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Thomas Hunig - One of the best experts on this subject based on the ideXlab platform.
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the rise and fall of the cd28 Superagonist tgn1412 and its return as tab08 a personal account
FEBS Journal, 2016Co-Authors: Thomas HunigAbstract:Two decades ago, we discovered 'Superagonistic' monoclonal antibodies specific for the CD28 molecule which are able to polyclonally activate T cells, in particular regulatory T cells, and are therapeutically active in many rodent models of autoimmunity, inflammation, transplantation, and tissue repair. A phase I trial of the human CD28 Superagonist TGN1412 failed in 2006 due to an unexpected cytokine release syndrome, but after it became clear that dose-reduction allows to preferentially address regulatory T cells also in humans, clinical development was resumed under the name TAB08. Here, I recount the story of CD28 Superagonist development from a personal perspective with an emphasis on the dramatic events during and after the 2006 phase I trial, the reasons for the failure of preclinical research to warn of the impending cytokine storm, and on the research which allowed resumption of clinical development.
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from tgn1412 to tab08 the return of cd28 Superagonist therapy to clinical development for the treatment of rheumatoid arthritis
Clinical and Experimental Rheumatology, 2016Co-Authors: Dmitry Tyrsin, Sergey Chuvpilo, Alexey A Matskevich, Daniil Nemenov, Paula S Romer, Paula Tabares, Thomas HunigAbstract:CD28 Superagonists (CD28SA) are CD28-specific monoclonal antibodies which are able to activate T-cells without overt TCR engagement. In rodents, CD28SA efficiently activate regulatory T-cells and are therapeutically effective in multiple models of autoimmunity, inflammation and transplantation. However, a phase I study of the human CD28SA TGN1412 in 2006 resulted in a life-threatening cytokine storm. This brief review summarises preclinical work before and since the failed phase I trial with an emphasis on understanding the reasons why there had been no warning of toxicity, and how a novel assay paved the way for a new phase I, phase Ib (both completed), and an ongoing phase II study.
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in vitro polyclonal activation of conventional t cells with a cd28 Superagonist protects mice from acute graft versus host disease
European Journal of Immunology, 2015Co-Authors: Niklas Beyersdorf, Thomas Hunig, Sandra Werner, Nelli Wolf, Thomas KerkauAbstract:: Upon transplantation of T cells from a CD28 Superagonist (CD28-SA) treated donor into an irradiated allogeneic host, the CD28-SA-induced activation and expansion of Treg cells inhibits acute graft versus host disease (aGvHD), while not abrogating the desired graft versus tumor effect. Human peripheral blood CD4(+) T cells, however, harbor only very few Treg cells. Therefore, we studied whether polyclonal in vitro prestimulation of conventional, that is Treg -cell-depleted, CD4(+) T cells of C57BL/6 mice with CD28-SA-coated paramagnetic beads is sufficient to protect recipient BALB/c mice from aGvHD. CD28-SA prestimulation of conventional CD4(+) T cells efficiently protected BALB/c recipient mice from aGvHD and CD28-SA-stimulated CD4(+) and CD8(+) T cells were capable of mediating long-term protection from the BCL1 lymphoma. The recently completed successful phase I testing of the human CD28-SA TGN1412/TAB08 should greatly facilitate further development of this straightforward method into a novel immunotherapy for patients.
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response to storm forecasting additional lessons from the cd28 Superagonist tgn1412 trial
Nature Reviews Immunology, 2012Co-Authors: Thomas HunigAbstract:Response to 'Storm forecasting: additional lessons from the CD28 Superagonist TGN1412 trial'
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the storm has cleared lessons from the cd28 Superagonist tgn1412 trial
Nature Reviews Immunology, 2012Co-Authors: Thomas HunigAbstract:The life-threatening cytokine-release syndrome suffered by six volunteers in a Phase I clinical trial following administration of the CD28 Superagonist antibody TGN1412 (developed by TeGenero) in March 2006 was completely unpredicted by the preclinical studies. Here, Thomas Hunig, main founder of TeGenero, describes the recent investigations into what went wrong and discusses the lessons learnt for future clinical trials.
Hing C. Wong - One of the best experts on this subject based on the ideXlab platform.
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an il 15 Superagonist alt 803 enhances antibody dependent cell mediated cytotoxicity elicited by the monoclonal antibody neo 201 against human carcinoma cells
Cancer Biotherapy and Radiopharmaceuticals, 2019Co-Authors: Massimo Fantini, Hing C. Wong, Justin M David, Christina M Annunziata, Philip M Arlen, Kwong Y TsangAbstract:Abstract Background: A major mechanism of action for therapeutic antibodies is antibody-dependent cell-mediated cytotoxicity (ADCC). ALT-803 is an interleukin-15 Superagonist complex that enhances ...
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therapeutic effects of 2b8t2m a novel fusion of alt 803 an il 15 Superagonist with 4 single chains of anti cd20 antibody in combination with expanded natural killer cells against rituximab sensitive and resistant burkitt lymphoma bl
Journal of Clinical Oncology, 2018Co-Authors: Yaya Chu, Hing C. Wong, Peter R. Rhode, Emily K Jeng, Sarah Alter, Matthew J Barth, Dean A Lee, Mitchell S CairoAbstract:32Background: Patients retreated with rituximab often relapse which limit patient treatment options (Goldman/Cairo, Leukemia, 2013). Our group has successfully expanded functional and active peripheral blood NK cells (exPBNK) to target BL (Chu/Cairo, et al, Can Imm Res, 2015). 2B8T2M was generated by fusing ALT-803, an IL-15 Superagonist, to four single-chains of rituximab (Liu/Wong, et al, JBC, 2016). 2B8T2M displayed tri-specific CD20 binding activity, activated NK cells to enhance antibody-dependent cellular cytotoxicity, and induced apoptosis of B-lymphoma cells (Liu/Wong, et al, JBC, 2016). Methods: ALT-803 and 2B8T2M were generously provided by Altor BioScience Corporation. NK expansion, NK receptors expression and cytotoxicity were examined as we previous described (Chu/Cairo, et al, Can Imm Res 2015). IFNg and granzyme B levels were examined by ELISA assays. Equal doses of IgG, Rituximab, ALT-803, Rituximab+ALT-803, obinutuzumab (obinu, generously provided by Christian Klein, PhD from Roche) were ...
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phase ib trial of alt 803 an il 15 Superagonist plus bcg for the treatment of bcg naive patients with non muscle invasive bladder cancer
Journal of Clinical Oncology, 2018Co-Authors: Charles J Rosser, Liza Hernandez, Jeffrey W Nix, Lydia Ferguson, Hing C. WongAbstract:510Background: The current standard of care for patients with high risk NMIBC is a TURBT or biopsy followed by a 6-week induction course of intravesical BCG and supplementary maintenance therapies every 3 months thereafter (Lamm 2000). While clinical response is significantly improved with BCG, 50% of patients are still expected to recur within 12 months (Sfakianos 2014). The pursuit of novel agents to prevent progression and recurrence of NMIBC remains critical. This phase Ib clinical trial evaluates the safety and tolerability of ALT-803, an IL-15 Superagonist, plus BCG in BCG-naive NMIBC patients. Methods: A dose escalation 3+3 design was employed to evaluate intravesical ALT-803 plus 50 mg BCG in BCG-naive patients with intermediate or high-risk Ta, T1 or Tis stage NMIBC. Patients received intravesical ALT-803 in conjunction with BCG weekly for 6 consecutive weeks (induction) and then encouraged (but not required) to receive maintenance BCG alone as per standard practices. Patients had a routine cysto...
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abstract p3 05 04 an il 15 Superagonist enhances antibody dependent cell mediated cytotoxicity against breast cancer cells regardless of fcgr3a cd16 genotype and rescues nk cell from tgf β1 induced immunosuppression
Cancer Research, 2018Co-Authors: R Fujii, Hing C. Wong, J Schlom, J W HodgeAbstract:It has been reported that the Natural killer (NK) cell with FCGR3A (CD16a) V genotype is associated with enhanced clinical response to IgG1 monoclonal Ab (mAb) therapy such as trastuzumab, rituximab and cetuximab (1,2), suggesting a role of antibody-dependent cell-mediated cytotoxicity (ADCC) induced by NK cells. NK cells express three types of polymorphism of CD16; FcγRIIIa-158 VV, VF, FF, which are derived from the genotype of FCGR3A. It is a clinical challenge to improve the outcome in patients with FCGR3A 158FF genotype whose NK cells have lower affinity to mAb and mediate poor ADCC activity. The IL-15 Superagonist/IL-15Rα-Fc fusion complex (ALT-803) activates the IL-15 receptor on CD8 T cells and NK cells, inducing their expansion, cytotoxity, and ADCC against B cell lymphoma (3, 4, 5). Here, we examined the effect of ALT803 on NK cell-mediated ADCC activity by the the anti-HER2 IgG1 mAb trastuzumab in HER2+ cell lines (SKBR3, BT474, MDA-MB-453). In addition, we used the anti-epidermal growth factor receptor(EGFR) IgG1 mAb cetuximab in EGFR positive TNBC cell lines (MDA-MB-231, SUM149, BT549). Finally, we examined the anti-PD-L1 IgG1 mAb avelumab was used for PD-L1 positive breast cancer cell lines (MDA-MB-231, BT549). Trastuzumab, cetuximab, and avelumab all significantly increased NK cell-induced lysis via ADCC. ALT803 significantly further increased both NK induced lysis and ADCC activity in all the cell lines. There was a significant positive correlation for the mean of ADCC lysis induced by NK cells from three FF (21%), three VF (33%), three VV (45%) donors. ALT803 significantly increased the mean of ADCC lysis by NK cells from all donors of each genotype to the same extent. ALT803 increased the expression of NK cell-activating receptors and cytotoxic granules regardless of the genotype of NK cell FCGR3A in terms VV, VF, or FF. We further examined the potential of ALT803 for NK cell-cytotoxicity suppressed by TGF-β1 which is one of the main barriers to immunity in the tumor microenvionment (TME). NK cells treated with TGF-β1 showed lower expression of activating receptors and cytotoxic granules, culminating in decreased lysis of MDA-MB231. ALT803 inhibited TGF-β1 from down-regulating the expression of NK cell-activating receptors and cytotoxic granules, and from suppressing the cytotoxicity of NK cells to MDA-MB231. In conclusion, the IL-15 Superagonist ALT803 can potentially increase the clinical benefit of ADCC-based mAb therapy for breast cancer patients, regardless of the genotype of FCGR3A. Moreover, ALT803 prevented NK cell-cytotoxity from TGF-β1-induced suppression, providing a rationale for ALT803 therapy to overcome TME-mediated immunosuppression. References (1) Gavin et. al. JAMA Oncol.2017;3(3) (2) Musolino et. al. J Clin Oncol.2008;26(33) (3) Xu et. al. Cancer Res.2013;73(10) (4) Kim et. al. Oncotarget.2016;7(13) (5) Rosario et. al. Clin. Cancer Res. 2016; 22(3) Citation Format: Fujii R, Wong HC, Schlom J, Hodge JW. An IL-15 Superagonist enhances antibody-dependent cell-mediated cytotoxicity against breast cancer cells regardless of FCGR3A (CD16) genotype and rescues NK cell from TGF-β1-induced immunosuppression [abstract]. In: Proceedings of the 2017 San Antonio Breast Cancer Symposium; 2017 Dec 5-9; San Antonio, TX. Philadelphia (PA): AACR; Cancer Res 2018;78(4 Suppl):Abstract nr P3-05-04.
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new interleukin 15 Superagonist il 15sa significantly enhances graft versus tumor activity
Oncotarget, 2017Co-Authors: Cavan P Bailey, Hing C. Wong, Emily K Jeng, Tulin Budakalpdogan, Christopher Sauter, Michelle M Panis, Cihangir Buyukgoz, Neal Flomenberg, Onder AlpdoganAbstract:// Cavan P. Bailey 1 , Tulin Budak-Alpdogan 3 , Christopher T. Sauter 1 , Michelle M. Panis 1 , Cihangir Buyukgoz 1 , Emily K. Jeng 2 , Hing C. Wong 2 , Neal Flomenberg 1 and Onder Alpdogan 1 1 Department of Medical Oncology, Kimmel Cancer Center, Thomas Jefferson University, Philadelphia, PA, USA 2 Altor BioScience Corporation, Miramar, FL, USA 3 Department of Hematology and Oncology, MD Anderson Cancer Center at Cooper, Camden, NJ, USA Correspondence to: Onder Alpdogan, email: onder.alpdogan@jefferson.edu Keywords: stem cell transplantation, interleukin-15, cytokine therapy, graft-versus-tumor activity, animal models Received: August 15, 2016 Accepted: April 28, 2017 Published: May 15, 2017 ABSTRACT Interleukin-15 (IL-15) is a potent cytokine that increases CD8 + T and NK cell numbers and function in experimental models. However, obstacles remain in using IL-15 therapeutically, specifically its low potency and short in vivo half-life. To help overcome this, a new IL-15 Superagonist complex comprised of an IL-15N72D mutation and IL-15RαSu/Fc fusion (IL-15SA, also known as ALT-803) was developed. IL-15SA exhibits a significantly longer serum half-life and increased in vivo activity against various tumors. Herein, we evaluated the effects of IL-15SA in recipients of allogeneic hematopoietic stem cell transplantation. Weekly administration of IL-15SA to transplant recipients significantly increased the number of CD8 + T cells (specifically CD44 + memory/activated phenotype) and NK cells. Intracellular IFN-γ and TNF-α secretion by CD8 + T cells increased in the IL-15SA-treated group. IL-15SA also upregulated NKG2D expression on CD8 + T cells. Moreover, IL-15SA enhanced proliferation and cytokine secretion of adoptively transferred CFSE-labeled T cells in syngeneic and allogeneic models by specifically stimulating the slowly proliferative and nonproliferative cells into actively proliferating cells. We then evaluated IL-15SA’s effects on anti-tumor activity against murine mastocytoma (P815) and murine B cell lymphoma (A20). IL-15SA enhanced graft-versus-tumor (GVT) activity in these tumors following T cell infusion. Interestingly, IL-15 SA administration provided GVT activity against A20 lymphoma cells in the murine donor leukocyte infusion (DLI) model without increasing graft versus host disease. In conclusion, IL-15SA could be a highly potent T- cell lymphoid growth factor and novel immunotherapeutic agent to complement stem cell transplantation and adoptive immunotherapy.
Marvin C. Gershengorn - One of the best experts on this subject based on the ideXlab platform.
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taltirelin is a Superagonist at the human thyrotropin releasing hormone receptor
Frontiers in Endocrinology, 2012Co-Authors: Nanthakumar Thirunarayanan, B M Raaka, Marvin C. GershengornAbstract:Taltirelin (TAL) is a thyrotropin-releasing hormone (TRH) analog that is approved for use in humans in Japan. In this study, we characterized TAL binding to and signaling by the human TRH receptor (TRH-R) in a model cell system. We found that TAL exhibited lower binding affinities than TRH and lower signaling potency via the inositol-1,4,5-trisphosphate/calcium pathway than TRH. However, TAL exhibited higher intrinsic efficacy than TRH in stimulating inositol-1,4,5-trisphosphate second messenger generation. This is the first study that elucidates the pharmacology of TAL at TRH-R and shows that TAL is a Superagonist at TRH-R. We suggest the superagonism exhibited by TAL may in part explain its higher activity in mediating CNS effects in humans compared to TRH.
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taltirelin is a Superagonist at the human thyrotropin releasing hormone receptor
Frontiers in Endocrinology, 2012Co-Authors: Nanthakumar Thirunarayanan, B M Raaka, Marvin C. GershengornAbstract:Taltirelin (TAL) is a thyrotropin-releasing hormone (TRH) analog that is approved for use in humans in Japan. In this study, we characterized TAL binding to and signaling by the human TRH receptor (TRH-R) in a model cell system. We found that TAL exhibited lower binding affinities than TRH and lower signaling potency via the inositol-1,4,5-trisphosphate/calcium pathway than TRH. However, TAL exhibited higher intrinsic efficacy than TRH in stimulating inositol-1,4,5-trisphosphate second messenger generation. This is the first study that elucidates the pharmacology of TAL at TRH-R and shows that TAL is a Superagonist at TRH-R. We suggest the superagonism exhibited by TAL may in part explain its higher activity in mediating central nervous system effects in humans compared to TRH.
Emily K Jeng - One of the best experts on this subject based on the ideXlab platform.
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therapeutic effects of 2b8t2m a novel fusion of alt 803 an il 15 Superagonist with 4 single chains of anti cd20 antibody in combination with expanded natural killer cells against rituximab sensitive and resistant burkitt lymphoma bl
Journal of Clinical Oncology, 2018Co-Authors: Yaya Chu, Hing C. Wong, Peter R. Rhode, Emily K Jeng, Sarah Alter, Matthew J Barth, Dean A Lee, Mitchell S CairoAbstract:32Background: Patients retreated with rituximab often relapse which limit patient treatment options (Goldman/Cairo, Leukemia, 2013). Our group has successfully expanded functional and active peripheral blood NK cells (exPBNK) to target BL (Chu/Cairo, et al, Can Imm Res, 2015). 2B8T2M was generated by fusing ALT-803, an IL-15 Superagonist, to four single-chains of rituximab (Liu/Wong, et al, JBC, 2016). 2B8T2M displayed tri-specific CD20 binding activity, activated NK cells to enhance antibody-dependent cellular cytotoxicity, and induced apoptosis of B-lymphoma cells (Liu/Wong, et al, JBC, 2016). Methods: ALT-803 and 2B8T2M were generously provided by Altor BioScience Corporation. NK expansion, NK receptors expression and cytotoxicity were examined as we previous described (Chu/Cairo, et al, Can Imm Res 2015). IFNg and granzyme B levels were examined by ELISA assays. Equal doses of IgG, Rituximab, ALT-803, Rituximab+ALT-803, obinutuzumab (obinu, generously provided by Christian Klein, PhD from Roche) were ...
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new interleukin 15 Superagonist il 15sa significantly enhances graft versus tumor activity
Oncotarget, 2017Co-Authors: Cavan P Bailey, Hing C. Wong, Emily K Jeng, Tulin Budakalpdogan, Christopher Sauter, Michelle M Panis, Cihangir Buyukgoz, Neal Flomenberg, Onder AlpdoganAbstract:// Cavan P. Bailey 1 , Tulin Budak-Alpdogan 3 , Christopher T. Sauter 1 , Michelle M. Panis 1 , Cihangir Buyukgoz 1 , Emily K. Jeng 2 , Hing C. Wong 2 , Neal Flomenberg 1 and Onder Alpdogan 1 1 Department of Medical Oncology, Kimmel Cancer Center, Thomas Jefferson University, Philadelphia, PA, USA 2 Altor BioScience Corporation, Miramar, FL, USA 3 Department of Hematology and Oncology, MD Anderson Cancer Center at Cooper, Camden, NJ, USA Correspondence to: Onder Alpdogan, email: onder.alpdogan@jefferson.edu Keywords: stem cell transplantation, interleukin-15, cytokine therapy, graft-versus-tumor activity, animal models Received: August 15, 2016 Accepted: April 28, 2017 Published: May 15, 2017 ABSTRACT Interleukin-15 (IL-15) is a potent cytokine that increases CD8 + T and NK cell numbers and function in experimental models. However, obstacles remain in using IL-15 therapeutically, specifically its low potency and short in vivo half-life. To help overcome this, a new IL-15 Superagonist complex comprised of an IL-15N72D mutation and IL-15RαSu/Fc fusion (IL-15SA, also known as ALT-803) was developed. IL-15SA exhibits a significantly longer serum half-life and increased in vivo activity against various tumors. Herein, we evaluated the effects of IL-15SA in recipients of allogeneic hematopoietic stem cell transplantation. Weekly administration of IL-15SA to transplant recipients significantly increased the number of CD8 + T cells (specifically CD44 + memory/activated phenotype) and NK cells. Intracellular IFN-γ and TNF-α secretion by CD8 + T cells increased in the IL-15SA-treated group. IL-15SA also upregulated NKG2D expression on CD8 + T cells. Moreover, IL-15SA enhanced proliferation and cytokine secretion of adoptively transferred CFSE-labeled T cells in syngeneic and allogeneic models by specifically stimulating the slowly proliferative and nonproliferative cells into actively proliferating cells. We then evaluated IL-15SA’s effects on anti-tumor activity against murine mastocytoma (P815) and murine B cell lymphoma (A20). IL-15SA enhanced graft-versus-tumor (GVT) activity in these tumors following T cell infusion. Interestingly, IL-15 SA administration provided GVT activity against A20 lymphoma cells in the murine donor leukocyte infusion (DLI) model without increasing graft versus host disease. In conclusion, IL-15SA could be a highly potent T- cell lymphoid growth factor and novel immunotherapeutic agent to complement stem cell transplantation and adoptive immunotherapy.
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a novel fusion of alt 803 interleukin il 15 Superagonist with an antibody demonstrates antigen specific antitumor responses
Journal of Biological Chemistry, 2016Co-Authors: Bai Liu, Kaiping Han, Xiaoyun Zhu, Emily K Jeng, Lin Kong, Warren D Marcus, Hao Hong, Xiaoyue Chen, Sarah Alter, Mark P RubinsteinAbstract:IL-15 and its receptor α (IL-15Rα) are co-expressed on antigen-presenting cells, allowing transpresentation of IL-15 to immune cells bearing IL-2RβγC and stimulation of effector immune responses. We reported previously that the high-affinity interactions between an IL-15 Superagonist (IL-15N72D) and the extracellular IL-15Rα sushi domain (IL-15RαSu) could be exploited to create a functional scaffold for the design of multivalent disease-targeted complexes. The IL-15N72D·IL-15RαSuFc complex, also known as ALT-803, is a multimeric complex constructed by fusing IL-15N72D·IL-15RαSu to the Fc domain of IgG1. ALT-803 is an IL-15 Superagonist complex that has been developed as a potent antitumor immunotherapeutic agent and is in clinical trials. Here we describe the creation of a novel fusion molecule, 2B8T2M, using the ALT-803 scaffold fused to four single chains of the tumor-targeting monoclonal antibody rituximab. This molecule displays trispecific binding activity through its recognition of the CD20 molecule on tumor cells, stimulation via IL-2RβγC displayed on immune effector cells, and binding to Fcγ receptors on natural killer cells and macrophages. 2B8T2M activates natural killer cells to enhance antibody-dependent cellular cytotoxicity, mediates complement-dependent cytotoxicity, and induces apoptosis of B-lymphoma cells. Compared with rituximab, 2B8T2M exhibits significantly stronger antitumor activity in a xenograft SCID mouse model and depletes B cells in cynomolgus monkeys more efficiently. Thus, ALT-803 can be modified as a functional scaffold for creating multispecific, targeted IL-15-based immunotherapeutic agents and may serve as a novel platform to improve the antitumor activity and clinical efficacy of therapeutic antibodies.
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abstract 3245 il 15 Superagonist il 15rαsushi fc fusion complex il 15sa il 15rαsu fc alt 803 markedly enhances specific subpopulations of nk and memory cd8 t cells and mediates potent anti tumor activity of murine breast and colon carcinomas
Cancer Research, 2016Co-Authors: Peter S Kim, Hing C. Wong, Emily K Jeng, Sarah Alter, Anna R Kwilas, Jeffrey Schlom, James W HodgeAbstract:Interleukin (IL)-15-N72D Superagonist-complexed with IL-15RαSushi-Fc fusion protein (IL-15SA/IL-15RαSu-Fc; ALT-803) has been reported to exhibit significant anti-tumor activity in murine myeloma, rat bladder cancer, and murine glioblastoma models. In this study, we examined the immunomodulatory and anti-tumor effects of IL-15SA/IL-15RαSu-Fc in tumor-free and highly metastatic tumor-bearing mice. Here, IL-15SA/IL-15RαSu-Fc significantly expanded NK and CD8+ T cells. In examining natural killer (NK) cell subsets, the greatest significant increase was in highly cytotoxic and migrating (CD11b+, CD27hi; high effector) NK cells, leading to enhanced function on a per-cell basis. CD8+ T cell subset analysis determined that IL-15SA/IL-15RαSu-Fc significantly increased IL-15 responding memory (CD122+, CD44+) CD8+ T cells, in particular those having the innate (NKG2D+, PD1-) phenotype. In 4T1 breast tumor-bearing mice, IL-15SA/IL-15RαSu-Fc induced significant anti-tumor activity against spontaneous pulmonary metastases, depending on CD8+ T and NK cells, and resulting in prolonged survival. Similar anti-tumor activity was seen in the experimental pulmonary metastasis model of CT26 colon carcinoma cells, particularly when IL-15SA/IL-15RαSu-Fc was combined with a cocktail of checkpoint inhibitors, anti-CTLA-4 and anti-PD-L1. Altogether, these studies showed for the first time that IL-15SA/IL-15RαSu-Fc (1) promoted the development of high effector NK cells, (2) enhanced function of NK cells, and (3) played a vital role in reducing tumor metastasis and ultimately survival, especially in combination with checkpoint inhibitors. Citation Format: Peter S. Kim, Anna R. Kwilas, Wenxin Xu, Sarah Alter, Emily K. Jeng, Hing C. Wong, Jeffrey Schlom, James W. Hodge. IL-15 Superagonist/IL-15RαSushi-Fc fusion complex (IL-15SA/IL-15RαSu-Fc; ALT-803) markedly enhances specific subpopulations of NK and memory CD8+ T cells, and mediates potent anti-tumor activity of murine breast and colon carcinomas. [abstract]. In: Proceedings of the 107th Annual Meeting of the American Association for Cancer Research; 2016 Apr 16-20; New Orleans, LA. Philadelphia (PA): AACR; Cancer Res 2016;76(14 Suppl):Abstract nr 3245.
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combination therapy of an il 15 Superagonist complex alt 803 and a tumor targeting monoclonal antibody promotes direct antitumor activity and protective vaccinal effect in a syngenic mouse melanoma model
Journal for ImmunoTherapy of Cancer, 2015Co-Authors: Xiaoyue Chen, Peter R. Rhode, Kaiping Han, Bai Liu, Emily K Jeng, Lin Kong, Mark P Rubinstein, Sarah Alter, Terra Noel, Hing C. WongAbstract:Cytokine-based and antibody-targeted immunotherapies have both been important approaches in the treatment of malignant cancers. However, combinational therapies of cytokines and tumor-targeting antibodies remain to be further explored, especially in advanced solid tumors. In this study, C57BL/6 mice bearing established subcutaneous B16F10 melanoma were treated with mouse melanoma targeting anti-gp75 monoclonal antibody (mAb), TA99, combined with interleukin (IL)-15 based Superagonist ALT-803. This soluble protein complex consists of an IL-15 Superagonist mutant (IL-15N72D) associated with an IL-15 receptor α Sushi domain - human IgG1 Fc fusion protein. Compared to native IL-15, ALT-803 possesses superior in vivo biologic activity for stimulating NK and CD8+ memory T cells. The combined ALT-803+TA99 therapy significantly exceeded either monotherapy in inhibiting melanoma tumor growth (p < 0.001) and prolonging survival (p < 0.01) of B16F10 tumor-bearing mice. Through immune cell depletion studies and immunophenotyping of peripheral cells as well as tumor-infiltrating leukocyte subsets, we found that ALT-803 enhances TA99-mediated antitumor immunity through activation of NK cells and expansion of the CD8+CD44high memory T cell arm. In contrast, CD4+ T cells were shown to play more of a suppressive role in the therapeutic effect of ALT-803+TA99, possibly through involvement of regulatory T cells or ALT-803-mediated induction of PD-L1 on CD4+ T cells in the periphery and tumor microenvironment. Addition of anti-PD-L1 mAb to ALT-803+TA99 therapy resulted in a further increase in antitumor activity against subcutaneous B16F10 tumors. Furthermore, tumor-bearing mice that survived due to ALT-803+TA99 combination therapy exhibited long term antitumor memory against B16F10 tumor cell rechallenge. Immune-depletion studies revealed that this antitumor memory was associated with CD4+ T cells, CD8+ T cells and NK cells. Our findings suggest a therapeutic opportunity for ALT-803 in combination with tumor-targeting antibodies to simultaneously augment targeted antitumor activities of therapeutic antibodies and induce a long-term vaccinal effect which will provide durable responses in the treated host.
Malgorzata Dukat - One of the best experts on this subject based on the ideXlab platform.
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“Methylene Bridge” to 5-HT3 Receptor Antagonists: Conformationally Constrained Phenylguanidines
ACS chemical neuroscience, 2018Co-Authors: Ahmed S. Abdelkhalek, Genevieve S Alley, Osama I. Alwassil, Shailesh Khatri, Philip D. Mosier, Heather L. Nyce, Michael M. White, Marvin K. Schulte, Malgorzata DukatAbstract:Arylguanidines, depending upon their aromatic substitution pattern, display varying actions at 5-HT3 receptors (e.g., partial agonist, agonist, Superagonist). Here, we demonstrate that conformational constraint of these agents as dihydroquinazolines (such as A6CDQ; 1) results in their conversion to 5-HT3 receptor antagonists. We examined the structure-activity relationships of 1. Replacement/removal of any of the guanidinium nitrogen atoms of 1 resulted in decreased affinity. All three nitrogen atoms of 1 are necessary for optimal binding affinity at 5-HT3 receptors. Introduction of substituents as small as an N2-methyl group abolishes affinity. The results are consistent with homology modeling/docking studies and binding data from site-directed mutagenesis studies. Introducing a "methylene bridge" to the arylguanidine structure, regardless of its functional activity, results in a 5-HT3 receptor antagonist.
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Superagonist full agonist partial agonist and antagonist actions of arylguanidines at 5 hydroxytryptamine 3 5 ht3 subunit a receptors
ACS Chemical Neuroscience, 2016Co-Authors: Katie Alix, Shailesh Khatri, Philip D. Mosier, Heather L. Nyce, Michael M. White, Marvin K. Schulte, Samantha Casterlow, Dong Yan, Malgorzata DukatAbstract:Introduction of minor variations to the substitution pattern of arylguanidine 5-hydroxytryptamine-3 (5-HT3) receptor ligands resulted in a broad spectrum of functionally-active ligands from antagonist to Superagonist. For example, (i) introduction of an additional Cl-substituent(s) to our lead full agonist N-(3-chlorophenyl)guanidine (mCPG, 2; efficacy % = 106) yielded Superagonists 7–9 (efficacy % = 186, 139, and 129, respectively), (ii) a positional isomer of 2, p-Cl analog 11, displayed partial agonist actions (efficacy % = 12), and (iii) replacing the halogen atom at the meta or para position with an electron donating OCH3 group or a stronger electron withdrawing (i.e., CF3) group resulted in antagonists 13–16. We posit based on combined mutagenesis, crystallographic, and computational analyses that for the 5-HT3 receptor, the arylguanidines that are better able to simultaneously engage the primary and complementary subunits, thus keeping them in close proximity, have greater agonist character while t...
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Superagonist, Full Agonist, Partial Agonist, and Antagonist Actions of Arylguanidines at 5‑Hydroxytryptamine‑3 (5-HT3) Subunit A Receptors
2016Co-Authors: Katie Alix, Shailesh Khatri, Heather L. Nyce, Michael M. White, Marvin K. Schulte, Samantha Casterlow, Dong Yan, Philip D. Mosier, Malgorzata DukatAbstract:Introduction of minor variations to the substitution pattern of arylguanidine 5-hydroxytryptamine-3 (5-HT3) receptor ligands resulted in a broad spectrum of functionally-active ligands from antagonist to Superagonist. For example, (i) introduction of an additional Cl-substituent(s) to our lead full agonist N-(3-chlorophenyl)guanidine (mCPG, 2; efficacy % = 106) yielded Superagonists 7–9 (efficacy % = 186, 139, and 129, respectively), (ii) a positional isomer of 2, p-Cl analog 11, displayed partial agonist actions (efficacy % = 12), and (iii) replacing the halogen atom at the meta or para position with an electron donating OCH3 group or a stronger electron withdrawing (i.e., CF3) group resulted in antagonists 13–16. We posit based on combined mutagenesis, crystallographic, and computational analyses that for the 5-HT3 receptor, the arylguanidines that are better able to simultaneously engage the primary and complementary subunits, thus keeping them in close proximity, have greater agonist character while those that are deficient in this ability are antagonists
