Center for Molecular Medicine and Immunology

Avon-by-the-Sea, NJ, United States

Center for Molecular Medicine and Immunology

Avon-by-the-Sea, NJ, United States

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Cardillo T.M.,Immunomedics, Inc. | Govindan S.V.,Immunomedics, Inc. | Sharkey R.M.,Center for Molecular Medicine and Immunology | Trisal P.,Immunomedics, Inc. | Goldenberg D.M.,Center for Molecular Medicine and Immunology
Clinical Cancer Research | Year: 2011

Purpose: Evaluate the efficacy of an SN-38-anti-Trop-2 antibody-drug conjugate (ADC) against several human solid tumor types, and to assess its tolerability in mice and monkeys, the latter with tissue cross-reactivity to hRS7 similar to humans. Experimental Design: Two SN-38 derivatives, CL2-SN-38 and CL2A-SN-38, were conjugated to the anti-Trop-2-humanized antibody, hRS7. The immunoconjugates were characterized in vitro for stability, binding, and cytotoxicity. Efficacy was tested in five different human solid tumor-xenograft models that expressed Trop-2 antigen. Toxicity was assessed in mice and in Cynomolgus monkeys. Results: The hRS7 conjugates of the two SN-38 derivatives were equivalent in drug substitution (∼6), cell binding (K d ∼ 1.2 nmol/L), cytotoxicity (IC 50 ∼ 2.2 nmol/L), and serum stability in vitro (t/ 1/2 ∼ 20 hours). Exposure of cells to the ADC demonstrated signaling pathways leading to PARP cleavage, but differences versus free SN-38 in p53 and p21 upregulation were noted. Significant antitumor effects were produced by hRS7-SN-38 at nontoxic doses in mice bearing Calu-3 (P ≤ 0.05), Capan-1 (P < 0.018), BxPC-3 (P < 0.005), and COLO 205 tumors (P < 0.033) when compared to nontargeting control ADCs. Mice tolerated a dose of 2 x 12 mg/kg (SN-38 equivalents) with only short-lived elevations in ALT and AST liver enzyme levels. Cynomolgus monkeys infused with 2 x 0.96 mg/kg exhibited only transient decreases in blood counts, although, importantly, the values did not fall below normal ranges. Conclusions: The anti-Trop-2 hRS7-CL2A-SN-38 ADC provides significant and specific antitumor effects against a range of human solid tumor types. It is well tolerated in monkeys, with tissue Trop-2 expression similar to humans, at clinically relevant doses, and warrants clinical investigation. ©2011 American Association for Cancer Research.


Govindan S.V.,Immunomedics, Inc. | Goldenberg D.M.,Center for Molecular Medicine and Immunology
Expert Opinion on Biological Therapy | Year: 2012

Introduction: Antibodydrug conjugates (ADCs), as well as antibody conjugates of protein toxins (immunotoxins) and cytokines (immunocytokines), are showing clinical efficacy, with manageable toxicities, in cancer treatment. Areas covered: The utility of an ADC is governed by the antibody and the target, as well as by the druglinker component of the conjugate. The conjugation site, conjugating group, drug/antibody ratios and site-specific conjugation for product homogeneity are all aspects to consider in optimizing the ADC and enhancing its therapeutic window. Immunotoxin and immunocytokine construction by recombinant methods can be modulated to improve efficacy and reduce toxicity. The Dock-and-Lock (DNL) platform technology provides a flexible approach to assemble mono- or bispecific constructs carrying multiple toxin or cytokine molecules for targeted therapy. Expert opinion: Conjugation chemistry and recombinant technologies have had a significant impact on the therapeutic prospects of immunoconjugates, particularly in hematopoietic diseases. Continued concerted efforts from different scientific disciplines are needed, together with newer treatment paradigms, for greater progress in the more challenging therapy of solid tumors. © 2012 Informa UK, Ltd.


Wallace D.J.,University of California at Los Angeles | Goldenberg D.M.,Center for Molecular Medicine and Immunology | Goldenberg D.M.,Immunomedics, Inc.
Lupus | Year: 2013

Epratuzumab (EMab, UCB, Immunomedics) is a humanized monoclonal antibody targeting CD22 that is being studied in clinical trials for patients with a variety of rheumatic and hematologic conditions, including systemic lupus erythematosus (SLE). An overview of its mechanism of action is followed by a summary of completed lupus studies, and a preview of studies in progress. The agent clearly has anti-inflammatory activity and is a potentially useful agent in the management of autoimmune disorders. © The Author(s), 2013. Reprints and permissions: http://www.sagepub.co.uk/journalsPermissions.nav.


Patent
Center For Molecular Medicine And Immunology and Immunomedics, Inc. | Date: 2011-03-11

The present invention concerns methods and compositions for inhibiting angiogenesis and/or tumor growth, survival and/or metastasis. In particular embodiments, the methods and compositions may concern ligands against placenta growth factor (PlGF), such as BP-1, BP-2, BP-3 or BP-4. Some methods may comprise administering one or more PlGF ligands, alone or in combination with one or more other agents, such as chemotherapeutic agents, other anti-angiogenic agents, immunotherapeutic agents or radioimmunotherapeutic agents to a subject. The PlGF ligands are effective to inhibit angiogenesis, tumor cell motility, tumor metastasis, tumor growth and/or tumor survival. In certain embodiments, PlGF ligands may be administered to subjects to ameliorate other angiogenesis related conditions, such as macular degeneration. In some embodiments, PlGF expression levels may be determined by any known method to select those patients most likely to respond to PlGF targeted therapies.


Grant
Agency: Department of Health and Human Services | Branch: | Program: STTR | Phase: Phase I | Award Amount: 191.14K | Year: 2011

DESCRIPTION (provided by applicant): Control of GVHD by milatuzumab in hu-SCID mice Dendritic cells (DCs) are the primary initiator of graft-versus-host disease (GVHD), a major and life- threatening complication of allogeneic hematopoietic stem cell transplantation (alloHSCT). Depletion of DCs has been demonstrated to be an effective approach for control of GVHD. We recently found that milatuzumab, a humanized anti-CD74 monoclonal antibody, can efficiently deplete myeloid DCs from human peripheral blood mononuclear cells, and potently suppress the proliferation of alloreactive T cells without impairing CMV-specific CD8+ T cells in allogeneic mixed leukocyte cultures, suggesting that milatuzumab may be developed as a novel mAb for prophylactic and/or therapeutic control of GVHD. In this proposed study, we will evaluate the efficacy of this novel mAb for its prophylactic efficacy against GVHD in a human-PBL-SCID mouse model. We will also investigate whether milatuzumab, while controlling GVHD, has any detrimental effect on the third-party immunity in this model, including anti-viral and graft-versus-leukemic functions, which will provide key safety information for clinical use of this mAb in patients undergoing allo-hematopoietic stem cell transplant. We believe that this STTR project, through the collaboration between Immunomedics, Inc., and the Center for Molecular Medicine and Immunology, could lead to the development of a novel class of monoclonal antibodies for better control of GVHD through depletion of CD74-expressing myeloid DCs. PUBLIC HEALTH RELEVANCE: Control of GVHD by milatuzumab in hu-SCID mice Graft-versus-host disease (GVHD) is a major life-threatening complication of allogeneic hematopoietic stem cell transplantation. Milatuzumab, a humanized anti-CD74 monoclonal antibody, can efficiently deplete dendritic cells from human peripheral mononuclear cells, suggesting its potential to prevent and/or treat GVHD. We will evaluate the preventive efficacy of milatuzumab on GVHD in a humanized mouse model, and while controlling GVHD, if it has any harmful effect on the host immunity against pathogens and leukemia, including anti-viral and graft-versus-leukemic functions. This preclinical study could provide valuable information to justify future clinical investigations.


Patent
Center For Molecular Medicine And Immunology and Immunomedics, Inc. | Date: 2011-01-11

Disclosed herein are methods and compositions comprising interferon- (IFN-) and anti-CD74 or anti-HLA-DR antibodies. In preferred embodiments, the IFN- increases the expression of CD74 and/or HLA-DR in target cells and increases the sensitivity of the cells to the cytotoxic effects of the anti-CD74 or anti-HLA-DR antibodies. The compositions and methods are of use to treat diseases involving CD74^(+) and/or HLA-DR^(+) cells, such as cancer cells, autoimmune disease cells or immune dysfunction disease cells.


Patent
Immunomedics, Inc. and Center For Molecular Medicine And Immunology | Date: 2012-08-06

Disclosed herein are methods and compositions comprising interferon- (IFN-) and anti-CD74 or anti-HLA-DR antibodies. In preferred embodiments, the IFN- increases the expression of CD74 and/or HLA-DR in target cells and increases the sensitivity of the cells to the cytotoxic effects of the anti-CD74 or anti-HLA-DR antibodies. The compositions and methods are of use to treat diseases involving CD74^(+) and/or HLA-DR^(+) cells, such as cancer cells, autoimmune disease cells or immune dysfunction disease cells.


Goldenberg D.M.,Center for Molecular Medicine and Immunology | Sharkey R.M.,Center for Molecular Medicine and Immunology
Expert Opinion on Biological Therapy | Year: 2012

Introduction: Over a half a century ago, radiolabeled antibodies were shown to localize selectively in tissues based on the expression of unique antigens. Antibodies have since become the de facto targeting agent, even inspiring the development of non-antibody compounds for targeting purposes. Areas covered: In this article, we review various aspects of how antibodies are transforming the way cancer is being detected and treated, with the growing demand for unconjugated and many new antibody conjugates. While unconjugated antibodies continue to garner most of the attention, interest in new antibody drug conjugates and immunotoxins has expanded over the past few years. However, there continues to be active research with new radioimmunoconjugates for imaging and therapy, particularly with α-emitters, as well as antibody-targeted cytokines and other biological response modifiers. Expert opinion: The increasing number of new agents being developed and tested clinically suggests that antibody-targeted compounds will have an expanding role in the future. © 2012 Informa UK, Ltd.


Sharkey R.M.,Center for Molecular Medicine and Immunology | Karacay H.,Center for Molecular Medicine and Immunology | Goldenberg D.M.,Center for Molecular Medicine and Immunology
Cancer | Year: 2010

Radioimmunotherapy of non-Hodgkin lymphoma comprises a 90Y- or 131I-labeled murine anti-CD20 IgG, but both agents also include a substantial dose of unlabeled anti-CD20 IgG given immediately before the radioconjugate to reduce its uptake in the spleen (primary normal B-cell antigen sink); this extends its plasma half-life and improves tumor visualization. Thus, these treatments combine an effective anti-CD20 radioconjugate with an unconjugated anti-CD20 antibody that is also therapeutically active, but the large anti-CD20 IgG predose (∼900 mg) may diminish the tumor localization of the radioimmunoconjugate (eg, 10-35 mg). We have examined alternative approaches that enhance radionuclide targeting and improve antitumor responses. One uses a 90Y-labeled anti-CD22 IgG (epratuzumab) combined with an antibody therapy regimen of a humanized anti-CD20 IgG (veltuzumab). Pretargeted radionuclide therapy using a trivalent, humanized, recombinant bispecific anti-CD20 antibody with a 90Y-hapten-peptide is another highly effective method that is also less toxic than directly radiolabeled IgG. Finally, all approaches benefit from the addition of a consolidation-dosing regimen of the anti-CD20 IgG antibody. This article reviews these various options and discusses how some fundamental changes could potentially enhance the response and duration from radionuclide-targeted therapy. © 2010 American Cancer Society.


The present invention concerns methods and compositions for subunit-based vaccines for inducing immunity against poxvirus infections, such as smallpox. Preferred embodiments concern immunoconjugates comprising one or more subunit antigenic peptides attached to an antibody or fragment thereof that targets antigen-producing cells (APCs). More preferably, the antibody binds to HLA-DR and the antigenic peptide is from an immunomodulating factor, such as the viral IL-18 binding protein (vIL18BP). However, mixtures of antigenic peptides from different viral proteins may also be used. The vaccine is capable of inducing immunity against poxvirus without risk of disseminated infection in immunocompromised hosts or transmission to susceptible contacts.

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