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Joana M Murad, David J Graber, Charles L Sentman
Chimeric antigen receptors (CAR)-T cell therapy has recently made promising advances towards treatment of B-cell malignancies. This approach makes use of an antibody-derived single chain variable fragment (scFv)-based CAR to target the CD19 antigen. Currently scFvs are the most common strategy for creation of CARs, but tumor cells can also be targeted using non-antibody based approaches with designs focused on the interaction between natural receptors and their ligands. This emerging strategy has been used in unique ways to target multiple tumor types, including solid and haematological malignancies...
June 2018: Best Practice & Research. Clinical Haematology
De-Xiu Bu, Reshma Singh, Eugene E Choi, Marco Ruella, Selene Nunez-Cruz, Keith G Mansfield, Paul Bennett, Nathanial Barton, Qilong Wu, Jiquan Zhang, Yongqiang Wang, Lai Wei, Shawn Cogan, Tucker Ezell, Shree Joshi, Kellie J Latimer, Brian Granda, William R Tschantz, Regina M Young, Heather A Huet, Celeste J Richardson, Michael C Milone
Multiple myeloma has a continued need for more effective and durable therapies. B cell maturation antigen (BCMA), a plasma cell surface antigen and member of the tumor necrosis factor (TNF) receptor superfamily, is an attractive target for immunotherapy of multiple myeloma due to its high prevalence on malignant plasma cells. The current work details the pre-clinical evaluation of BCMA expression and development of a chimeric antigen receptor (CAR) targeting this antigen using a fully human single chain variable fragment (scFv)...
May 25, 2018: Oncotarget
So Hee Dho, Soo Yong Kim, Chaeuk Chung, Eun Ha Cho, So-Young Lee, Ji Young Kim, Lark Kyun Kim, Sung-Won Min, Jichul Lee, Sung Hee Jung, Jae Cheong Lim
Decay-accelerating factor (CD55 or DAF) inhibits complement-dependent cytotoxicity. We determined that CD55 is overexpressed in 76.47% of human non-small cell lung cancer tissue specimens. We therefore developed a lutetium-177-labeled chimeric monoclonal antibody against CD55. CD55-specific single-chain variable fragment (scFv) was selected from a naïve chicken scFv phage-display library, converted to IgG, and radiolabeled with lutetium-177 to generate a 177 Lu-anti-CD55 antibody. We then charaterized the biodistribution of this antibody in a mouse model of pleural metastatic lung cancer...
June 12, 2018: Scientific Reports
Jan-G Vermeulen, Felicity Burt, Esta van Heerden, Errol Cason, Muriel Meiring
The development of therapeutic antibodies in their various forms has been a constant challenge since the development of the first monoclonal antibodies in 1975. This is especially true for the development of therapeutic single chain variable (scFv) fragments in Escherichia coli. In a previous study the selection of a tissue factor inhibiting single chain variable fragment (TFI-scFv) isolated from the Thomlinson I + J phage libraries was described. Although the initial findings were promising, additional characterization of the antibody fragment and subsequent application was hampered due low protein yield...
June 9, 2018: Protein Expression and Purification
João C Fernandes
Over the past decades, conventional antibodies have been dissected through different strategies into smaller antigen-binding fragments. Therapeutic solutions built on such fragments can offer several advantages, including the capacity to access challenging epitopes, reduced immunogenicity, lower production costs, and higher stability. Although the development of antibody fragments for cancer therapy has received more attention than any other potential therapeutic application, the development of pharmacological tools based on these molecules for the treatment of autoimmune diseases (AIDs) has been growing at a fast pace...
June 8, 2018: Drug Discovery Today
F Verachi, Z Percario, P Di Bonito, E Affabris, C Amici, L Accardi
In Human Papillomaviruses- (HPV-) associated carcinogenesis, continuous expression of the E6 oncoprotein supports its value as a potential target for the development of diagnostics and therapeutics for HPV cancer. We previously reported that the I7 single-chain antibody fragment (scFv) specific for HPV16 E6, expressed as an intrabody by retroviral system, could inhibit significantly the growth of cervical cancer cells in vitro and was even able to reduce tumor development in experimental HPV-related cancer models...
2018: BioMed Research International
Shirin Khajeh, Mohammad Reza Tohidkia, Ayuob Aghanejad, Tayebeh Mehdipour, Farzaneh Fathi, Yadollah Omidi
Glycine-extended gastrin 17 (G17-Gly), a dominant processing intermediate of gastrin gene, has been implicated in the development or maintenance of colorectal cancers (CRCs). Hence, neutralizing G17-Gly activity by antibody entities can provide a potential therapeutic strategy in the patients with CRCs. To this end, we isolated fully human antibody fragments from a phage antibody library through biopanning against different epitopes of G17-Gly in order to obtain the highest possible antibody diversity. ELISA screening and sequence analysis identified 2 scFvs and 4 VL antibody fragments...
June 9, 2018: Artificial Cells, Nanomedicine, and Biotechnology
Hossein Safarpour, Morteza Shahmirzaie, Elham Rezaee, Mahmood Barati, Mohammad Reza Safarnejad, Farshad H Shirazi
Tumor necrosis factor alpha (TNF-α) expression amplifies to excess amounts in several disorders such as rheumatoid arthritis and psoriasis. Although, Anti-TNF biologics have revolutionized the treatment of these autoimmune diseases, formation of anti-drug antibodies (ADA) has dramatically affected their use. The next generation antibodies ( e.g. Fab, scFv) have not only reduced resulted immunogenicity, but also proved several benefits including better tumor penetration and more rapid blood clearance. Using affinity selection procedures in this study, a scFv antibody clone was isolated from naïve Tomlinson I phage display library that specifically recognizes and binds to TNF-α...
2018: Iranian Journal of Pharmaceutical Research: IJPR
Xuchu Que, Ming-Yow Hung, Calvin Yeang, Ayelet Gonen, Thomas A Prohaska, Xiaoli Sun, Cody Diehl, Antti Määttä, Dalia E Gaddis, Karen Bowden, Jennifer Pattison, Jeffrey G MacDonald, Seppo Ylä-Herttuala, Pamela L Mellon, Catherine C Hedrick, Klaus Ley, Yury I Miller, Christopher K Glass, Kirk L Peterson, Christoph J Binder, Sotirios Tsimikas, Joseph L Witztum
Oxidized phospholipids (OxPL) are ubiquitous, are formed in many inflammatory tissues, including atherosclerotic lesions, and frequently mediate proinflammatory changes 1 . Because OxPL are mostly the products of non-enzymatic lipid peroxidation, mechanisms to specifically neutralize them are unavailable and their roles in vivo are largely unknown. We previously cloned the IgM natural antibody E06, which binds to the phosphocholine headgroup of OxPL, and blocks the uptake of oxidized low-density lipoprotein (OxLDL) by macrophages and inhibits the proinflammatory properties of OxPL2-4 ...
June 6, 2018: Nature
Wen Jiang, Songjie Feng, Shisheng Huang, Wenxia Yu, Guanglei Li, Guang Yang, Yajing Liu, Yu Zhang, Lei Zhang, Yu Hou, Jia Chen, Jieping Chen, Xingxu Huang
Base editor (BE), containing a cytidine deaminase and catalytically defective Cas9, has been widely used to perform base editing. However, the narrow editing window of BE limits its utility. Here, we developed a new editing technology named as base editor for programming larger C to U (T) scope (BE-PLUS) by fusing 10 copies of GCN4 peptide to nCas9(D10A) for recruiting scFv-APOBEC-UGI-GB1 to the target sites. The new system achieves base editing with a broadened window, resulting in an increased genome-targeting scope...
June 6, 2018: Cell Research
Elena Ambrogini, Xuchu Que, Shuling Wang, Fumihiro Yamaguchi, Robert S Weinstein, Sotirios Tsimikas, Stavros C Manolagas, Joseph L Witztum, Robert L Jilka
Atherosclerosis and osteoporosis are epidemiologically linked and oxidation specific epitopes (OSEs), such as phosphocholine (PC) of oxidized phospholipids (PC-OxPL) and malondialdehyde (MDA), are pathogenic in both. The proatherogenic effects of OSEs are opposed by innate immune antibodies. Here we show that high-fat diet (HFD)-induced bone loss is attenuated in mice expressing a single chain variable region fragment of the IgM E06 (E06-scFv) that neutralizes PC-OxPL, by increasing osteoblast number and stimulating bone formation...
June 6, 2018: Nature Communications
Minsung Kim, Suhkneung Pyo, Chung Hyo Kang, Chong Ock Lee, Heung Kyoung Lee, Sang Un Choi, Chi Hoon Park
Gastric cancer is a malignancy that has a high mortality rate. Although progress has been made in the treatment of gastric cancer, many patients experience cancer recurrence and metastasis. Folate receptor 1 (FOLR1) is overexpressed on the cell surface in over one-third of gastric cancer patients, but rarely is expressed in normal tissue. This makes FOLR1 a potential target for chimeric antigen receptor (CAR) T cell immunotherapy, although the function of FOLR1 has not been elucidated. CAR are engineered fusion receptor composed of an antigen recognition region and signaling domains...
2018: PloS One
Pranveer Singh
Recent advances in Recombinant antibody technology / Antibody Engineering has given impetus to the genetic manipulation of antibody fragments that has paved the way for better understanding of the structure and functions of immunoglobulins and also has escalated their use in immunotherapy. Bacterial expression system such as Escherichia coli has complemented this technique through the expression of recombinant antibodies. Present communication has attempted to optimize the expression and refolding protocol of single chain fragment variable (ScFv) and single chain antigen binding fragment (ScFab) using E...
July 2018: Biochemistry and Biophysics Reports
Kasper Mølgaard, Seandean L Harwood, Marta Compte, Nekane Merino, Jaume Bonet, Ana Alvarez-Cienfuegos, Kasper Mikkelsen, Natalia Nuñez-Prado, Ana Alvarez-Mendez, Laura Sanz, Francisco J Blanco, Luis Alvarez-Vallina
The recruitment of T-cells by bispecific antibodies secreted from adoptively transferred, gene-modified autologous cells has shown satisfactory results in preclinical cancer models. Even so, the approach's translation into the clinic will require incremental improvements to its efficacy and reduction of its toxicity. Here, we characterized a tandem T-cell recruiting bispecific antibody intended to benefit gene-based immunotherapy approaches, which we call the light T-cell engager (LiTE), consisting of an EGFR-specific single-domain VHH antibody fused to a CD3-specific scFv...
June 4, 2018: Cancer Immunology, Immunotherapy: CII
Farnaz Fahimi, Shamim Sarhaddi, Mehdi Fouladi, Naser Samadi, Javid Sadeghi, Asal Golchin, Mohammad Reza Tohidkia, Jaleh Barar, Yadollah Omidi
Infection with Helicobacter pylori may result in the emergence of gastric adenocarcinoma. Among various toxins assisting pathogenesis of H. pylori, the vacuolating cytotoxin A (VacA) is one of the most potent toxins known as the major cause of the peptic ulcer and gastric adenocarcinoma. To isolate single-chain variable fragments (scFvs) against two conserved regions of VacA, we capitalized on the phage display technology and a solution-phase biopanning (SPB). Characterization of scFvs was carried out by enzyme-linked immunosorbent assay (ELISA), immunoblotting, and surface plasmon resonance (SPR)...
June 3, 2018: Applied Microbiology and Biotechnology
Jeffrey W Froude, Andrew S Herbert, Thibaut Pelat, Sebastian Miethe, Samantha E Zak, Jennifer M Brannan, Russell R Bakken, Alexander R Steiner, Gang Yin, Trevor J Hallam, Aaron K Sato, Michael Hust, Philippe Thullier, John M Dye
Sudan virus (SUDV) and Ebola viruses (EBOV) are both members of the Ebolavirus genus and have been sources of epidemics and outbreaks for several decades. We present here the generation and characterization of cross-reactive antibodies to both SUDV and EBOV, which were produced in a cell-free system and protective against SUDV in mice. A non-human primate, cynomolgus macaque, was immunized with viral-replicon particles expressing the glycoprotein of SUDV-Boniface (8A). Two separate antibody fragment phage display libraries were constructed after four immunogen injections...
May 26, 2018: Viruses
Sayed Shahabuddin Hoseini, Hongfen Guo, Zhihao Wu, Miho Nakajima Hatano, Nai-Kong V Cheung
Acute myeloid leukemia (AML), the most common acute leukemia in adults and the second most common cancer in children, is still a lethal disease in the majority of patients, but immunologic approaches have improved outcome. Bispecific antibodies (BsAbs) are novel immunotherapeutics that can redirect immune cells against AML. We now report a tetravalent (2+2) humanized BsAb in the immunoglobulin G light chain single chain fragment variable [IgG(L)-scFv] format to engage polyclonal T cells to kill CD33+ AML targets...
June 12, 2018: Blood Advances
Calvin Yeang, Devin Hasanally, Xuchu Que, Ming-Yow Hung, Aleksandra Stemankovic, David Chan, Rakesh Chaudhary, Victoria Margulets, Andrea L Edel, Masahiko Hoshijima, Yusu Gu, William Bradford, Nancy Dalton, Phuong Miu, David Y C Cheung, Davinder S Jassal, Grant N Pierce, Kirk L Peterson, Lorrie A Kirshenbaum, Joseph L Witztum, Sotirios Tsimikas, Amir Ravandi
Aims: Myocardial ischemia followed by reperfusion (IR) causes an oxidative burst resulting in cellular dysfunction. Little is known about the impact of oxidative stress on cardiomyocyte lipids and their role in cardiac cell death. Our goal was to identify oxidized phosphatidylcholine-containing phospholipids (OxPL) generated during IR, and to determine their impact on cell viability and myocardial infarct size. Methods and Results: OxPL were quantitated in isolated rat cardiomyocytes using mass spectrophotometry following 24 hours of IR...
May 30, 2018: Cardiovascular Research
Haibo Han, Shanshan Wang, Ying Hu, Zhaowei Li, Wei Yang, Yunwei Lv, Limin Wang, Lianhai Zhang, Jiafu Ji
Although chimeric antigen receptor T cell (CAR-T) therapies for certain types of solid tumors have been used in clinical trials, novel CARs that are able to target gastric cancer (GC) are still required. In our previous study, monoclonal antibody 3H11 (mAb 3H11), generated from immunization with five human GC cell lines, was demonstrated to have a 93.5% positive reaction with a clear membrane location and more than 5% cancer cell staining in GC tissues in our previous study. In the present study, 3H11-CARs were designed for modified T cell therapy...
May 2018: Oncology Letters
Chang-Yu Chang, Fu-Ling Chang, Chen-Wei Chiang, Yan-Ni Lo, Tsai-Yu Lin, Wang-Chuan Chen, Keng-Chang Tsai, Yu-Ching Lee
To understand the mechanism for inhibition of hepatitis B virus (HBV) infection is important. In this study, single-chain variable fragment (scFv) antibodies were generated and directed to the pre-S2 epitope of HBV surface antigen (HBsAg). These human scFvs were isolated from a person with history of HBV infection by phage display technology. An evaluation of panning efficiency revealed that the eluted phage titer was increased, indicating that specific clones were enriched after panning. Selected scFvs were characterized with the recombinant HBsAg through Western blotting and enzyme-linked immunosorbent assay to confirm the binding ability...
May 30, 2018: Viral Immunology
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