V S Goldmacher

ImmunoGen, Inc., Waltham, Massachusetts, United States

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Publications (90)564.91 Total impact

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    ABSTRACT: A majority of ovarian and non-small cell lung adenocarcinoma cancers overexpress folate receptor α (FRα). Here we report the development of an anti-FRα antibody drug conjugate (ADC), consisting of a FRα-binding antibody attached to a highly potent maytansinoid that induces cell cycle arrest and cell death by targeting microtubules. From screening a large panel of anti-FRα monoclonal antibodies, we selected the humanized antibody, M9346A as the best antibody for targeted delivery of a maytansinoid payload into FRα-positive cells. We compared M9346A conjugates with various linker/maytansinoid combinations, and found that a conjugate, now denoted as IMGN853, with the N-succinimidyl 4-(2-pyridyldithio)-2-sulfobutanoate (sulfo-SPDB) linker and N2'-deacetyl-N2'-(4-mercapto-4-methyl-1-oxopentyl)-maytansine (DM4) exhibited the most potent antitumor activity in several FRα-expressing xenograft tumor models. The level of expression of FRα on the surface of cells was a major determinant in the sensitivity of tumor cells to the cytotoxic effect of the conjugate. Efficacy studies of IMGN853 in xenografts of ovarian cancer and non-small cell lung cancer cell lines and of a patient tumor-derived xenograft model demonstrated that the ADC was highly active against tumors that expressed FRα at levels similar to those found on a large fraction of ovarian and NSCLC patient tumors, as assessed by immunohistochemistry. IMGN853 displayed cytotoxic activity against FRα-negative cancer cells situated near FRα-positive cancer cells (bystander cytotoxic activity), indicating its ability to eradicate tumors with heterogeneous expression of FRα. Together, these findings support the clinical development of IMGN853 as a novel targeted therapy for patients with FRα-expressing tumors. Copyright © 2015, American Association for Cancer Research.
    Molecular Cancer Therapeutics 04/2015; DOI:10.1158/1535-7163.MCT-14-1095 · 6.11 Impact Factor
  • Victor S Goldmacher, Godfrey Amphlett, Lintao Wang, Alex Lazar
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    ABSTRACT: The maytansinoid antibody-drug conjugates (ADCs) in clinical development for cancer therapy each contain a derivative of the microtubule-targeting agent, maytansine, covalently attached to the antibody via an engineered linker. A sample of any of these conjugate contains molecules with different numbers of maytansinoid molecules, or "drug" loads, the relative abundance of which can be determined by mass spectrometry. We examined the accuracy of the Poisson distribution and the binomial distribution in predicting the relative abundance of species with different drug loads for three antibody-maytansinoid conjugates with different antibodies and linker-maytansinoid pairings. We used variance, calculated from the experimental mass distribution data, as the parameter to determine the optimal value n of the binomial distribution number of trials. The accuracy of the Poisson distribution in predicting distribution of the species abundance in these conjugates varied among the conjugates. In contrast, the accuracy of the binomial distribution was similar for all three conjugates and comparable to the best accuracy of the Poisson distribution, as supported by a paired t-test.
    Molecular Pharmaceutics 01/2015; DOI:10.1021/mp5007536 · 4.79 Impact Factor
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    ABSTRACT: The microtubule-targeting maytansinoids accumulate in cells and induce mitotic arrest at 250- to 1000-fold lower concentrations than those required for their association with tubulin or microtubules. To identify the mechanisms of this intracellular accumulation and exceptional cytotoxicity of maytansinoids we studied interaction of a highly cytotoxic maytansinoid, S-methyl DM1 and several other maytansinoids with cells. S-methyl DM1 accumulated inside the cells with a markedly higher apparent affinity than to tubulin or microtubules. The apparent affinities of maytansinoids correlated with their cytotoxicities. The number of intracellular binding sites for S-methyl DM1 in MCF7 cells was comparable to the number of tubulin molecules per cell (~ 4-6 × 107 copies). Efflux of 3 [H]-S-methyl DM1 from cells was enhanced in the presence of an excess of non-labeled S-methyl DM1, indicating that re-binding of 3 [H]-S-methyl DM1 to intracellular binding sites contributed to its intracellular retention. Liposomes loaded with non-polymerized tubulin recapitulated the apparent high-affinity association of S-methyl DM1 to cells. We propose a model for the intracellular accumulation of maytansinoids in which molecules of the compounds diffuse into a cell and associate with tubulin. Affinities of maytansinoids for individual tubulin molecules are weak, but the high intracellular concentration of tubulin favors, after dissociation of a compound-tubulin complex, their re-binding to a tubulin molecule, or to a tip of a microtubule in the same cell, over their efflux. As a result, a significant fraction of microtubule tips is occupied with a maytansinoid when added to cells at sub-nanomolar concentrations, inducing mitotic arrest and cell death.
    PLoS ONE 01/2015; 10(2):e0117523. DOI:10.1371/journal.pone.0117523 · 3.53 Impact Factor
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    ABSTRACT: Purpose: The CD38 cell surface antigen is expressed in diverse hematologic malignancies including multiple myeloma (MM), B-cell non-Hodgkin lymphoma (NHL), B-cell chronic lymphocytic leukemia (B-CLL), B-cell acute lymphoblastic leukemia (ALL) and T-cell ALL. Here we assessed the anti-tumor activity of the anti-CD38 antibody SAR650984. Experimental Design: Activity of SAR650984 was examined on lymphoma, leukemia and MM cell lines, primary MM samples and MM xenograft models in immunodeficient mice. Results: We identified a humanized anti-CD38 antibody with strong pro-apoptotic activity independent of cross-linking agents, and potent effector functions including complement-dependent cytotoxicity (CDC), antibody-dependent cell-mediated cytotoxicity (ADCC), and antibody-dependent cellular phagocytosis (ADCP), equivalent in vitro to rituximab in CD20+ and CD38+ models. This unique antibody, termed SAR650984, inhibited the ADP-ribosyl cyclase activity of CD38, likely through an allosteric antagonism as suggested by 3D structure analysis of the complex. In vivo, SAR650984 was active in diverse NHL, ALL and MM CD38+ tumor xenograft models. SAR650984 demonstrated single agent activity comparable to rituximab or cyclophosphamide in Daudi or SU-DHL-8 lymphoma xenograft models with induction of the pro-apoptotic marker cleaved capase 7. In addition, SAR650984 had more potent anti-tumor activity than bortezomib in NCI-H929 and Molp-8 MM xenograft studies. Consistent with its mode of action, SAR650984 demonstrated potent pro-apoptotic activity against CD38+ human primary MM cells. Conclusions: These results validate CD38 as a therapeutic target and support the current evaluation of this unique CD38-targeting functional antibody in Phase I clinical trials in patients with CD38+ B-cell malignancies.
    Clinical Cancer Research 07/2014; 20(17). DOI:10.1158/1078-0432.CCR-14-0695 · 8.19 Impact Factor
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    ABSTRACT: There are considerable differences in tumour biology between adult and paediatric cancers. The existence of cancer initiating cells/cancer stem cells (CIC/CSC) in paediatric solid tumours is currently unclear. Here, we show the successful propagation of primary human Wilms' tumour (WT), a common paediatric renal malignancy, in immunodeficient mice, demonstrating the presence of a population of highly proliferative CIC/CSCs capable of serial xenograft initiation. Cell sorting and limiting dilution transplantation analysis of xenograft cells identified WT CSCs that harbour a primitive undifferentiated - NCAM1 expressing - "blastema" phenotype, including a capacity to expand and differentiate into the mature renal-like cell types observed in the primary tumour. WT CSCs, which can be further enriched by aldehyde dehydrogenase activity, overexpressed renal stemness and genes linked to poor patient prognosis, showed preferential protein expression of phosphorylated PKB/Akt and strong reduction of the miR-200 family. Complete eradication of WT in multiple xenograft models was achieved with a human NCAM antibody drug conjugate. The existence of CIC/CSCs in WT provides new therapeutic targets. →See accompanying article http://dx.doi.org/10.1002/emmm.201202173.
    EMBO Molecular Medicine 01/2013; 5(1). DOI:10.1002/emmm.201201516 · 8.25 Impact Factor
  • C. Audette, Y. Kovtun, V. S. Goldmacher
    Cancer Research 06/2012; 72(8 Supplement):5677-5677. DOI:10.1158/1538-7445.AM2012-5677 · 9.28 Impact Factor
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    ABSTRACT: The synthesis and biological evaluation of phosphate prodrugs of analogues of 1 (CC-1065) and their conjugates with antibodies are described. The phosphate group on the 1,2,9,9a-tetrahydrocyclopropa[c]benz[e]indol-4-one (CBI) portion of the compounds confers enhanced solubility and stability in aqueous solutions. In the presence of phosphatases, these compounds convert into active DNA-alkylating agents. The synthesis of the prodrugs was achieved sequentially through coupling of CBI with a bis-indolyl moiety, followed by attachment of a thiol-containing linker, and conversion of the hydroxyl group of CBI into a phosphate prodrug. The linkers incorporated into the prodrugs enable conjugation to an antibody via either a stable disulfide or thioether bond, in aqueous buffer solutions containing as little as 5% organic cosolvent, resulting in exclusively monomeric and stable antibody-cytotoxic prodrug conjugates. Two disulfide-containing linkers differing in the degree of steric hindrance were used in antibody conjugates to test the effect of different rates of intracellular disulfide cleavage and effector release on biological activity. The prodrugs can be converted to the active cytotoxic compounds through the action of endogenous phosphatases. Antibody-prodrug conjugates displayed potent antigen-selective cytotoxic activity in vitro and antitumor activity in vivo.
    Journal of Medicinal Chemistry 12/2011; 55(2):766-82. DOI:10.1021/jm201284m · 5.48 Impact Factor
  • O. Ab, V. S. Goldmacher, L. M. Bartle, X. Sun, H. K. Erickson
    Molecular Cancer Therapeutics 11/2011; 10(Supplement 1):C61-C61. DOI:10.1158/1535-7163.TARG-11-C61 · 6.11 Impact Factor
  • Cancer Research 07/2011; 71(8 Supplement):4576-4576. DOI:10.1158/1538-7445.AM2011-4576 · 9.28 Impact Factor
  • C. N. Carrigan, S. Xu, K. Foley, O. Ab, V. S. Goldmacher, G. Payne
    Cancer Research 07/2011; 71(8 Supplement):3617-3617. DOI:10.1158/1538-7445.AM2011-3617 · 9.28 Impact Factor
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    ABSTRACT: The synthesis and biological evaluation of hydrophilic heterobifunctional cross-linkers for conjugation of antibodies with highly cytotoxic agents are described. These linkers contain either a negatively charged sulfonate group or a hydrophilic, noncharged PEG group in addition to an amine-reactive N-hydroxysuccinimide (NHS) ester and sulfhydryl reactive termini. These hydrophilic linkers enable conjugation of hydrophobic organic molecule drugs, such as a maytansinoid, at a higher drug/antibody ratio (DAR) than hydrophobic SPDB and SMCC linkers used earlier without triggering aggregation or loss of affinity of the resulting conjugate. Antibody-maytansinoid conjugates (AMCs) bearing these sulfonate- or PEG-containing hydrophilic linkers were, depending on the nature of the targeted cells, equally to more cytotoxic to antigen-positive cells and equally to less cytotoxic to antigen-negative cells than conjugates made with SPDB or SMCC linkers and thus typically displayed a wider selectivity window, particularly against multidrug resistant (MDR) cancer cell lines in vitro and tumor xenograft models in vivo.
    Journal of Medicinal Chemistry 05/2011; 54(10):3606-23. DOI:10.1021/jm2002958 · 5.48 Impact Factor
  • Victor S Goldmacher, Yelena V Kovtun
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    ABSTRACT: One approach to improving activity of anticancer drugs is to conjugate them to antibodies that recognize tumor-associated, cell-surface antigens. The antibody-drug conjugate concept evolved following major advances, first, in the development of humanized and fully human antibodies; second, in the discoveries of highly cytotoxic compounds ('drugs) linkable to antibodies; and finally, in the optimization of linkers that couple the drug to the antibody and provide sufficient stability of the antibody-drug conjugate in the circulation, optimal activation of the drug in the tumor, and the ability of the activated drug to overcome multidrug resistance. In this article, we will review the considerations for selecting a target antigen, the design of the conjugate, and the pre-clinical and clinical experiences with the current generation of antibody-drug conjugates.
    Therapeutic delivery 03/2011; 2(3):397-416. DOI:10.4155/tde.10.98
  • EJC Supplements 11/2010; 8(7):77-77. DOI:10.1016/S1359-6349(10)71941-8 · 9.39 Impact Factor
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    ABSTRACT: Conjugation of cytotoxic compounds to antibodies that bind to cancer-specific antigens makes these drugs selective in killing cancer cells. However, many of the compounds used in such antibody-drug conjugates (ADC) are substrates for the multidrug transporter MDR1. To evade the MDR1-mediated resistance, we conjugated the highly cytotoxic maytansinoid DM1 to antibodies via the maleimidyl-based hydrophilic linker PEG(4)Mal. Following uptake into target cells, conjugates made with the PEG(4)Mal linker were processed to a cytotoxic metabolite that was retained by MDR1-expressing cells better than a metabolite of similar conjugates prepared with the nonpolar linker N-succinimidyl-4-(maleimidomethyl)cyclohexane-1-carboxylate (SMCC). In accord, PEG(4)Mal-linked conjugates were more potent in killing MDR1-expressing cells in culture. In addition, PEG(4)Mal-linked conjugates were markedly more effective in eradicating MDR1-expressing human xenograft tumors than SMCC-linked conjugates while being tolerated similarly, thus showing an improved therapeutic index. This study points the way to the development of ADCs that bypass multidrug resistance.
    Cancer Research 03/2010; 70(6):2528-37. DOI:10.1158/0008-5472.CAN-09-3546 · 9.28 Impact Factor
  • Carol A. Vater, Victor S. Goldmacher
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    ABSTRACT: The original rationale underlying the development of antibody–cytotoxic compound conjugates (ACC) was to improve the selectivity of cytotoxic anti-cancer drugs by targeting them to tumors with the help of antibodies. The ACC concept has since matured significantly, following several key advancements: (i) generation of technologies for creating humanized and fully human monoclonal antibodies; (ii) development of conjugatable cytotoxic compounds of sufficient potency to be effective in eradicating tumor cells in an antigen-selective manner; (iii) advances in knowledge and antibody engineering to maximize anti-tumor cell effect or functions; and (iv) optimization of linkers used to conjugate cytotoxic compounds to antibodies in order to achieve both maximal stability of the ACC in the circulation and maximal release of the active cytotoxic component within targeted tumor cells. In this chapter we will focus on our present understanding of what makes an effective ACC for the treatment of oncology patients. We will discuss parameters that are important for the selection of antigen targets, antibodies, cytotoxic compounds, and linkers, and current approaches being taken to further improve the efficacy of ACCs. In addition, we will review preclinical and clinical experiences with the current generation of ACCs.
    12/2009: pages 331-369;
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    ABSTRACT: Apoptosis is a major problem in animal cell cultures during production of biopharmaceuticals, such as recombinant proteins or viral vectors. A 293 cell line constitutively expressing vMIA (viral mitochondria-localized inhibitor of apoptosis) was constructed and examined on production of a model recombinant protein, green fluorescent protein (GFP) in the adenovirus-293 expression system, and on production of a model infectious adenoviral vector. vMIA-293 cells were more resistant than the parental 293 cells to apoptosis induced by either oxidative stress, or by adenovirus infection. The yield of GFP produced in vMIA-293 cell cultures was consistently higher (approximately 140%) compared to that in the parental cells. vMIA reduced production of adenovirus infectious particles, which was not due to a decline of adenovirus replication, since adenoviral DNA replication rate in vMIA-293 cells was higher than that in the parental cells. In conclusion, introduction of the vMIA gene into the 293 cell line is a promising strategy to improve recombinant protein production in the adenovirus-293 expression system.
    Protein Expression and Purification 12/2008; 64(2):179-84. DOI:10.1016/j.pep.2008.11.004 · 1.51 Impact Factor
  • EJC Supplements 10/2008; 6(12):164-164. DOI:10.1016/S1359-6349(08)72452-2 · 9.39 Impact Factor
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    ABSTRACT: Apoptosis is increasingly implicated as an early line of defense against viral infections. Viruses have devised numerous strategies to delay apoptosis of infected cells. Many viruses encode cell death suppressors that target mitochondrial apoptotic signaling pathway, indicating the importance of this pathway in the anti-viral response. Human and primate cytomegaloviruses encode the viral mitochondria-localized inhibitor of apoptosis vMIA, but no overt homologue of vMIA was identified in any non-primate cytomegalovirus. Here we report that m38.5 protein encoded by murine cytomegalovirus, which is unrelated to vMIA in its amino acid sequence, delays death receptor ligation-induced cell death, and that m38.5 associates with Bax, recruits it to mitochondria, and blocks Bax-mediated but not Bak-mediated mitochondrial outer membrane permeabilization. Thus, primate and murine cytomegaloviruses have evolved non-homologous but functionally similar cell death suppressors selectively targeting the Bax-mediated branch of the mitochondrial apoptotic signaling pathway, indicating the importance of this branch in the response of diverse host organisms against cytomegalovirus infections.
    Apoptosis 10/2008; 13(9):1100-10. DOI:10.1007/s10495-008-0245-2 · 3.61 Impact Factor
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    British Journal of Haematology 05/2008; 141(1):129-31. DOI:10.1111/j.1365-2141.2008.07000.x · 4.96 Impact Factor
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    ABSTRACT: The viral mitochondrial inhibitor of apoptosis (vMIA) encoded by the human cytomegalovirus exerts cytopathic effects and neutralizes the proapoptotic endogenous Bcl-2 family member Bax by recruiting it to mitochondria, inducing its oligomerization and membrane insertion. Using a combination of computational modeling and mutational analyses, we addressed the structure-function relationship of the molecular interaction between the protein Bax and the viral antiapoptotic protein vMIA. We propose a model in which vMIA exhibits an overall fold similar to Bcl-X(L). In contrast to Bcl-X(L), however, this predicted conformation of vMIA does not bind to the BH3 domain of Bax and rather engages in electrostatic interactions that involve a stretch of amino acids between the BH3 and BH2 domains of Bax and an alpha-helical domain located within the previously defined Bax-binding domain of vMIA, between the putative BH1-like and BH2-like domains. According to this model, vMIA is likely to bind Bax preferentially in its membrane-inserted conformation. The capacity of vMIA to cause fragmentation of the mitochondrial network and disorganization of the actin cytoskeleton is independent of its Bax-binding function. We found that Delta131-147 vMIA mutant, which lacks both the Bax-binding function and cell-death suppression but has intact mitochondria-targeting capacity, is similar to vMIA in its ability to disrupt the mitochondrial network and to disorganize the actin cytoskeleton. vMIADelta131-147 is a dominant-negative inhibitor of the antiapoptotic function of wild-type vMIA. Our experiments with vMIADelta131-147 suggest that vMIA forms homo-oligomers, which may engage in cooperative and/or multivalent interactions with Bax, leading to its functional neutralization.
    Oncogene 12/2007; 26(50):7067-80. DOI:10.1038/sj.onc.1210511 · 8.56 Impact Factor

Publication Stats

4k Citations
564.91 Total Impact Points

Institutions

  • 1989–2013
    • ImmunoGen, Inc.
      Waltham, Massachusetts, United States
  • 2006
    • Children's National Medical Center
      • Center for Cancer and Immunology Research
      Washington, Washington, D.C., United States
  • 2003
    • Stony Brook University
      • Department of Chemistry
      Stony Brook, NY, United States
  • 1988–1989
    • Dana-Farber Cancer Institute
      Boston, Massachusetts, United States
  • 1984
    • Kemerovo Cardiology Centre
      Shcheglovsk, Kemerovo, Russia