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Bispecific antibody

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https://www.readbyqxmd.com/read/29151956/strategies-for-bispecific-single-chain-antibody-in-cancer-immunotherapy
#1
REVIEW
Shu-Juan Zhou, Jia Wei, Shu Su, Fang-Jun Chen, Yu-Dong Qiu, Bao-Rui Liu
Genetic engineering has resulted in more than 50 recombinant bispecific antibody formats over the past two decades. Bispecific scFv antibodies represent a successful and promising immunotherapy platform that retargets cytotoxic T cells to tumor cells, with one scFv directed to tumor-associated antigens and the other to T cells. Based on this antibody construct, strategies for both specific tumor targeting and T cell activation are reviewed here. Three distinct types of tumor antigens are considered to optimize specificity and safety in bispecific scFv based treatment: cancer-testis antigens, neo-antigens and virus-associated antigens...
2017: Journal of Cancer
https://www.readbyqxmd.com/read/29150443/kinetic-mechanism-of-controlled-fab-arm-exchange-for-the-formation-of-bispecific-immunoglobulin-g1-antibodies
#2
Dennis R Goulet, Steven J Orcutt, Adam Zwolak, Theo Rispens, Aran Labrijn, Rob N de Jong, William M Atkins, Mark L Chiu
Bispecific antibodies (bsAbs) combine the antigen specificities of two distinct Abs and demonstrate therapeutic promise based on novel mechanisms of action. Among the many platforms for creating bsAbs, controlled Fab-arm exchange (cFAE) has proven useful based on minimal changes to native Ab structure and the simplicity with which bsAbs can be formed from two parental Abs. Despite a published protocol for cFAE and its widespread use in the pharmaceutical industry, the reaction mechanism has not been determined...
November 17, 2017: Journal of Biological Chemistry
https://www.readbyqxmd.com/read/29147028/cancer-bispecific-antibody-directs-t-cells-to-solid-tumours
#3
Megan Cully
No abstract text is available yet for this article.
November 17, 2017: Nature Reviews. Drug Discovery
https://www.readbyqxmd.com/read/29142899/enhancing-the-antitumor-potency-of-t-cells-redirected-by-bispecific-antibodies
#4
EDITORIAL
Chien-Hsing Chang, David M Goldenberg
No abstract text is available yet for this article.
September 2017: Oncoscience
https://www.readbyqxmd.com/read/29139290/decomposing-dynamical-couplings-in-mutated-scfv-antibody-fragments-into-stabilizing-and-destabilizing-effects
#5
Azhagiya Singam Ettayapuram Ramaprasad, Shahid Uddin, Jose Casas-Finet, Donald J Jacobs
Conformational fluctuations within scFv antibodies are characterized by a novel perturbation-response decomposition of molecular dynamics trajectories. Both perturbation and response profiles are stratified into stabilizing and destabilizing conditions. The linker between the VH and VL domains exhibits the dominant dynamical response by being coupled to nearly the entire protein, responding to both stabilizing and destabilizing perturbations. Perturbations within complementarity-determining regions (CDR) induce rich behavior in dynamic response...
November 15, 2017: Journal of the American Chemical Society
https://www.readbyqxmd.com/read/29138497/rapid-purification-of-human-bispecific-antibodies-via-selective-modulation-of-protein-a-binding
#6
Adam Zwolak, Catherine N Leettola, Susan H Tam, Dennis R Goulet, Mehabaw G Derebe, Jose R Pardinas, Songmao Zheng, Rose Decker, Eva Emmell, Mark L Chiu
Methods to rapidly generate high quality bispecific antibodies (BsAb) having normal half-lives are critical for therapeutic programs. Here, we identify 3 mutations (T307P, L309Q, and Q311R or "TLQ") in the Fc region of human IgG1 which disrupt interaction with protein A while enhancing interaction with FcRn. The mutations are shown to incrementally alter the pH at which a mAb elutes from protein A affinity resin. A BsAb comprised of a TLQ mutant and a wild-type IgG1 can be efficiently separated from contaminating parental mAbs by differential protein A elution starting from either a) purified parental mAbs, b) in-supernatant crossed parental mAbs, or c) co-transfected mAbs...
November 14, 2017: Scientific Reports
https://www.readbyqxmd.com/read/29137228/a-native-like-bispecific-antibody-suppresses-the-inflammatory-cytokine-response-by-simultaneously-neutralizing-tumor-necrosis-factor-alpha-and-interleukin-17a
#7
Tianshu Xu, Tianlei Ying, Lili Wang, Xiaohua Douglas Zhang, Ying Wang, Lishan Kang, Tao Huang, Liang Cheng, Liping Wang, Qi Zhao
Anti-tumor necrosis factor (TNF) therapies are successful in the treatment of inflammatory disorders. However, some patients with rheumatoid arthritis (RA) fail to response anti-TNF drugs due to the compensation of other inflammatory signals. In this study, to reduce compensatory responses of interleukin-17A (IL-17A) during TNF-α inhibition, we generated an IgG-like bispecific antibodiy (bsAb) against TNF-α and IL-17A through a combination method of electrostatic Fc pairing and light chain crossover. This bsAb exhibited relatively high stability comparable to natural IgG antibodies, and retained the unaltered affinities to both of two targets...
October 10, 2017: Oncotarget
https://www.readbyqxmd.com/read/29129068/structural-and-functional-characterization-of-a-hole-hole-homodimer-variant-in-a-knob-into-hole-bispecific-antibody
#8
Hui-Min Zhang, Charlene Li, Ming Lei, Victor Lundin, Ho Young Lee, Milady Ninonuevo, Kevin Lin, Guanghui Han, Wendy Sandoval, Dongsheng Lei, Gang Ren, Jennifer Zhang, Hongbin Liu
Bispecific antibodies have great potential to be the next-generation biotherapeutics due to their ability to simultaneously recognize two different targets. Compared to conventional monoclonal antibodies, knob-into-hole bispecific antibodies face unique challenges in production and characterization due to the increase in variant possibilities, such as homodimerization in covalent and non-covalent forms. In this study, a storage- and pH-sensitive hydrophobic interaction chromatography (HIC) profile change was observed for the hole-hole homodimer, and the multiple HIC peaks were explored and shown to be conformational isomers...
November 12, 2017: Analytical Chemistry
https://www.readbyqxmd.com/read/29128855/selective-inhibition-of-ido1-d-1-methyl-tryptophan-d-1mt-effectively-increased-epcam-cd3-bispecific-bite-antibody-mt110-efficacy-against-ido1-hi-breast-cancer-via-enhancing-immune-cells-activity
#9
Ri Hong, Yuhai Zhou, Xiujuan Tian, Lijuan Wang, Xiaoyun Wu
MuS110 and MT110 are BiTE antibodies bispecific for CD3 and EpCAM, which is the most frequently and highly expressed tumor-associated antigen on breast cancer. And pronounced expression of IDO1 has also been reported in breast cancer. Our study aimed to investigate whether IDO1 inhibitor D-1MT combing with MuS110/MT110 had synergistic antitumor effects on IDO expressing EpCAM-positive breast cancer cells in vitro and in vivo. Data suggested that the expression of IDO1 on Epcam-positive breast cancer 4T1 and MCF-7 decreased MuS110/MT110 antitumor efficacy by the suppression of T cells activation in vitro...
November 9, 2017: International Immunopharmacology
https://www.readbyqxmd.com/read/29126850/psma-targeted-bispecific-fab-conjugates-that-engage-t-cells
#10
James T Patterson, Jason Isaacson, Lisa Kerwin, Ghazi Atassi, Rohit Duggal, Damien Bresson, Tong Zhu, Heyue Zhou, Yanwen Fu, Gunnar F Kaufmann
Bioconjugate formats provide alternative strategies for antigen targeting with bispecific antibodies. Here, PSMA-targeted Fab conjugates were generated using different bispecific formats. Interchain disulfide bridging of an αCD3 Fab enabled installation of either the PSMA-targeting small molecule DUPA (SynFab) or the attachment of an αPSMA Fab (BisFab) by covalent linkage. Optimization of the reducing conditions was critical for selective interchain disulfide reduction and good bioconjugate yield. Activity of αPSMA/CD3 Fab conjugates was tested by in vitro cytotoxicity assays using prostate cancer cell lines...
October 6, 2017: Bioorganic & Medicinal Chemistry Letters
https://www.readbyqxmd.com/read/29120405/site-specific-antibody-conjugation-for-adc-and-beyond
#11
REVIEW
Qun Zhou
Antibody-drug conjugates (ADCs) have become a promising class of antitumor agents with four conjugates being approved by regulatory agencies for treating cancer patients. To improve the conventional conjugations that are currently applied to generate these heterogeneous products, various site-specific approaches have been developed. These methods couple cytotoxins or chemotherapeutic drugs to specifically defined sites in antibody molecules including cysteine, glutamine, unnatural amino acids, short peptide tags, and glycans...
November 9, 2017: Biomedicines
https://www.readbyqxmd.com/read/29118005/redirecting-t-cells-to-hematological-malignancies-with-bispecific-antibodies
#12
Mireya Paulina Velasquez, Challice L Bonifant, Stephen Gottschalk
There is a need to improve outcomes for patients with recurrent and/or refractory hematological malignancies. Immunotherapy holds the promise to meet this need since it does not rely on the cytotoxic mechanism of conventional therapies. Among different forms of immunotherapy, redirecting T cells to hematological malignancies with bispecific antibodies (BsAbs) is an attractive strategy. BsAbs are an 'off-the-shelf' product that is easily scalable in contrast to adoptive T-cell therapies. Among these, the bispecific T-cell engager (BiTE) blinatumomab has emerged as the most successful BsAb to date...
November 8, 2017: Blood
https://www.readbyqxmd.com/read/29107292/fgf21-mimetic-antibody-stimulates-ucp1-independent-brown-fat-thermogenesis-via-fgfr1-%C3%AE-klotho-complex-in-non-adipocytes
#13
Mark Z Chen, Joshua C Chang, Jose Zavala-Solorio, Lance Kates, Minh Thai, Annie Ogasawara, Xiaobo Bai, Sean Flanagan, Victor Nunez, Khanhky Phamluong, James Ziai, Robert Newman, Søren Warming, Ganesh Kolumam, Junichiro Sonoda
OBJECTIVE: Fibroblast Growth Factor 21 (FGF21) is a potent stimulator of brown fat thermogenesis that improves insulin sensitivity, ameliorates hepatosteatosis, and induces weight loss by engaging the receptor complex comprised of Fibroblast Growth Factor Receptor 1 (FGFR1) and the requisite coreceptor βKlotho. Previously, recombinant antibody proteins that activate the FGFR1/βKlotho complex were proposed to act as an FGF21-mimetic; however, in vivo action of these engineered proteins has not been well studied...
November 2017: Molecular Metabolism
https://www.readbyqxmd.com/read/29107128/targeted-cancer-therapy-through-antibody-fragments-decorated-nanomedicines
#14
REVIEW
Abbas Alibakhshi, Fatemeh Abarghooi Kahaki, Shahrzad Ahangarzadeh, Hajar Yaghoobi, Fatemeh Yarian, Roghaye Arezumand, Javad Ranjbari, Ahad Mokhtarzadeh, Miguel de la Guardia
Active targeting in cancer nanomedicine, for improved delivery of agents and diagnose, has been reviewed as a successful way for facilitating active uptake of theranostic agents by the tumor cells. The application of a targeting moiety in the targeted carrier complexes can play an important role in differentiating between tumor and healthy tissues. The pharmaceutical carriers, as main part of complexes, can be polymeric nanoparticles, micelles, liposomes, nanogels and carbon nanotubes. The antibodies are among the natural ligands with highest affinity and specificity to target pharmaceutical nanoparticle conjugates...
November 3, 2017: Journal of Controlled Release: Official Journal of the Controlled Release Society
https://www.readbyqxmd.com/read/29082835/efficacy-and-safety-of-bispecific-t-cell-engager-blinatumomab-and-the-potential-to-improve-leukemia-free-survival-in-b-cell-acute-lymphoblastic-leukemia
#15
Josep-Maria Ribera
Immunotherapy is a promising modality of treatment of neoplastic diseases, including acute lymphoblastic leukemia (ALL). The CD19/CD3-bispecific T cell-engaging (BiTE®) monoclonal antibody blinatumomab can transiently bind cytotoxic T cells to CD19(+) target B cells of ALL inducing their serial lysis. Areas covered: This review focuses on the efficacy and safety of blinatumomab used for the treatment of relapsed/refractory (R/R) ALL and minimal residual disease (MRD)-positive B-cell precursor (BCP) ALL in adults and children, as well as the future prospects of this drug in the treatment of ALL...
October 30, 2017: Expert Review of Hematology
https://www.readbyqxmd.com/read/29071472/immune-interventions-to-eliminate-the-hiv-reservoir
#16
Denise C Hsu, Jintanat Ananworanich
Inducing HIV remission is a monumental challenge. A potential strategy is the "kick and kill" approach where latently infected cells are first activated to express viral proteins and then eliminated through cytopathic effects of HIV or immune-mediated killing. However, pre-existing immune responses to HIV cannot eradicate HIV infection due to the presence of escape variants, inadequate magnitude, and breadth of responses as well as immune exhaustion. The two major approaches to boost immune-mediated elimination of infected cells include enhancing cytotoxic T lymphocyte mediated killing and harnessing antibodies to eliminate HIV...
October 26, 2017: Current Topics in Microbiology and Immunology
https://www.readbyqxmd.com/read/29070979/recombinant-antibodies-to-arm-cytotoxic-lymphocytes-in-cancer-immunotherapy
#17
REVIEW
Joachim Koch, Michael Tesar
Immunotherapy has the potential to support and expand the body's own armamentarium of immune effector functions, which have been circumvented during malignant transformation and establishment of cancer and is presently considered to be the most promising treatment option for cancer patients. Recombinant antibody technologies have led to a multitude of novel antibody formats, which are in clinical development and hold great promise for future therapies. Among these formats, bispecific antibodies are extremely versatile due to their high efficacy to recruit and activate anti-tumoral immune effector cells, their excellent safety profile, and the opportunity for use in combination with cellular therapies...
September 2017: Transfusion Medicine and Hemotherapy
https://www.readbyqxmd.com/read/29067496/a-cd3-bispecific-molecule-targeting-p-cadherin-demonstrates-t-cell-mediated-regression-of-established-solid-tumors-in-mice
#18
Timothy S Fisher, Andrea T Hooper, Justin Lucas, Tracey H Clark, Allison K Rohner, Bryan Peano, Mark W Elliott, Konstantinos Tsaparikos, Hui Wang, Jonathan Golas, Maria Gavriil, Nahor Haddish-Berhane, Lioudmila Tchistiakova, Hans-Peter Gerber, Adam R Root, Chad May
Strong evidence exists supporting the important role T cells play in the immune response against tumors. Still, the ability to initiate tumor-specific immune responses remains a challenge. Recent clinical trials suggest that bispecific antibody-mediated retargeted T cells are a promising therapeutic approach to eliminate hematopoietic tumors. However, this approach has not been validated in solid tumors. PF-06671008 is a dual-affinity retargeting (DART(®))-bispecific protein engineered with enhanced pharmacokinetic properties to extend in vivo half-life, and designed to engage and activate endogenous polyclonal T cell populations via the CD3 complex in the presence of solid tumors expressing P-cadherin...
October 24, 2017: Cancer Immunology, Immunotherapy: CII
https://www.readbyqxmd.com/read/29059207/targeting-mesothelin-receptors-with-drug-loaded-bacterial-nanocells-suppresses-human-mesothelioma-tumour-growth-in-mouse-xenograft-models
#19
Mohamed A Alfaleh, Christopher B Howard, Ilya Sedliarou, Martina L Jones, Reema Gudhka, Natasha Vanegas, Jocelyn Weiss, Julia H Suurbach, Christopher J de Bakker, Michael R Milne, Bree A Rumballe, Jennifer A MacDiarmid, Himanshu Brahmbhatt, Stephen M Mahler
Human malignant mesothelioma is a chemoresistant tumour that develops from mesothelial cells, commonly associated with asbestos exposure. Malignant mesothelioma incidence rates in European countries are still rising and Australia has one of the highest burdens of malignant mesothelioma on a population basis in the world. Therapy using systemic delivery of free cytotoxic agents is associated with many undesirable side effects due to non-selectivity, and is thus dose-limited which limits its therapeutic potential...
2017: PloS One
https://www.readbyqxmd.com/read/29050699/how-should-we-treat-a-patient-with-relapsed-ph-negative-b-all-and-what-novel-approaches-are-being-investigated
#20
REVIEW
Nicola Gökbuget
Despite significant improvements in outcome of newly diagnosed B-precursor ALL, the results in relapsed or refractory adult ALL are overall poor. Large retrospective studies revealed significant differences in terms of outcome, with particularly poor response rates in early or refractory relapses, whereas late relapses usually respond very well to repeated standard induction. Particularly new immunotherapy compounds like the CD19 bispecific antibody Blinatumomab and the conjugated CD22 antibody Inotuzumab yielded promising response rates compared to standard therapies in randomised trials...
September 2017: Best Practice & Research. Clinical Haematology
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