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antibody-drug conjugates

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https://www.readbyqxmd.com/read/29453628/safety-tolerability-and-preliminary-activity-of-imgn529-a-cd37-targeted-antibody-drug-conjugate-in-patients-with-relapsed-or-refractory-b-cell-non-hodgkin-lymphoma-a-dose-escalation-phase-i-study
#1
Anastasios Stathis, Ian W Flinn, Sumit Madan, Kami Maddocks, Arnold Freedman, Steven Weitman, Emanuele Zucca, Mihaela C Munteanu, M Lia Palomba
Background CD37 is expressed on B-cell lymphoid malignancies, thus making it an attractive candidate for targeted therapy in non-Hodgkin lymphoma (NHL). IMGN529 is an antibody-drug conjugate comprising a CD37-binding antibody linked to the maytansinoid DM1, a potent anti-mitotic agent. Methods This first-in-human, phase 1 trial recruited adult patients with relapsed or refractory B-cell NHL. The primary objective was to determine the maximum tolerated dose (MTD) and recommended phase 2 dose. Secondary objectives were to evaluate safety, pharmacokinetics, and preliminary clinical activity...
February 17, 2018: Investigational New Drugs
https://www.readbyqxmd.com/read/29452665/novel-agents-for-relapsed-and-refractory-follicular-lymphoma
#2
REVIEW
Chan Yoon Cheah, Nathan H Fowler
Follicular lymphoma is one of the most common non-Hodgkin's lymphomas. Although current frontline regimens are associated with high response rates, most patients still relapse. When progression is discovered, re-establishing the diagnosis and ruling out transformation in paramount. The outcomes following relapse have been improving due to the activity and increasing availability of novel agents with various mechanisms of action. Despite these advances, single agent activity is limited and the disease remains incurable in the majority of cases...
March 2018: Best Practice & Research. Clinical Haematology
https://www.readbyqxmd.com/read/29448116/immunoliposomes-in-clinical-oncology-state-of-the-art-and-future-perspectives
#3
REVIEW
María Merino, Sara Zalba, María J Garrido
Liposomal formulations entrapping a vast number of molecules have improved cancer therapies overcoming certain pharmacokinetic (PK) and pharmacodynamic limitations, many of which are associated with tumor characteristics. In this context, immunoliposomes represent a new strategy that has been widely investigated in preclinical cancer models with promising results, although few have reached the stage of clinical trials. This contrasts with the emerging clinical application of monoclonal antibodies (mAbs). This formulation allows the conjugation of different mAbs or antibody derivatives, such as monovalent variable fragments Fab', to the polymers covering the surface of liposomes...
February 12, 2018: Journal of Controlled Release: Official Journal of the Controlled Release Society
https://www.readbyqxmd.com/read/29446615/leveraging-engineering-of-cells-for-drug-delivery
#4
Zhaowei Chen, Quanyin Hu, Zhen Gu
Cell therapy has become a momentum-gathering treatment strategy for a variety of diseases, including cancer, diabetes, hemophilia, and cardiomyopathy. However, clinical applications of conventional cell therapies have often been compromised by rapid decline in viability and function of the transplanted cells due to host recognition and subsequent foreign body rejection. Along this line, cell engineering technologies such as cell encapsulation within microcapsules and immobilization in porous scaffolds have been implemented to address the immunosuppression concerns...
February 15, 2018: Accounts of Chemical Research
https://www.readbyqxmd.com/read/29440297/mi130004-a-novel-antibody-drug-conjugate-combining-trastuzumab-with-a-molecule-of-marine-origin-shows-outstanding-in-vivo-activity-against-her2-expressing-tumors
#5
Pablo M Aviles, Juan Manuel Dominguez, María José Guillén-Navarro, Maria Jose Muñoz-Alonso, Cristina Mateo, Raquel Rodriguez-Acebes, Jose Manuel Molina-Guijarro, Andrés Francesch, Juan Fernando Martínez-Leal, Simon Munt, Carlos M Galmarini, Carmen Cuevas
In the search for novel payloads to design new antibody-drug conjugates (ADCs), marine compounds represent an interesting opportunity given their unique chemical features. PM050489 is a marine compound that binds β-tubulin at a new site and disrupts the microtubule network hence leading to mitotic aberrations and cell death. PM050489 has been conjugated to trastuzumab via Cys residues through a non-cleavable linker and the resulting ADC, named MI130004, has been studied. Analysis of MI130004 delivered data consistent with the presence of two molecules of PM050489 per antibody molecule, likely bound to both sides of the intermolecular disulfide bond connecting the antibody light and heavy chains...
February 13, 2018: Molecular Cancer Therapeutics
https://www.readbyqxmd.com/read/29440294/in-vitro-and-in-vivo-activity-of-imgn853-an-antibody-drug-conjugate-targeting-folate-receptor-alpha-linked-to-dm4-in-biologically-aggressive-endometrial-cancers
#6
Gary Altwerger, Elena Bonazzoli, Stefania Bellone, Tomomi Egawa-Takata, Gulden Menderes, Francesca Pettinella, Anna Bianchi, Francesco Riccio, Jacqueline Feinberg, Luca Zammataro, Chanhee Han, Ghanshyam Yadav, Katherine Dugan, Ashley Morneault, Jose F Ponte, Natalia Buza, Pei Hui, Serena Wong, Babak Litkouhi, Elena Ratner, Dan-Arin Silasi, Gloria S Huang, Masoud Azodi, Peter E Schwartz, Alessandro D Santin
Grade 3 endometrioid and uterine serous carcinomas (USC) account for the vast majority of endometrial cancer deaths. The purpose of this study was to determine folic acid receptor alpha (FR⍺) expression in these biologically aggressive (Type II) endometrial cancers,and evaluate FR⍺ as a targetable receptor for IMGN853 (Mirvetuximab soravtansine). The expression of FR⍺ was evaluated by immunohistochemistry (IHC) and flow cytometry in 90 endometrioid and USC samples. The in vitro cytotoxic activity and bystander effect were studied in primary uterine cancer cell lines expressing differential levels of FR⍺...
February 13, 2018: Molecular Cancer Therapeutics
https://www.readbyqxmd.com/read/29440292/a-dna-interacting-payload-designed-to-eliminate-cross-linking-improves-the-therapeutic-index-of-antibody-drug-conjugates-adcs
#7
Michael L Miller, Manami Shizuka, Alan Wilhelm, Paulin Salomon, Emily E Reid, Leanne Lanieri, Surina Sikka, Erin K Maloney, Lauren Harvey, Qifeng Qiu, Katie E Archer, Chen Bai, Dilrukshi Vitharana, Luke Harris, Rajeeva Singh, Jose F Ponte, Nicholas C Yoder, Yelena Kovtun, Katharine C Lai, Olga Ab, Jan Pinkas, Thomas A Keating, Ravi V J Chari
Tumor-selective delivery of cytotoxic agents in the form of antibody-drug conjugates (ADCs) is now a clinically validated approach for cancer treatment. In an attempt to improve the clinical success rate of ADCs, emphasis has been recently placed on the use of DNA-cross-linking pyrrolobenzodiazepine compounds as the payload. Despite promising early clinical results with this class of ADCs, doses achievable have been low due to systemic toxicity. Here, we describe the development of a new class of potent DNA-interacting agents wherein changing the mechanism of action from a cross-linker to a DNA alkylator improves the tolerability of the ADC...
February 13, 2018: Molecular Cancer Therapeutics
https://www.readbyqxmd.com/read/29439419/immunoconjugates-for-osteosarcoma-therapy-preclinical-experiences-and-future-perspectives
#8
REVIEW
Daniele Mercatelli, Massimo Bortolotti, Alberto Bazzocchi, Andrea Bolognesi, Letizia Polito
Osteosarcoma (OS) is an aggressive osteoid-producing tumor of mesenchymal origin, which represents the most common primary bone malignancy. It is characterized by a complex and frequently uncertain etiology. The current standard care for high-grade OS treatment is neoadjuvant chemotherapy, followed by surgery and post-operative chemotherapy. In order to ameliorate survival rates of patients, new therapeutic approaches have been evaluated, mainly immunotherapy with antibody-drug conjugates or immunoconjugates...
February 10, 2018: Biomedicines
https://www.readbyqxmd.com/read/29438695/eradication-of-triple-negative-breast-cancer-cells-by-targeting-glycosylated-pd-l1
#9
Chia-Wei Li, Seung-Oe Lim, Ezra M Chung, Yong-Soo Kim, Andrew H Park, Jun Yao, Jong-Ho Cha, Weiya Xia, Li-Chuan Chan, Taewan Kim, Shih-Shin Chang, Heng-Huan Lee, Chao-Kai Chou, Yen-Liang Liu, Hsin-Chih Yeh, Evan P Perillo, Andrew K Dunn, Chu-Wei Kuo, Kay-Hooi Khoo, Jennifer L Hsu, Yun Wu, Jung-Mao Hsu, Hirohito Yamaguchi, Tzu-Hsuan Huang, Aysegul A Sahin, Gabriel N Hortobagyi, Stephen S Yoo, Mien-Chie Hung
Protein glycosylation provides proteomic diversity in regulating protein localization, stability, and activity; it remains largely unknown whether the sugar moiety contributes to immunosuppression. In the study of immune receptor glycosylation, we showed that EGF induces programmed death ligand 1 (PD-L1) and receptor programmed cell death protein 1 (PD-1) interaction, requiring β-1,3-N-acetylglucosaminyl transferase (B3GNT3) expression in triple-negative breast cancer. Downregulation of B3GNT3 enhances cytotoxic T cell-mediated anti-tumor immunity...
February 12, 2018: Cancer Cell
https://www.readbyqxmd.com/read/29438689/glycans-pave-the-way-for-immunotherapy-in-triple-negative-breast-cancer
#10
Mariana Salatino, María Romina Girotti, Gabriel A Rabinovich
The clinical efficacy of therapies targeting the PD-1/PD-L1 pathway is still limited. In this issue of Cancer Cell, Li and colleagues identify a PD-L1 glycosylation-based mechanism in triple-negative breast cancer that fosters immunosuppression by enhancing interactions with PD-1. Targeting glycosylated PD-L1 with a drug-conjugated antibody opens new avenues for treatment.
February 12, 2018: Cancer Cell
https://www.readbyqxmd.com/read/29438441/development-of-vaccine-for-dyslipidemia-targeted-to-a-proprotein-convertase-subtilisin-kexin-type-9-pcsk9-epitope-in-mice
#11
Ryo Kawakami, Yoichi Nozato, Hironori Nakagami, Yuka Ikeda, Munehisa Shimamura, Shota Yoshida, Jiao Sun, Tomohiro Kawano, Yoichi Takami, Takahisa Noma, Hiromi Rakugi, Tetsuo Minamino, Ryuichi Morishita
Proprotein convertase subtilisin/kexin type 9 (PCSK9) regulates expression of low-density lipoprotein (LDL) receptors via receptor internalization and subsequent lysosomal degradation. Thus, an anti-PCSK9 antibody is well known as an anti-hyperlipidemia drug. Here, we aimed to develop vaccine for a long-term treatment of dyslipidemia targeted to PCSK9. In This study, we designed a peptide vaccine for mouse PCSK-9, which consisted of short peptides conjugated to keyhole limpet hemocyanin (KLH) as a carrier protein...
2018: PloS One
https://www.readbyqxmd.com/read/29436897/influence-of-disulfide-bond-isoforms-on-drug-conjugation-sites-in-cysteine-linked-igg2-antibody-drug-conjugates
#12
Lily Liu-Shin, Adam Fung, Arun Malhotra, Gayathri Ratnaswamy
Cysteine-linked antibody-drug conjugates (ADCs) produced from IgG2 monoclonal antibodies (mAbs) are more heterogeneous than ADCs generated from IgG1 mAbs, as IgG2 ADCs are composed of a wider distribution of molecules, typically containing 0 - 12 drug-linkers per antibody. The three disulfide isoforms (A, A/B, and B) of IgG2 antibodies confer differences in solvent accessibilities of the interchain disulfides and contribute to the structural heterogeneity of cysteine-linked ADCs. ADCs derived from either IgG2-A or IgG2-B mAbs were compared to better understand the role of disulfide isoforms on attachment sites and distribution of conjugated species...
February 13, 2018: MAbs
https://www.readbyqxmd.com/read/29436549/enhanced-delivery-of-sirna-to-triple-negative-breast-cancer-cells-in-vitro-and-in-vivo-through-functionalizing-lipid-coated-calcium-phosphate-nanoparticles-with-dual-target-ligands
#13
Jie Tang, Christopher B Howard, Stephen M Mahler, Kristofer J Thurecht, Leaf Huang, Zhi Ping Xu
The conjugation of ligands to nanoparticle platforms for the target delivery of therapeutic agents to the tumor tissue is one of the promising anti-cancer strategies. However, conventional nanoparticle platforms are not so effective in terms of the selectivity and transfection efficiency. In this study, we designed and developed a dual-target drug/gene delivery system based on lipid-coated calcium phosphate (LCP) nanoparticles (NPs) for significantly enhanced siRNA cellular uptake and transfection efficiency...
February 13, 2018: Nanoscale
https://www.readbyqxmd.com/read/29435295/identification-of-candidate-responders-for-anti-pd-l1-pd-1-immunotherapy-rova-t-therapy-or-ezh2-inhibitory-therapy-in-small-cell-lung-cancer
#14
Motonobu Saito, Katsuharu Saito, Kouya Shiraishi, Daichi Maeda, Hiroyuki Suzuki, Yoshihiro Minamiya, Koji Kono, Takashi Kohno, Akiteru Goto
A useful candidate for small-cell lung cancer (SCLC) therapy is immune checkpoint blockade therapy targeting programmed death-1 (PD-1) and its ligand, PD-L1. Furthermore, rovalpituzumab tesirine (Rova-T), a delta-like protein 3 (DLL3)-targeted antibody-drug conjugate, and enhancer of zeste homologue 2 (EZH2) inhibitor are expected to be the first targeted therapy for SCLC. The aim of the present study was to evaluate PD-L1, DLL3 and EZH2 expression in SCLCs to find a candidate responder to those therapies. Immunohistochemical (IHC) staining for PD-L1, DLL3 and EZH2 was performed in 20 patients with SCLC and the clinicopathological characteristics and IHC staining intensity were compared...
February 2018: Molecular and Clinical Oncology
https://www.readbyqxmd.com/read/29435172/promiximab-duocarmycin-a-new-cd56-antibody-drug-conjugates-is-highly-efficacious-in-small-cell-lung-cancer-xenograft-models
#15
Lin Yu, Ying Lu, Yuqin Yao, Yu Liu, Yuxi Wang, Qinhuai Lai, Ruirui Zhang, Wenting Li, Ruixue Wang, Yuyin Fu, Yiran Tao, Shuli Yi, Lantu Gou, Ligong Chen, Jinliang Yang
Small cell lung cancer (SCLC) is of a highly invasive and metastatic lung cancer subtype and there had not been effective targeted therapies. CD56, a cell surface marker highly expressed on most SCLC, is a promising therapeutic target for treatment of this aggressive cancer. In this study, we generated a novel anti-CD56 antibody named promiximab, characterized by high affinity, internalization and tumor specificity. Then, the promiximab was conjugated with a potent DNA alkylating agent duocarmycin via reduced interchain disulfides to yield the promiximab-Duocarmycin (promiximab-DUBA) conjugates...
January 12, 2018: Oncotarget
https://www.readbyqxmd.com/read/29433317/bioconjugation-through-mesitylene-thiol-alkylation
#16
Fernando Albericio, Ivan Tomillero, Gema Perez-Chacon, Beatriz Somovilla-Crespo, Francisco Sanchez-Madrid, Juan M Dominguez, Carmen Cuevas, Juan M Zapata, Hortensia Rodriguez
The design and generation of complex multifunctional macromolecular structures by bioconjugation is a hot topic due to increasing interest conjugates with therapeutic applications. In this regard, the development of efficient, selective, and safe conjugation methods is a major objective. In this report, we describe the use of the bis(bromomethyl)benzene scaffold as a linker for bioconjugation with special emphasis in antibody conjugation. We first performed the monothioalkylation of 1,3,5-tris(bromomethyl)benzene, which rendered the reactive dibromotrimethylbenzyl derivatives to be used in thiol bis-alkylation...
February 13, 2018: Bioconjugate Chemistry
https://www.readbyqxmd.com/read/29425028/high-throughput-cysteine-scanning-to-identify-stable-antibody-conjugation-sites-for-maleimide-and-disulfide-based-linkers
#17
Rachana Ohri, Sunil Bhakta, Aimee Fourie-O'Donohue, Josefa Dela Cruz-Chuh, Siao Ping Tsai, Ryan Cook, Binqing Wei, Carl Ng, Athena W Wong, Aaron B Bos, Farzam Farahi, Jiten Bhakta, Thomas H Pillow, Helga Raab, Richard Vandlen, Paul Polakis, Yichin Liu, Hans Erickson, Jagath R Junutula, Katherine R Kozak
THIOMAB antibody technology utilizes cysteine residues engineered onto an antibody to allow for site-specific conjugation. The technology has enabled the exploration of different attachment sites on the antibody in combination with small molecules, peptides, or proteins to yield antibody conjugates with unique properties. As reported previously ( Shen , B. Q. , et al. ( 2012 ) Nat. Biotechnol. 30 , 184 - 189 ; Pillow , T. H. , et al. ( 2017 ) Chem. Sci. 8 , 366 - 370 ), the specific location of the site of conjugation on an antibody can impact the stability of the linkage to the engineered cysteine for both thio-succinimide and disulfide bonds...
February 9, 2018: Bioconjugate Chemistry
https://www.readbyqxmd.com/read/29424243/forward-i-a-phase-iii-study-of-mirvetuximab-soravtansine-versus-chemotherapy-in-platinum-resistant-ovarian-cancer
#18
Kathleen N Moore, Ignace Vergote, Ana Oaknin, Nicoletta Colombo, Susana Banerjee, Amit Oza, Patricia Pautier, Karim Malek, Michael J Birrer
Mirvetuximab soravtansine, an antibody-drug conjugate that binds with high affinity to folate receptor-α to provide tumor-directed delivery of the potent microtubule-disrupting agent DM4, has emerged as a promising investigational agent for the treatment of ovarian cancer, particularly in the setting of platinum-resistant disease. Here we describe the rationale and design of FORWARD I (NCT02631876), the first randomized, multicenter Phase III study to compare the safety and efficacy of mirvetuximab soravtansine versus investigator's choice of chemotherapy in women with folate receptor-α-positive, platinum-resistant epithelial ovarian, primary peritoneal or fallopian tube cancer...
February 9, 2018: Future Oncology
https://www.readbyqxmd.com/read/29423862/establishing-in-vitro-in-vivo-correlation-for-antibody-drug-conjugate-efficacy-a-pk-pd-modeling-approach
#19
Dhaval K Shah, Frank Loganzo, Nahor Haddish-Berhane, Sylvia Musto, Hallie S Wald, Frank Barletta, Judy Lucas, Tracey Clark, Steve Hansel, Alison Betts
The objective of this manuscript was to establish in vitro-in vivo correlation (IVIVC) between the in vitro efficacy and in vivo efficacy of antibody drug conjugates (ADCs), using a PK/PD modeling approach. Nineteen different ADCs were used to develop IVIVC. In vitro efficacy of ADCs was evaluated using a kinetic cell cytotoxicity assay. The cytotoxicity data obtained from in vitro studies was characterized using a novel mathematical model, parameter estimates from which were used to derive an in vitro efficacy matrix for each ADC, termed as 'in vitro tumor static concentration' (TSCin vitro)...
February 8, 2018: Journal of Pharmacokinetics and Pharmacodynamics
https://www.readbyqxmd.com/read/29421563/lipophilic-indocarbocyanine-conjugates-for-efficient-incorporation-of-enzymes-antibodies-and-small-molecules-into-biological-membranes
#20
Weston J Smith, Huy Tran, James I Griffin, Jessica Jones, Vivian P Vu, Lizanne Nilewski, Nathan Gianneschi, Dmitri Simberg
Decoration of cell membranes with biomolecules, targeting ligands and imaging agents is an emerging strategy to improve functionality of cell-based therapies. Compared to covalent chemistry or genetic expression on the cell surface, lipid painting (i.e., incorporation of lipid-conjugated molecules into the cell bilayer) is a fast, non-damaging and less expensive approach. Previous studies demonstrated excellent incorporation and retention of distearyl indocarbocyanine dye DiI in membranes of cells in vitro and in vivo...
February 2, 2018: Biomaterials
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