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Belleville, NJ, United States

Goldenberg D.M.,Garden State Cancer Center
Expert Opinion on Biological Therapy

Introduction: The crosstalk between tumor and stromal cells has become an increasing important subject of the biology of oncogenesis, also involving new therapy paradigms for treating tumor-reactive host cells and vasculature. Areas covered: This article describes the long-term propagation in hamsters of a human glioblastoma which was derived from the in-vivo fusion of the human tumor cells with hamster stromal cells. The hybrid tumor cells retained at least seven human genes, of which three were able to translate their protein products during serial passages in vitro and in vivo, as well as features of the original tumor's histological appearance. This heterospecific fusion of cancer and normal host stromal cells is discussed as a mechanism for the horizontal transmission of malignancy, which may be a more common phenomenon in human cancer than appreciated previously. Expert opinion: Cellcell fusion in vivo is one of several mechanisms by which genetic information can be transmitted from tumor to host cells, resulting in new and different (more aggressive) tumor cell populations. © 2012 Informa UK, Ltd. Source

McBride W.J.,Immunomedics, Inc. | Sharkey R.M.,Immunomedics, Inc. | Goldenberg D.M.,Garden State Cancer Center
EJNMMI Research

Targeted agents are increasingly used for treating cancer and other diseases, but patients may need to be carefully selected to maximize the potential for therapeutic benefit. One way to select patients is to bind an imaging radionuclide to a targeting agent of interest, so that its uptake in specific sites of disease can be visualized by positron-emission tomography (PET) or single-photon emission computed tomography. 18F is the most commonly used radionuclide for PET imaging. Its half-life of approximately 2 h is suited for sameday imaging of many compounds that clear quickly from the body to allow visualization of uptake in the intended target. A significant impediment to its use, however, is the challenging coupling of 18F to a carbon atom of the targeting agent. Because fluorine binds to aluminum, we developed a procedure where the Al18F complex could be captured by a chelate, thereby greatly simplifying the way that imaging agents can be fluorinated for PET imaging. This article reviews our experience with this technology. © 2013 McBride et al.; licensee Springer. Source

Govindan S.V.,Immunomedics, Inc. | Goldenberg D.M.,Garden State Cancer Center

Targeting of radiation, drugs, and protein toxins to cancers selectively with monoclonal antibodies (MAbs) has been a topic of considerable interest and an area of continued development. Radioimmunotherapy (RAIT) of lymphoma using directly labeled MAbs is of current interest after approval of two radiolabeled anti-CD20 MAbs, as illustrated with the near 100% overall response rate obtained in a recent clinical trial using an investigational radiolabeled anti-CD22 MAb, 90Y-epratuzumab. The advantage of pretargeted RAIT over directly labeled MAbs is continuing to be validated in preclinical models of lymphoma and solid tumors. Importantly, the advantages of combining RAIT with radiation sensitizers, with immunotherapy, or a drug conjugate targeting a different antigen are being studied clinically and preclinically. The area of drug-conjugated antibodies is progressing with encouraging data published for the trastuzumab-DM1 conjugate in a phase I clinical trial in HER2-positive breast cancer. The Dock-and-Lock platform technology has contributed to the design and the evaluation of complex antibody-cytokine and antibody-toxin conjugates. This review describes the advances made in these areas, with illustrations taken from advances made in the authors' institutions. ©2010 with author. Published by TheScientificWorld. Source

Goldenberg D.M.,Garden State Cancer Center | Morschhauser F.,Center Hospitalier Regional | Wegener W.A.,Immunomedics, Inc.
Leukemia and Lymphoma

Veltuzumab is a humanized, anti-CD20 monoclonal IgG1 antibody (MAb), constructed recombinantly on the framework regions of epratuzumab, with complementarity-determining regions (CDRs) identical to rituximab, except for a single amino acid in CDR3 of the variable heavy chain. Veltuzumab showed anti-proliferative, apoptotic, and antibody-dependent cellular cytotoxicity effects invitro similar to rituximab, but with significantly slower off-rates and increased complement-dependent cytotoxicity in several human lymphoma cell lines. In addition, very low doses of veltuzumab, given either intravenously or subcutaneously, depleted B cells in normal cynomolgus monkeys, and controlled tumor growth in mice bearing human lymphomas. Clinically, veltuzumab has been studied in>150 patients with lymphomas and autoimmune diseases. In non-Hodgkin lymphoma (NHL), infusions of 80750mg/m2 were well tolerated when given once-weekly for four doses, with the only toxicity being transient mildmoderate infusion reactions. Objective tumor responses, including durable complete responses, occurred at all dose levels. Subcutaneous injections of low doses (80320mg) have also proved to be safe and pharmacologically active, producing objective responses, including durable complete responses, at rates comparable to those reported with rituximab, in patients with NHL and immune thrombocytopenia. © 2010 Informa Healthcare USA, Inc. Source

Gupta P.,Immunomedics, Inc. | Goldenberg D.M.,Garden State Cancer Center | Rossi E.A.,IBC Pharmaceuticals | Chang C.-H.,Immunomedics, Inc.

We have generated hexavalent antibodies (HexAbs) comprising 6 Fabs tethered to one Fc of human IgG1. Three such constructs, 20-20, a monospecific HexAb comprising 6 Fabs of veltuzumab (humanized anti-CD20 immunoglobulin G1κ [IgG1κ]), 20-22, a bispecific HexAb comprising veltuzumab and 4 Fabs of epratuzumab (humanized anti-CD22 IgG1κ), and 22-20, a bispecific HexAb comprising epratuzumab and 4 Fabs of veltuzumab, were previously shown to inhibit proliferation of several lymphoma cell lines at nanomolar concentrations in the absence of a crosslinking antibody. We now report an in-depth analysis of the apoptotic and survival signals induced by the 3 HexAbs in Burkitt lymphomas and provide in vitro cytotoxicity data for additional lymphoma cell lines and also chronic lymphocytic leukemia patient specimens. Among the key findings are the significant increase in the levels of phosphorylated p38 and phosphatase and tensin homolog deleted on chromosome 10 (PTEN) by all 3 HexAbs and the notable differences in the signaling events triggered by the HexAbs from those incurred by crosslinking veltuzumab or rituximab with a secondary antibody. Thus, the greatly enhanced direct toxicity of these HexAbs correlates with their ability to alter the basal expression of various intracellular proteins involved in regulating cell growth, survival, and apoptosis, with the net outcome leading to cell death. © 2010 by The American Society of Hematology. Source

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