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Sharkey R.M.,Garden State Cancer Center | Karacay H.,Garden State Cancer Center | Govindan S.V.,Immunomedics, Inc. | Goldenberg D.M.,Garden State Cancer Center
Molecular Cancer Therapeutics | Year: 2011

Chemoimmunotherapy with antibody - drug conjugates (ADC) is emerging as a promising therapy for solid tumors, whereas radioimmunotherapy (RAIT) of solid tumors has been relatively ineffective because of their resistance to radiation. We developed antibody - SN-38 conjugates that have significant antitumor activity in xenograft models at nontoxic doses. The goal of this study was to determine if an ADC could be combined with RAIT to enhance efficacy without a commensurate increase in host toxicity. Nude mice bearing human pancreatic cancer xenografts (Capan-1 and BxPC-3) were treated with a single dose of 90Y-labeled antimucin antibody (hPAM4; clivatuzumab tetraxetan) alone or in combination with an anti-Trop-2-SN-38 conjugate, typically administered twice weekly over 4 weeks. The combination, even at RAIT's maximum tolerated dose, controlled tumor progression and cured established xenografts significantly better than the individual treatments without appreciable toxicity. The ADC could be started 1 week after or up to 2 weeks before RAIT with similar enhanced responses, but delaying RAIT for 2 weeks after the ADC was less effective. A nonspecific ADC provided additional benefit over using free drug (irinotecan), but the response was enhanced with the specific ADC. When targeting Capan-1 with ample mucin, hPAM4 could be used as the RAIT and the ADC agent without losing effectiveness, but in BxPC-3 with less mucin, targeting of different antigens was preferred. These studies show the feasibility of combining ADC and RAIT for improved efficacy without increased toxicity. ©2011 AACR.


McBride W.J.,Immunomedics, Inc. | Sharkey R.M.,Immunomedics, Inc. | Goldenberg D.M.,Garden State Cancer Center
EJNMMI Research | Year: 2013

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.


Sharkey R.M.,Garden State Cancer Center | Govindan S.V.,Immunomedics, Inc. | Cardillo T.M.,Immunomedics, Inc. | Goldenberg D.M.,Garden State Cancer Center
Molecular Cancer Therapeutics | Year: 2012

We previously found that slowly internalizing antibodies conjugated with SN-38 could be used successfully when prepared with a linker that allows approximately 50% of the IgG-bound SN-38 to dissociate in serum every 24 hours. In this study, the efficacy of SN-38 conjugates prepared with epratuzumab (rapidly internalizing) and veltuzumab (slowly internalizing), humanized anti-CD22 and anti-CD20 IgG, respectively, was examined for the treatment of B-cell malignancies. Both antibody-drug conjugates had similar nanomolar activity against a variety of human lymphoma/leukemia cell lines, but slow release of SN-38 compromised potency discrimination in vitro even against an irrelevant conjugate. When SN-38 was stably linked to the anti-CD22 conjugate, its potency was reduced 40- to 55-fold. Therefore, further studies were conducted only with the less stable, slowly dissociating linker. In vivo, similar antitumor activity was found between CD22 and CD20antibody-drug conjugate in mice-bearing Ramosxenografts, even thoughRamos expressed 15-fold more CD20 than CD22, suggesting that the internalization of the epratuzumab-SN-38 conjugate (Emab-SN-38) enhanced its activity. Emab-SN-38 was more efficacious than a nonbinding, irrelevant IgG-SN-38 conjugate in vivo, eliminating a majority of well-established Ramos xenografts at nontoxic doses. In vitro and in vivo studies showed that Emab-SN-38 could be combined with unconjugated veltuzumab for a more effective treatment. Thus, Emab-SN-38 is active in lymphoma and leukemia at doses well below toxic levels and therefore represents a new promising agent with therapeutic potential alone or combined with anti-CD20 antibody therapy. ©2011 AACR.


Govindan S.V.,Immunomedics, Inc. | Goldenberg D.M.,Garden State Cancer Center
TheScientificWorldJournal | Year: 2010

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.


Goldenberg D.M.,Garden State Cancer Center | Morschhauser F.,Center Hospitalier Regional | Wegener W.A.,Immunomedics, Inc.
Leukemia and Lymphoma | Year: 2010

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.


Gupta P.,Immunomedics, Inc. | Goldenberg D.M.,Garden State Cancer Center | Rossi E.A.,IBC Pharmaceuticals | Chang C.-H.,Immunomedics, Inc.
Blood | Year: 2010

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.


D'Souza C.A.,Immunomedics, Inc. | McBride W.J.,Immunomedics, Inc. | Sharkey R.M.,Garden State Cancer Center | Todaro L.J.,City College of New York | Goldenberg D.M.,Garden State Cancer Center
Bioconjugate Chemistry | Year: 2011

The coordination chemistry of a new pentadentate bifunctional chelator (BFC), NODA-MPAA 1, containing the 1,4,7-triazacyclononane-1,4-diacetate (NODA) motif with a methylphenylacetic acid (MPAA) backbone, and its ability to form stable Al 18F chelates were investigated. The organofluoroaluminates were easily accessible from the reaction of 1 and AlF 3. X-ray diffraction studies revealed aluminum at the center of a slightly distorted octahedron, with fluorine occupying one of the axial positions. The tert-butyl protected prochelator 7, which can be synthesized in one step, is useful for coupling to biomolecules on solid phase or in solution. High yield (55-89%) aqueous 18F-labeling was achieved in 10-15 min with a tumor-targeting peptide 4 covalently linked to 1. Defluorination was not observed for at least 4 h in human serum at 37 °C. These results demonstrate the facile application of Al 18F chelation using BFC 1 as a versatile labeling method for radiofluorinating other heat-stable peptides for positron emission imaging. © 2011 American Chemical Society.


Gold D.V.,Garden State Cancer Center | Newsome G.,Garden State Cancer Center | Liu D.,Immunomedics, Inc. | Goldenberg D.M.,Garden State Cancer Center | Goldenberg D.M.,Immunomedics, Inc.
Molecular Cancer | Year: 2013

Background: PAM4, an antibody that has high specificity for pancreatic ductal adenocarcinoma (PDAC), compared to normal pancreas, benign lesions of the pancreas, and cancers originating from other tissues, is being investigated as a biomarker for early detection, as well as antibody-targeted imaging and therapy. Therefore, the identity of the antigen bound by this monoclonal antibody (MAb) can provide information leading to improved use of the antibody. Prior results suggested the antigen is a mucin-type glycoprotein rich in cysteine disulfide bridges that provide stable conformation for the PAM4-epitope.Methods: Indirect and sandwich enzyme immunoassays (EIA) were performed to compare and contrast the reactivity of PAM4 with several anti-mucin antibodies having known reactivity to specific mucin species (e.g., MUC1, MUC4, MUC5AC, etc.). Studies designed to block reactivity of PAM4 with its specific antigen also were performed.Results: We demonstrate that MAbs 2-11 M1 and 45 M1, each reactive with MUC5AC, are able to provide signal in a heterologous sandwich immunoassay where PAM4 is the capture antibody. Further, we identify MAbs 21 M1, 62 M1, and 463 M1, each reactive with MUC5AC, as inhibiting the reaction of PAM4 with its specific epitope. MAbs directed to MUC1, MUC3, MUC4, MUC16 and CEACAM6 are not reactive with PAM4-captured antigen, nor are they able to block the reaction of PAM4 with its antigen.Conclusions: These data implicate MUC5AC as a specific mucin species to which PAM4 is reactive. Furthermore, this realization may allow for the improvement of the current PAM4 serum-based immunoassay for detection of early-stage PDAC by the application of anti-MUC5AC MAbs as probes in this sandwich EIA. © 2013 Gold et al.; licensee BioMed Central Ltd.


Goldenberg D.M.,Garden State Cancer Center
Expert Opinion on Biological Therapy | Year: 2012

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.


Taylor A.P.,Garden State Cancer Center | Leon E.,Garden State Cancer Center | Goldenberg D.M.,Garden State Cancer Center
British Journal of Cancer | Year: 2010

Background:During metastasis, cancer cells migrate away from the primary tumour and invade the circulatory system and distal tissues. The stimulatory effect of growth factors has been implicated in the migration process. Placental growth factor (PlGF), expressed by 30-50% of primary breast cancers, stimulates measurable breast cancer cell motility in vitro within 3 h. This implies that PlGF activates intracellular signalling kinases and cytoskeletal remodelling necessary for cellular migration. The PlGF-mediated motility is prevented by an Flt-1-antagonising peptide, BP-1, and anti-PlGF antibody. The purpose of this study was to determine the intracellular effects of PlGF and the inhibiting peptide, BP-1.Methods:Anti-PlGF receptor (anti-Flt-1) antibody and inhibitors of intracellular kinases were used for analysis of PlGF-delivered intracellular signals that result in motility. The effects of PlGF and BP-1 on kinase activation, intermediate filament (IF) protein stability, and the actin cytoskeleton were determined by immunohistochemistry, cellular migration assays, and immunoblots.Results:Placental growth factor stimulated phosphorylation of extracellular-regulated kinase (ERK)1/2 (pERK) in breast cancer cell lines that also increased motility. In the presence of PlGF, BP-1 decreased cellular motility, reversed ERK1/2 phosphorylation, and decreased nuclear and peripheral pERK1/2. ERK1/2 kinases are associated with rearrangements of the actin and IF components of the cellular cytoskeleton. The PlGF caused rearrangements of the actin cytoskeleton, which were blocked by BP-1. The PlGF also stabilised cytokeratin 19 and vimentin expression in MDA-MB-231 human breast cancer cells in the absence of de novo transcription and translation.Conclusions:The PlGF activates ERK1/2 kinases, which are associated with cellular motility, in breast cancer cells. Several of these activating events are blocked by BP-1, which may explain its anti-tumour activity. © 2010 Cancer Research UK All rights reserved.

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