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Bispecific antibody

Tong Wang, Fumou Sun, Yang Wang, Jiahao Jiang, Mingzhu Pan, Minne Yuan, Hang Zhang, Xiaodian Du, Kamal Hezam, Kai Song, Min Wang, Juan Zhang
Colorectal carcinoma (CRC) is one of the most common malignant cancers worldwide. The poor response of CRC to chemotherapy has whipped up the interest in targeted therapy with monoclonal antibodies for its potential efficiency. However, cetuximab, as one of the first-line targeted drugs in the treatment of CRC, has drug resistance and poor prognosis in clinic. To address this, a novel bispecific protein with CRC targeting and natural killer (NK) cell triggering was used for treatment. NK cell-mediated immunosurveillance is normally activated by the activating receptor natural killer cell receptor NK group 2, member D (NKG2D), which binds its key ligand major histocompatibility complex (MHC) class I-related chain A (MICA) expressed on the tumor cells...
April 2018: Journal of Immunotherapy
Jens H W Pahl, Joachim Koch, Jana-Julia Gotz, Annette Arnold, Uwe Reusch, Thorsten Gantke, Erich Rajkovic, Martin S Treder, Adelheid Cerwenka
CD16A is a potent cytotoxicity receptor on human NK cells, which can be exploited by therapeutic bispecific antibodies. So far, the effects of CD16A-mediated activation on NK cell effector functions beyond classical antibody-dependent cytotoxicity have remained poorly elucidated. Here, we investigated NK cell responses after exposure to therapeutic antibodies such as the tetravalent bispecific antibody AFM13 (CD30/CD16A), designed for the treatment of Hodgkin lymphoma and other CD30+ lymphomas. Our results reveal that CD16A engagement enhanced subsequent IL2 and IL15¬-driven NK cell proliferation and expansion...
March 7, 2018: Cancer Immunology Research
Kshitij Wagh, Michael S Seaman, Marshall Zingg, Tomas Fitzsimons, Dan H Barouch, Dennis R Burton, Mark Connors, David D Ho, John R Mascola, Michel C Nussenzweig, Jeffrey Ravetch, Rajeev Gautam, Malcolm A Martin, David C Montefiori, Bette Korber NCT02960581.
March 5, 2018: PLoS Pathogens
Eric Sanchez, Edward J Tanenbaum, Saurabh Patil, Mingjie Li, Camilia M Soof, Aleksandra Vidisheva, Gabriel N Waterman, Tara Hekmati, George Tang, Cathy S Wang, Haiming Chen, James Berenson
B-cell maturation antigen (BCMA) is a cell membrane bound tumor necrosis factor receptor family member that is expressed exclusively on late stage normal and malignant B-cells and plasma cells. Addition of two of its ligands, B-cell activating factor and a proliferation inducting ligand, to normal B-cells cause B-cell proliferation and antibody production. Serum BCMA is elevated among patients with multiple myeloma (MM) and chronic lymphocytic leukemia (CLL), and is a prognostic and monitoring tool for these patients...
March 7, 2018: Expert Review of Molecular Diagnostics
Elisabeth K Nyakatura, Samantha E Zak, Anna Z Wec, Daniel Hofmann, Sergey Shulenin, Russell R Bakken, M Javad Aman, Kartik Chandran, John M Dye, Jonathan R Lai
Filoviruses (family Filoviridae ) include five ebolaviruses and Marburg virus. These pathogens cause a rapidly progressing and severe viral disease with high mortality rates (generally 30%-90%). Outbreaks of filovirus disease are sporadic and, until recently, were limited to less than 500 cases. However, the 2013-2016 epidemic in western Africa, caused by Ebola virus (EBOV), illustrated the potential of filovirus outbreaks to escalate to a much larger scale (over 28,000 suspected cases). Monoclonal antibodies (mAbs) against the envelope glycoprotein represent a promising therapeutic platform for managing filovirus infections...
March 2, 2018: Journal of Biological Chemistry
James J Steinhardt, Javier Guenaga, Hannah L Turner, Krisha McKee, Mark K Louder, Sijy O'Dell, Chi-I Chiang, Lin Lei, Andrey Galkin, Alexander K Andrianov, Nicole A Doria-Rose, Robert T Bailer, Andrew B Ward, John R Mascola, Yuxing Li
HIV-1 broadly neutralizing antibodies (bNAbs) are being explored as passively administered therapeutic and preventative agents. However, the extensively diversified HIV-1 envelope glycoproteins (Env) rapidly acquire mutations to evade individual bNAbs in monotherapy regimens. The use of a "single" agent to simultaneously target distinct Env epitopes is desirable to overcome viral diversity. Here, we report the use of tandem single-chain variable fragment (ScFv) domains of two bNAbs, specific for the CD4-binding site and V3 glycan patch, to form anti-HIV-1 bispecific ScFvs (Bi-ScFvs)...
February 28, 2018: Nature Communications
Sharon M Sagnella, Jennifer Trieu, Himanshu Brahmbhatt, Jennifer A MacDiarmid, Alex MacMillan, Renee M Whan, Christopher M Fife, Joshua A McCarroll, Andrew J M Gifford, David S Ziegler, Maria Kavallaris
Advanced stage neuroblastoma is an aggressive disease with limited treatment options for patients with drug resistant tumors. Targeted delivery of chemotherapy for pediatric cancers offers promise to improve treatment efficacy and reduce toxicity associated with systemic chemotherapy. The EnGeneIC delivery vehicle (EDVTM) is a nanocell which can package chemotherapeutic drugs and target tumors via attachment of bispecific proteins to the surface of the nanocell. Phase 1 trials in adults with refractory tumors have shown an acceptable safety profile...
February 28, 2018: Molecular Cancer Therapeutics
Alexey Teplyakov, Galina Obmolova, Jinquan Luo, Gary L Gilliland
CD19 is a transmembrane protein expressed on malignant B cells, but not in other lineages or other tissues, which makes it an attractive target for monoclonal antibody-mediated immunotherapy. Anti-CD19 antibody B43 was utilized in a bispecific T-cell engager (BiTE) blinatumomab, that demonstrated potency for the treatment of relapsed acute lymphoblastic leukemia. To gain insight into the mechanism of action of the antibody, the crystal structure of B43 Fab was determined in complex with CD19 and in the unbound form...
February 28, 2018: Proteins
Sally Yu Shi, Ya-Wen Lu, Zhi Liu, Jennitte Stevens, Christopher M Murawsky, Vicki Wilson, Zhonghua Hu, William G Richards, Mark Leo Michaels, Jun Zhang, Wei Yan, Yang Li
Bispecific antibodies have become important formats for therapeutic discovery. They allow for potential synergy by simultaneously engaging two separate targets and enable new functions that are not possible to achieve by using a combination of two monospecific antibodies. Antagonistic antibodies dominate drug discovery today, but only a limited number of agonistic antibodies (i.e. those that activate receptor signaling) have been described. For receptors formed by two components, engaging both of these components simultaneously may be required for agonistic signaling...
February 26, 2018: Journal of Biological Chemistry
Hoan N Le, Josiane Silva Quetz, Vuvi G Tran, Vien T M Le, Fábio Aguiar-Alves, Marcos G Pinheiro, Lily Cheng, Li Yu, Bret R Sellman, Charles K Stover, Antonio DiGiandomenico, Binh An Diep
Pseudomonas aeruginosa is among the most formidable antibiotic-resistant pathogens and a leading cause of hospital-associated infections. With dwindling options for antibiotic resistant infections, a new paradigm for treatment and disease resolution is required. MEDI3902, a bispecific antibody targeting the P. aeruginosa type-3-secretion (T3S) protein PcrV and Psl exopolysaccharide, was previously shown to mediate potent protective activity in murine infection models. With the current challenges associated with clinical development of narrow-spectrum agents, robust preclinical efficacy data in multiple animal species are desirable...
February 26, 2018: Antimicrobial Agents and Chemotherapy
Archana Thakur, Manley Huang, Lawrence G Lum
Monoclonal antibody-based targeted therapy has greatly improved treatment options for patients. However, long-term efficacy of such antibodies is limited by resistance mechanisms. New insights into the mechanisms by which tumors evade immune control have driven innovative therapeutic strategies to eliminate cancer by re-directing immune cells to tumors. Advances in protein engineering technology have generated multiple bispecific antibody (BsAb) formats capable of targeting multiple antigens as a single agent...
February 20, 2018: Blood Reviews
Sven Mathias, Simon Fischer, René Handrick, Jürgen Fieder, Patrick Schulz, Harald Bradl, Ingo Gorr, Martin Gamer, Kerstin Otte
With the advance of complex biological formats such as bispecific antibodies or fusion proteins, mammalian expression systems often show low performance. Described determining factors may be accumulation or haltering of heterologous proteins within the different cellular compartments disturbing transport or secretion. In case of the investigated bispecific antibody (bsAb)-producing Chinese hamster ovary (CHO) cell line neither impaired transcription nor decreased translation processes were identified and thus satisfactorily explained its low production capacity...
March 1, 2018: Journal of Biotechnology
Yesim Dargaud, Anne Lienhart, Maissaa Janbain, Sandra LeQuellec, Nathalie Enjolras, Claude Negrier
Emicizumab is a recombinant, humanized, bispecific, monoclonal antibody that bridges activated factor IX and factor X to restore the function of deficient factor VIII. Treatment of bleeding in patients with hemophilia and inhibitors involves the use of bypassing agents (BPA).These molecules are also used for the management of breakthrough bleeds in patients on prophylaxis with emicizumab, with increased concerns about the risks of combining two procoagulant drugs. Using thrombin generation assay, we tailored the dosage of activated prothrombin complex concentrate (APCC) and successfully treated an acute spontaneous arterial bleeding in a patient on prophylaxis with emicizumab 1...
February 22, 2018: Haematologica
Suncica Bjelica, Juan Francisco Santibanez
BACKGROUND: IL-17A is a founding member of the IL-17 family that has been implicated in the pathogenesis of inflammatory-associated diseases such as cancer and autoimmune disease. In cancer, IL-17A participates in many key events for tumor development, in part by affecting innate and adaptive immune system and also by direct modulation of many pro-tumor events. Moreover, IL-17A dysregulation at the site of inflammation is associated with rheumatoid arthritis, multiple sclerosis, psoriasis, among others...
February 19, 2018: Recent Patents on Anti-cancer Drug Discovery
Mahiuddin Ahmed, Andres Lopez-Albaitero, Dmitry Pankov, Brian H Santich, Hong Liu, Su Yan, Jingyi Xiang, Pei Wang, Aisha N Hasan, Annamalai Selvakumar, Richard J O'Reilly, Cheng Liu, Nai-Kong V Cheung
EBV infection is associated with a number of malignancies of clinical unmet need, including Hodgkin lymphoma, nasopharyngeal carcinoma, gastric cancer, and posttransplant lymphoproliferative disease (PTLD), all of which express the EBV protein latent membrane protein 2A (LMP2A), an antigen that is difficult to target by conventional antibody approaches. To overcome this, we utilized phage display technology and a structure-guided selection strategy to generate human T cell receptor-like (TCR-like) monoclonal antibodies with exquisite specificity for the LMP2A-derived nonamer peptide, C426LGGLLTMV434 (CLG), as presented on HLA-A*02:01...
February 22, 2018: JCI Insight
Daniela Schmid, Annette Buntz, Thi Ngoc Hanh Phan, Klaus Mayer, Eike Hoffmann, Irmgard Thorey, Jens Niewöhner, Katrin Vasters, Ranjan Sircar, Olaf Mundigl, Roland E Kontermann, Ulrich Brinkmann
A transcellular shuttle system was generated for delivery of non-covalently linked payloads across blood-brain-barrier (BBB) endothelial cells. Transcytosis enabling shuttles are composed of bispecific antibodies (bsAbs) that simultaneously bind transferrin receptor (TfR) and haptens such as digoxigenin or biocytinamide. Haptenylated payloads are attached to these vehicles via non-covalent hapten-antibody complexation. This enables targeting to and internalization into human BBB-derived microvascular endothelial HCMEC/D3 cells...
December 20, 2017: Biological Chemistry
Andrew D Tustian, Linus Laurin, Henrik Ihre, Travis Tran, Robert Stairs, Hanne Bak
There is strong interest in the production of bispecific monoclonal antibodies that can simultaneously bind two distinct targets or epitopes to achieve novel mechanisms of action and efficacy. Regeneron's bispecific technology, based upon a standard IgG, consists of a heterodimer of two different heavy chains, and a common light chain. Coexpression of two heavy chains leads to the formation of two parental IgG impurities, the removal of which is facilitated by a dipeptide substitution in the Fc portion of one of the heavy chains that ablates Fc Protein A binding...
February 21, 2018: Biotechnology Progress
Olivia Campagne, Audrey Delmas, Sylvain Fouliard, Marylore Chenel, Gurunadh R Chichili, Hua Li, Ralph Alderson, Jean-Michel Scherrmann, Donald E Mager
PURPOSE: Flotetuzumab (MGD006 or S80880) is a bispecific molecule that recognizes CD3 and CD123 membrane proteins, redirecting T-cells to kill CD123-expressing cells for the treatment of acute myeloid leukemia. In this study, we developed a mathematical model to characterize MGD006 exposure-response relationships and to assess the impact of its immunogenicity in cynomolgus monkeys. EXPERIMENTAL DESIGN: 32 animals received multiple escalating doses (100-300-600-1000 ng/kg/day) via intravenous infusion continuously 4-days a week...
February 20, 2018: Clinical Cancer Research: An Official Journal of the American Association for Cancer Research
Xilin Wu, Jia Guo, Mengyue Niu, Minghui An, Li Liu, Hui Wang, Xia Jin, Qi Zhang, Ka Shing Lam, Tongjin Wu, Hua Wang, Qian Wang, Yanhua Du, Jingjing Li, Lin Cheng, Hang Ying Tang, Hong Shang, Linqi Zhang, Paul Zhou, Zhiwei Chen
The discovery of an HIV-1 cure remains a medical challenge because the virus rebounds quickly after the cessation of combination antiretroviral drug therapy (cART). Here, we investigate the potential of an engineered tandem bi-specific broadly neutralizing antibody (bs-bnAb) as an innovative product for HIV-1 prophylactic and therapeutic interventions. We discovered that by preserving two scFv binding domains of each parental bnAb, a single-gene-encoded tandem bs-bnAb, namely BiIA-SG, displayed significantly improved breadth and potency...
February 20, 2018: Journal of Clinical Investigation
Hao He, Christopher B Howard, Yinghui Chen, Shihui Wen, Gungun Lin, Jiajia Zhou, Kristofer J Thurecht, Dayong Jin
Upconversion nanoparticles (UCNPs) are new optical probes for biological applications. For specific biomolecular recognition to be realized for diagnosis and imaging, the key lies in developing a stable and easy-to-use bioconjugation method for antibody modification. Current methods are not yet satisfactory regarding conjugation time, stability, and binding efficiency. Here, we report a facile and high-yield approach based on a bispecific antibody (BsAb) free of chemical reaction steps. One end of the BsAb is designed to recognize methoxy polyethylene glycol-coated UCNPs, and the other end of the BsAb is designed to recognize the cancer antigen biomarker...
February 22, 2018: Analytical Chemistry
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