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  • American Association for Cancer Research (AACR)  (4)
  • 1
    Online Resource
    Online Resource
    Abstract S1-07: HER2 T cell dependent bispecific antibody (HER2-TDB) for treatment of HER2 positive breast cancer
    American Association for Cancer Research (AACR) ; 2015
    In:  Cancer Research Vol. 75, No. 9_Supplement ( 2015-05-01), p. S1-07-S1-07
    Details
    In: Cancer Research, American Association for Cancer Research (AACR), Vol. 75, No. 9_Supplement ( 2015-05-01), p. S1-07-S1-07
    Abstract: Based on recent clinical success of tumor immunotherapies that block immune suppressive mechanisms to restore T cell function, there is a profound interest in the clinical development of T cell targeted therapies. We have produced a trastuzumab-based HER2 T cell dependent bispecific antibody (HER2-TDB) that conditionally activates T cells resulting in lysis of HER2 expressing cancer cells at low picomolar concentrations. Due to its unique mechanism of action, which is unrelated to HER2 signaling or sensitivity to chemotherapeutic agents, HER2-TDB can eliminate cells refractory to currently approved HER2 therapies. The potent anti-tumor activity of HER2-TDB was demonstrated using four model systems including MMTV-huHER2 and huCD3 transgenic mice. We demonstrate inhibitory effect of PD-L1 expression on the activity of bispecific T cell recruiting antibodies. This resistance mechanism is reversed by anti-PD-L1 treatment and combination of HER2-TDB with anti-PD-L1 immune therapy resulted in enhanced inhibition of tumor growth, increased response rates and durable responses. Significance: This report presents a new immunotherapy for HER2+ breast cancer with an alternative, extremely potent mechanism of action that is effective in cells resistant to current HER2 targeted therapies. Several significant advances are provided to bispecific T cell recruiting antibodies: we characterize a critical resistance mechanism, a potential diagnostic marker, a novel transgenic efficacy model and significantly improve the drug-like properties by using technology based on full length antibodies with natural architecture. Finally we demonstrate the benefit of combining two immune therapies: direct polyclonal recruitment of T cell activity together with inhibiting the T cell suppressive PD-1/PD-L1 signaling results in enhanced and durable long term responses. Citation Format: Teemu T Junttila, Ji Li, Jennifer Johnston, Maria Hristopoulos, Robyn Clark, Diego Ellerman, Bu-Er Wang, Yijin Li, Mary Mathieu, Guangmin Li, Judy Young, Elizabeth Luis, Gail Lewis Phillips, Eric Stefanich, Cristoph Spiess, Andrew Polson, Bryan Irving, Justin M Scheer, Melissa R Junttila, Mark S Dennis, Robert Kelley, Klara Totpal, Allen Ebens. HER2 T cell dependent bispecific antibody (HER2-TDB) for treatment of HER2 positive breast cancer [abstract]. In: Proceedings of the Thirty-Seventh Annual CTRC-AACR San Antonio Breast Cancer Symposium: 2014 Dec 9-13; San Antonio, TX. Philadelphia (PA): AACR; Cancer Res 2015;75(9 Suppl):Abstract nr S1-07.
    Type of Medium: Online Resource
    ISSN: 0008-5472 , 1538-7445
    URL: Article
    DOI: 10.1158/1538-7445.SABCS14-S1-07
    RVK:
    XA 36000
    RVK:
    XA 10000
    Language: English
    Publisher: American Association for Cancer Research (AACR)
    Publication Date: 2015
    detail.hit.zdb_id: 2036785-5
    detail.hit.zdb_id: 1432-1
    detail.hit.zdb_id: 410466-3
    Location Call Number Limitation Availability
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    Online Resource
  • 2
    Online Resource
    Online Resource
    Abstract 549: A novel T cell engaging bispecific antibody induces specific and efficacious lysis of small cell lung cancer cells in vitro and potent T cell re-directed anti-tumor activity in vivo
    American Association for Cancer Research (AACR) ; 2019
    In:  Cancer Research Vol. 79, No. 13_Supplement ( 2019-07-01), p. 549-549
    Details
    In: Cancer Research, American Association for Cancer Research (AACR), Vol. 79, No. 13_Supplement ( 2019-07-01), p. 549-549
    Abstract: Small cell lung cancer (SCLC) is the most lethal and aggressive subtype of lung carcinoma characterized by highly chemotherapy resistant recurrence in the majority of patients. To effectively treat SCLC we have developed a unique T cell engaging bi-specific antibody that can potently re-direct T cells to specifically lyse SCLC cells expressing Delta-like Ligand 3 (DLL3). DLL3 is frequently expressed on the cell surface of neuroendocrine tumors, with no to very little expression in normal tissues, thus making DLL3 an ideal targeting antigen with which to safely re-direct cytolytic T cells to tumor cells. The bi-specific monovalent DLL3/CD3 IgG-like T cell Engager (ITE) is designed to have sustained serum exposure and simultaneously bind to CD3 on T cells and DLL3 on SCLC cells, resulting in formation of the cytolytic synapse. In vitro, unstimulated peripheral blood mononuclear cells (PBMCs) were co-cultured with several DLL3 expressing SCLC cell lines and increasing concentrations of the DLL3/CD3 ITE. The DLL3/CD3 ITE induced potent dose-dependent lysis of SCLC cell lines with EC90 values ranging from 15 to 150 ng/mL, whereas viability of DLL3-negative cells was unaffected, demonstrating the specificity of the DLL3/CD3 ITE for the DLL3 antigen. In addition, the DLL3/CD3 ITE induced DLL3-dependent activation and proliferation of T cells, and granzyme B and cytokine secretion. In vivo anti-tumor activity of the DLL3/CD3 ITE was assessed in NOG mice bearing subcutaneous xenografts of the SHP77 SCLC cell line and reconstituted with human T cells. Complete tumor regressions were observed with a dose of 0.25 mg/kg administered once weekly by i.v. administration, with the onset of activity being observed after the first dose. Consistent with the mode-of-action the DLL3/CD3 ITE led to a profound infiltration of both CD8 and CD4 T cell subsets in the tumors, which correlated with cleaved caspase 3 expression on tumor cells and tumor shrinkage. The inflammatory tumor microenvironment that was created by treatment with the DLL3/CD3 ITE also led to an increase of PD-1 on T cells and PD-L1 on the tumor cells. The DLL3/CD3 ITE shows cross-reactivity to both DLL3 and CD3 of human and cynomolgus monkey origin respectively, thus allowing the assessment of pharmacodynamics, pharmacokinetics, and safety in cynomolgus monkeys. In a single dose study in cynomolgus monkeys, the DLL3/CD3 ITE demonstrated antibody-like pharmacokinetic properties. These pre-clinical data demonstrate that the DLL3/CD3 ITE is a highly potent, efficacious, and DLL3-selective T cell redirecting agent, and supports future clinical development. Citation Format: Susanne Hipp, Vladimir Voynov, Barbara Drobits-Handl, Francesca Trapani, Craig Giragossian, Justin M. Scheer, Paul J. Adam. A novel T cell engaging bispecific antibody induces specific and efficacious lysis of small cell lung cancer cells in vitro and potent T cell re-directed anti-tumor activity in vivo [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2019; 2019 Mar 29-Apr 3; Atlanta, GA. Philadelphia (PA): AACR; Cancer Res 2019;79(13 Suppl):Abstract nr 549.
    Type of Medium: Online Resource
    ISSN: 0008-5472 , 1538-7445
    URL: Article
    DOI: 10.1158/1538-7445.AM2019-549
    RVK:
    XA 36000
    RVK:
    XA 10000
    Language: English
    Publisher: American Association for Cancer Research (AACR)
    Publication Date: 2019
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    detail.hit.zdb_id: 1432-1
    detail.hit.zdb_id: 410466-3
    Location Call Number Limitation Availability
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    Online Resource
  • 3
    Online Resource
    Online Resource
    A Bispecific DLL3/CD3 IgG-Like T-Cell Engaging Antibody Induces Antitumor Responses in Small Cell Lung Cancer
    American Association for Cancer Research (AACR) ; 2020
    In:  Clinical Cancer Research Vol. 26, No. 19 ( 2020-10-01), p. 5258-5268
    Details
    In: Clinical Cancer Research, American Association for Cancer Research (AACR), Vol. 26, No. 19 ( 2020-10-01), p. 5258-5268
    Abstract: Small cell lung cancer (SCLC) is the most lethal and aggressive subtype of lung carcinoma characterized by highly chemotherapy-resistant recurrence in the majority of patients. To effectively treat SCLC, we have developed a unique and novel IgG-like T-cell engaging bispecific antibody (ITE) that potently redirects T-cells to specifically lyse SCLC cells expressing Delta-like ligand 3 (DLL3), an antigen that is frequently expressed on the cell surface of SCLC cells, with no to very little detectable expression in normal tissues. Experimental Design: The antitumor activity and mode of action of DLL3/CD3 ITE was evaluated in vitro using SCLC cell lines and primary human effector cells and in vivo in an SCLC xenograft model reconstituted with human CD3+ T-cells. Results: Selective binding of DLL3/CD3 ITE to DLL3-positive tumor cells and T-cells induces formation of an immunological synapse resulting in tumor cell lysis and activation of T-cells. In a human T-cell engrafted xenograft model, the DLL3/CD3 ITE leads to an increase in infiltration of T-cells into the tumor tissue resulting in apoptosis of the tumor cells and tumor regression. Consistent with the mode of action, the DLL3/CD3 ITE treatment led to upregulation of PD-1, PD-L1, and LAG-3. Conclusions: This study highlights the ability of the DLL3/CD3 ITE to induce strictly DLL3-dependent T-cell redirected lysis of tumor cells and recruitment of T-cells into noninflamed tumor tissues leading to tumor regression in a preclinical in vivo model. These data support clinical testing of the DLL3/CD3 ITE in patients with SCLC.
    Type of Medium: Online Resource
    ISSN: 1078-0432 , 1557-3265
    URL: Article
    DOI: 10.1158/1078-0432.CCR-20-0926
    RVK:
    XA 36791
    Language: English
    Publisher: American Association for Cancer Research (AACR)
    Publication Date: 2020
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    detail.hit.zdb_id: 2036787-9
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  • 4
    Online Resource
    Online Resource
    Antitumor Efficacy of a Bispecific Antibody That Targets HER2 and Activates T Cells
    American Association for Cancer Research (AACR) ; 2014
    In:  Cancer Research Vol. 74, No. 19 ( 2014-10-01), p. 5561-5571
    Details
    In: Cancer Research, American Association for Cancer Research (AACR), Vol. 74, No. 19 ( 2014-10-01), p. 5561-5571
    Abstract: Clinical results from the latest strategies for T-cell activation in cancer have fired interest in combination immunotherapies that can fully engage T-cell immunity. In this study, we describe a trastuzumab-based bispecific antibody, HER2-TDB, which targets HER2 and conditionally activates T cells. HER2-TDB specifically killed HER2-expressing cancer cells at low picomolar concentrations. Because of its unique mechanism of action, which is independent of HER2 signaling or chemotherapeutic sensitivity, HER2-TDB eliminated cells refractory to currently approved HER2 therapies. HER2-TDB exhibited potent antitumor activity in four preclinical model systems, including MMTV-huHER2 and huCD3 transgenic mice. PD-L1 expression in tumors limited HER2-TDB activity, but this resistance could be reversed by anti–PD-L1 treatment. Thus, combining HER2-TDB with anti–PD-L1 yielded a combination immunotherapy that enhanced tumor growth inhibition, increasing the rates and durability of therapeutic response. Cancer Res; 74(19); 5561–71. ©2014 AACR.
    Type of Medium: Online Resource
    ISSN: 0008-5472 , 1538-7445
    URL: Article
    DOI: 10.1158/0008-5472.CAN-13-3622-T
    RVK:
    XA 36000
    RVK:
    XA 10000
    Language: English
    Publisher: American Association for Cancer Research (AACR)
    Publication Date: 2014
    detail.hit.zdb_id: 2036785-5
    detail.hit.zdb_id: 1432-1
    detail.hit.zdb_id: 410466-3
    Location Call Number Limitation Availability
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