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Antibody engineering

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https://www.readbyqxmd.com/read/28546337/pet-guided-evaluation-and-optimization-of-internalized-antibody-drug-conjugates-targeting-erythropoietin-producing-hepatoma-a2-receptor
#1
Orit Jacobson, Haojun Chen, Gang Niu, Dale O Kiesewetter, Qing Li, Gengcheng Yang, Kimberly Cook, Lan Xu, William Dall'Acqua, Ping Tsui, Li Peng, Xiaoyuan Chen
The erythropoietin producing hepatoma A2 receptor (EphA2) is a tyrosine kinase overexpressed by tumor stroma and cancer cells. High expression level of EphA2 predicts poor prognosis, correlating with disease progression and metastasis. Therefore, EphA2 is a relevant therapeutic target for human cancer. Antibodies, selectively bound to EphA2 receptor, can induce rapid receptor phosphorylation that results in antibody internalization and degradation. This internalization mechanism has been exploited with the development of antibody-drug conjugates (ADC) for cancer chemotherapy...
May 25, 2017: Journal of Nuclear Medicine: Official Publication, Society of Nuclear Medicine
https://www.readbyqxmd.com/read/28544881/mammalian-systems-biotechnology-reveals-global-cellular-adaptations-in-a-recombinant-cho-cell-line
#2
Faraaz Noor Khan Yusufi, Meiyappan Lakshmanan, Ying Swan Ho, Bernard Liat Wen Loo, Pramila Ariyaratne, Yuansheng Yang, Say Kong Ng, Tessa Rui Min Tan, Hock Chuan Yeo, Hsueh Lee Lim, Sze Wai Ng, Ai Ping Hiu, Chung Ping Chow, Corrine Wan, Shuwen Chen, Gavin Teo, Gao Song, Ju Xin Chin, Xiaoan Ruan, Ken Wing Kin Sung, Wei-Shou Hu, Miranda Gek Sim Yap, Muriel Bardor, Niranjan Nagarajan, Dong-Yup Lee
Effective development of host cells for therapeutic protein production is hampered by the poor characterization of cellular transfection. Here, we employed a multi-omics-based systems biotechnology approach to elucidate the genotypic and phenotypic differences between a wild-type and recombinant antibody-producing Chinese hamster ovary (CHO) cell line. At the genomic level, we observed extensive rearrangements in specific targeted loci linked to transgene integration sites. Transcriptional re-wiring of DNA damage repair and cellular metabolism in the antibody producer, via changes in gene copy numbers, was also detected...
May 24, 2017: Cell Systems
https://www.readbyqxmd.com/read/28542473/stably-engineered-nanobubbles-and-ultrasound-an-effective-platform-for-enhanced-macromolecular-delivery-to-representative-cells-of-the-retina
#3
Sachin S Thakur, Micheal S Ward, Amirali Popat, Nicole B Flemming, Marie-Odile Parat, Nigel L Barnett, Harendra S Parekh
Herein we showcase the potential of ultrasound-responsive nanobubbles in enhancing macromolecular permeation through layers of the retina, ultimately leading to significant and direct intracellular delivery; this being effectively demonstrated across three relevant and distinct retinal cell lines. Stably engineered nanobubbles of a highly homogenous and echogenic nature were fully characterised using dynamic light scattering, B-scan ultrasound and transmission electron microscopy (TEM). The nanobubbles appeared as spherical liposome-like structures under TEM, accompanied by an opaque luminal core and darkened corona around their periphery, with both features indicative of efficient gas entrapment and adsorption, respectively...
2017: PloS One
https://www.readbyqxmd.com/read/28541812/engineering-humanized-antibody-framework-sequences-for-optimal-site-specific-conjugation-of-cytotoxins
#4
Jared L Spidel, Earl F Albone, Xin Cheng, Benjamin Vaessen, Sara Jacob, Andrew Z Milinichik, Arielle Verdi, J Bradford Kline, Luigi Grasso
The prevailing techniques used to generate antibody-drug conjugates (ADCs) involve random conjugation of the linker-drug to multiple lysines or cysteines in the antibody. Engineering natural and non-natural amino acids into an antibody has been demonstrated to be an effective strategy to produce homogeneous ADC products with defined drug-to-antibody ratios. We recently reported an efficient residue-specific conjugation technology (RESPECT) where thiol-reactive payloads can be efficiently conjugated to a native unpaired cysteine in position 80 (C80) of rabbit light chains...
May 25, 2017: MAbs
https://www.readbyqxmd.com/read/28539655/angiopoietin-1-enhances-neutrophil-chemotaxis-in-vitro-and-migration-in-vivo-through-interaction-with-cd18-and-release-of-ccl4
#5
Amanda Burnett, Ingrid Gomez, David Davila De Leon, Mark Ariaans, Pavlos Progias, Richard A Kammerer, Guillermo Velasco, Marie Marron, Paul Hellewell, Victoria Ridger
Angiopoietins are a family of growth factors that are ligands for the tyrosine kinase receptor, Tie2. Angiopoietin 1 (Ang-1) is agonistic for Tie2, plays a key role in blood vessel maturation and stability and has been shown to possess anti-inflammatory properties. However, Tie2 expression has been demonstrated on human neutrophils and the observation that neutrophils migrate in response to Ang-1 in vitro has confounded research into its exact role in inflammation as well as its potential use as a therapeutic agent...
May 24, 2017: Scientific Reports
https://www.readbyqxmd.com/read/28536786/future-prospects-for-human-tissue-engineered-urethra-transplantation-decellularization-and-recellularization-based-urethra-regeneration
#6
Abdol-Mohammad Kajbafzadeh, Reza Abbasioun, Shabnam Sabetkish, Nastaran Sabetkish, Parvin Rahmani, Kamyar Tavakkolitabassi, Hamid Arshadi
To evaluate the histological characteristics of decellularized human urethra after transplantation into the rat omentum and compare in vivo cell seeding with perfusion-based and cell sheet urethral regeneration. Eight adult human male urethras accompanied with the surrounding corpus spongiosum were obtained. The tissues were decellularized with detergent-based method. The efficacy of decellularization and extracellular matrix preservation was evaluated by several techniques. Decellularized scaffolds were transplanted into the omentum of 12 male rats and located into the scrotum...
May 23, 2017: Annals of Biomedical Engineering
https://www.readbyqxmd.com/read/28536379/plant-toxin-based-immunotoxins-for-cancer-therapy-a-short-overview
#7
REVIEW
Letizia Polito, Alice Djemil, Massimo Bortolotti
Immunotoxins are chimeric proteins obtained by linking a toxin to either an intact antibody or an antibody fragment. Conjugation can be obtained by chemical or genetic engineering, where the latter yields recombinant conjugates. An essential requirement is that the target molecule recognized by the antibody is confined to the cell population to be deleted, or at least that it is not present on stem cells or other cell types essential for the organism's survival. Hundreds of different studies have demonstrated the potential for applying immunotoxins to many models in pre-clinical studies and in clinical trials...
June 1, 2016: Biomedicines
https://www.readbyqxmd.com/read/28534525/covalently-linked-dengue-virus-envelope-glycoprotein-dimers-reduce-exposure-of-the-immunodominant-fusion-loop-epitope
#8
Alexander Rouvinski, Wanwisa Dejnirattisai, Pablo Guardado-Calvo, Marie-Christine Vaney, Arvind Sharma, Stéphane Duquerroy, Piyada Supasa, Wiyada Wongwiwat, Ahmed Haouz, Giovanna Barba-Spaeth, Juthathip Mongkolsapaya, Félix A Rey, Gavin R Screaton
A problem in the search for an efficient vaccine against dengue virus is the immunodominance of the fusion loop epitope (FLE), a segment of the envelope protein E that is buried at the interface of the E dimers coating mature viral particles. Anti-FLE antibodies are broadly cross-reactive but poorly neutralizing, displaying a strong infection enhancing potential. FLE exposure takes place via dynamic 'breathing' of E dimers at the virion surface. In contrast, antibodies targeting the E dimer epitope (EDE), readily exposed at the E dimer interface over the region of the conserved fusion loop, are very potent and broadly neutralizing...
May 23, 2017: Nature Communications
https://www.readbyqxmd.com/read/28529904/mini-review-of-conventional-and-hypofractionated-radiation-therapy-combined-with-immunotherapy-for-non-small-cell-lung-cancer
#9
REVIEW
Allison M Campbell, Roy H Decker
A successful antitumoral response requires immunological activation as well as an antigenic pool capable of stimulating both the innate and the adaptive immune system. Recent advances in immunotherapy have been aimed at boosting the activation status of the innate and adaptive immune system, including cytokine administration, monoclonal antibodies engineered to target high yield elements in oncogenic signaling pathways, cancer vaccines, and checkpoint inhibitors. Herein, we examine the ways that radiation therapy induced cell death provides a pool of stimulus antigen, and draw parallels from the immunobiology of autoimmunity to explore how the immunogenicity of antigen derived from radiation-induced cell death might augment the antitumoral response...
April 2017: Translational Lung Cancer Research
https://www.readbyqxmd.com/read/28525897/a-cellular-platform-for-the-evaluation-of-immune-checkpoint-molecules
#10
Sabrina Jutz, Annika Hennig, Wolfgang Paster, Ömer Asrak, Dejana Dijanovic, Florian Kellner, Winfried F Pickl, Johannes B Huppa, Judith Leitner, Peter Steinberger
Blockade of the T cell coinhibitory molecules CTLA-4 and PD-1 has clinical utility to strengthen T cell responses. In addition to these immune checkpoints an ever-growing number of molecules has been implicated in generating coinhibitory signals in T cells. However, investigating coinhibitory molecules in primary human cells is complicated by the restricted expression and promiscuity of both coinhibitory receptors and their ligands. Here we have evaluated the potential of fluorescence-based transcriptional reporters based on the human Jurkat T cell line in conjunction with engineered T cell stimulator cell lines for investigating coinhibitory pathways...
May 4, 2017: Oncotarget
https://www.readbyqxmd.com/read/28525756/immunization-elicited-broadly-protective-antibody-reveals-ebolavirus-fusion-loop-as-a-site-of-vulnerability
#11
Xuelian Zhao, Katie A Howell, Shihua He, Jennifer M Brannan, Anna Z Wec, Edgar Davidson, Hannah L Turner, Chi-I Chiang, Lin Lei, J Maximilian Fels, Hong Vu, Sergey Shulenin, Ashley N Turonis, Ana I Kuehne, Guodong Liu, Mi Ta, Yimeng Wang, Christopher Sundling, Yongli Xiao, Jennifer S Spence, Benjamin J Doranz, Frederick W Holtsberg, Andrew B Ward, Kartik Chandran, John M Dye, Xiangguo Qiu, Yuxing Li, M Javad Aman
While neutralizing antibodies are highly effective against ebolavirus infections, current experimental ebolavirus vaccines primarily elicit species-specific antibody responses. Here, we describe an immunization-elicited macaque antibody (CA45) that clamps the internal fusion loop with the N terminus of the ebolavirus glycoproteins (GPs) and potently neutralizes Ebola, Sudan, Bundibugyo, and Reston viruses. CA45, alone or in combination with an antibody that blocks receptor binding, provided full protection against all pathogenic ebolaviruses in mice, guinea pigs, and ferrets...
May 18, 2017: Cell
https://www.readbyqxmd.com/read/28522587/preclinical-evaluation-of-medi0641-a-pyrrolobenzodiazepine-conjugated-antibody-drug-conjugate-targeting-5t4
#12
Jay Harper, Christopher Lloyd, Nazzareno Dimasi, Dorin Toader, Rose Marwood, Leeanne Lewis, David Bannister, Jelena Jovanovic, Ryan Fleming, Francois d'Hooge, Shenlan Mao, Allison M Marrero, Martin Korade, Patrick Strout, Linda Xu, Cui Chen, Leslie Wetzel, Shannon Breen, Lilian van Vlerken-Ysla, Sanjoo Jalla, Marlon Rebelatto, Helen Zhong, Elaine M Hurt, Mary Jane Hinrichs, Keven Huang, Philip W Howard, David A Tice, Robert E Hollingsworth, Ronald Herbst, Adeela Kamal
Antibody-drug conjugates (ADCs) are used to selectively deliver cytotoxic agents to tumors and have the potential for increased clinical benefit to cancer patients. 5T4 is an oncofetal antigen overexpressed on the cell surface in many carcinomas on both bulk tumor cells as well as cancer stem cells (CSCs), has very limited normal tissue expression, and can internalize when bound by an antibody. An anti-5T4 antibody was identified and optimized for efficient binding and internalization in a target-specific manner, and engineered cysteines were incorporated into the molecule for site-specific conjugation...
May 18, 2017: Molecular Cancer Therapeutics
https://www.readbyqxmd.com/read/28516782/exploring-site-specific-n-glycosylation-of-hek293-and-plant-produced-human-iga-isotypes
#13
Kathrin Göritzer, Daniel Maresch, Friedrich Altmann, Christian Obinger, Richard Strasser
The full potential of recombinant Immunoglobulin A as therapeutic antibody is not fully explored, owing to the fact that structure-function relationships of these extensively glycosylated proteins are not well understood. Here monomeric IgA1, IgA2m(1), and IgA2m(2) variants of the anti-HER2 antibody (IgG1) trastuzumab were expressed in glyco-engineered Nicotiana benthamiana plants and in human HEK293-6E cells. All three IgA isotypes were purified and subjected to biophysical and biochemical characterization...
May 26, 2017: Journal of Proteome Research
https://www.readbyqxmd.com/read/28515058/tissue-engineered-cartilage-constructed-by-a-biotin-conjugated-anti-cd44-avidin-binding-technique-for-the-repairing-of-cartilage-defects-in-the-weight-bearing-area-of-knee-joints-in-pigs
#14
H Lin, J Zhou, L Cao, H R Wang, J Dong, Z R Chen
OBJECTIVES: The lack of effective treatment for cartilage defects has prompted investigations using tissue engineering techniques for their regeneration and repair. The success of tissue-engineered repair of cartilage may depend on the rapid and efficient adhesion of transplanted cells to a scaffold. Our aim in this study was to repair full-thickness defects in articular cartilage in the weight-bearing area of a porcine model, and to investigate whether the CD44 monoclonal antibody biotin-avidin (CBA) binding technique could provide satisfactory tissue-engineered cartilage...
May 2017: Bone & Joint Research
https://www.readbyqxmd.com/read/28514874/oncolytic-recombinant-vesicular-stomatitis-virus-vsv-is-nonpathogenic-and-non-transmissible-in-pigs-a-natural-host-of-vsv
#15
Lauro Velazquez-Salinas, Shruthi Naik, Steven Pauszek, Kah-Whye Peng, Stephen J Russell, Luis Rodriguez
Vesicular stomatitis virus (VSV) is a negative-stranded RNA virus that naturally causes disease in livestock including horses, cattle and pigs. The two main identified VSV strains are the New Jersey (VSNJV) and Indiana (VSIV) strains. VSV is a rapidly replicating, potently immunogenic virus that has been engineered to develop novel oncolytic therapies for cancer treatment. Swine are a natural host for VSV and provide a relevant and well-established model, amenable to biological sampling to monitor virus shedding and neutralizing antibodies...
May 17, 2017: Human Gene Therapy. Clinical Development
https://www.readbyqxmd.com/read/28514851/blood-brain-barrier-penetrating-biologic-tnf-%C3%AE-inhibitor-for-alzheimer-s-disease
#16
Rudy Chang, Jillian Knox, Jae Chang, Aram Derbedrossian, Vitaly Vasilevko, David Cribbs, Ruben J Boado, William M Pardridge, Rachita Sumbria
OBJECTIVE: Tumor necrosis factor alpha (TNF-α) driven processes are involved at multiple stages of Alzheimer's disease (AD) pathophysiology and disease progression. Biologic TNF-α inhibitors (TNFIs) are the most potent class of TNFIs but cannot be developed for AD since these macromolecules do not cross the blood-brain barrier (BBB). A BBB-penetrating TNFI was engineered by the fusion of the extracellular domain of the type II human TNF receptor (TNFR) to a chimeric monoclonal antibody (MAb) against the mouse transferrin receptor (TfR), designated as the cTfRMAb-TNFR fusion protein...
May 17, 2017: Molecular Pharmaceutics
https://www.readbyqxmd.com/read/28514732/structural-basis-of-a-novel-heterodimeric-fc-for-bispecific-antibody-production
#17
Hudie Wei, Haiyan Cai, Yuhao Jin, Pilin Wang, Qingqing Zhang, Yihui Lin, Weixiao Wang, Jinke Cheng, Naiyan Zeng, Ting Xu, Aiwu Zhou
Bispecific antibodies provide an efficient tool for combinational clinical therapy. Here we have engineered a heterodimeric Fc for bispecific antibodies production by combining the knob-into-hole and electrostatic steering strategies where a bulky hydrophobic residue Phe405 of the IgG CH3 interface is mutated to a charged residue Lys and Lys409 of the corresponding CH3 domain is mutated to Ala. The crystal structure of this Fc heterodimer solved here at 2.7Å resolution revealed how these two mutations resulted a complementary binding interface and explained why F405K mutation could effectively inhibit Fc homodimer formation during protein expression...
May 2, 2017: Oncotarget
https://www.readbyqxmd.com/read/28514686/glycine-substitution-at-helix-to-coil-transitions-facilitates-the-structural-determination-of-a-stabilized-subtype-c-hiv-envelope-glycoprotein
#18
Javier Guenaga, Fernando Garces, Natalia de Val, Robyn L Stanfield, Viktoriya Dubrovskaya, Brett Higgins, Barbara Carrette, Andrew B Ward, Ian A Wilson, Richard T Wyatt
Advances in HIV-1 envelope glycoprotein (Env) design generate native-like trimers and high-resolution clade A, B, and G structures and elicit neutralizing antibodies. However, a high-resolution clade C structure is critical, as this subtype accounts for the majority of HIV infections worldwide, but well-ordered clade C Env trimers are more challenging to produce due to their instability. Based on targeted glycine substitutions in the Env fusion machinery, we defined a general approach that disfavors helical transitions leading to post-fusion conformations, thereby favoring the pre-fusion state...
May 16, 2017: Immunity
https://www.readbyqxmd.com/read/28513912/improving-theranostics-in-pancreatic-cancer
#19
Jeremy King, Michael Bouvet, Gagandeep Singh, John Williams
BACKGROUND: Pancreatic cancer is the fourth most deadly cancer in the United States, and is expected to be the second most deadly by 2030. The major difficulty in treating pancreatic cancer is the late onset of symptoms. Generally, patients show metastatic disease by the time of diagnosis, with a survival rate of 5% beyond 5 years. In patients without metastatic disease, surgical resection increases 5 year survival rate to 25%. The remaining 75% succumb to undetected metastases. Clearly, improvements to both detection, surgical intervention, and therapeutic strategies will be needed to improve patient outcome in pancreatic cancer...
May 17, 2017: Journal of Surgical Oncology
https://www.readbyqxmd.com/read/28512452/towards-identifying-protective-b-cell-epitopes-the-pspa-story
#20
REVIEW
Naeem Khan, Arif T Jan
Pneumococcal surface protein A (PspA) is one of the most abundant cell surface protein of Streptococcus pneumoniae (S. pneumoniae). PspA variants are structurally and serologically diverse and help evade complement-mediated phagocytosis of S. pneumoniae, which is essential for its survival in the host. PspA is currently been screened for employment in the generation of more effective (serotype independent) vaccine to overcome the limitations of polysaccharide based vaccines, providing serotype specific immune responses...
2017: Frontiers in Microbiology
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