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https://www.readbyqxmd.com/read/28514732/structural-basis-of-a-novel-heterodimeric-fc-for-bispecific-antibody-production
#1
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/28500232/nkg2d-ligand-targeted-bispecific-t-cell-engagers-lead-to-robust-antitumor-activity-against-diverse-human-tumors
#2
Claire Godbersen, Tiffany A Coupet, Amelia M Huehls, Tong Zhang, Michael B Battles, Jan L Fisher, Marc S Ernstoff, Charles L Sentman
Two new bispecific T cell engaging (BiTE) molecules with specificity for NKG2D ligands were developed and functionally characterized. One, huNKG2D-OKT3, was derived from the extracellular portion of the human NKG2D receptor fused to a CD3ε binding single-chain variable fragment (scFv), known as OKT3. NKG2D has multiple ligands, including MICA, which are expressed by a variety of malignant cells. A second molecule, B2-OKT3, was created in the tandem scFv BiTE format that targets MICA on tumor cells and CD3ε on human T cells...
May 12, 2017: Molecular Cancer Therapeutics
https://www.readbyqxmd.com/read/28498434/a-ligand-based-and-enediyne-energized-bispecific-fusion-protein-targeting-epidermal-growth-factor-receptor-and-insulin-like-growth-factor-1-receptor-shows-potent-antitumor-efficacy-against-esophageal-cancer
#3
Hai-Ying Cao, Xiao-Fang Guo, Xiao-Fei Zhu, Sai-Sai Li, Yong-Su Zhen
Recent studies have revealed that the epidermal growth factor receptor (EGFR) and insulin-like growth factor-1 receptor (IGF-1R) are overexpressed in various types of human tumors and are attractive targets for anticancer drugs. In the present study, the expression of EGFR and IGF-1R in esophageal squamous cell carcinoma (ESCC) and adjacent normal tissues in a tissue microarray was firstly detected by immunohistochemical staining. In addition, their co-overexpression was observed in 48 out of 75 (64%) patients...
April 27, 2017: Oncology Reports
https://www.readbyqxmd.com/read/28497577/the-least-speciose-amongst-the-most-speciose-natural-history-correlates-of-mono-and-bispecific-genera-of-rodentia-and-soricomorpha
#4
Giovanni Amori, Alessandra Maria Bissattini, Spartaco Gippoliti, Leonardo Vignoli, Luigi Maiorano, Luca Luiselli
Mono-and bispecific genera are of special concern as they represent unique phylogenetic/evolutionary trajectories within larger clades. In addition, as phylogenetically older taxa are supposed to be exposed to higher rarity and extinction risk, mono- and bispecific genera may be intrinsically more prone to extinction risks than multispecies genera, although extinction risks also depend on the ecological and biological strategy of the species. Here, the distribution across biogeographical zones and the threatening levels of two speciose orders of mammals (mono- and bispecific genera of Rodentia and Soricomorpha) are investigated in order to highlight major patterns at the worldwide scale...
May 11, 2017: Integrative Zoology
https://www.readbyqxmd.com/read/28472610/nature-functions-and-clinical-implications-of-igg4-autoantibodies-in-systemic-lupus-erythematosus-and-rheumatoid-arthritis
#5
Qingjun Pan, Qiaofen Lan, Yanxia Peng, Jun Cai, Jian Zheng, Carol Dickerson, Haiyan Xiao, Hua-Feng Liu
Protective autoantibodies in homeostasis, clinical relevance, and therapeutic potential have gained wide attention. Recent studies showed that IgG4 autoantibodies play crucial roles in systemic lupus erythematosus (SLE) and rheumatoid arthritis (RA). In one aspect, IgG4 autoantibodies can bind autoantigens in competition with other classes of immunoglobulins (e.g., IgG1, IgG2a) to form non-inflammatory immune-complexes (ICs), which have a limited ability to induce immune responses because of the low affinity of IgG4 for both Fc receptors and the C1 complement molecule, resulting in reduced inflammatory response in SLE and RA...
March 2017: Discovery Medicine
https://www.readbyqxmd.com/read/28469973/the-development-of-bispecific-antibodies-and-their-applications-in-tumor-immune-escape
#6
REVIEW
Xiaolong Zhang, Yuanyuan Yang, Dongmei Fan, Dongsheng Xiong
During the past two decades, a great evolution of bispecific antibodies (BsAbs) for therapeutic applications has been made. BsAbs can bind simultaneously two different antigens or epitopes, which leads to a wide range of applications including redirecting T cells or NK cells to tumor cells, blocking two different signaling pathways, dual targeting of different disease mediators, and delivering payloads to targeted sites. Aside from approved catumaxomab (anti-CD3 and anti-EpCAM) and blinatumomab (anti-CD3 and anti-CD19), many more BsAbs are now in various phases of clinical development...
2017: Experimental Hematology & Oncology
https://www.readbyqxmd.com/read/28463232/bispecific-antibody-targets-multiple-pseudomonas-aeruginosa-evasion-mechanisms-in-the-lung-vasculature
#7
Ajitha Thanabalasuriar, Bas G J Surewaard, Michelle E Willson, Arpan S Neupane, Charles K Stover, Paul Warrener, George Wilson, Ashley E Keller, Bret R Sellman, Antonio DiGiandomenico, Paul Kubes
Pseudomonas aeruginosa is a major cause of severe infections that lead to bacteremia and high patient mortality. P. aeruginosa has evolved numerous evasion and subversion mechanisms that work in concert to overcome immune recognition and effector functions in hospitalized and immunosuppressed individuals. Here, we have used multilaser spinning-disk intravital microscopy to monitor the blood-borne stage in a murine bacteremic model of P. aeruginosa infection. P. aeruginosa adhered avidly to lung vasculature, where patrolling neutrophils and other immune cells were virtually blind to the pathogen's presence...
May 2, 2017: Journal of Clinical Investigation
https://www.readbyqxmd.com/read/28461199/new-structural-formats-of-therapeutic-antibodies-for-rheumatology
#8
Christophe Dumet, Jérémy Pottier, Valérie Gouilleux, Hervé Watier
Pharmaceutical companies strive continuously to develop better medications in order to remain competitive. In the arena of monoclonal antibodies and related biologics (fusion proteins containing an IgG Fc fragment), the thrust is not only toward identifying new targets, but also toward developing new molecular formats. Here, new-generation antibodies used to treat rheumatic diseases are discussed, with emphasis on relations linking structure to pharmacological effects and on the improvements expected from the new formats...
April 28, 2017: Joint, Bone, Spine: Revue du Rhumatisme
https://www.readbyqxmd.com/read/28460483/a-bispecific-enediyne-energized-fusion-protein-targeting-both-epidermal-growth-factor-receptor-and-insulin-like-growth-factor-1-receptor-showing-enhanced-antitumor-efficacy-against-non-small-cell-lung-cancer
#9
Xiao-Fang Guo, Xiao-Fei Zhu, Hai-Ying Cao, Gen-Shen Zhong, Liang Li, Bao-Guo Deng, Ping Chen, Pei-Zhen Wang, Qing-Fang Miao, Yong-Su Zhen
Epidermal growth factor receptor (EGFR) and insulin-like growth factor 1 receptor (IGF-1R) both overexpressed on non-small cell lung cancer (NSCLC) and are known cooperatively to promote tumor progression and drug resistance. This study was to construct a novel bispecific fusion protein EGF-IGF-LDP-AE consisting of EGFR and IGF-IR specific ligands (EGF and IGF-1) and lidamycin, an enediyne antibiotic with potent antitumor activity, and investigate its antitumor efficacy against NSCLC. Binding and internalization assays showed that EGF-IGF-LDP protein could bind to NSCLC cells with high affinity and then internalized into cells with higher efficiency than that of monospecific proteins...
April 18, 2017: Oncotarget
https://www.readbyqxmd.com/read/28459560/nongenetic-reprogramming-of-the-ligand-specificity-of-growth-factor-receptors-by-bispecific-dna-aptamers
#10
Ryosuke Ueki, Saki Atsuta, Ayaka Ueki, Shinsuke Sando
The reprogramming of receptor-ligand interactions affords an opportunity to direct cells to respond to user-defined external cues. Although this has often been achieved via the genetic engineering of receptors, an alternative, nongenetic approach is highly demanded. In this article, we propose the design of oligonucleotide-based synthetic switches that feature the ability to reprogram the ligand specificity of the growth factor receptor. We demonstrated that our synthetic switches induced growth factor signaling via the formation of the dynamic complex with specific external cues that would otherwise not induce the signaling...
May 8, 2017: Journal of the American Chemical Society
https://www.readbyqxmd.com/read/28455964/bispecific-protein-targets-prostate-cancer
#11
Antony W Burgess
News on: PSMA-homing dsRNA chimeric protein vector kills prostate cancer cells and activates anti-tumor bystander responses, by Langut et al. Oncotarget. 2017; 8:24046-62. doi: 10.18632/oncotarget.15733.
April 23, 2017: Oncotarget
https://www.readbyqxmd.com/read/28453885/lineage-switch-under-blinatumomab-treatment-of-relapsed-common-acute-lymphoblastic-leukemia-without-mll-rearrangement
#12
Annabelle Zoghbi, Udo Zur Stadt, Beate Winkler, Ingo Müller, Gabriele Escherich
Blinatumomab is a bispecific T-cell engaging αCD19 antibody used in refractory or relapsed B-cell precursor acute lymphoblastic leukemia (ALL). Recently, lineage switch to a myeloid phenotype has been described following CD19 targeting treatment in three pediatric patients with mixed lineage leukemia (MLL) rearranged ALL. We report the case of a female who received blinatumomab for a first relapse of ALL without MLL alterations. She suffered from a second relapse early after hematopoietic stem cell transplantation and was treated with blinatumomab again...
April 28, 2017: Pediatric Blood & Cancer
https://www.readbyqxmd.com/read/28451690/factor-viiia-mimetic-cofactor-activity-of-a-bispecific-antibody-to-factors-ix-ixa-and-x-xa-emicizumab-depends-on-its-ability-to-bridge-the-antigens
#13
Takehisa Kitazawa, Keiko Esaki, Tatsuhiko Tachibana, Shinya Ishii, Tetsuhiro Soeda, Atsushi Muto, Yoshiki Kawabe, Tomoyuki Igawa, Hiroyuki Tsunoda, Keiji Nogami, Midori Shima, Kunihiro Hattori
Emicizumab, a humanised bispecific antibody recognising factors (F) IX/IXa and X/Xa, can accelerate FIXa-catalysed FX activation by bridging FIXa and FX in a manner similar to FVIIIa. However, details of the emicizumab-antigen interactions have not been reported so far. In this study, we first showed by surface plasmon resonance analysis that emicizumab bound FIX, FIXa, FX, and FXa with moderate affinities (KD = 1.58, 1.52, 1.85, and 0.978 µM, respectively). We next showed by immunoblotting analysis that emicizumab recognised the antigens' epidermal growth factor (EGF)-like domains...
April 28, 2017: Thrombosis and Haemostasis
https://www.readbyqxmd.com/read/28450393/immunoglobulin-domain-interface-exchange-as-a-platform-technology-for-the-generation-of-fc-heterodimers-and-bispecific-antibodies
#14
Darko Skegro, Cian Stutz, Romain Ollier, Emelie Svensson, Paul Wassmann, Bourquin Florence, Thierry Monney, Sunitha Gn, Stanislas Blein
Bispecific antibodies (bsAbs) are of significant importance to the development of novel antibody-based therapies, and heavy chain (Hc) heterodimers represent a major class of bispecific drug candidates. Current technologies for the generation of Hc heterodimers are suboptimal and often suffer from contamination by homodimers posing purification challenges. Here, we introduce a new technology based on biomimicry wherein the protein-protein interfaces of two different immunoglobulin (Ig) constant domain pairs are exchanged in part or fully to design new heterodimeric domains...
April 27, 2017: Journal of Biological Chemistry
https://www.readbyqxmd.com/read/28444391/dual-display-phage-selection-driven-by-co-engagement-of-two-targets-by-two-different-antibody-fragments
#15
Séverine Fagète, Ledicia Botas-Perez, Irène Rossito-Borlat, Kenneth Adea, Franck Gueneau, Ulla Ravn, François Rousseau, Marie Kosco-Vilbois, Nicolas Fischer, Oliver Hartley
Antibody phage display technology has supported the emergence of numerous therapeutic antibodies. The development of bispecific antibodies, a promising new frontier in antibody therapy, could be facilitated by new phage display approaches that enable pairs of antibodies to be co-selected based on co-engagement of their respective targets. We describe such an approach, making use of two complementary leucine zipper domains that heterodimerize with high affinity. Phagemids encoding a first antibody fragment (scFv) fused to phage coat protein via the first leucine zipper are rescued in bacteria expressing a second scFv fused to the second leucine zipper as a soluble periplasmic protein, so that it is acquired by phage during assembly...
April 24, 2017: Protein Engineering, Design & Selection: PEDS
https://www.readbyqxmd.com/read/28435472/simultaneous-targeting-of-cd44-and-epcam-with-a-bispecific-aptamer-effectively-inhibits-intraperitoneal-ovarian-cancer-growth
#16
Jingying Zheng, Shuhua Zhao, Xiaolin Yu, Shuang Huang, Hong Yan Liu
CD44 and EpCAM play crucial roles in intraperitoneal ovarian cancer development. In this study, we developed an RNA-based bispecific CD44-EpCAM aptamer that is capable of blocking CD44 and EpCAM simultaneously by fusing single CD44 and EpCAM aptamers with a double stranded RNA adaptor. With the aid of a panel of ovarian cancer cell lines, we found that bispecific CD44-EpCAM aptamer was much more effective than either single CD44 or EpCAM aptamer in the ability to inhibit cell growth and to induce apoptosis...
2017: Theranostics
https://www.readbyqxmd.com/read/28428282/whither-radioimmunotherapy-to-be-or-not-to-be
#17
Damian J Green, Oliver W Press
Therapy of cancer with radiolabeled monoclonal antibodies has produced impressive results in preclinical experiments and in clinical trials conducted in radiosensitive malignancies, particularly B-cell lymphomas. Two "first-generation," directly radiolabeled anti-CD20 antibodies, (131)iodine-tositumomab and (90)yttrium-ibritumomab tiuxetan, were FDA-approved more than a decade ago but have been little utilized because of a variety of medical, financial, and logistic obstacles. Newer technologies employing multistep "pretargeting" methods, particularly those utilizing bispecific antibodies, have greatly enhanced the therapeutic efficacy of radioimmunotherapy and diminished its toxicities...
May 1, 2017: Cancer Research
https://www.readbyqxmd.com/read/28428075/immunotherapy-of-hepatocellular-carcinoma-using-chimeric-antigen-receptors-and-bispecific-antibodies
#18
Sayed Shahabuddin Hoseini, Nai-Kong V Cheung
Hepatocellular carcinoma (HCC) is one of the most lethal cancers worldwide with an overall survival rate of less than 15% in developed countries. Despite attempts at new therapeutic strategies, the majority of patients succumb to this cancer. Buttressed by the highly successful clinical impact in melanoma, immunotherapy is gaining momentum as the next treatment modality for many human cancers. Chimeric antigen receptors (CAR) contain the antigen binding moieties of a monoclonal antibody and the co-stimulatory and signaling domains associated with effector receptor signaling...
April 17, 2017: Cancer Letters
https://www.readbyqxmd.com/read/28422793/engineering-antibody-like-inhibitors-to-prevent-and-treat-hiv-1-infection
#19
Matthew R Gardner, Michael Farzan
PURPOSE OF REVIEW: Here we discuss recently developed HIV-1 entry inhibitors that can target multiple epitopes on the HIV-1 envelope glycoprotein (Env), with an emphasis on eCD4-Ig. Some of these inhibitors are more potent and broader than any single antibody characterized to date. We also discuss the use of recombinant adeno-associated virus (rAAV) vectors as a platform for long-term expression of these inhibitors. RECENT FINDINGS: Much of the exterior of HIV-1 Env can be targeted by broadly neutralizing antibodies (bNAbs)...
May 2017: Current Opinion in HIV and AIDS
https://www.readbyqxmd.com/read/28409770/acute-myeloid-leukemia-targets-for-bispecific-antibodies
#20
S S Hoseini, N K Cheung
No abstract text is available yet for this article.
April 14, 2017: Blood Cancer Journal
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