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Antibody engineering

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https://www.readbyqxmd.com/read/28817679/increased-half-life-and-enhanced-potency-of-fc-modified-human-pcsk9-monoclonal-antibodies-in-primates
#1
Yijun Shen, Hua Li, Li Zhao, Gang Li, Ben Chen, Qingsong Guo, Bei Gao, Jinsong Wu, Tong Yang, Li Jin, Yong Su
Blocking proprotein convertase subtilisin kexin type 9 (PCSK9) binding to low-density lipoprotein receptor (LDLR) can profoundly lower plasma LDL levels. Two anti-PCKS9 monoclonal antibodies (mAbs), alirocumab and evolocumab, were approved by the FDA in 2015. The recommended dose is 75 mg to 150 mg every two weeks for alirocumab and 140mg every two weeks or 420 mg once a month for evolocumab. This study attempted to improve the pharmacokinetic properties of F0016A, an IgG1 anti-PCKS9 mAb, to generate biologically superior molecules...
2017: PloS One
https://www.readbyqxmd.com/read/28816559/the-role-of-the-lectin-like-oxldl-receptor-lox-1-in-traffic-generated-air-pollution-exposure-mediated-alteration-of-the-brain-microvasculature-in-apolipoprotein-apo-e-knockout-mice
#2
JoAnn Lucero, Usa Suwannasual, Lindsay M Herbert, Jacob D McDonald, Amie K Lund
Recent studies have shown a strong correlation between air pollution-exposure and detrimental outcomes in the central nervous system, including alterations in blood brain barrier (BBB) integrity, neuroinflammation, and neurodegeneration. However, the mechanisms mediating these pathologies have not yet been fully elucidated. We have previously reported that exposure to traffic-generated air pollution results in increased circulating oxidized low-density lipoprotein (oxLDL), associated with alterations in BBB integrity, in atherosclerotic Apolipoprotein E null (ApoE(-/-)) mice...
August 17, 2017: Inhalation Toxicology
https://www.readbyqxmd.com/read/28815272/gold-nanoparticle-based-localized-surface-plasmon-immunosensor-for-staphylococcal-enterotoxin-a-sea-detection
#3
Maroua Ben Haddada, David Hu, Michèle Salmain, Lu Zhang, Chen Peng, Yi Wang, Bo Liedberg, Souhir Boujday
We describe the engineering of stable gold nanoparticle (AuNP) bioconjugates for the detection of staphylococcal enterotoxin A (SEA) using localized surface plasmon resonance (LSPR). Two types of AuNP bioconjugates were prepared by covalently attaching anti-SEA antibody (Ab) or SEA to AuNPs. This was achieved by reacting Traut's reagent with lysine residues of both proteins to generate thiol groups that bind to gold atoms on the AuNP surface. These bioconjugates were characterized in-depth by absorption spectroscopy, cryo-transmission electron microscopy, dynamic light scattering, and zeta potential measurements...
August 16, 2017: Analytical and Bioanalytical Chemistry
https://www.readbyqxmd.com/read/28814834/intracellular-trafficking-of-new-anticancer-therapeutics-antibody-drug-conjugates
#4
REVIEW
Muhammad Kalim, Jie Chen, Shenghao Wang, Caiyao Lin, Saif Ullah, Keying Liang, Qian Ding, Shuqing Chen, Jinbiao Zhan
Antibody-drug conjugate (ADC) is a milestone in targeted cancer therapy that comprises of monoclonal antibodies chemically linked to cytotoxic drugs. Internalization of ADC takes place via clathrin-mediated endocytosis, caveolae-mediated endocytosis, and pinocytosis. Conjugation strategies, endocytosis and intracellular trafficking optimization, linkers, and drugs chemistry present a great challenge for researchers to eradicate tumor cells successfully. This inventiveness of endocytosis and intracellular trafficking has given considerable momentum recently to develop specific antibodies and ADCs to treat cancer cells...
2017: Drug Design, Development and Therapy
https://www.readbyqxmd.com/read/28812882/aberrantly-large-single-channel-conductance-of-polyhistidine-arm-containing-protein-nanopores
#5
Avinash Kumar Thakur, Motahareh Ghahari Larimi, Kristin Gooden, Liviu Movileanu
There have been only a few studies reporting on the impact of polyhistidine affinity tags on the structure, function, and dynamics of proteins. Because of their relatively short size, they are often assumed to have little or no effect on the conformation and activity of a protein. Here, using membrane protein design and single-molecule electrophysiology, we determined that the presence of a hexahistidine arm at the N-terminus of a truncated FhuA-based protein nanopore, leaving the C-terminus untagged, produces an unusual increase in the unitary conductance up to ~8 nS in 1 M KCl...
August 16, 2017: Biochemistry
https://www.readbyqxmd.com/read/28811974/ex-vivo-assessment-of-drug-response-on-breast-cancer-primary-tissue-with-preserved-microenvironments
#6
Manuele G Muraro, Simone Muenst, Valentina Mele, Luca Quagliata, Giandomenica Iezzi, Alexandar Tzankov, Walter P Weber, Giulio C Spagnoli, Savas D Soysal
Interaction between cancerous, non-transformed cells, and non-cellular components within the tumor microenvironment plays a key role in response to treatment. However, short-term culture or xenotransplantation of cancer specimens in immunodeficient animals results in dramatic modifications of the tumor microenvironment, thus preventing reliable assessment of compounds or biologicals of potential therapeutic relevance. We used a perfusion-based bioreactor developed for tissue engineering purposes to successfully maintain the tumor microenvironment of freshly excised breast cancer tissue obtained from 27 breast cancer patients and used this platform to test the therapeutic effect of antiestrogens as well as checkpoint-inhibitors on the cancer cells...
2017: Oncoimmunology
https://www.readbyqxmd.com/read/28811604/multimerization-is-required-for-antigen-binding-activity-of-an-engineered-igm-igg-chimeric-antibody-recognizing-a-skin-related-antigen
#7
Kwesi Teye, Koji Hashimoto, Sanae Numata, Kunihiro Ohta, Marek Haftek, Takashi Hashimoto
Monoclonal antibodies offer great tools for research. We encountered a potentially useful mouse IgM monoclonal antibody whose antigen is expressed in normal skin but lost in human skin cancer. Because IgM is difficult to work with and the antigen was unknown, we decided to convert the IgM (µ) to IgG (γ) version. After cDNA for the antibody was obtained by RACE PCR, we made a series of molecules with different combinations of IgM and IgG domains. Whereas VH-Cµ1-Cµ2-Cγ3 and VH-Cµ1-Cµ2-Hinge-Cγ2-Cγ3 functionally bound to the antigen, VH-Cγ1-Hinge-Cγ2-Cγ3, VH-Cµ1-Hinge-Cγ2-Cγ3, and VH-Cµ1-Cµ2-Cγ2-Cγ3 did not...
August 15, 2017: Scientific Reports
https://www.readbyqxmd.com/read/28809479/natural-seminal-amyloids-as-targets-for-development-of-synthetic-inhibitors-of-hiv-transmission
#8
Daniel A Sheik, Stephen Dewhurst, Jerry Yang
Amyloids refer to a class of protein or peptide aggregates that are heterogeneous in size, morphology, and composition, and are implicated to play a central role in many neurodegenerative and systemic diseases. The strong correlation between biological activity and extent of aggregation of amyloidogenic proteins and peptides has led to an explosion of research efforts to target these materials with synthetic molecules or engineered antibodies to try to attenuate their function in disease pathology. Although many of these efforts to attenuate amyloid function have shown great promise in laboratory settings, the vast majority of work has been focused on targeting amyloids associated with neurologic diseases, which has been met with significant additional challenges that preclude clinical evaluation...
August 15, 2017: Accounts of Chemical Research
https://www.readbyqxmd.com/read/28807998/immunogenicity-and-structures-of-a-rationally-designed-prefusion-mers-cov-spike-antigen
#9
Jesper Pallesen, Nianshuang Wang, Kizzmekia S Corbett, Daniel Wrapp, Robert N Kirchdoerfer, Hannah L Turner, Christopher A Cottrell, Michelle M Becker, Lingshu Wang, Wei Shi, Wing-Pui Kong, Erica L Andres, Arminja N Kettenbach, Mark R Denison, James D Chappell, Barney S Graham, Andrew B Ward, Jason S McLellan
Middle East respiratory syndrome coronavirus (MERS-CoV) is a lineage C betacoronavirus that since its emergence in 2012 has caused outbreaks in human populations with case-fatality rates of ∼36%. As in other coronaviruses, the spike (S) glycoprotein of MERS-CoV mediates receptor recognition and membrane fusion and is the primary target of the humoral immune response during infection. Here we use structure-based design to develop a generalizable strategy for retaining coronavirus S proteins in the antigenically optimal prefusion conformation and demonstrate that our engineered immunogen is able to elicit high neutralizing antibody titers against MERS-CoV...
August 14, 2017: Proceedings of the National Academy of Sciences of the United States of America
https://www.readbyqxmd.com/read/28807154/total-internal-reflectance-fluorescence-imaging-of-genetically-engineered-ryanodine-receptor-targeted-ca-2-probes-in-rat-ventricular-myocytes
#10
Sara Pahlavan, Marin Morad
The details of cardiac Ca(2+) signaling within the dyadic junction remain unclear because of limitations in rapid spatial imaging techniques, and availability of Ca(2+) probes localized to dyadic junctions. To critically monitor ryanodine receptors' (RyR2) Ca(2+) nano-domains, we combined the use of genetically engineered RyR2-targeted pericam probes, (FKBP-YCaMP, Kd=150nM, or FKBP-GCaMP6, Kd=240nM) with rapid total internal reflectance fluorescence (TIRF) microscopy (resolution, ∼80nm). The punctate z-line patterns of FKBP,(2)-targeted probes overlapped those of RyR2 antibodies and sharply contrasted to the images of probes targeted to sarcoplasmic reticulum (SERCA2a/PLB), or cytosolic Fluo-4 images...
September 2017: Cell Calcium
https://www.readbyqxmd.com/read/28804866/virally-vectored-vaccine-delivery-medical-needs-mechanisms-advantages-and-challenges
#11
Daniel D Pinschewer
Vaccines represent one of the most successful chapters in the history of medicine. Over the past decades, the advent of recombinant cDNA technology has enabled the biomedical community to genetically engineer viruses for vaccine delivery purposes. As a starting point, this review evaluates the unmet medical needs, which drive scientists and industry to exploit such fundamentally new technology for human vaccination. The author discusses the molecular functioning, production and safety profile of replication-competent and -deficient viral vector systems, representing two fundamentally distinct classes of "genetic vaccines"...
August 14, 2017: Swiss Medical Weekly
https://www.readbyqxmd.com/read/28800217/engineering-antibody-reactivity-for-efficient-derivatization-to-generate-nav1-7-inhibitory-gptx-1-peptide-antibody-conjugates
#12
Kaustav Biswas, Thomas E Nixey, Justin K Murray, James R Falsey, Li Yin, Hantao Liu, Jacinthe Gingras, Brian E Hall, Brad Herberich, Jerry Ryan Holder, Hongyan Li, Joseph Ligutti, Min-Hwa Jasmine Lin, Dong Liu, Brian D Soriano, Marcus Soto, Linh Tran, Christopher M Tegley, Anrou Zou, Kannan Gunasekaran, Bryan D Moyer, Liz Doherty, Les P Miranda
The voltage-gated sodium channel NaV1.7 is a genetically-validated pain target under investigation for the development of analgesics. A therapeutic with a less frequent dosing regimen would be of value for treating chronic pain, however functional NaV1.7 targeting antibodies are not known. In this report we describe NaV1.7 inhibitory peptide-antibody conjugates as an alternate construct for potential prolonged channel blockade through chemical derivatization of engineered antibodies. We previously identified NaV1...
August 11, 2017: ACS Chemical Biology
https://www.readbyqxmd.com/read/28796529/designed-ankyrin-repeat-proteins-as-her2-targeting-domains-in-chimeric-antigen-receptor-engineered-t-cells
#13
Elizabeth Siegler, Si Li, Yu Jeong Kim, Pin Wang
Chimeric antigen receptor (CAR) engineering is a branch of cancer immunotherapy that equips immune cells to target tumor antigens expressed on the cell surface using antibody-derived single-chain variable fragments (scFvs). However, other antibody mimetics, such as designed ankyrin repeat proteins (DARPins), can also serve as antigen-binding domains in CARs. This study shows that CAR-engineered T (CAR-T) cells utilizing Her2-targeting DARPins G3 and 929 can target human epidermal growth factor receptor 2 (Her2)-overexpressing cancer cells as effectively as CAR-T cells with the scFv 4D5 in vitro, and G3 CAR-T cells can slow or eliminate tumor growth in vivo as effectively as 4D5 CAR-T cells...
June 22, 2017: Human Gene Therapy
https://www.readbyqxmd.com/read/28794021/structure-based-design-of-hepatitis-c-virus-vaccines-that-elicit-neutralizing-antibody-responses-to-a-conserved-epitope
#14
Brian G Pierce, Elisabeth N Boucher, Kurt H Piepenbrink, Monir Ejemel, Chelsea A Rapp, William D Thomas, Eric J Sundberg, Zhiping Weng, Yang Wang
Despite recent advances in therapeutic options, hepatitis C virus (HCV) remains a severe global disease burden, and a vaccine can substantially reduce its incidence. Due to its extremely high sequence variability, HCV can readily escape the immune response, thus an effective vaccine must target conserved, functionally important epitopes. Using the structure of a broadly neutralizing antibody in complex with a conserved linear epitope from the HCV E2 envelope glycoprotein (residues 412-423; epitope I), we performed structure-based design of immunogens to induce antibody responses to this epitope...
August 9, 2017: Journal of Virology
https://www.readbyqxmd.com/read/28792206/rapid-detection-of-infectious-envelope-proteins-by-magnetoplasmonic-toroidal-metasensors
#15
Arash Ahmadivand, Burak Gerislioglu, Pandiaraj Manickam, Ajeet Kaushik, Shekhar Bhansali, Madhavan Nair, Nezih Pala
Unconventional characteristics of magnetic toroidal multipoles have triggered researchers to study these unique resonant phenomena by using both 3D and planar resonators under intense radiation. Here, going beyond conventional planar unit cells, we report on the observation of magnetic toroidal modes using artificially engineered multi-metallic planar plasmonic resonators. The proposed micro-structures consist of iron (Fe) and titanium (Ti) components acting as magnetic resonators and torus, respectively. Our numerical studies and following experimental verifications show that the proposed structures allow for excitation of toroidal dipoles in the terahertz (THz) domain with the experimental Q-factor of ~18...
August 9, 2017: ACS Sensors
https://www.readbyqxmd.com/read/28791022/enhancing-stability-of-camelid-and-shark-single-domain-antibodies-an-overview
#16
REVIEW
Ellen R Goldman, Jinny L Liu, Dan Zabetakis, George P Anderson
Single domain antibodies (sdAbs) are gaining a reputation as superior recognition elements as they combine the advantages of the specificity and affinity found in conventional antibodies with high stability and solubility. Melting temperatures (Tms) of sdAbs cover a wide range from below 50 to over 80°C. Many sdAbs have been engineered to increase their Tm, making them stable until exposed to extreme temperatures. SdAbs derived from the variable heavy chains of camelid and shark heavy chain-only antibodies are termed VHH and VNAR, respectively, and generally exhibit some ability to refold and bind antigen after heat denaturation...
2017: Frontiers in Immunology
https://www.readbyqxmd.com/read/28790855/clinical-targeting-recombinant-immunotoxins-for-cancer-therapy
#17
REVIEW
Meng Li, Zeng-Shan Liu, Xi-Lin Liu, Qi Hui, Shi-Ying Lu, Lin-Lin Qu, Yan-Song Li, Yu Zhou, Hong-Lin Ren, Pan Hu
Recombinant immunotoxins (RITs) are proteins that contain a toxin fused to an antibody or small molecules and are constructed by the genetic engineering technique. RITs can bind to and be internalized by cells and kill cancerous or non-cancerous cells by inhibiting protein synthesis. A wide variety of RITs have been tested against different cancers in cell culture, xenograft models, and human patients during the past several decades. RITs have shown activity in therapy of several kinds of cancers, but different levels of side effects, mainly related to vascular leak syndrome, were also observed in the treated patients...
2017: OncoTargets and Therapy
https://www.readbyqxmd.com/read/28789584/monoclonal-antibodies-technologies-for-early-discovery-and-engineering
#18
Patrick J Kennedy, Carla Oliveira, Pedro L Granja, Bruno Sarmento
Antibodies are essential in modern life sciences biotechnology. Their architecture and diversity allow for high specificity and affinity to a wide array of biochemicals. Combining monoclonal antibody (mAb) technology with recombinant DNA and protein expression links antibody genotype with phenotype. Yet, the ability to select and screen for high affinity binders from recombinantly-displayed, combinatorial libraries unleashes the true power of mAbs and a flood of clinical applications. The identification of novel antibodies can be accomplished by a myriad of in vitro display technologies from the proven (e...
August 8, 2017: Critical Reviews in Biotechnology
https://www.readbyqxmd.com/read/28783665/structural-basis-for-potent-antibody-mediated-neutralization-of-human-cytomegalovirus
#19
Sumana Chandramouli, Enrico Malito, TuongVi Nguyen, Kate Luisi, Danilo Donnarumma, Yi Xing, Nathalie Norais, Dong Yu, Andrea Carfi
Human cytomegalovirus (HCMV) is the leading viral cause of birth defects and organ transplant rejection. The HCMV gH/gL/UL128/UL130/UL131A complex (Pentamer) is the main target of humoral responses and thus a key vaccine candidate. We report two structures of Pentamer bound to human neutralizing antibodies, 8I21 and 9I6, at 3.0 and 5.9 Å resolution, respectively. The HCMV gH/gL architecture is similar to that of Epstein-Barr virus (EBV) except for amino-terminal extensions on both subunits. The extension of gL forms a subdomain composed of a three-helix bundle and a β hairpin that acts as a docking site for UL128/UL130/UL131A...
June 30, 2017: Science Immunology
https://www.readbyqxmd.com/read/28780888/anti-gd2-immunotherapy-for-neuroblastomas
#20
Sameer Sait, Shakeel I Modak
Current therapeutic approaches for high-risk neuroblastoma (HR-NB) include high-dose chemotherapy, surgery and radiotherapy; interventions that are associated with long and short-term toxicities. Effective immunotherapy holds particular promise for improving survival and quality of life by reducing exposure to cytotoxic agents. GD2, a surface glycolipid is the most common target for immunotherapy. Areas covered: We review the status of anti-GD2 immunotherapies currently in clinical use for neuroblastomas and novel GD2-targeted strategies in preclinical development...
August 7, 2017: Expert Review of Anticancer Therapy
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