphomas, and as a targeted drug delivery system. Rituximab, a monoclonal CD20 antibody, was attached to the surfaces of doxorubicin-loaded microbubbles. RDM binding to B cell lymphoma cells was assessed using immunofluorescence. The cytotoxic effects of RDMs in combination with ultrasound (RDMs+US) were evaluated in vitro in CD20+ and CD20- cell lines, and its antitumor activities were assessed in Raji (CD20+) and Jurkat (CD20-) lymphoma cell-grafted mice...
November 25, 2016: Oncotarget
https://www.readbyqxmd.com/read/27896591/design-and-in-vitro-evaluation-of-bispecific-complexes-and-drug-conjugates-of-anticancer-peptide-lyp-1-in-human-breast-cancer
#6
Selin Seda Timur, Prashant Bhattarai, Reyhan Neslihan Gürsoy, İmran Vural, Ban-An Khaw
PURPOSE: LyP-1, a nine-amino-acid tumor homing peptide, selectively binds to its cognate receptor, p32. Overexpression of p32 in certain tumors should allow use of LyP-1 as a targeting agent for the delivery of therapeutic or diagnostic agents. Peptide conjugates are developed for enhanced pre-targeting of MDA-MB-231 breast cancer cells with peptide-antibody bispecific complexes and targeting with multiple-drug/-fluorophore-conjugated nano-polymers. METHODS: LyP-1-anti-DTPA bispecific antibody complexes (LyP-1-bsAbCx) were generated by conjugation of anti-DTPA antibody and LyP-1...
November 28, 2016: Pharmaceutical Research
https://www.readbyqxmd.com/read/27895526/development-of-a-simple-and-specific-direct-competitive-elisa-for-the-determination-of-artesunate-using-an-anti-artesunate-polyclonal-antiserum
#7
Yoshinori Mitsui
BACKGROUND: Since artesunate (ART) became a vital component of artemisinin (ARM)-based combination therapies for the treatment for malaria, counterfeit ART drugs have spread in regions of Southeast Asia and Africa. The consumption of counterfeit ART drugs has resulted in the death of many patients. Thus, evaluating the quality of ART drugs is needed. There are several methods for quantitating the ART content in tablets, the most common being a high-performance liquid chromatography. However, that method is hampered by the need for expensive equipment and a rather time-consuming process of extraction...
2016: Tropical Medicine and Health
https://www.readbyqxmd.com/read/27895507/fc-gamma-receptors-glycobiology-and-therapeutic-prospects
#8
REVIEW
Jerrard M Hayes, Mark R Wormald, Pauline M Rudd, Gavin P Davey
Therapeutic antibodies hold great promise for the treatment of cancer and autoimmune diseases, and developments in antibody-drug conjugates and bispecific antibodies continue to enhance treatment options for patients. Immunoglobulin (Ig) G antibodies are proteins with complex modifications, which have a significant impact on their function. The most important of these modifications is glycosylation, the addition of conserved glycans to the antibody Fc region, which is critical for its interaction with the immune system and induction of effector activities such as antibody-dependent cell cytotoxicity, complement activation and phagocytosis...
2016: Journal of Inflammation Research
https://www.readbyqxmd.com/read/27891093/targeting-strategies-for-renal-cell-carcinoma-from-renal-cancer-cells-to-renal-cancer-stem-cells
#9
REVIEW
Zhi-Xiang Yuan, Jingxin Mo, Guixian Zhao, Gang Shu, Hua-Lin Fu, Wei Zhao
Renal cell carcinoma (RCC) is a common form of urologic tumor that originates from the highly heterogeneous epithelium of renal tubules. Over the last decade, targeting therapies to renal cancer cells have transformed clinical care for RCC. Recently, it was proposed that renal cancer stem cells (CSCs) isolated from renal carcinomas were responsible for driving tumor growth and resistance to conventional chemotherapy and radiotherapy, according to the theory of CSCs; this has provided the rationale for therapies targeting this aggressive cell population...
2016: Frontiers in Pharmacology
https://www.readbyqxmd.com/read/27890855/linker-stability-influences-the-anti-tumor-activity-of-acetazolamide-drug-conjugates-for-the-therapy-of-renal-cell-carcinoma
#10
Samuele Cazzamalli, Alberto Dal Corso, Dario Neri
Small molecule-drug conjugates (SMDCs) are increasingly being considered as an alternative to antibody-drug conjugates (ADCs) for the selective delivery of anticancer agents to the tumor site, sparing normal tissues. Carbonic anhydrase IX (CAIX) is a membrane-bound enzyme, which is over-expressed in the majority of renal cell carcinomas and which can be efficiently targeted in vivo, using charged derivatives of acetazolamide, a small heteroaromatic sulfonamide. Here, we show that SMDC products, obtained by the coupling of acetazolamide with monomethyl auristatin E (MMAE) using dipeptide linkers, display a potent anti-tumoral activity in mice bearing xenografted SKRC-52 renal cell carcinomas...
November 24, 2016: Journal of Controlled Release: Official Journal of the Controlled Release Society
https://www.readbyqxmd.com/read/27889646/mirvetuximab-soravtansine-imgn853-a-folate-receptor-alpha-targeting-antibody-drug-conjugate-potentiates-the-activity-of-standard-of-care-therapeutics-in-ovarian-cancer-models
#11
Jose F Ponte, Olga Ab, Leanne Lanieri, Jenny Lee, Jennifer Coccia, Laura M Bartle, Marian Themeles, Yinghui Zhou, Jan Pinkas, Rodrigo Ruiz-Soto
Elevated folate receptor alpha (FRα) expression is characteristic of epithelial ovarian cancer (EOC), thus establishing this receptor as a candidate target for the development of novel therapeutics to treat this disease. Mirvetuximab soravtansine (IMGN853) is an antibody-drug conjugate (ADC) that targets FRα for tumor-directed delivery of the maytansinoid DM4, a potent agent that induces mitotic arrest by suppressing microtubule dynamics. Here, combinations of IMGN853 with approved therapeutics were evaluated in preclinical models of EOC...
November 24, 2016: Neoplasia: An International Journal for Oncology Research
https://www.readbyqxmd.com/read/27889561/inhibition-of-interleukin-5-induced-false-positive-anti-drug-antibody-responses-against-mepolizumab-through-the-use-of-a-competitive-blocking-antibody
#12
Karen Liao, Erik Meyer, Thomas N Lee, Amy Loercher, Daniel Sikkema
Mepolizumab, a humanized IgG1 monoclonal antibody that blocks native homodimeric interleukin-5 (IL-5) from binding to the IL-5 receptor, has recently been approved for treatment of severe eosinophilic asthma. Our initial immunogenicity assay method for phase I and II studies utilized a bridging electrochemiluminescence format with biotin and ruthenium-labelled mepolizumab linked by anti-drug antibodies (ADA). We discovered that IL-5 significantly increased in dosed subjects from a phase II study and that the increased IL-5 was in the form of a drug-bound complex...
November 24, 2016: Journal of Immunological Methods
https://www.readbyqxmd.com/read/27882199/straightforward-glycoengineering-approach-to-site-specific-antibody-pyrrolobenzodiazepine-conjugates
#13
Pamela Thompson, Ebele Ezeadi, Ian Hutchinson, Ryan Fleming, Binyam Bezabeh, Jia Lin, Shenlan Mao, Cui Chen, Luke Masterson, Haihong Zhong, Dorin Toader, Philip Howard, Herren Wu, Changshou Gao, Nazzareno Dimasi
Antibody-drug conjugates (ADCs) have become a powerful platform to deliver cytotoxic agents selectively to cancer cells. ADCs have traditionally been prepared by stochastic conjugation of a cytotoxic drug using an antibody's native cysteine or lysine residues. Through strategic selection of the mammalian expression host, we were able to introduce azide-functionalized glycans onto a homogeneously glycosylated anti-EphA2 monoclonal antibody in one step. Conjugation with an alkyne-bearing pyrrolobenzodiazepine dimer payload (SG3364) using copper-catalyzed click chemistry yielded a site-specific ADC with a drug-to-antibody ratio (DAR) of four...
November 10, 2016: ACS Medicinal Chemistry Letters
https://www.readbyqxmd.com/read/27882198/design-synthesis-and-cytotoxic-evaluation-of-novel-tubulysin-analogues-as-adc-payloads
#14
Carolyn A Leverett, Sai Chetan K Sukuru, Beth C Vetelino, Sylvia Musto, Kevin Parris, Jayvardhan Pandit, Frank Loganzo, Alison H Varghese, Guoyun Bai, Bin Liu, Dingguo Liu, Sarah Hudson, Venkata Ramana Doppalapudi, Joseph Stock, Christopher J O'Donnell, Chakrapani Subramanyam
The tubulysin class of natural products has attracted much attention from the medicinal chemistry community due to its potent cytotoxicity against a wide range of human cancer cell lines, including significant activity in multidrug-resistant carcinoma models. As a result of their potency, the tubulysins have become an important tool for use in targeted therapy, being widely pursued as payloads in the development of novel small molecule drug conjugates (SMDCs) and antibody-drug conjugates (ADCs). A structure-based and parallel medicinal chemistry approach was applied to the synthesis of novel tubulysin analogues...
November 10, 2016: ACS Medicinal Chemistry Letters
https://www.readbyqxmd.com/read/27882197/site-specific-tandem-knoevenagel-condensation-michael-addition-to-generate-antibody-drug-conjugates
#15
Romas A Kudirka, Robyn M Barfield, Jesse M McFarland, Penelope M Drake, Adam Carlson, Stefanie Bañas, Wes Zmolek, Albert W Garofalo, David Rabuka
Expanded ligation techniques are sorely needed to generate unique linkages for the growing field of functionally enhanced proteins. To address this need, we present a unique chemical ligation that involves the double addition of a pyrazolone moiety with an aldehyde-labeled protein. This ligation occurs via a tandem Knoevenagel condensation-Michael addition. A pyrazolone reacts with an aldehyde to generate an enone, which undergoes subsequent attack by a second pyrazolone to generate a bis-pyrazolone species...
November 10, 2016: ACS Medicinal Chemistry Letters
https://www.readbyqxmd.com/read/27882196/linker-immolation-determines-cell-killing-activity-of-disulfide-linked-pyrrolobenzodiazepine-antibody-drug-conjugates
#16
Donglu Zhang, Thomas H Pillow, Yong Ma, Josefa Dela Cruz-Chuh, Katherine R Kozak, Jack D Sadowsky, Gail D Lewis Phillips, Jun Guo, Martine Darwish, Peter Fan, Jingtian Chen, Changrong He, Tao Wang, Hui Yao, Zijin Xu, Jinhua Chen, John Wai, Zhonghua Pei, Cornelis E C A Hop, S Cyrus Khojasteh, Peter S Dragovich
Disulfide bonds could be valuable linkers for a variety of therapeutic applications requiring tunable cleavage between two parts of a molecule (e.g., antibody-drug conjugates). The in vitro linker immolation of β-mercaptoethyl-carbamate disulfides and DNA alkylation properties of associated payloads were investigated to understand the determinant of cell killing potency of anti-CD22 linked pyrrolobenzodiazepine (PBD-dimer) conjugates. Efficient immolation and release of a PBD-dimer with strong DNA alkylation properties were observed following disulfide cleavage of methyl- and cyclobutyl-substituted disulfide linkers...
November 10, 2016: ACS Medicinal Chemistry Letters
https://www.readbyqxmd.com/read/27882195/design-and-synthesis-of-tesirine-a-clinical-antibody-drug-conjugate-pyrrolobenzodiazepine-dimer-payload
#17
Arnaud C Tiberghien, Jean-Noel Levy, Luke A Masterson, Neki V Patel, Lauren R Adams, Simon Corbett, David G Williams, John A Hartley, Philip W Howard
Pyrrolobenzodiazepine dimers are an emerging class of warhead in the field of antibody-drug conjugates (ADCs). Tesirine (SG3249) was designed to combine potent antitumor activity with desirable physicochemical properties such as favorable hydrophobicity and improved conjugation characteristics. One of the reactive imines was capped with a cathepsin B-cleavable valine-alanine linker. A robust synthetic route was developed to allow the production of tesirine on clinical scale, employing a flexible, convergent strategy...
November 10, 2016: ACS Medicinal Chemistry Letters
https://www.readbyqxmd.com/read/27882194/optimization-of-tubulysin-antibody-drug-conjugates-a-case-study-in-addressing-adc-metabolism
#18
L Nathan Tumey, Carolyn A Leverett, Beth Vetelino, Fengping Li, Brian Rago, Xiaogang Han, Frank Loganzo, Sylvia Musto, Guoyun Bai, Sai Chetan K Sukuru, Edmund I Graziani, Sujiet Puthenveetil, Jeffrey Casavant, Anokha Ratnayake, Kimberly Marquette, Sarah Hudson, Venkata Ramana Doppalapudi, Joseph Stock, Lioudmila Tchistiakova, Andrew J Bessire, Tracey Clark, Judy Lucas, Christine Hosselet, Christopher J O'Donnell, Chakrapani Subramanyam
As part of our efforts to develop new classes of tubulin inhibitor payloads for antibody-drug conjugate (ADC) programs, we developed a tubulysin ADC that demonstrated excellent in vitro activity but suffered from rapid metabolism of a critical acetate ester. A two-pronged strategy was employed to address this metabolism. First, the hydrolytically labile ester was replaced by a carbamate functional group resulting in a more stable ADC that retained potency in cellular assays. Second, site-specific conjugation was employed in order to design ADCs with reduced metabolic liabilities...
November 10, 2016: ACS Medicinal Chemistry Letters
https://www.readbyqxmd.com/read/27882193/expanding-the-reach-of-antibody-drug-conjugates
#19
EDITORIAL
Ravi V J Chari
Antibody-drug conjugates (ADCs) represent an emerging new paradigm in cancer therapy. The approval of two ADCs has spurred considerable interest in this area of research, and over 55 ADCs are currently in clinical testing. In order to improve the clinical success rate of ADC therapy, all three components of the ADC: the antibody, linker, and payload have to be optimized. While considerable improvements have been made in antibody properties and target selection, medicinal chemistry efforts have lagged behind, and there is a significant need for innovation in linker design and payloads...
November 10, 2016: ACS Medicinal Chemistry Letters
https://www.readbyqxmd.com/read/27882192/next-generation-antibody-drug-conjugates-adcs-for-cancer-therapy
#20
EDITORIAL
Jagath Reddy Junutula, Hans-Peter Gerber
No abstract text is available yet for this article.
November 10, 2016: ACS Medicinal Chemistry Letters
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