Jayanthi Menon

Memorial Sloan Kettering Cancer Center

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Viviane Tabar

Memorial Sloan Kettering Cancer Center

Tamara Major

University of Belgrade

Fumiko Shimizu

Showa Women's University

Kara Olson

Regeneron (United States)

Gavin Thurston

Regeneron (United States)

Jessica R. Kirshner

Regeneron (United States)

Bindu Varghese

Carisma Therapeutics (United States)

Lorenz Studer

Memorial Sloan Kettering Cancer Center

Mark Tomishima

Memorial Sloan Kettering Cancer Center

Eric Smith

Regeneron (United States)

Cooperative Institutions

Memorial Sloan Kettering Cancer Center

Regeneron (United States)

Kettering University

Cornell University

Harvard University

New York Stem Cell Foundation

University of California, San Francisco

Institute of Developmental Physiology

Albert Einstein College of Medicine

Icahn School of Medicine at Mount Sinai

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A novel, native-format bispecific antibody triggering T-cell killing of B-cells is robustly active in mouse tumor models and cynomolgus monkeys

Scientific Reports (2015)

Eric Smith Kara Olson Lauric Haber Bindu Varghese Paurene Duramad

Bispecific antibodies, while showing great therapeutic potential, pose formidable challenges with respect to their assembly, stability, immunogenicity, and pharmacodynamics. Here we describe a novel class of bispecific antibodies with native human immunoglobulin format. The design exploits differences in the affinities of the immunoglobulin isotypes for Protein A, allowing efficient large-scale purification. Using this format, we generated a bispecific antibody, REGN1979, targeting the B cell marker, CD20, and the CD3 component of the T cell receptor, which triggers redirected killing of B cells. In mice, this antibody prevented growth of B cell tumors and also caused regression of large established tumors. In cynomolgus monkeys, low doses of REGN1979 caused prolonged depletion of B cells in peripheral blood with a serum half-life of approximately 14 days. Further, the antibody induced a deeper depletion of B cells in lymphoid organs than rituximab. This format has broad applicability for development of clinical bispecific antibodies.

Bispecific antibody

10.1038/srep17943

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Citations (143)

Inhibition of Notch Signaling in Glioblastoma Targets Cancer Stem Cells via an Endothelial Cell Intermediate

Stem Cells (2010)

Koos E. Hovinga Fumiko Shimizu Rong Wang Georgia Panagiotakos Maartje van der Heijden

Abstract Glioblastoma multiforme (GBM) is a highly heterogeneous malignant tumor. Recent data suggests the presence of a hierarchical organization within the GBM cell population that involves cancer cells with stem-like behavior, capable of repopulating the tumor and contributing to its resistance to therapy. Tumor stem cells are thought to reside within a vascular niche that provides structural and functional support. However, most GBM studies involve isolated tumor cells grown under various culture conditions. Here, we use a novel three-dimensional organotypic “explant” system of surgical GBM specimens that preserves cytoarchitecture and tumor stroma along with tumor cells. Notch inhibition in explants results in decreased proliferation and self-renewal of tumor cells but is also associated with a decrease in endothelial cells. When endothelial cells are selectively eliminated from the explants via a toxin conjugate, we also observed a decrease in self-renewal of tumor stem cells. These findings support a critical role for tumor endothelial cells in GBM stem cell maintenance, mediated at least in part by Notch signaling. The explant system further highlighted differences in the response to radiation between explants and isolated tumor neurospheres. Combination treatment with Notch blockade and radiation resulted in a substantial decrease in proliferation and in self-renewal in tumor explants while radiation alone was less effective. This data suggests that the Notch pathway plays a critical role in linking angiogenesis and cancer stem cell self-renewal and is thus a potential therapeutic target. Three-dimensional explant systems provide a novel approach for the study of tumor and microenvironment interactions.

Neurosphere

10.1002/stem.429

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Citations (288)

Human Embryonic Stem Cell-Derived Oligodendrocyte Progenitors Remyelinate the Brain and Rescue Behavioral Deficits following Radiation

Cell stem cell (2015)

Jinghua Piao Tamara Major Gordon Auyeung Edelweiss Policarpio Jayanthi Menon

Progenitor

10.1016/j.stem.2015.01.004

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Citations (176)

Transgene Excision Has No Impact on In Vivo Integration of Human iPS Derived Neural Precursors

PLoS ONE (2011)

Tamara Major Jayanthi Menon Gordon Auyeung Frank Soldner Dirk Hockemeyer

The derivation of induced human pluripotent stem cells (hiPS) has generated significant enthusiasm particularly for the prospects of cell-based therapy. But there are concerns about the suitability of iPS cells for in vivo applications due in part to the introduction of potentially oncogenic transcription factors via viral vectors. Recently developed lentiviral vectors allow the excision of viral reprogramming factors and the development of transgene-free iPS lines. However it is unclear if reprogramming strategy has an impact on the differentiation potential and the in vivo behavior of hiPS progeny. Here we subject viral factor-free, c-myc-free and conventionally reprogrammed four-factor human iPS lines to a further challenge, by analyzing their differentiation potential along the 3 neural lineages and over extended periods of time in vitro, as well as by interrogating their ability to respond to local environmental cues by grafting into the striatum. We demonstrate similar and efficient differentiation into neurons, astrocytes and oligodendrocytes among all hiPS and human ES line controls. Upon intracranial grafting in the normal rat (Sprague Dawley), precursors derived from all hiPS lines exhibited good survival and response to environmental cues by integrating into the subventricular zone, acquiring phenotypes typical of type A, B or C cells and migrating along the rostral migratory stream into the olfactory bulb. There was no teratoma or other tumor formation 12 weeks after grafting in any of the 26 animals used in the study. Thus neither factor excision nor persistence of c-myc impact the behavior of hiPS lines in vivo.

Reprogramming

10.1371/journal.pone.0024687

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Citations (18)

A Novel CD20xCD3 Bispecific Fully Human Antibody Induces Potent Anti-Tumor Effects Against B Cell Lymphoma in Mice

Blood (2014)

Bindu Varghese Jayanthi Menon Luis Rodríguez Lauric Haber Kara Olson

Raji cell

10.1182/blood.v124.21.4501.4501

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Citations (5)

Stoichiometric and temporal requirements of Oct4, Sox2, Klf4, and c-Myc expression for efficient human iPSC induction and differentiation

Proceedings of the National Academy of Sciences (2009)

Eirini P. Papapetrou Mark Tomishima Stuart M. Chambers Yvonne Mica Evan Reed

Human-induced pluripotent stem cells (hiPSCs) are generated from somatic cells by ectopic expression of the 4 reprogramming factors (RFs) Oct-4, Sox2, Klf4, and c-Myc. To better define the stoichiometric requirements and dynamic expression patterns required for successful hiPSC induction, we generated 4 bicistronic lentiviral vectors encoding the 4 RFs co-expressed with discernable fluorescent proteins. Using this system, we define the optimal stoichiometry of RF expression to be highly sensitive to Oct4 dosage, and we demonstrate the impact that variations in the relative ratios of RF expression exert on the efficiency of hiPSC induction. Monitoring of expression of each individual RF in single cells during the course of reprogramming revealed that vector silencing follows acquisition of pluripotent cell markers. Pronounced lentiviral vector silencing was a characteristic of successfully reprogrammed hiPSC clones, but lack of complete silencing did not hinder hiPSC induction, maintenance, or directed differentiation. The vector system described here presents a powerful tool for mechanistic studies of reprogramming and the optimization of hiPSC generation.

Reprogramming

KLF4

Ectopic expression

10.1073/pnas.0904825106

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Citations (281)

Therapeutic cloning in individual parkinsonian mice

Nature Medicine (2008)

Viviane Tabar Mark Tomishima Georgia Panagiotakos Sayaka Wakayama Jayanthi Menon

Cloning (programming)

10.1038/nm1732

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