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T cell dependent bispecific antibody

Wei Li, Hongjia Yang, Dimiter S Dimitrov
CD16A (FcγRIIIA) is an activating receptor mostly expressed on natural killer (NK) cells and monocytes/macrophages. It can mediate antibody-dependent cell-mediated cytotoxicity (ADCC) through low-affinity interaction with human immunoglobulin G (IgG) Fc. It can also mediate cell lysis if NK cells are guided by bispecific killer cells engagers (BiKEs). BiKEs showed some success in clinical trials of cancer and are promising candidate therapeutics. However, currently reported BiKEs are based on antibody fragments (scFvs) of relatively large size...
October 3, 2016: Experimental and Molecular Pathology
Judith Feucht, Simone Kayser, David Gorodezki, Mohamad Hamieh, Michaela Döring, Franziska Blaeschke, Patrick Schlegel, Hans Bösmüller, Leticia Quintanilla-Fend, Martin Ebinger, Peter Lang, Rupert Handgretinger, Tobias Feuchtinger
T-cell immunotherapies are promising options in relapsed/refractory B-precursor acute lymphoblastic leukemia (ALL). We investigated the effect of co-signaling molecules on T-cell attack against leukemia mediated by CD19/CD3-bispecific T-cell engager. Primary CD19+ ALL blasts (n≥10) and physiologic CD19+CD10+ bone marrow precursors were screened for 20 co-signaling molecules. PD-L1, PD-1, LAG-3, CD40, CD86, CD27, CD70 and HVEM revealed different stimulatory and inhibitory profiles of pediatric ALL compared to physiologic cells, with PD-L1 and CD86 as most prominent inhibitory and stimulatory markers...
September 30, 2016: Oncotarget
Gabriela Hernandez-Hoyos, Toddy Sewell, Robert Bader, Jeannette Bannink, Ruth A Chenault, Mollie Daugherty, Maria Dasovich, Hang Fang, Rebecca Gottschalk, John Kumer, Robert E Miller, Padma Ravikumar, Jennifer Wiens, Paul A Algate, David Bienvenue, Catherine J McMahan, Sateesh K Natarajan, Jane A Gross, John W Blankenship
Treatment of metastatic, castration-resistant prostate cancer (mCRPC) remains a highly unmet medical need and current therapies ultimately result in disease progression. Immunotherapy is a rapidly growing approach for treatment of cancer but has shown limited success to date in the treatment of mCRPC. We have developed a novel humanized bispecific antibody, MOR209/ES414, built on the ADAPTIR (modular protein technology) platform, to redirect T-cell cytotoxicity toward prostate cancer cells by specifically targeting T cells through CD3ε to prostate cancer cells expressing PSMA (prostate-specific membrane antigen)...
September 2016: Molecular Cancer Therapeutics
Szun Szun Tay, Hernan Carol, Maté Biro
Unprecedented clinical success has recently been achieved in cancer immunotherapy using cytotoxic T cells armed with activating tumor-specific Chimeric Antigen Receptors (CARs). Natural killer (NK) cells, potent cytotoxic effectors, also hold potential to be effectively harnessed for immunotherapy. The anti-tumor efficacy of NK cell therapies has been limited by a lack of antigen specificity and the poor persistence of NK cells in vivo. To address these limitations, Vallera and colleagues developed novel Trispecific Killer cell Engagers (TriKEs), reported in the Feb...
June 20, 2016: Human Vaccines & Immunotherapeutics
Jonathan E Benjamin, Anthony S Stein
Adults with relapsed/refractory B-acute lymphoblastic leukemia (ALL) have a complete remission (CR) rate of 20-45% and median overall survival of 3-9 months, depending on the duration of the first remission and number of lines of salvage therapy. Allogeneic hematopoietic stem cell transplantation (alloHSCT) is the only curative option for adult patients with relapsed/refractory ALL, and achievement of CR is a crucial step before alloHSCT. Blinatumomab is a bispecific T-cell engager (BiTE®) antibody construct with dual specificity for CD19 and CD3, simultaneously binding CD3-positive cytotoxic T cells and CD19-positive B cells, resulting in T-cell-mediated serial lysis of normal and malignant B cells...
June 2016: Therapeutic Advances in Hematology
Min Zhu, Benjamin Wu, Christian Brandl, Jessica Johnson, Andreas Wolf, Andrew Chow, Sameer Doshi
BACKGROUND AND OBJECTIVES: Blinatumomab is a bispecific T-cell engager (BiTE(®)) antibody construct that transiently links CD19-positive B cells to CD3-positive T cells, resulting in induction of T-cell-mediated serial lysis of B cells and concomitant T-cell proliferation. Blinatumomab showed anti-leukemia activity in clinical trials and was approved by the US Food and Drug Administration for the treatment of Philadelphia chromosome-negative relapsed/refractory B-cell precursor acute lymphoblastic leukemia (r/r ALL)...
October 2016: Clinical Pharmacokinetics
Elodie Picarda, Kim C Ohaegbulam, Xingxing Zang
B7-H3 (CD276) is an important immune checkpoint member of the B7 and CD28 families. Induced on antigen-presenting cells, B7-H3 plays an important role in the inhibition of T-cell function. Importantly, B7-H3 is highly overexpressed on a wide range of human solid cancers and often correlates with both negative prognosis and poor clinical outcome in patients. Challenges remain to identify the receptor(s) of B7-H3 and thus better elucidate the role of the B7-H3 pathway in immune responses and tumor evasion. With a preferential expression on tumor cells, B7-H3 is an attractive target for cancer immunotherapy...
July 15, 2016: Clinical Cancer Research: An Official Journal of the American Association for Cancer Research
Uwe Reusch, Kimberly Harrington, Chelsea Gudgeon, Ivica Fucek, Kristina Ellwanger, Michael Weichel, Stefan Knackmuss, Eugene Zhukovsky, Judith A Fox, Lori A Kunkel, Jeanmarie Guenot, Roland B Walter
PURPOSE: Randomized studies with gemtuzumab ozogamicin have validated CD33 as a target for antigen-specific immunotherapy of acute myeloid leukemia (AML). Here, we investigated the potential of CD33/CD3-directed tandem diabodies (TandAbs) as novel treatment approach for AML. These tetravalent bispecific antibodies provide two binding sites for each antigen to maintain the avidity of a bivalent antibody and have a molecular weight exceeding the renal clearance threshold, thus offering a longer half-life compared to smaller antibody constructs...
May 17, 2016: Clinical Cancer Research: An Official Journal of the American Association for Cancer Research
Joerg U Schmohl, Martin Felices, Elizabeth Taras, Jeff S Miller, Daniel A Vallera
Previously, we constructed a bispecific NK-cell-engager (BiKE) bearing single-chain variable fragments (scFv) against CD16 on NK cells and EpCAM on tumor cells. This BiKE facilitated antigen-specific antibody-dependent cell-mediated cytotoxicity (ADCC) but did not induce NK cell expansion. We incorporated a modified interleukin-15 cross-linker to create a trispecific construct (TriKE) in order to improve activation, proliferation, and survival of NK cells. Synthesis and assembly of hybrid genes encoding the TriKE was accomplished using DNA-shuffling and DNA-ligation techniques...
August 2016: Molecular Therapy: the Journal of the American Society of Gene Therapy
Chia-Yen Lu, Gregory J Chen, Pei-Han Tai, Yu-Chen Yang, Yu-Shen Hsu, Mingi Chang, Chuan-Lung Hsu
Bispecific antibodies (bsAbs) are second generation antibodies for therapeutic application in immunotherapy. One of the major strategies of the bsAb platform is the recruitment of immune effector T cells by incorporating an anti-CD3 domain. A bispecific T-cell engager (BiTE), with one end having an affinity for CD3 and the other end with affinity for CD19, has been approved in the US and Europe for the treatment of acute lymphoblastic leukemia. However, due to their small size and lack of Fc region, these single-chain variable fragment (scFv) bsAbs have short half-lives in vivo...
May 13, 2016: Biochemical and Biophysical Research Communications
Matthias Klinger, Jonathan Benjamin, Roman Kischel, Sabine Stienen, Gerhard Zugmaier
Bispecific T-cell engager (BiTE(®)) antibody constructs represent a novel immunotherapy that bridges cytotoxic T cells to tumor cells, thereby inducing target cell-dependent polyclonal T-cell activation and proliferation, and leading to apoptosis of bound tumor cells. Anti-CD19 BiTE(®) blinatumomab has demonstrated clinical activity in Philadelphia chromosome (Ph)-negative relapsed or refractory (r/r) acute lymphoblastic leukemia (ALL) eventually resulting in conditional approval by the U.S. Food and Drug Administration in 2014...
March 2016: Immunological Reviews
Katayoun Rezvani, Rayne H Rouce
Natural killer (NK) cells are essential components of the innate immune system and play a critical role in host immunity against cancer. Recent progress in our understanding of NK cell immunobiology has paved the way for novel NK cell-based therapeutic strategies for the treatment of cancer. In this review, we will focus on recent advances in the field of NK cell immunotherapy, including augmentation of antibody-dependent cellular cytotoxicity, manipulation of receptor-mediated activation, and adoptive immunotherapy with ex vivo-expanded, chimeric antigen receptor (CAR)-engineered, or engager-modified NK cells...
2015: Frontiers in Immunology
Muneera Al-Hussaini, Michael P Rettig, Julie K Ritchey, Darja Karpova, Geoffrey L Uy, Linda G Eissenberg, Feng Gao, William C Eades, Ezio Bonvini, Gurunadh R Chichili, Paul A Moore, Syd Johnson, Lynne Collins, John F DiPersio
T-cell-directed killing of tumor cells using bispecific antibodies is a promising approach for the treatment of hematologic malignancies. Here we describe our preclinical work with a dual-affinity retargeting (DART) molecule generated from antibodies to CD3 and CD123, designed to redirect T cells against acute myeloid leukemia blasts. The CD3×CD123 DART (also referred to as MGD006/S80880) consists of 2 independent polypeptides, each composed of the VH of 1 antibody in tandem with the VL of the other antibody...
January 7, 2016: Blood
Francesca Ferrari, Stefania Bellone, Jonathan Black, Carlton L Schwab, Salvatore Lopez, Emiliano Cocco, Elena Bonazzoli, Federica Predolini, Gulden Menderes, Babak Litkouhi, Elena Ratner, Dan-Arin Silasi, Masoud Azodi, Peter E Schwartz, Alessandro D Santin
BACKGROUND: Uterine and ovarian carcinosarcomas (CS) are rare but highly aggressive gynecologic tumors which carry an extremely poor prognosis. We evaluated the expression levels of EpCAM and the in vitro activity of solitomab, a bispecific single-chain antibody construct which targets epithelial-cell-adhesion-molecule (EpCAM) on tumor cells and also contains a CD3 binding region, against primary uterine and ovarian CS cell lines. METHODS: EpCAM expression was evaluated by flow cytometry in a total of 5 primary CS cell lines...
October 17, 2015: Journal of Experimental & Clinical Cancer Research: CR
Julia A M Sung, Joy Pickeral, Liqin Liu, Sherry A Stanfield-Oakley, Chia-Ying Kao Lam, Carolina Garrido, Justin Pollara, Celia LaBranche, Mattia Bonsignori, M Anthony Moody, Yinhua Yang, Robert Parks, Nancie Archin, Brigitte Allard, Jennifer Kirchherr, JoAnn D Kuruc, Cynthia L Gay, Myron S Cohen, Christina Ochsenbauer, Kelly Soderberg, Hua-Xin Liao, David Montefiori, Paul Moore, Syd Johnson, Scott Koenig, Barton F Haynes, Jeffrey L Nordstrom, David M Margolis, Guido Ferrari
Enhancement of HIV-specific immunity is likely required to eliminate latent HIV infection. Here, we have developed an immunotherapeutic modality aimed to improve T cell-mediated clearance of HIV-1-infected cells. Specifically, we employed Dual-Affinity Re-Targeting (DART) proteins, which are bispecific, antibody-based molecules that can bind 2 distinct cell-surface molecules simultaneously. We designed DARTs with a monovalent HIV-1 envelope-binding (Env-binding) arm that was derived from broadly binding, antibody-dependent cellular cytotoxicity-mediating antibodies known to bind to HIV-infected target cells coupled to a monovalent CD3 binding arm designed to engage cytolytic effector T cells (referred to as HIVxCD3 DARTs)...
November 2, 2015: Journal of Clinical Investigation
Snezana Vasiljevic, Emma V Beale, Camille Bonomelli, Iona S Easthope, Laura K Pritchard, Gemma E Seabright, Alessandro T Caputo, Christopher N Scanlan, Martin Dalziel, Max Crispin
Effective use of adenovirus-5 (Ad5) in cancer therapy is heavily dependent on the degree to which the virus's natural tropism can be subverted to one that favours tumour cells. This is normally achieved through either engineering of the viral fiber knob or the use of bispecific adaptors that display both adenovirus and tumour antigen receptors. One of the main limitations of these strategies is the need to tailor each engineering event to any given tumour antigen. Here, we explore bispecific adaptors that can utilise established anti-cancer therapeutic antibodies...
December 2015: Molecular Immunology
Kimberly H Harrington, Chelsea J Gudgeon, George S Laszlo, Kathryn J Newhall, Angus M Sinclair, Stanley R Frankel, Roman Kischel, Guang Chen, Roland B Walter
The CD33/CD3-bispecific T-cell engaging (BiTE) antibody construct, AMG 330, potently lyses CD33+ leukemic cells in vitro. Using specimens from 41 patients with acute myeloid leukemia (AML), we studied the factors that might contribute to clinical response or resistance. For this purpose, thawed aliquots of primary AML samples were immunophenotypically characterized and subjected to various doses of AMG 330 in the presence or absence of healthy donor T-cells. After 48 hours, drug-specific cytotoxicity was quantified and correlated with CD33 expression levels, amounts of T-cells present, and other disease characteristics...
2015: PloS One
G S Laszlo, C J Gudgeon, K H Harrington, R B Walter
Preclinical and emerging clinical studies demonstrate that bispecific T-cell engaging (BiTE) antibody constructs can potently lyse targeted tumor cells, but the determinants for their activity remain incompletely understood. Using human acute myeloid leukemia (AML) cell lines engineered to overexpress individual T-cell ligands, we found that expression of the inhibitory ligands, PD-L1 and PD-L2, reduced the cytolytic activity of the BiTE antibody construct targeting CD33, AMG 330; conversely, expression of the activating ligands, CD80 and CD86, augmented the cytotoxic activity of AMG 330...
2015: Blood Cancer Journal
Stefania Bellone, Jonathan Black, Diana P English, Carlton L Schwab, Salvatore Lopez, Emiliano Cocco, Elena Bonazzoli, Federica Predolini, Francesca Ferrari, Elena Ratner, Dan-Arin Silasi, Masoud Azodi, Peter E Schwartz, Alessandro D Santin
BACKGROUND: Uterine serous carcinoma is an aggressive form of endometrial cancer that carries an extremely poor prognosis. Solitomab is a novel bispecific single-chain antibody construct that targets epithelial cell adhesion molecule on tumor cells and also contains a CD3 binding region. We evaluated the expression levels of epithelial cell adhesion molecule and the in vitro activity of solitomab against primary uterine serous carcinoma cell lines in vitro and ex-vivo in the ascites of patients with uterine serous carcinoma...
January 2016: American Journal of Obstetrics and Gynecology
Liping L Sun, Diego Ellerman, Mary Mathieu, Maria Hristopoulos, Xiaocheng Chen, Yijin Li, Xiaojie Yan, Robyn Clark, Arthur Reyes, Eric Stefanich, Elaine Mai, Judy Young, Clarissa Johnson, Mahrukh Huseni, Xinhua Wang, Yvonne Chen, Peiyin Wang, Hong Wang, Noel Dybdal, Yu-Waye Chu, Nicholas Chiorazzi, Justin M Scheer, Teemu Junttila, Klara Totpal, Mark S Dennis, Allen J Ebens
Bispecific antibodies and antibody fragments in various formats have been explored as a means to recruit cytolytic T cells to kill tumor cells. Encouraging clinical data have been reported with molecules such as the anti-CD19/CD3 bispecific T cell engager (BiTE) blinatumomab. However, the clinical use of many reported T cell-recruiting bispecific modalities is limited by liabilities including unfavorable pharmacokinetics, potential immunogenicity, and manufacturing challenges. We describe a B cell-targeting anti-CD20/CD3 T cell-dependent bispecific antibody (CD20-TDB), which is a full-length, humanized immunoglobulin G1 molecule with near-native antibody architecture constructed using "knobs-into-holes" technology...
May 13, 2015: Science Translational Medicine
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