78 results on '"Zalevsky J"'
Search Results
2. β-Arrestin-Dependent Endocytosis of Proteinase-Activated Receptor 2 Is Required for Intracellular Targeting of Activated ERK1/2
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DeFea, K. A., Zalevsky, J., Thoma, M. S., Déry, O., Mullins, R. D., and Bunnett, N. W.
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- 2000
Catalog
3. LBA68 Bempegaldesleukin (BEMPEG) plus nivolumab (NIVO) compared to the investigator’s choice of sunitinib or cabozantinib in previously untreated advanced renal cell carcinoma (RCC): Results from a phase III randomized study (PIVOT-09)
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Tannir, N., primary, Formiga, M.N., additional, Agarwal, N., additional, Pal, S.K., additional, Cho, D., additional, George, D.J., additional, Hong, W., additional, Tang, L., additional, Qureshi, A., additional, Tagliaferri, M.A., additional, Zalevsky, J., additional, and Penkov, K.D., additional more...
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- 2022
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4. 140P Preliminary results from PROPEL: A phase I/II study of bempegaldesleukin (BEMPEG: NKTR-214) plus pembrolizumab (PEMBRO) with or without chemotherapy in patients with metastatic NSCLC
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Felip, E., Spigel, D.R., Juan Vidal, O.J., Beck, J.T., Aguado de la Rosa, C., Johnson, D.H., Spath-Schwalbe, E., Reinacher-Schick, A., Rodriguez Abreu, D., Altan, M., Reinmuth, N., Edelman, M.J., Reck, M., Zhao, Q., Banerjee, S., Chaudhry, S., Chien, D., Tagliaferri, M.A., Zalevsky, J., and Ganti, A. more...
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- 2021
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5. 83P Evaluation of concordance between PD-L1 immunohistochemistry 28-8 and 22C3 pharmDx assays in metastatic urothelial carcinoma (mUC) in PIVOT-10
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Siefker-Radtke, A.O., primary, Hoch, U., additional, Loriot, Y., additional, Balar, A.V., additional, Bilen, M.A., additional, Tannir, N.M., additional, Cho, D.C., additional, Choudhury, A., additional, Chien, D., additional, Yu, D., additional, Currie, S.L., additional, Novotny, J., additional, Santiago, L., additional, Tagliaferri, M.A., additional, Zalevsky, J., additional, and Huddart, R.A., additional more...
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- 2021
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6. 1026TiP A phase Ib/II, open-label, multicenter, dose-escalation and dose-expansion study of NKTR-255 plus cetuximab as a salvage regimen in patients with solid tumors
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Altan, M., primary, Patnaik, A., additional, Barve, M.A., additional, Dunn, L., additional, Cobb, P.W., additional, Rosenberg, A., additional, Sharma, S., additional, Sukari, A., additional, Lee, Z., additional, Marcondes, M.Q., additional, Zalevsky, J., additional, Tagliaferri, M.A., additional, Kotzin, B., additional, and Sacco, A.G., additional more...
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- 2021
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7. THU0054 NKTR-358, A NOVEL IL-2 CONJUGATE, STIMULATES HIGH LEVELS OF REGULATORY T CELLS IN PATIENTS WITH SYSTEMIC LUPUS ERYTHEMATOSUS
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Siddhanti, S., primary, Fanton, C., additional, Dixit, N., additional, Lu, L., additional, Chindalore, V., additional, Levin, R., additional, Diab, I., additional, Furie, R., additional, Zalevsky, J., additional, and Kotzin, B., additional more...
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- 2020
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8. REVEAL: A phase I/II, open-label, multicenter, dose escalation and dose expansion study of NKTR-262 [TLR 7/8 agonist] plus NKTR-214 [CD122-biased agonist] with or without nivolumab (nivo) in patients (pts) with locally advanced or metastatic solid tumor malignancies
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Diab, A., primary, Marcondes, M., additional, Tagliaferri, M.A., additional, Hoch, U., additional, Zhang, J., additional, Rubas, W., additional, Kivimae, S., additional, Zalevsky, J., additional, Conley, A.P., additional, Borazanci, E., additional, and D'Angelo, S.P., additional more...
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- 2018
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9. P2.07-062 PIVOT-02: Phase 1/2 Study of NKTR-214 and Nivolumab in Patients with Locally Advanced or Metastatic Solid Tumor Malignancies
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Papadimitrakopoulou, V., primary, Tannir, N., additional, Bernatchez, C., additional, Haymaker, C., additional, Bentebibel, S., additional, Curti, B., additional, Wong, M., additional, Gergel, I., additional, Tagliaferri, M., additional, Zalevsky, J., additional, Hoch, U., additional, Aung, S., additional, Imperiale, M., additional, Cho, D., additional, Tykodi, S., additional, Puzanov, I., additional, Kluger, H., additional, Hurwitz, M., additional, Hwu, P., additional, Sznol, M., additional, and Diab, A., additional more...
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- 2017
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10. PIVOT-02: A phase 1/2, open-label, multicenter, dose escalation and dose expansion study of NKTR-214 and nivolumab in patients with select, locally advanced or metastatic solid tumor malignancies
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Diab, A., primary, Hurwitz, M.E., additional, Tannir, N., additional, Bernatchez, C., additional, Haymaker, C., additional, Bentebibel, S.E., additional, Curti, B.D., additional, Wong, M.K.K., additional, Gergel, I., additional, Tagliaferri, M., additional, Zalevsky, J., additional, Hoch, U., additional, Aung, S., additional, Imperiale, M., additional, Cho, D., additional, Tykodi, S.S., additional, Puzanov, I., additional, Kluger, H., additional, Hwu, P., additional, and Sznol, M., additional more...
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- 2017
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11. [Beta]-Arrestin--dependent Endocytosis of Proteinase-activated Receptor 2 Is Required for Intracellular Targeting of Activated ERK1/2
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DeFea, K.A., Zalevsky, J., Thoma, M.S., Dery, O., Mullins, R.D., and Bunnett, N.W.
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Protein kinases -- Research ,Cytosol -- Research ,Cell receptors -- Research ,Biological sciences - Abstract
Recently, a requirement for [Beta]-arrestin--mediated endocytosis in the activation of extracellular signal--regulated kinases 1 and 2 (ERK1/2) by several G protein-coupled receptors (GPCRs) has been proposed. However, the importance of this requirement for function of ERK1/2 is unknown. We report that agonists of G[Alpha]q-coupled proteinase--activated receptor 2 (PAR2) stimulate formation of a multiprotein signaling complex, as detected by gel filtration, immunoprecipitation and immunofluorescence. The complex, which contains internalized receptor, [Beta]-arrestin, raf-1, and activated ERK, is required for ERK1/2 activation. However, ERK1/2 activity is retained in the cytosol and neither translocates to the nucleus nor causes proliferation. In contrast, a mutant PAR2 (PAR2[Delta]ST363/6A), which is unable to interact with [Beta]-arrestin and, thus, does not desensitize or internalize, activates ERK1/2 by a distinct pathway, and fails to promote both complex formation and cytosolic retention of the activated ERK1/2. Whereas wild-type PAR2 activates ERK1/2 by a PKC-dependent and probably a ras-independent pathway, PAR2([Delta]ST363/6A) appears to activate ERK1/2 by a ras-dependent pathway, resulting in increased cell proliferation. Thus, formation of a signaling complex comprising PAR2, [Beta]-arrestin, raf-1, and activated ERK1/2 might ensure appropriate subcellular localization of PAR2-mediated ERK activity, and thereby determine the mitogenic potential of receptor agonists. Key words: subcellular localization * MAP kinase * cytosol * receptor trafficking more...
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- 2000
12. Combining complementary mechanisms of immune activation: NKTR-214, a biased IL-2 pathway agonist and immune checkpoint antagonists
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Charych, D.H., primary, Kuo, P., additional, Addepalli, M., additional, Dixit, V., additional, Pena, R., additional, Rubas, W., additional, Hoch, U., additional, Langowski, J., additional, Doberstein, S.K., additional, and Zalevsky, J., additional more...
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- 2016
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13. 446TiP - REVEAL: A phase I/II, open-label, multicenter, dose escalation and dose expansion study of NKTR-262 [TLR 7/8 agonist] plus NKTR-214 [CD122-biased agonist] with or without nivolumab (nivo) in patients (pts) with locally advanced or metastatic solid tumor malignancies
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Diab, A., Marcondes, M., Tagliaferri, M.A., Hoch, U., Zhang, J., Rubas, W., Kivimae, S., Zalevsky, J., Conley, A.P., Borazanci, E., and D'Angelo, S.P.
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- 2018
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14. 1212TiP - PIVOT-02: A phase 1/2, open-label, multicenter, dose escalation and dose expansion study of NKTR-214 and nivolumab in patients with select, locally advanced or metastatic solid tumor malignancies
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Diab, A., Hurwitz, M.E., Tannir, N., Bernatchez, C., Haymaker, C., Bentebibel, S.E., Curti, B.D., Wong, M.K.K., Gergel, I., Tagliaferri, M., Zalevsky, J., Hoch, U., Aung, S., Imperiale, M., Cho, D., Tykodi, S.S., Puzanov, I., Kluger, H., Hwu, P., and Sznol, M. more...
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- 2017
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15. Soluble TNF mediates the transition from pulmonary inflammation to fibrosis
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Oikonomou, N. Harokopos, V. Zalevsky, J. Valavanis, C. Kotaniduo, A. Szymkowski, D.E. Kollias, G. Aidinis, V.
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Background. Fibrosis, the replacement of functional tissue with excessive fibrous tissue, can occur in all the main tissues and organ systems, resulting in various pathological disorders. Idiopathic Pulmonary Fibrosis is a prototype fibrotic disease involving abnormal wound healing in response to multiple sites of ongoing alveolar epithelial injury. Methodology/Principal Findings. To decipher the role of TNF and TNF-mediated inflammation in the development of fibrosis, we have utilized the bleomycin-induced animal model of Pulmonary Fibrosis and a series of genetically modified mice lacking components of TNF signaling. Transmembrane TNF expression is shown to be sufficient to elicit an inflammatory response, but inadequate for the transition to the fibrotic phase of the disease. Soluble TNF expression is shown to be crucial for lymphocyte recruitment, a prerequisite for TGF-b1 expression and the development of fibrotic lesions. Moreover, through a series of bone marrow transfers, the necessary TNF expression is shown to originate from the non-hematopoietic compartment further localized in apoptosing epithelial cells. Conclusions. These results suggest a primary detrimental role of soluble TNF in the pathologic cascade, separating it from the beneficial role of transmembrane TNF, and indicate the importance of assessing the efficacy of soluble TNF antagonists in the treatment of Idiopathic Pulmonary Fibrosis. © 2006 Oikonomou et al. more...
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- 2006
16. 1078P - Combining complementary mechanisms of immune activation: NKTR-214, a biased IL-2 pathway agonist and immune checkpoint antagonists
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Charych, D.H., Kuo, P., Addepalli, M., Dixit, V., Pena, R., Rubas, W., Hoch, U., Langowski, J., Doberstein, S.K., and Zalevsky, J.
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- 2016
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17. Inhibition of B Cell Receptor-Mediated B Cell Activation and IgE secretion by Coengagement of Surface IgE and FcγRIIb with Fc-Engineered Antibodies
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Szymkowski, D.E., primary, Horton, H.H., additional, Chu, S.Y., additional, Zalevsky, J., additional, Herman, H., additional, Pong, E., additional, and Desjarlais, J.R., additional
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- 2010
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18. Phase I study of an anti-CD30 Fc engineered humanized monoclonal antibody in Hodgkin lymphoma (HL) or anaplastic large cell lymphoma (ALCL) patients: Safety, pharmacokinetics (PK), immunogenicity, and efficacy
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Blum, K. A., primary, Smith, M., additional, Fung, H., additional, Zalevsky, J., additional, Combs, D., additional, Ramies, D. A., additional, and Younes, A., additional
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- 2009
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19. beta-arrestin-dependent endocytosis of proteinase-activated receptor 2 is required for intracellular targeting of activated ERK1/2.
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DeFea, KA, Zalevsky, J, Thoma, MS, Déry, O, Mullins, RD, Bunnett, NW, DeFea, KA, Zalevsky, J, Thoma, MS, Déry, O, Mullins, RD, and Bunnett, NW
- Abstract
Recently, a requirement for beta-arrestin-mediated endocytosis in the activation of extracellular signal-regulated kinases 1 and 2 (ERK1/2) by several G protein-coupled receptors (GPCRs) has been proposed. However, the importance of this requirement for function of ERK1/2 is unknown. We report that agonists of Galphaq-coupled proteinase-activated receptor 2 (PAR2) stimulate formation of a multiprotein signaling complex, as detected by gel filtration, immunoprecipitation and immunofluorescence. The complex, which contains internalized receptor, beta-arrestin, raf-1, and activated ERK, is required for ERK1/2 activation. However, ERK1/2 activity is retained in the cytosol and neither translocates to the nucleus nor causes proliferation. In contrast, a mutant PAR2 (PAR2deltaST363/6A), which is unable to interact with beta-arrestin and, thus, does not desensitize or internalize, activates ERK1/2 by a distinct pathway, and fails to promote both complex formation and cytosolic retention of the activated ERK1/2. Whereas wild-type PAR2 activates ERK1/2 by a PKC-dependent and probably a ras-independent pathway, PAR2(deltaST363/6A) appears to activate ERK1/2 by a ras-dependent pathway, resulting in increased cell proliferation. Thus, formation of a signaling complex comprising PAR2, beta-arrestin, raf-1, and activated ERK1/2 might ensure appropriate subcellular localization of PAR2-mediated ERK activity, and thereby determine the mitogenic potential of receptor agonists. more...
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- 2000
20. Transgene-mediated cosuppression in the C. elegans germ line.
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Dernburg, A F, Zalevsky, J, Colaiácovo, M P, and Villeneuve, A M
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Functional silencing of chromosomal loci can be induced by transgenes (cosuppression) or by introduction of double-stranded RNA (RNAi). Here, we demonstrate the generality of and define rules for a transgene-mediated cosuppression phenomenon in the Caenorhabditis elegans germ line. Functional repression is not a consequence of persistent physical association between transgenes and endogenous genes or of mutations in affected genes. The cosuppression mechanism likely involves an RNA mediator that defines its target specificity, reminiscent of RNAi. Cosuppression is strongly abrogated in rde-2 and mut-7 mutants, but is not blocked in an rde-1 mutant, indicating that cosuppression and RNAi have overlapping but distinct genetic requirements. more...
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- 2000
21. Maximizing cancer therapy via complementary mechanisms of immune activation: PD-1 blockade, neoantigen vaccination, and Tregs depletion
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Deborah H. Charych, Elena Di Matteo, Anna Morena D'Alise, Gabriella Cotugno, Maria De Lucia, Veronica Bignone, Fabio Giovanni Tucci, Guido Leoni, Rosa Bartolomeo, Elisa Scarselli, Elisa Micarelli, Jonathan Zalevsky, Alfredo Nicosia, Linda Nocchi, Francesca Langone, Rosa Maria Vitale, Fulvia Troise, Irene Garzia, Armin Lahm, D'Alise, A. M., Leoni, G., de Lucia, M., Langone, F., Nocchi, L., Tucci, F. G., Micarelli, E., Cotugno, G., Troise, F., Garzia, I., Vitale, R., Bignone, V., Matteo, E. D., Bartolomeo, R., Charych, D. H., Lahm, A., Zalevsky, J., Nicosia, A., and Scarselli, E. more...
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Cancer Research ,combined modality therapy ,medicine.medical_treatment ,T cell ,Programmed Cell Death 1 Receptor ,Immunology ,Gene Expression ,chemical and pharmacologic phenomena ,Cancer Vaccines ,T-Lymphocytes, Regulatory ,Mice ,Immune system ,medicine ,Animals ,Humans ,tumor microenvironment ,Immunology and Allergy ,RC254-282 ,Pharmacology ,Tumor microenvironment ,Animal ,business.industry ,Neoplasms. Tumors. Oncology. Including cancer and carcinogens ,Cancer ,Basic Tumor Immunology ,adaptive immunity ,Immunotherapy ,vaccination ,medicine.disease ,Acquired immune system ,Vaccination ,medicine.anatomical_structure ,Oncology ,Cancer cell ,Cancer research ,Molecular Medicine ,Female ,business ,Cancer Vaccine ,Human - Abstract
BackgroundA number of different immune pathways are involved in the effective killing of cancer cells, collectively named as the ‘Cancer Immunity Cycle’. Anti-PD-1 checkpoint blockade (CPB) therapy is active on one of these pathways and reinvigorates anticancer T cell immunity, leading to long-term responses in a limited fraction of patients with cancer. We have previously shown that neoantigens-based adenovirus vectored vaccine in combination with anti-PD-1 further expands pre-existing anticancer immunity and elicits novel neoantigen-specific T cells thereby increasing efficacy to 50% of tumor clearance in mice. Here we added a third component to the CPB plus vaccine combination, which is able to modify the suppressive tumor microenvironment by reducing the number of tumor-infiltrating regulatory T cells (Tregs), as strategy for improving the therapeutic efficacy and overcoming resistance.MethodsThe antitumor efficacy of anti-PD-1, neoantigen vaccine and Treg modulating agents, either Bempegaldesleukin (BEMPEG: NKTR-214) or an anti-CTLA-4 mAb with Treg-depleting activity, was investigated in murine tumor models. We evaluated tumor growth in treated animals, neoantigen-specific T cells in tumors, tumor-infiltrating lymphocytes (TILs) and intratumoral Tregs.ResultsThe addition of BEMPEG or anti-CTLA-4 to the combination of vaccine and anti-PD-1 led to complete eradication of large tumors in nearby 100% of treated animals, in association with expansion and activation of cancer neoantigen-specific T cells and reduction of tumor-infiltrating Tregs.ConclusionThese data support the notion that the integrated regulation of three steps of the cancer immunity cycle, including expansion of neoantigen-specific T cells, reversal of the exhausted T cell phenotype together with the reduction of intratumoral Tregs may represent a novel rationally designed drug combination approach to achieve higher cure rates. more...
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- 2021
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22. Bempegaldesleukin plus nivolumab in first-line advanced/metastatic urothelial carcinoma: Results from a phase II single-arm study (PIVOT-10).
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Siefker-Radtke AO, Huddart RA, Bilen MA, Balar A, Castellano D, Sridhar SS, De Giorgi U, Penkov K, Vasiliev A, Peer A, Järvinen R, Harputluoğlu H, Koshkin VS, Poushnejad S, Wang T, Qureshi A, Tagliaferri MA, Zalevsky J, and Loriot Y more...
- Abstract
Background: In PIVOT-02, bempegaldesleukin (BEMPEG), a pegylated interleukin-2 cytokine prodrug, in combination with nivolumab (NIVO), a Programmed cell death protein 1 inhibitor, demonstrated the potential to provide additional benefits over immune checkpoint inhibitor monotherapy in patients with urothelial carcinoma, warranting further investigation. We evaluated BEMPEG plus NIVO in cisplatin-ineligible patients with previously untreated locally advanced or metastatic urothelial carcinoma., Methods: This open-label, multicenter, single-arm, phase II study enrolled patients with locally advanced/surgically unresectable or metastatic urothelial carcinoma and who were ineligible for cisplatin-based treatment. Patients received BEMPEG plus NIVO were administered intravenously every 3 weeks for ≤2 years or until progression or unacceptable toxicity. The primary endpoint was objective response rate (ORR) by blinded independent central review (BICR) in patients with low programmed death ligand-1 (PD-L1) expression. Secondary endpoints included ORR and duration of response in the overall population. Progression-free survival (PFS) and overall survival (OS) were exploratory endpoints., Results: One hundred and eighty-eight patients were enrolled; 123 patients were PD-L1 low (combined positive score [CPS] <10; 65.4%), 59 were PD-L1 high (31.4%; CPS ≥10), and 6 had PD-L1 status unknown (3.2%). ORR per blinded independent central review in patients with PD-L1-low tumors was 17.9% (95% confidence interval [CI] 11.6-25.8) while in all treated patients was 19.7% (95% CI 14.3-26.1). Median PFS and OS in the overall population were 3.0 months and 12.6 months, respectively. BEMPEG plus NIVO combination was well tolerated, with a safety profile similar to previously reported trials; no new or unexpected safety signals were reported., Conclusions: BEMPEG plus NIVO did not meet the efficacy threshold for ORR in patients with previously untreated locally advanced or metastatic urothelial carcinoma and low PD-L1 expression., Competing Interests: Declaration of competing interest ASR has received grants from Basilea Pharmaceutic, Bristol Myers Squibb, Janssen, Loxo, Merck, Millenium and Nektar and participated in advisory boards for Abbvie, Astellas, AstraZeneca, Basilea, Bicycle Therapeutics, Bristol Myers Squibb, Janssen, Loxo, Merck, Mirati, Nektar, Genetech, G1 Therapeutics, Gilead, Ideeya Biosciences, Immunomedics, Seattle Genetics and Taiho. MB has received grants from AAA, AstraZeneca, Bayer, Bristol Myers Squibb, Genentech, Genome & Company, Incyte, Merck, Nektar, Peloton Therapeutics, Pfizer, Roche, SeaGen, Tricon Pharmaceuticals, Xencor and received honoraria for ad boards from AstraZeneca, Bayer, BMS, Calithera Biosciences, Eisai, EMD Serono, Exelixis, Genomic Health, Janssen, Nektar, Pfizer, Sanofi and SeaGen. SS has received consulting fees from Astellas, AstraZeneca, Bayer, Bicycle Therapeutics, BMS, Eisai, EMD Serono, Gilead, Ipsen, Janssen, Merck, Pfizer and Seagen and research funding from EMD Serono, Janssen and Seagen. KP has received consulting fees from Nektar and contracted research for AstraZeneca, Merck, Nektar, Pfizer, Regeneron Pharmaceuticals and Roche. TW is a shareholder of stocks in Nektar Therapeutics. AQ is a shareholder of stocks in Bristol Myers Squibb. MT is a shareholder of stocks at Nektar Therapeutics. JZ is a shareholder of stocks at Nektar Therapeutics. YL has received consulting fees and honoraria from Astellas, AstraZeneca, BMS, Gilead, Janssen, Merck KGaA, MSD, Pfizer, Roche, Seattle Genetics and Tahio and received support for travel from AstraZeneca, MSD and Pfizer. RH, AB, DC, UDG, AV, AP, RJ, HH, VK, SP have declared no conflicts of interest., (Copyright © 2024. Published by Elsevier Inc.) more...
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- 2024
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23. The regulatory T cell-selective interleukin-2 receptor agonist rezpegaldesleukin in the treatment of inflammatory skin diseases: two randomized, double-blind, placebo-controlled phase 1b trials.
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Silverberg JI, Rosmarin D, Chovatiya R, Bieber T, Schleicher S, Beck L, Gooderham M, Chaudhry S, Fanton C, Yu D, Levy J, Liu Y, Miyazaki T, Tagliaferri M, Schmitz C, Nirula A, Kotzin B, and Zalevsky J more...
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- Humans, Double-Blind Method, Male, Female, Adult, Middle Aged, Receptors, Interleukin-2, Young Adult, Treatment Outcome, Aged, Adolescent, T-Lymphocytes, Regulatory drug effects, T-Lymphocytes, Regulatory immunology, Dermatitis, Atopic drug therapy, Dermatitis, Atopic immunology, Psoriasis drug therapy, Psoriasis immunology
- Abstract
Regulatory T cell (Treg) impairment is implicated in the pathogenesis of chronic inflammatory diseases, but relatively little is known about the therapeutic potential of Treg restoration. Here we present clinical evidence for the Treg-selective interleukin-2 receptor agonist rezpegaldesleukin (REZPEG) in two randomized, double-blind, placebo-controlled Phase 1b trials in patients with moderate-to-severe atopic dermatitis (AD) (NCT04081350) or chronic plaque psoriasis (PsO) (NCT04119557). Key inclusion criteria for AD included an Eczema Area and Severity Index (EASI) score ≥ 16 and a validated Investigator Global Assessment for Atopic Dermatitis (vIGA-AD) ≥ 3, and for PsO included a Psoriasis Area and Severity Index (PASI) score of ≥ 12 and a static Physician's Global Assessment (sPGA) score of ≥ 3. REZPEG is safe and well-tolerated and demonstrates consistent pharmacokinetics in participants receiving subcutaneous doses of 10 to 12 µg/kg or 24 µg/kg once every 2 weeks for 12 weeks, meeting the primary and secondary objectives, respectively. AD patients receiving the higher dose demonstrate an 83% improvement in EASI score after 12 weeks of treatment. EASI improvement of ≥ 75% (EASI-75) and vIGA-AD responses are maintained for 36 weeks after treatment discontinuation in 71% and 80% of week 12 responders, respectively. These exploratory clinical improvements are accompanied by sustained increases in CD25
bright Tregs. REZPEG thus represents a homeostatic approach to cutaneous disease therapy and holds clinical potential in providing long-term, treatment-free disease control., (© 2024. The Author(s).) more...- Published
- 2024
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24. Recent patents in allergy and immunology: The interleukin-2 receptor pathway agonist rezpegaldesleukin (REZPEG) for the rescue of regulatory T cells in chronic inflammatory and autoimmune diseases.
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Fanton C and Zalevsky J
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- Humans, Patents as Topic, Receptors, Interleukin-2, Inflammation immunology, Chronic Disease, Animals, Signal Transduction drug effects, Autoimmune Diseases immunology, Autoimmune Diseases drug therapy, T-Lymphocytes, Regulatory immunology
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- 2024
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25. Bempegaldesleukin Plus Nivolumab Versus Sunitinib or Cabozantinib in Previously Untreated Advanced Clear Cell Renal Cell Carcinoma: A Phase III Randomized Study (PIVOT-09).
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Tannir NM, Formiga MN, Penkov K, Kislov N, Vasiliev A, Gunnar Skare N, Hong W, Dai S, Tang L, Qureshi A, Zalevsky J, Tagliaferri MA, George D, Agarwal N, and Pal S
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- Humans, Female, Male, Middle Aged, Aged, Adult, Interleukin-2 administration & dosage, Interleukin-2 therapeutic use, Interleukin-2 adverse effects, Interleukin-2 analogs & derivatives, Aged, 80 and over, Carcinoma, Renal Cell drug therapy, Carcinoma, Renal Cell pathology, Anilides administration & dosage, Anilides therapeutic use, Kidney Neoplasms drug therapy, Kidney Neoplasms pathology, Antineoplastic Combined Chemotherapy Protocols therapeutic use, Antineoplastic Combined Chemotherapy Protocols adverse effects, Nivolumab administration & dosage, Nivolumab therapeutic use, Nivolumab adverse effects, Pyridines administration & dosage, Pyridines therapeutic use, Sunitinib therapeutic use, Sunitinib administration & dosage, Polyethylene Glycols administration & dosage, Polyethylene Glycols adverse effects
- Abstract
Purpose: Bempegaldesleukin (BEMPEG) is a pegylated interleukin (IL)-2 cytokine prodrug engineered to provide controlled and sustained activation of the clinically validated IL-2 pathway, with the goal of preferentially activating and expanding effector CD8
+ T cells and natural killer cells over immunosuppressive regulator T cells in the tumor microenvironment. The open-label, phase III randomized controlled PIVOT-09 trial investigated the efficacy and safety of BEMPEG plus nivolumab (NIVO) as first-line treatment for advanced/metastatic clear cell renal cell carcinoma (ccRCC) with intermediate-/poor-risk disease., Methods: Patients with previously untreated advanced/metastatic ccRCC were randomly assigned (1:1) to BEMPEG plus NIVO, or investigator's choice of tyrosine kinase inhibitor (TKI; sunitinib or cabozantinib). Coprimary end points were objective response rate (ORR) by blinded independent central review and overall survival (OS) in patients with International Metastatic RCC Database Consortium (IMDC) intermediate-/poor-risk disease., Results: Overall, 623 patients were randomly assigned to BEMPEG plus NIVO (n = 311) or TKI (n = 312; sunitinib n = 225, cabozantinib n = 87), of whom 514 (82.5%) had IMDC intermediate-/poor-risk disease. In patients with IMDC intermediate-/poor-risk disease, ORR with BEMPEG plus NIVO versus TKI was 23.0% (95% CI, 18.0 to 28.7) versus 30.6% (95% CI, 25.1 to 36.6; difference, -7.7 [95% CI, -15.2 to -0.2]; P = .0489), and median OS was 29.0 months versus not estimable (hazard ratio, 0.82 [95% CI, 0.61 to 1.10]; P = .192), respectively. More frequent all-grade treatment-related adverse events (TRAEs) with BEMPEG plus NIVO versus TKI included pyrexia (32.6% v 2.0%) and pruritus (31.3% v 8.8%). Grade 3/4 TRAEs were less frequent with BEMPEG plus NIVO (25.8%) versus TKI (56.5%)., Conclusion: First-line BEMPEG plus NIVO for advanced/metastatic ccRCC did not improve efficacy in patients with intermediate-/poor-risk disease but led to fewer grade 3/4 TRAEs versus TKI. more...- Published
- 2024
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26. Bempegaldesleukin plus Nivolumab in First-line Metastatic Urothelial Carcinoma: Results from PIVOT-02.
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Siefker-Radtke AO, Cho DC, Diab A, Sznol M, Bilen MA, Balar AV, Grignani G, Puente E, Tang L, Chien D, Hoch U, Choudhury A, Yu D, Currie SL, Tagliaferri MA, Zalevsky J, Hurwitz ME, and Tannir NM
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- Antineoplastic Combined Chemotherapy Protocols adverse effects, Humans, Interleukin-2 therapeutic use, Nivolumab adverse effects, Carcinoma, Transitional Cell drug therapy, Carcinoma, Transitional Cell secondary, Prodrugs therapeutic use, Urinary Bladder Neoplasms drug therapy, Urinary Bladder Neoplasms etiology
- Abstract
Background: Despite recent changes in the treatment landscape, there remains an unmet need for effective, tolerable, chemotherapy-free treatments for patients with advanced/metastatic urothelial carcinoma (mUC), especially cisplatin-ineligible patients., Objective: To evaluate the immunostimulatory interleukin-2 cytokine prodrug bempegaldesleukin (BEMPEG) plus nivolumab in patients with advanced/mUC from the phase 2 multicenter PIVOT-02 study., Design, Setting, and Participants: This open-label, multicohort phase 1/2 study enrolled patients with previously untreated locally advanced/surgically unresectable or mUC (N = 41)., Intervention: Patients received BEMPEG 0.006 mg/kg plus nivolumab 360 mg intravenously every 3 wk., Outcome Measurements and Statistical Analysis: The primary objectives were safety and the objective response rate (ORR) in patients with measurable disease at baseline and at least one postbaseline tumor response assessment (response-evaluable). Secondary objectives were overall survival (OS) and progression-free survival (PFS). Exploratory biomarker analyses via univariate logistic regression were performed to test the association between potential biomarkers (CD8
+ tumor-infiltrating lymphocytes, tumor mutational burden, and IFN-γ gene expression profile) and response., Results and Limitations: The ORR was 35% (13/37 evaluable patients) and the complete response rate was 19% (7/37 patients); the median duration of response was not reached. Median PFS was 4.1 mo (95% confidence interval [CI] 2.1-8.7) and median OS was 23.7 mo (95% CI 15.8-not reached). Overall, 40/41 patients (98%) experienced at least one treatment-related adverse event (TRAE); grade 3/4 TRAEs occurred in 11 patients (27%), most commonly pyrexia (4.9%; 2 patients). Exploratory biomarker analyses showed no association between biomarkers and response. Limitations include the small sample size and single-arm design., Conclusions: BEMPEG plus nivolumab was well tolerated and showed antitumor activity as first-line treatment in patients with locally advanced/mUC., Patient Summary: We investigated an immune-stimulating prodrug called bempegaldesleukin plus the antibody nivolumab as the first therapy for patients with advanced or metastatic cancer of the urinary tract. This combination had manageable treatment-related side effects and was effective in a subset of patients. This trial is registered at ClinicalTrials.gov as NCT02983045., (Copyright © 2022 European Association of Urology. Published by Elsevier B.V. All rights reserved.) more...- Published
- 2022
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27. Bempegaldesleukin plus nivolumab in first-line renal cell carcinoma: results from the PIVOT-02 study.
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Tannir NM, Cho DC, Diab A, Sznol M, Bilen MA, Balar AV, Grignani G, Puente E, Tang L, Chien D, Hoch U, Choudhury A, Yu D, Currie SL, Tagliaferri MA, Zalevsky J, Siefker-Radtke AO, and Hurwitz ME
- Subjects
- Female, Humans, Interleukin-2 therapeutic use, Male, Nivolumab therapeutic use, Antineoplastic Combined Chemotherapy Protocols adverse effects, Carcinoma, Renal Cell drug therapy, Carcinoma, Renal Cell pathology, Kidney Neoplasms drug therapy, Kidney Neoplasms pathology
- Abstract
Background: Immune checkpoint inhibitor-based combinations have expanded the treatment options for patients with renal cell carcinoma (RCC); however, tolerability remains challenging. The aim of this study was to evaluate the safety and efficacy of the immunostimulatory interleukin-2 cytokine prodrug bempegaldesleukin (BEMPEG) plus nivolumab (NIVO) as first-line therapy in patients with advanced clear-cell RCC., Methods: This was an open-label multicohort, multicenter, single-arm phase 1/2 study; here, we report results from the phase 1/2 first-line RCC cohort (N=49). Patients received BEMPEG 0.006 mg/kg plus NIVO 360 mg intravenously every 3 weeks. The primary objectives were safety and objective response rate (ORR; patients with measurable disease at baseline and at least one postbaseline tumor response assessment). Secondary objectives included overall survival (OS) and progression-free survival (PFS). Exploratory biomarker analyses: association between baseline biomarkers and ORR., Results: At a median follow-up of 32.7 months, the ORR was 34.7% (17/49 patients); 3/49 patients (6.1%) had a complete response. Of the 17 patients with response, 14 remained in response for >6 months, and 6 remained in response for >24 months. Median PFS was 7.7 months (95% CI 3.8 to 13.9), and median OS was not reached (95% CI 37.3 to not reached). Ninety-eight per cent (48/49) of patients experienced ≥1 treatment-related adverse event (TRAE) and 38.8% (19/49) had grade 3/4 TRAEs, most commonly syncope (8.2%; 4/49) and increased lipase (6.1%; 3/49). No association between exploratory biomarkers and ORR was observed. Limitations include the small sample size and single-arm design., Conclusions: BEMPEG plus NIVO showed preliminary antitumor activity as first-line therapy in patients with advanced clear-cell RCC and was well tolerated. These findings warrant further investigation., Competing Interests: Competing interests: AOS-R received research funding from BioClin Therapeutics, Bristol Myers Squibb, Janssen, Merck Sharp & Dohme, Michael and Sherry Sutton Fund for Urothelial Cancer, Nektar Therapeutics, US National Institutes of Health, and Takeda. She has also served as an advisor/consultant to AstraZeneca, Bavarian Nordic, BioClin Therapeutics, Bristol Myers Squibb, EMD Serono, Genentech, Inovio Pharmaceuticals, Janssen, Merck, US National Comprehensive Cancer Network, Nektar Therapeutics, and Seattle Genetics. DCC has received consulting fees from Pfizer, Nectar, Torque, and Puretech. AD has been an advisory board member for Nektar Therapeutics. MS has served as a consultant/advisor for Genentech-Roche, Bristol Myers Squibb, AstraZeneca/MedImmune, Pfizer, Novartis, Kyowa-Kirin, Amgen, Merus, Seattle Genetics, Immune Design, Prometheus, Anaeropharma, Astellas-Agensys, Immunova, Nektar Therapeutics, Neostem, Pierre-Fabre, Eli Lilly, Symphogen, Lion Biotechnologies, Amphivena, and Adaptive Biotechnologies. MAB has acted as a paid consultant for, and/or as a member of the advisory boards of, Exelixis, Bayer, BMS, Eisai, Pfizer, AstraZeneca, Janssen, Genomic Health, Nektar Therapeutics, and Sanofi and has received grants to his institution from Xencor, Bayer, Bristol Myers Squibb, Genentech/Roche, Seattle Genetics, Incyte, Nektar Therapeutics, AstraZeneca, Tricon Pharmaceuticals, Peleton Therapeutics, and Pfizer for work performed as outside of the current study. AVB has received institutional research funding from AstraZeneca/MedImmune, F Hoffmann–La Roche/Genentech, Merck, and Seattle Genetics; and honoraria from AstraZeneca/MedImmune, F Hoffmann–La Roche/Genentech and Merck. He has also served as an advisor/consultant to AstraZeneca/MedImmune, Cerulean Pharma, F Hoffmann–La Roche/Genentech, Incyte, Merck, Nektar Therapeutics, Pfizer/EMD Serono, and Seattle Genetics/Astellas. GG has received grants and personal fees from PharmaMar, grants from Novartis, and personal fees from Lilly, Pfizer, Bayer, and Eisai, outside the submitted work. EP, LT, DC, UH, AC, and DY are employees of, and have ownership interest (eg, stock) in, Nektar Therapeutics. SLC is a former employee of, and has ownership interest (eg, stock) in, Nektar Therapeutics. MAT is the chief medical officer at Nektar Therapeutics and has ownership interest (eg, stock) in the company. JZ is the chief research and development officer at Nektar Therapeutics and has ownership interest (eg, stock) in the company. MEH has had a consulting or advisory Role with Nektar Therapeutics, Janssen, Crispr Therapeutics, Bristol Myers Squibb/Celgene, and Exelixis; and has received research funding from Apexigen, Astellas Pharma, AstraZeneca/MedImmune, Bayer, Bristol Myers Squibb, Corvus Pharmaceuticals, Lilly, Endocyte, Genentech, Genmab, Innocrin Pharma, Iovance Biotherapeutics, Merck, Nektar Therapeutics, Novartis, Pfizer, Progenics, Sanofi/Aventis, Seattle Genetics, Torque, Unum Therapeutics, and Achilles Therapeutics. NMT has received grant support, consulting fees, and honoraria from Bristol Myers Squibb; grant support from Epizyme and Mirati Therapeutics; grant support, consulting fees, and honoraria from, and served on an advisory board for, Exelixis and Novartis; received consulting fees and honoraria from Argos Therapeutics and Pfizer; and received consulting fees and honoraria from, and served on an advisory board for, Eisai, Nektar Therapeutics, and Oncorena., (© Author(s) (or their employer(s)) 2022. Re-use permitted under CC BY-NC. No commercial re-use. See rights and permissions. Published by BMJ.) more...
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- 2022
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28. Selective expansion of regulatory T cells by NKTR-358 in healthy volunteers and patients with systemic lupus erythematosus.
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Fanton C, Furie R, Chindalore V, Levin R, Diab I, Dixit N, Haglund C, Gibbons J, Hanan N, Dickerson D, Zalevsky J, and Kotzin BL
- Abstract
Objective: To evaluate NKTR-358, a polyethylene glycol-interleukin-2 conjugate composition designed to selectively induce regulatory T cells (Tregs), in first-in-human studies., Methods: Healthy volunteers and patients with systemic lupus erythematosus (SLE) received single- or multiple-dose (biweekly) NKTR-358 or placebo in two sequential, randomized, phase 1 studies (single ascending dose [SAD; NCT04133116] and multiple ascending dose [MAD; NCT03556007]). Primary objectives were safety and tolerability; secondary objectives included pharmacokinetics (PK) and immune effects of NKTR-358; exploratory objectives included effects on SLE disease activity., Results: There were eight ascending dose cohorts in the SAD study (0.3-28.0 μg/kg: n = 76; placebo: n = 24) and four in the MAD study (3-24.0 μg/kg: n = 36; placebo: n = 12). Most adverse events (AEs) were grade 1-2 injection-site reactions, with no treatment-related serious or severe AEs, or deaths. PK data showed dose proportionality and prolonged exposure (mean half-life: 7.4-12.9 days). Dose-dependent, selective, and sustained increases in percentages and absolute numbers of total CD4
+ Tregs and CD25bright Tregs were observed, with no significant changes in conventional CD4+ and CD8+ T cells, and low-level increases in natural killer cells. At the highest doses tested, administration of NKTR-358 resulted in a 12-17-fold increase in CD25bright Tregs over baseline that was sustained for 20-30 days., Conclusion: NKTR-358 was well tolerated, had a suitable PK profile for biweekly dosing, and led to marked and selective dose-dependent increases in CD25bright Tregs, with no significant changes in conventional T cells. These results provide strong support for further testing in SLE and other inflammatory diseases., Competing Interests: The authors declare the following financial interests/personal relationships which may be considered as potential competing interests: CF, RF, VC, RL, ID, ND, CH, JG, NH, JZ and BK report financial support was provided by Nektar Therapeutics. CF reports a relationship with Nektar Therapeutics that includes: employment and equity or stocks. RF reports a relationship with Nektar Therapeutics that includes: consulting or advisory. RF reports a relationship with Genentech/Roche that incudes personal fees and grants. RF reports a relationship with AstraZeneca that includes: consulting or advisory. RF reports a relationship with Mallinckrodt Pharmaceuticals that includes: consulting or advisory. VC reports a relationship with AbbVie Inc that includes: funding grants. VC reports a relationship with Amgen Inc that includes: funding grants. VC reports a relationship with Boehringer Ingelheim Corp USA that includes: funding grants. VC reports a relationship with Boston Pharmaceuticals that includes: funding grants. VC reports a relationship with Eli Lilly and Company that includes: funding grants. VC reports a relationship with EMD Serono Inc that includes: funding grants. VC reports a relationship with Genentech that includes: funding grants. VC reports a relationship with GlaxoSmithKline USA that includes: funding grants. VC reports a relationship with Merck & Co Inc that includes: funding grants. VC reports a relationship with Nektar Therapeutics that includes: funding grants. VC reports a relationship with Novartis that includes: funding grants. VC reports a relationship with Pfizer that includes: funding grants. VC reports a relationship with Roche that includes: funding grants. VC reports that Pinnacle Research Group/Anniston Medical Clinic also received funding from Astellas Pharma Global Development Inc. RL reports a relationship with Gilead Sciences Inc that includes: consulting or advisory. RL reports a relationship with Exagen Inc that includes: consulting or advisory. RL reports a relationship with Myriad Genetics Inc that includes: consulting or advisory. RL reports a relationship with Sanofi that includes: paid expert testimony and speaking and lecture fees. RL reports a relationship with Regeneron Pharmaceuticals Inc that includes: paid expert testimony and speaking and lecture fees. RL reports a relationship with Bristol Myers Squibb Co that includes: paid expert testimony and speaking and lecture fees. RL reports a relationship with AbbVie that includes: paid expert testimony and speaking and lecture fees. ND reports a relationship with Nektar Therapeutics that includes: employment and equity or stocks. CH reports a relationship with Nektar Therapeutics that includes: employment and equity or stocks. JG reports a relationship with Nektar Therapeutics that includes: employment and equity or stocks. NH reports a relationship with GlaxoSmithKline that includes: employment. DD reports a relationship with PRA Health Sciences that includes: employment. DD reports a relationship with ICON plc that includes: employment. JZ reports a relationship with Nektar Therapeutics that includes: employment and equity or stocks. BK reports a relationship with Nektar Therapeutics that includes: employment and equity or stocks. ID has no known competing financial interests or personal relationships that could have appeared to influence the work reported in this paper., (© 2022 The Authors.) more...- Published
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29. NKTR-255 is a polymer-conjugated IL-15 with unique mechanisms of action on T and natural killer cells.
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Robinson TO, Hegde SM, Chang A, Gangadharan A, Rivas S, Madakamutil L, Zalevsky J, Miyazaki T, and Schluns KS
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- Animals, CD8-Positive T-Lymphocytes immunology, Female, Immunologic Memory, Interleukin-15 chemistry, Interleukin-15 Receptor alpha Subunit physiology, Interleukin-2 Receptor beta Subunit agonists, Killer Cells, Natural immunology, Male, Mice, Mice, Inbred BALB C, Mice, Inbred C57BL, Polyethylene Glycols chemistry, CD8-Positive T-Lymphocytes drug effects, Interleukin-15 pharmacology, Killer Cells, Natural drug effects
- Abstract
NKTR-255 is a PEG conjugate of recombinant human IL-15 (rhIL-15) being examined as a potential cancer immunotherapeutic. Since IL-15 responses can be mediated by trans or cis presentation via IL-15Rα or soluble IL-15/IL-15Rα complexes, we investigated the role of IL-15Rα in driving NKTR-255 responses using defined naive and memory OVA-specific CD8+ T cells (OT-I) and NK cells in mice. NKTR-255 induced a 2.5- and 2.0-fold expansion of CD8+ T and NK cells, respectively, in WT mice. In adoptive transfer studies, proliferation of naive and memory WT OT-I T cells in response to NKTR-255 was not impaired in IL-15Rα-/- mice, suggesting trans presentation was not utilized by NKTR-255. Interestingly, naive IL-15Rα-/- OT-I cells had deficient responses to NKTR-255, while memory IL-15Rα-/- OT-I cell responses were partially impaired, suggesting that naive CD8+ T cells are more dependent on cis presentation of NKTR-255 than memory CD8+ T cells. In bone marrow chimera studies, IL-15Rα-/- and WT NK cells present in WT recipients had similar responses to NKTR-255, suggesting that cis presentation is not utilized by NK cells. NKTR-255 could form soluble complexes with IL-15Rα; binding to murine IL-15Rα generated superagonists that preferentially stimulated NK cells, showing that conversion to IL-15Rβ agonist biases the response toward NK cells. These findings highlight the ability of NKTR-255 to utilize IL-15Rα for cis presentation and act as an IL-15Rαβ agonist on CD8+ T cells. more...
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- 2021
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30. Bempegaldesleukin Plus Nivolumab in First-Line Metastatic Melanoma.
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Diab A, Tykodi SS, Daniels GA, Maio M, Curti BD, Lewis KD, Jang S, Kalinka E, Puzanov I, Spira AI, Cho DC, Guan S, Puente E, Nguyen T, Hoch U, Currie SL, Lin W, Tagliaferri MA, Zalevsky J, Sznol M, and Hurwitz ME more...
- Subjects
- Aged, Antineoplastic Combined Chemotherapy Protocols adverse effects, Europe, Female, Humans, Immune Checkpoint Inhibitors adverse effects, Interleukin-2 adverse effects, Interleukin-2 therapeutic use, Male, Melanoma mortality, Melanoma secondary, Middle Aged, Neoplasm Staging, Nivolumab adverse effects, Polyethylene Glycols adverse effects, Progression-Free Survival, Skin Neoplasms mortality, Skin Neoplasms pathology, Time Factors, United States, Antineoplastic Combined Chemotherapy Protocols therapeutic use, Immune Checkpoint Inhibitors therapeutic use, Interleukin-2 analogs & derivatives, Melanoma drug therapy, Nivolumab therapeutic use, Polyethylene Glycols therapeutic use, Skin Neoplasms drug therapy
- Abstract
Purpose: Therapies that produce deep and durable responses in patients with metastatic melanoma are needed. This phase II cohort from the international, single-arm PIVOT-02 study evaluated the CD122-preferential interleukin-2 pathway agonist bempegaldesleukin (BEMPEG) plus nivolumab (NIVO) in first-line metastatic melanoma., Methods: A total of 41 previously untreated patients with stage III/IV melanoma received BEMPEG 0.006 mg/kg plus NIVO 360 mg once every 3 weeks for ≤ 2 years; 38 were efficacy-evaluable (≥ 1 postbaseline scan). Primary end points were safety and objective response rate (blinded independent central review); other end points included progression-free survival, overall survival (OS), and exploratory biomarkers., Results: At 29.0 months' median follow-up, the objective response rate was 52.6% (20 of 38 patients), and the complete response rate was 34.2% (13 of 38 patients). Median change in size of target lesions from baseline was -78.5% (response-evaluable population); 47.4% (18 of 38 patients) experienced complete clearance of target lesions. Median progression-free survival was 30.9 months (95% CI, 5.3 to not estimable). Median OS was not reached; the 24-month OS rate was 77.0% (95% CI, 60.4 to 87.3). Grade 3 and 4 treatment-related and immune-mediated adverse events occurred in 17.1% (7 of 41) and 4.9% (2 of 41) of patients, respectively. Increased polyfunctional responses in CD8+ and CD4+ T cells were seen in blood after treatment, driven by cytokines with effector functions. Early on-treatment blood biomarkers (CD8+ polyfunctional strength difference and eosinophils) correlated with treatment response., Conclusion: BEMPEG in combination with NIVO was tolerated, with relatively low rates of grade 3 and 4 treatment-related and immune-mediated adverse events. The combination had encouraging antitumor activity in first-line metastatic melanoma, including an extended median progression-free survival. Exploratory analyses associated noninvasive, on-treatment biomarkers with response, before radiologic evidence was observed., Competing Interests: Adi DiabHonoraria: Array BioPharmaConsulting or Advisory Role: Nektar, CureVac, Celgene, IderaResearch Funding: Nektar, Idera, Celgene, Pfizer, Merck, ApexigenTravel, Accommodations, Expenses: Nektar Scott S. TykodiConsulting or Advisory Role: Merck, Intellisphere LLC, Natera, Bristol Myers Squibb, ExelixisResearch Funding: Genentech, Bristol Myers Squibb, Merck Sharp & Dohme, Calithera Biosciences, Pfizer, Jounce Therapeutics, Nektar, Exelixis, Clinigen GroupPatents, Royalties, Other Intellectual Property: Patent pending Gregory A. DanielsHonoraria: Sanofi/RegeneronConsulting or Advisory Role: Sanofi/RegeneronSpeakers' Bureau: Regeneron, Array BioPharma, Sanofi/RegeneronResearch Funding: Bristol Myers Squibb, Amgen, Viralytics, Nektar, Merck Michele MaioStock and Other Ownership Interests: Theravance, Epigen TherapeuticsHonoraria: Bristol Myers Squibb, AstraZeneca, Roche, MSD, Merck, Amgen, Pierre Fabre, Alfasigma, Sanofi, LillyConsulting or Advisory Role: Bristol Myers Squibb, Roche, AstraZeneca, MSD, Merck, Pierre Fabre, AlfasigmaPatents, Royalties, Other Intellectual Property: DNA hypomethylating agents for cancer therapyTravel, Accommodations, Expenses: Bristol Myers Squibb, AstraZeneca, Roche, MSD, Merck, Amgen, Pierre Fabre, Alfasigma Brendan D. CurtiHonoraria: Clinigen Group, NektarConsulting or Advisory Role: MerckResearch Funding: Bristol Myers Squibb, Galectin Therapeutics, Clinigen GroupPatents, Royalties, Other Intellectual Property: Biomarkers for OX40 responseTravel, Accommodations, Expenses: Agonox Karl D. LewisHonoraria: Array BioPharma, Iovance BiotherapeuticsConsulting or Advisory Role: Array BioPharma, Merck, Roche, Regeneron, Sanofi, Iovance BiotherapeuticsResearch Funding: Roche/Genentech, Merck, Array BioPharma, Incyte, Nektar, Iovance Biotherapeutics, Bristol Myers Squibb, Kartos Therapeutics, OncoSec, Regeneron, Alkermes, Neon Therapeutics, Ultimovacs, Senhwa Biosciences, Replimune, AmgenTravel, Accommodations, Expenses: Merck, Roche/Genentech, Regeneron, Neon Therapeutics, AlkermesUncompensated Relationships: Roche/Genentech, Regeneron Sekwon JangConsulting or Advisory Role: Bristol Myers Squibb, EMD Serono, Novartis, Sanofi, Sun Biopharma, Genentech Ewa KalinkaHonoraria: Bristol Myers Squibb, MSD, AstraZeneca, Regeneron, Nektar, RocheConsulting or Advisory Role: Bristol Myers SquibbSpeakers' Bureau: Bristol Myers Squibb, RocheResearch Funding: Bristol Myers Squibb, Merck Sharp & Dohme, Nektar, AstraZeneca, RocheTravel, Accommodations, Expenses: Roche Igor PuzanovStock and Other Ownership Interests: CelldexConsulting or Advisory Role: Amgen, Iovance Biotherapeutics, Merck, Roche, Nouscom, Seneca Therapeutics Alexander I. SpiraStock and Other Ownership Interests: LillyHonoraria: CytomX Therapeutics, AstraZeneca/MedImmune, Merck, Takeda, Amgen, Janssen Oncology, Novartis, Bristol Myers Squibb, BayerConsulting or Advisory Role: Array BioPharma, Incyte, Amgen, Novartis, AstraZeneca/MedImmune, Mirati Therapeutics, Gritstone Oncology, Jazz Pharmaceuticals, Merck, Bristol Myers SquibbResearch Funding: Roche, AstraZeneca, Boehringer Ingelheim, Astellas Pharma, MedImmune, Novartis, Newlink Genetics, Incyte, AbbVie, Ignyta, LAM Therapeutics, Trovagene, Takeda, Macrogenics, CytomX Therapeutics, Astex Pharmaceuticals, Bristol Myers Squibb, Loxo, Arch Therapeutics, Gritstone Oncology, Plexxikon, Amgen, Daiichi Sankyo, ADC Therapeutics, Janssen Oncology, Mirati Therapeutics, Rubius Therapeutics Daniel C. ChoConsulting or Advisory Role: Nektar, Pfizer, Werewolf TherapeuticsExpert Testimony: Genentech, Abbott/AbbVie Shanhong GuanEmployment: Nektar TherapeuticsStock and Other Ownership Interests: Nektar Therapeutics Erika PuenteEmployment: NektarStock and Other Ownership Interests: Nektar Tuan NguyenEmployment: Nektar, Theravance TherapeuticsStock and Other Ownership Interests: Nektar, Theravance Ute HochOther Relationship: Nektar Sue L. CurrieEmployment: NektarStock and Other Ownership Interests: Nektar Wei LinEmployment: Erasca Inc, NektarLeadership: Erasca IncStock and Other Ownership Interests: Nektar, Erasca IncTravel, Accommodations, Expenses: Nektar, Erasca Inc Mary A. TagliaferriEmployment: NektarLeadership: Nektar, ENZO BiochemStock and Other Ownership Interests: NektarPatents, Royalties, Other Intellectual Property: US 10576121Travel, Accommodations, Expenses: Nektar Jonathan ZalevskyEmployment: NektarLeadership: NektarStock and Other Ownership Interests: NektarTravel, Accommodations, Expenses: Nektar Mario SznolStock and Other Ownership Interests: Amphivena, Intensity Therapeutics, Adaptive Biotechnologies, Actym Therapeutics, Torque, Nextcure, EvolveImmune Therapeutics, Johnson & Johnson/Janssen, GlaxoSmithKlineConsulting or Advisory Role: Bristol Myers Squibb, AstraZeneca/MedImmune, Nektar, Lilly, Adaptimmune, Seattle Genetics, Pierre Fabre, Molecular Partners, AbbVie, Pieris Pharmaceuticals, Innate Pharma, Immunocore, Genocea Biosciences, Anaeropharma, Zelluna, Boston Pharmaceuticals, Alligator Bioscience, Servier, Dragonfly Therapeutics, Verastem, Boehringer Ingelheim, Agenus, Numab, BioNTech AG, Genentech/Roche, Gilead Sciences, Jazz Pharmaceuticals, Targovax, Sapience Therapeutics, Pfizer, Tessa Therapeutics, OncoSec, Trillium Therapeutics, StCube, Simcha, ITeos TherapeuticsOther Relationship: Haymarket Media, Physicians' Education Resource, DAVAOncology, CEC Oncology Michael E. HurwitzEmployment: Pfizer, Gamida Cell, ArvinasConsulting or Advisory Role: Nektar, Janssen, Crispr Therapeutics, Bristol Myers Squibb/Celgene, ExelixisResearch Funding: Apexigen, Astellas Pharma, AstraZeneca/MedImmune, Bayer, Bristol Myers Squibb, Corvus Pharmaceuticals, Lilly, Endocyte, Genentech, Genmab, Innocrin Pharma, Iovance Biotherapeutics, Merck, Nektar, Novartis, Pfizer, Progenics, Sanofi/Aventis, Seattle Genetics, Torque, Unum Therapeutics, Achilles TherapeuticsNo other potential conflicts of interest were reported. more...
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31. Phase I study protocol: NKTR-255 as monotherapy or combined with daratumumab or rituximab in hematologic malignancies.
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Shah N, Perales MA, Turtle CJ, Cairo MS, Cowan AJ, Saeed H, Budde LE, Tan A, Lee Z, Kai K, Marcondes MQ, Zalevsky J, Tagliaferri MA, and Patel KK
- Subjects
- Drug Therapy, Combination, Humans, Interleukin-15 chemistry, Polyethylene Glycols chemistry, Antibodies, Monoclonal therapeutic use, Antineoplastic Agents therapeutic use, Hematologic Neoplasms drug therapy, Interleukin-15 therapeutic use, Rituximab therapeutic use
- Abstract
NKTR-255 is an investigational polyethylene glycol-modified recombinant human IL-15 (rhIL-15) receptor agonist, designed to improve the immunotherapeutic and anti-cancer benefit observed with rhIL-15 while circumventing the toxicities associated with this therapy. In preclinical studies, NKTR-255 has demonstrated enhanced proliferation and function of CD8
+ T cells and natural killer cells, as well as enhanced anti-tumor activity and survival both as monotherapy and in combination with monoclonal antibodies in multiple cancer models. Here, we describe the rationale and design of the first-in-human Phase I, dose-escalation and dose-expansion study of NKTR-255 alone and in combination with daratumumab or rituximab in adults with relapsed/refractory multiple myeloma or non-Hodgkin's lymphoma that will determine the maximum tolerated dose and recommended Phase II dose for NKTR-255. more...- Published
- 2021
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32. In vivo and in vitro Characterization of a Partial Mu Opioid Receptor Agonist, NKTR-181, Supports Future Therapeutic Development.
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Lee AS, Tiwari S, Bishop I, Matossian V, Romaneschi N, Miyazaki T, VanderVeen L, Zalevsky J, DeFea K, Cahill CM, and Walwyn WM
- Abstract
Mu opioid receptor (MOPr) agonists are well-known and frequently used clinical analgesics but are also rewarding due to their highly addictive and often abusive properties. This may lead to opioid use disorder (OUD) a disorder that effects millions of people worldwide. Therefore, novel compounds are urgently needed to treat OUD. As opioids are effective analgesics and OUD often occurs in conjunction with chronic pain, these novel compounds may be opioids, but they must have a low abuse liability. This could be mediated by diminishing or slowing blood-brain barrier transport, slowing target receptor binding kinetics, and showing a long half-life. NKTR-181 is a PEGylated oxycodol and a MOPr agonist that has slowed blood-brain barrier transport, a long half-life, and diminished likeability in clinical trials. In this study, we examined the signaling and behavioral profile of NKTR-181 in comparison with oxycodone to determine whether further therapeutic development of this compound may be warranted. For this preclinical study, we used a number of in vitro and in vivo assays. The signaling profile of NKTR-181 was determined by the electrophysiological assessment of MOPr-Ca
2+ channel inhibition in the nociceptive neurons of rodent dorsal root ganglia. Heterologous cell-based assays were used to assess biased agonism and receptor trafficking. Different rodent behavioral models were used to define the NKTR-181-induced relief of effective and reflexive nociception and drug-seeking behavior as assessed by an intravenous self-administration (IVSA) of NKTR-181. We found that NKTR-181 and oxycodone are partial agonists in G-protein signaling and Ca2+ channel inhibition assays and promote limited MOPr desensitization. However, NKTR-181 inhibits Ca2+ channels by a different mechanism than oxycodone and induces a different pattern of arrestin recruitment. In addition, NKTR-181 has a slower receptor on-rate and a slower rate of Ca2+ channel coupling than oxycodone. This signaling profile is coupled with a slower onset of antinociception and limited drug-seeking behavior in comparison with oxycodone. Together with its known long half-life and slow blood-brain barrier transport, these data suggest that NKTR-181 could be further studied as a pharmacotherapeutic treatment modality for OUD., Competing Interests: KD was employed by company KiloDalton Consulting. The remaining authors declare that the research was conducted in the absence of any commercial or financial relationships that could be construed as a potential conflict of interest., (Copyright © 2021 Lee, Tiwari, Bishop, Matossian, Romaneschi, Miyazaki, VanderVeen, Zalevsky, DeFea, Cahill and Walwyn.) more...- Published
- 2021
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33. Preclinical Assessment of the Analgesic Pharmacology of NKTR-181 in Rodents.
- Author
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Kopruszinski CM, Swiokla J, Lee YS, Navratilova E, VanderVeen L, Yang M, Liu Y, Miyazaki T, Schmidt WK, Zalevsky J, and Porreca F
- Subjects
- Animals, Dose-Response Relationship, Drug, Drug Evaluation, Preclinical methods, Female, Male, Mice, Pain Measurement methods, Rats, Rats, Sprague-Dawley, Receptors, Opioid, mu physiology, Rodentia, Analgesics, Opioid pharmacology, Morphinans pharmacology, Morphine pharmacology, Pain Measurement drug effects, Receptors, Opioid, mu agonists
- Abstract
Objective: Pharmacological evaluation of the mu-opioid receptor (MOR) agonist properties of NKTR-181 in rodent models., Methods: Graded noxious stimulus intensities were used in rats to establish the antinociceptive potency and efficacy of NKTR-181 relative to morphine, fentanyl, and oxycodone. Characteristics of MOR agonist actions, as measured by antinociceptive tolerance and cross-tolerance, as well as opioid-induced hyperalgesia (OIH) and naloxone-precipitated withdrawal in NKTR-181- and morphine-dependent in mice, were compared., Results: NKTR-181 showed dose- and time-related antinociception with similar maximal effects to morphine in the rat and mouse hot-water tail-flick test. No sex or species differences were observed in NKTR-181 or morphine antinociception. Rats treated with NKTR-181 and morphine exhibited decreases in both potency and maximal efficacy as nociceptive stimulus intensity was increased from a water temperature of 50 °C to 54 °C. Evaluation of antinociception at a high stimulus intensity revealed that oxycodone and fentanyl exhibited greater efficacy than either NKTR-181 or morphine. The relative potency difference between NKTR-181 and morphine across all tail-flick studies was determined to be 7.6-fold (90% confidence interval, 2.6, 21.5). The peak antinociceptive effect of NKTR-181 was delayed compared to that of the other opioids and cumulative drug effects were not observed. Repeated treatment with escalating, approximately equi-analgesic doses of NKTR-181 or morphine, produced antinociceptive tolerance and cross-tolerance. Under these pharmacological conditions, OIH and naloxone-precipitated physical dependence were similar for NKTR-181 and morphine., Conclusions: NKTR-181 had a slower onset, but similar efficacy, to morphine in the models studied supporting reduced abuse potential while maintaining analgesic effect in comparison with current opioids. more...
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- 2021
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34. NKTR-358: A novel regulatory T-cell stimulator that selectively stimulates expansion and suppressive function of regulatory T cells for the treatment of autoimmune and inflammatory diseases.
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Dixit N, Fanton C, Langowski JL, Kirksey Y, Kirk P, Chang T, Cetz J, Dixit V, Kim G, Kuo P, Maiti M, Tang Y, VanderVeen LA, Zhang P, Lee M, Ritz J, Kamihara Y, Ji C, Rubas W, Sweeney TD, Doberstein SK, and Zalevsky J more...
- Abstract
Impaired interleukin-2 (IL-2) production and regulatory T-cell dysfunction have been implicated as immunological mechanisms central to the pathogenesis of multiple autoimmune and inflammatory diseases. NKTR-358, a novel regulatory T-cell stimulator, is an investigational therapeutic that selectively restores regulatory T-cell homeostasis in these diseases. We investigated NKTR-358's selectivity for regulatory T-cells, receptor-binding properties, ex vi vo and in vivo pharmacodynamics, ability to suppress conventional T-cell proliferation in mice and non-human primates, and functional activity in a murine model of systemic lupus erythematosus. In vitro, NKTR-358 demonstrated decreased affinity for IL-2Rα, IL-2Rβ, and IL-2Rαβ compared with recombinant human IL-2 (rhIL-2). A single dose of NKTR-358 in cynomolgus monkeys produced a greater than 15-fold increase in regulatory T-cells, and the increase lasted until day 14, while daily rhIL-2 administration for 5 days only elicited a 3-fold increase, which lasted until day 7. Repeated dosing of NKTR-358 over 6 months in cynomolgus monkeys elicited cyclical, robust increases in regulatory T-cells with no loss in drug activity over the course of treatment. Regulatory T-cells isolated from NKTR-358-treated mice displayed a sustained, higher suppression of conventional T-cell proliferation than regulatory T-cells isolated from vehicle-treated mice. NKTR-358 treatment in a mouse model (MRL/MpJ-Fas
lpr ) of systemic lupus erythematosus for 12 weeks maintained elevated regulatory T-cells for the treatment duration and ameliorated disease progression. Together, these results suggest that NKTR-358 has the ability to elicit sustained and preferential proliferation and activation of regulatory T-cells without corresponding effects on conventional T-cells, with improved pharmacokinetics compared with rhIL-2., Competing Interests: The authors declare the following financial interests/personal relationships which may be considered as potential competing interests. All authors, except JR and YK, were employees and shareholders of Nektar Therapeutics during this study. JR reports research funding from Amgen, Equillium, and Kite Pharma and consulting income from Aleta Biotherapeutics, Avrobio, Celgene, Falcon Therapeutics, LifeVault Bio, Rheos Medicines, Tal, and TScan Therapeutics. YK has no known competing financial interests or personal relationships that could have appeared to influence the work reported in this paper., (© 2021 The Authors.) more...- Published
- 2021
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35. NKTR-255, a novel polymer-conjugated rhIL-15 with potent antitumor efficacy.
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Miyazaki T, Maiti M, Hennessy M, Chang T, Kuo P, Addepalli M, Obalapur P, Sheibani S, Wilczek J, Pena R, Quach P, Cetz J, Moffett A, Tang Y, Kirk P, Huang J, Sheng D, Zhang P, Rubas W, Madakamutil L, Kivimäe S, and Zalevsky J more...
- Subjects
- Animals, Antineoplastic Agents pharmacokinetics, Antineoplastic Agents pharmacology, Burkitt Lymphoma pathology, Cell Degranulation drug effects, Cell Line, Tumor, Cell Proliferation drug effects, Cytokines metabolism, Female, HEK293 Cells, Humans, Interleukin-15 pharmacokinetics, Interleukin-15 pharmacology, Lymphocyte Activation drug effects, Lymphocytes immunology, Lymphocytes metabolism, Mice, Inbred BALB C, Mice, Inbred C57BL, Mice, Knockout, Mice, SCID, Polyethylene Glycols pharmacokinetics, Polyethylene Glycols pharmacology, Receptors, Interleukin-15 genetics, Receptors, Interleukin-15 metabolism, Signal Transduction, Tumor Microenvironment, Mice, Antineoplastic Agents therapeutic use, Burkitt Lymphoma drug therapy, Interleukin-15 therapeutic use, Lymphocytes drug effects, Polyethylene Glycols therapeutic use, Receptors, Interleukin-15 agonists
- Abstract
Background: NKTR-255 is a novel polyethylene glycol-conjugate of recombinant human interleukin-15 (rhIL-15), which was designed to retain all known receptor binding interactions of the IL-15 molecule. We explored the biologic and pharmacologic differences between endogenous IL-15 receptor α (IL-15Rα)-dependent (NKTR-255 and rhIL-15) and IL-15Rα-independent (precomplexed rhIL-15/IL-15Rα) cytokines., Methods: In vitro pharmacological properties of rhIL-15, NKTR-255 and precomplex cytokines (rhIL-15/IL-15Rα and rhIL-15 N72D/IL-15Rα Fc) were investigated in receptor binding, signaling and cell function. In vivo pharmacokinetic (PK) and pharmacodynamic profile of the cytokines were evaluated in normal mice. Finally, immunomodulatory effect and antitumor activity were assessed in a Daudi lymphoma model., Results: NKTR-255 and rhIL-15 exhibited similar in vitro properties in receptor affinity, signaling and leukocyte degranulation, which collectively differed from precomplexed cytokines. Notably, NKTR-255 and rhIL-15 stimulated greater granzyme B secretion in human peripheral blood mononuclear cells versus precomplexed cytokines. In vivo, NKTR-255 exhibited a PK profile with reduced clearance and a longer half-life relative to rhIL-15 and demonstrated prolonged IL-15R engagement in lymphocytes compared with only transient engagement observed for rhIL-15 and precomplexed rhIL-15 N72D/IL-15Rα Fc. As a consequent, NKTR-255 provided a durable and sustained proliferation and activation of natural killer (NK) and CD8
+ T cells. Importantly, NKTR-255 is more effective than the precomplexed cytokine at inducing functionally competent, cytotoxic NK cells in the tumor microenvironment and the properties of NKTR-255 translated into superior antitumor activity in a B-cell lymphoma model versus the precomplexed cytokine., Conclusions: Our results show that the novel immunotherapeutic, NKTR-255, retains the full spectrum of IL-15 biology, but with improved PK properties, over rhIL-15. These findings support the ongoing phase 1 first-in-human trial (NCT04136756) of NKTR-255 in participants with relapsed or refractory hematologic malignancies, potentially advancing rhIL-15-based immunotherapies for the treatment of cancer., Competing Interests: Competing interests: All authors are current or former employees of Nektar Therapeutics and/or have Nektar Therapeutics stock ownership interests to disclose. PKu is currently employed by Gilead Sciences. MA is currently employed by HIBC Biopharma. PKi is currently employed by Immunocore. LM is currently employed by Invivoscribe., (© Author(s) (or their employer(s)) 2021. Re-use permitted under CC BY-NC. No commercial re-use. See rights and permissions. Published by BMJ.) more...- Published
- 2021
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36. Bempegaldesleukin (BEMPEG; NKTR-214) efficacy as a single agent and in combination with checkpoint-inhibitor therapy in mouse models of osteosarcoma.
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Hennessy M, Wahba A, Felix K, Cabrera M, Segura MG, Kundra V, Ravoori MK, Stewart J, Kleinerman ES, Jensen VB, Gopalakrishnan V, Pena R, Quach P, Kim G, Kivimäe S, Madakamutil L, Overwijk WW, Zalevsky J, and Gordon N more...
- Subjects
- Animals, Bone Neoplasms immunology, Bone Neoplasms pathology, Cell Line, Tumor, Female, Humans, Immune Checkpoint Inhibitors administration & dosage, Interleukin-2 administration & dosage, Interleukin-2 pharmacology, Lung Neoplasms drug therapy, Lung Neoplasms immunology, Lung Neoplasms secondary, Mice, Inbred BALB C, Mice, Inbred C3H, Osteosarcoma immunology, Osteosarcoma pathology, Polyethylene Glycols administration & dosage, Survival Analysis, T-Lymphocytes drug effects, T-Lymphocytes immunology, T-Lymphocytes pathology, Treatment Outcome, Tumor Burden drug effects, Tumor Burden immunology, Mice, Antineoplastic Combined Chemotherapy Protocols pharmacology, Bone Neoplasms drug therapy, Disease Models, Animal, Interleukin-2 analogs & derivatives, Osteosarcoma drug therapy, Polyethylene Glycols pharmacology
- Abstract
Survival of patients with relapsed/refractory osteosarcoma has not improved in the last 30 years. Several immunotherapeutic approaches have shown benefit in murine osteosarcoma models, including the anti-programmed death-1 (anti-PD-1) and anti-cytotoxic T-lymphocyte antigen-4 (anti-CTLA-4) immune checkpoint inhibitors. Treatment with the T-cell growth factor interleukin-2 (IL-2) has shown some clinical benefit but has limitations due to poor tolerability. Therefore, we evaluated the efficacy of bempegaldesleukin (BEMPEG; NKTR-214), a first-in-class CD122-preferential IL-2 pathway agonist, alone and in combination with anti-PD-1 or anti-CTLA-4 immune checkpoint inhibitors in metastatic and orthotopic murine models of osteosarcoma. Treatment with BEMPEG delayed tumor growth and increased overall survival of mice with K7M2-WT osteosarcoma pulmonary metastases. BEMPEG also inhibited primary tumor growth and metastatic relapse in lungs and bone in the K7M3 orthotopic osteosarcoma mouse model. In addition, it enhanced therapeutic activity of anti-CTLA-4 and anti-PD-1 checkpoint blockade in the DLM8 subcutaneous murine osteosarcoma model. Finally, BEMPEG strongly increased accumulation of intratumoral effector T cells and natural killer cells, but not T-regulatory cells, resulting in improved effector:inhibitory cell ratios. Collectively, these data in multiple murine models of osteosarcoma provide a path toward clinical evaluation of BEMPEG-based regimens in human osteosarcoma., (© 2020 The Authors. International Journal of Cancer published by John Wiley & Sons Ltd on behalf of Union for International Cancer Control.) more...
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- 2021
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37. Engineering IL-2 to Give New Life to T Cell Immunotherapy.
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Overwijk WW, Tagliaferri MA, and Zalevsky J
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- Animals, Humans, Neoplasms immunology, Autoimmunity, Bioengineering methods, Cell- and Tissue-Based Therapy methods, Immunotherapy methods, Interleukin-2 immunology, Neoplasms therapy, T-Lymphocytes immunology
- Abstract
Interleukin-2 (IL-2) is integral to immune system regulation. Its opposing immunostimulatory and immunosuppressive actions make it an attractive therapeutic target for cancer and autoimmune diseases. A challenge in developing IL-2-directed anticancer therapies has been how to stimulate effector T cells (Teffs) without inducing regulatory T cells (Tregs) in the tumor microenvironment; conversely, IL-2 therapy for autoimmune diseases requires Treg induction without further stimulation of Teffs. High-dose IL-2 is approved for melanoma and renal cell carcinoma, but its therapeutic value is limited by a need for frequent dosing at specialist centers, its short half-life, severe toxicity, and a lack of efficacy in most patients. Re-engineered IL-2 therapeutics are designed to have longer in vivo half-lives, target specific IL-2 receptor conformations to stimulate specific T cell subsets, or localize to target tissues to optimize efficacy and reduce toxicity. We discuss recent studies that elucidate the potential of newly engineered IL-2-based therapeutics for cancer and autoimmune diseases. more...
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- 2021
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38. Mobilization of pre-existing polyclonal T cells specific to neoantigens but not self-antigens during treatment of a patient with melanoma with bempegaldesleukin and nivolumab.
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Veatch JR, Singhi N, Jesernig B, Paulson KG, Zalevsky J, Iaccucci E, Tykodi SS, and Riddell SR
- Subjects
- Adult, Humans, Male, Melanoma pathology, Nivolumab pharmacology, Young Adult, Autoantigens metabolism, Melanoma drug therapy, Nivolumab therapeutic use, T-Lymphocytes immunology
- Abstract
T cells that recognize self-antigens and mutated neoantigens are thought to mediate antitumor activity of immune checkpoint blockade (ICB) in melanoma. Few studies have analyzed self and neoantigen-specific T cell responses in patients responding to ICB. Here, we report a patient with metastatic melanoma who had a durable clinical response after treatment with the programmed cell death protein 1 inhibitor, nivolumab, combined with the first-in-class CD122-preferential interleukin-2 pathway agonist, bempegaldesleukin (BEMPEG, NKTR-214). We used a combination of antigen-specific T cell expansion and measurement of interferon-γ secretion to identify multiple CD4
+ and CD8+ T cell clones specific for neoantigens, lineage-specific antigens and cancer testis antigens in blood and tumor from this patient prior to and after therapy. Polyclonal CD4+ and CD8+ T cells specific to multiple neoantigens but not self-antigens were highly enriched in pretreatment tumor compared with peripheral blood. Neoantigen, but not self-antigen-specific T cell clones expanded in frequency in the blood during successful treatment. There was evidence of dramatic immune infiltration into the tumor on treatment, and a modest increase in the relative frequency of intratumoral neoantigen-specific T cells. These observations suggest that diverse CD8+ and CD4+ T cell clones specific for neoantigens present in tumor before treatment had a greater role in immune tumor rejection as compared with self-antigen-specific T cells in this patient. Trial registration number: NCT02983045., Competing Interests: Competing interests: JRV, BJ and SR have equity interest in Lyell Immunopharma, and JZ and EE are employees of Nektar therapeutics, and this paper discusses use of an investigational drug owned by Nektar therapeutics., (© Author(s) (or their employer(s)) 2020. Re-use permitted under CC BY-NC. No commercial re-use. See rights and permissions. Published by BMJ.) more...- Published
- 2020
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39. Bempegaldesleukin (NKTR-214) plus Nivolumab in Patients with Advanced Solid Tumors: Phase I Dose-Escalation Study of Safety, Efficacy, and Immune Activation (PIVOT-02).
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Diab A, Tannir NM, Bentebibel SE, Hwu P, Papadimitrakopoulou V, Haymaker C, Kluger HM, Gettinger SN, Sznol M, Tykodi SS, Curti BD, Tagliaferri MA, Zalevsky J, Hannah AL, Hoch U, Aung S, Fanton C, Rizwan A, Iacucci E, Liao Y, Bernatchez C, Hurwitz ME, and Cho DC more...
- Subjects
- Adult, Aged, Antineoplastic Agents, Immunological adverse effects, Antineoplastic Combined Chemotherapy Protocols adverse effects, Carcinoma, Non-Small-Cell Lung genetics, Carcinoma, Non-Small-Cell Lung immunology, Carcinoma, Renal Cell genetics, Carcinoma, Renal Cell immunology, Female, Gene Expression Regulation, Neoplastic drug effects, Humans, Immune Checkpoint Inhibitors adverse effects, Immunotherapy, Interleukin-2 administration & dosage, Interleukin-2 adverse effects, Kidney Neoplasms genetics, Kidney Neoplasms immunology, Lung Neoplasms genetics, Lung Neoplasms immunology, Lymphocyte Count, Lymphocytes, Tumor-Infiltrating drug effects, Lymphocytes, Tumor-Infiltrating immunology, Male, Melanoma genetics, Melanoma immunology, Middle Aged, Nivolumab adverse effects, Polyethylene Glycols adverse effects, Programmed Cell Death 1 Receptor antagonists & inhibitors, Treatment Outcome, Young Adult, Antineoplastic Agents, Immunological administration & dosage, Antineoplastic Combined Chemotherapy Protocols administration & dosage, Carcinoma, Non-Small-Cell Lung drug therapy, Carcinoma, Renal Cell drug therapy, Immune Checkpoint Inhibitors administration & dosage, Interleukin-2 analogs & derivatives, Kidney Neoplasms drug therapy, Lung Neoplasms drug therapy, Melanoma drug therapy, Nivolumab administration & dosage, Polyethylene Glycols administration & dosage
- Abstract
This single-arm, phase I dose-escalation trial (NCT02983045) evaluated bempegaldesleukin (NKTR-214/BEMPEG), a CD122-preferential IL2 pathway agonist, plus nivolumab in 38 patients with selected immunotherapy-naïve advanced solid tumors (melanoma, renal cell carcinoma, and non-small cell lung cancer). Three dose-limiting toxicities were reported in 2 of 17 patients during dose escalation [hypotension ( n = 1), hyperglycemia ( n = 1), metabolic acidosis ( n = 1)]. The most common treatment-related adverse events (TRAE) were flu-like symptoms (86.8%), rash (78.9%), fatigue (73.7%), and pruritus (52.6%). Eight patients (21.1%) experienced grade 3/4 TRAEs; there were no treatment-related deaths. Total objective response rate across tumor types and dose cohorts was 59.5% (22/37), with 7 complete responses (18.9%). Cellular and gene expression analysis of longitudinal tumor biopsies revealed increased infiltration, activation, and cytotoxicity of CD8
+ T cells, without regulatory T-cell enhancement. At the recommended phase II dose, BEMPEG 0.006 mg/kg plus nivolumab 360 mg every 3 weeks, the combination was well tolerated and demonstrated encouraging clinical activity irrespective of baseline PD-L1 status. SIGNIFICANCE: These data show that BEMPEG can be successfully combined with a checkpoint inhibitor as dual immunotherapy for a range of advanced solid tumors. Efficacy was observed regardless of baseline PD-L1 status and baseline levels of tumor-infiltrating lymphocytes, suggesting therapeutic potential for patients with poor prognostic risk factors for response to PD-1/PD-L1 blockade. See related commentary by Rouanne et al., p. 1097 . This article is highlighted in the In This Issue feature, p. 1079 ., (©2020 American Association for Cancer Research.) more...- Published
- 2020
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40. Human Abuse Potential of Oral NKTR-181 in Recreational Opioid Users: A Randomized, Double-Blind, Crossover Study.
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Ge X, Henningfield JE, Siddhanti S, Jobes J, Lu L, Xie S, Ziola M, Kelsh D, Vince B, Di Fonzo CJ, Tagliaferri M, Zalevsky J, Doberstein SK, Hoch U, and Eldon MA
- Subjects
- Administration, Oral, Adult, Cross-Over Studies, Dose-Response Relationship, Drug, Double-Blind Method, Female, Humans, Male, Oxycodone administration & dosage, Recreational Drug Use, Analgesics, Opioid administration & dosage, Morphinans administration & dosage
- Abstract
Objective: To evaluate the human abuse potential, pharmacokinetics, pharmacodynamics, and safety of oral NKTR-181 (oxycodegol), a novel full mu-opioid receptor agonist, relative to oral oxycodone., Design: This double-blind, randomized, single-dose, crossover human abuse potential study was conducted in healthy, adult, non-physically dependent recreational opioid users., Setting: Inpatient clinical research site., Subjects: Seventy-one subjects randomized (95.7% male, 65.2% African American, mean age = 31.7 years)., Methods: The primary objective was to compare two therapeutic doses of NKTR-181 (400 and 600 mg) with 40 and 60 mg of oxycodone and a supratherapeutic dose (1200 mg) of NKTR-181 with 60 mg of oxycodone using visual analog scale (VAS) ratings for Drug Liking "at this moment" (Drug Liking). Secondary objectives included VAS ratings for other subjective measures, and central nervous system (CNS) mu-opioid effects were assessed using pupillometry. Each subject received single oral doses of five treatments and matching placebo., Results: Compared with 40 and 60 mg of oxycodone, the maximum mean Drug Liking score at 400 and 600 mg NKTR-181 was significantly lower, and the rate of onset and extent of Drug Liking for all NKTR-181 doses in the first two hours postdose were also significantly lower. Delayed attenuated Drug Liking and pupillary miosis response following administration of NKTR-181 vs oxycodone were consistent with slower NKTR-181 CNS entry kinetics and mu-opioid receptor binding. No adverse events were rated as severe, and somnolence and dizziness occurred more frequently when subjects received oxycodone., Conclusions: NKTR-181 at oral doses of 400 and 600 mg showed significantly fewer and less severe subjective effects accepted as representative of opioid abuse potential, such as lower peak Drug Liking in recreational opioid users, than 40 and 60 mg of oxycodone., (© 2019 American Academy of Pain Medicine.) more...
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- 2020
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41. Persistence of adoptively transferred T cells with a kinetically engineered IL-2 receptor agonist.
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Parisi G, Saco JD, Salazar FB, Tsoi J, Krystofinski P, Puig-Saus C, Zhang R, Zhou J, Cheung-Lau GC, Garcia AJ, Grasso CS, Tavaré R, Hu-Lieskovan S, Mackay S, Zalevsky J, Bernatchez C, Diab A, Wu AM, Comin-Anduix B, Charych D, and Ribas A more...
- Subjects
- Animals, Humans, Interleukin-2 administration & dosage, Interleukin-2 immunology, Lymphocyte Activation drug effects, Melanoma genetics, Melanoma immunology, Melanoma, Experimental, Mice, Mice, Inbred C57BL, Receptors, Interleukin-2 genetics, Adoptive Transfer, Interleukin-2 agonists, Interleukin-2 analogs & derivatives, Melanoma drug therapy, Polyethylene Glycols administration & dosage, Receptors, Interleukin-2 immunology, T-Lymphocytes immunology
- Abstract
Interleukin-2 (IL-2) is a component of most protocols of adoptive cell transfer (ACT) therapy for cancer, but is limited by short exposure and high toxicities. NKTR-214 is a kinetically-engineered IL-2 receptor βγ (IL-2Rβγ)-biased agonist consisting of IL-2 conjugated to multiple releasable polyethylene glycol chains resulting in sustained signaling through IL-2Rβγ. We report that ACT supported by NKTR-214 increases the proliferation, homing and persistence of anti-tumor T cells compared to ACT with IL-2, resulting in superior antitumor activity in a B16-F10 murine melanoma model. The use of NKTR-214 increases the number of polyfunctional T cells in murine spleens and tumors compared to IL-2, and enhances the polyfunctionality of T and NK cells in the peripheral blood of patients receiving NKTR-214 in a phase 1 trial. In conclusion, NKTR-214 may have the potential to improve the antitumor activity of ACT in humans through increased in vivo expansion and polyfunctionality of the adoptively transferred T cells. more...
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- 2020
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42. Bempegaldesleukin selectively depletes intratumoral Tregs and potentiates T cell-mediated cancer therapy.
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Sharma M, Khong H, Fa'ak F, Bentebibel SE, Janssen LME, Chesson BC, Creasy CA, Forget MA, Kahn LMS, Pazdrak B, Karki B, Hailemichael Y, Singh M, Vianden C, Vennam S, Bharadwaj U, Tweardy DJ, Haymaker C, Bernatchez C, Huang S, Rajapakshe K, Coarfa C, Hurwitz ME, Sznol M, Hwu P, Hoch U, Addepalli M, Charych DH, Zalevsky J, Diab A, and Overwijk WW more...
- Subjects
- Animals, Antibodies, Monoclonal, Humanized administration & dosage, CD8-Positive T-Lymphocytes immunology, Carcinoma, Renal Cell genetics, Carcinoma, Renal Cell immunology, Cohort Studies, Drug Therapy, Combination, Female, Humans, Interferon-gamma genetics, Interferon-gamma immunology, Interleukin-2 administration & dosage, Interleukin-2 agonists, Interleukin-2 immunology, Ipilimumab administration & dosage, Lymphocyte Activation drug effects, Melanoma genetics, Melanoma immunology, Mice, Mice, Inbred C57BL, Receptors, Interleukin-2 genetics, Receptors, Interleukin-2 immunology, Tumor Necrosis Factor-alpha genetics, Tumor Necrosis Factor-alpha immunology, Carcinoma, Renal Cell drug therapy, Interleukin-2 analogs & derivatives, Melanoma drug therapy, Polyethylene Glycols administration & dosage, Prodrugs administration & dosage, T-Lymphocytes, Regulatory immunology
- Abstract
High dose interleukin-2 (IL-2) is active against metastatic melanoma and renal cell carcinoma, but treatment-associated toxicity and expansion of suppressive regulatory T cells (Tregs) limit its use in patients with cancer. Bempegaldesleukin (NKTR-214) is an engineered IL-2 cytokine prodrug that provides sustained activation of the IL-2 pathway with a bias to the IL-2 receptor CD122 (IL-2Rβ). Here we assess the therapeutic impact and mechanism of action of NKTR-214 in combination with anti-PD-1 and anti-CTLA-4 checkpoint blockade therapy or peptide-based vaccination in mice. NKTR-214 shows superior anti-tumor activity over native IL-2 and systemically expands anti-tumor CD8
+ T cells while inducing Treg depletion in tumor tissue but not in the periphery. Similar trends of intratumoral Treg dynamics are observed in a small cohort of patients treated with NKTR-214. Mechanistically, intratumoral Treg depletion is mediated by CD8+ Teff-associated cytokines IFN-γ and TNF-α. These findings demonstrate that NKTR-214 synergizes with T cell-mediated anti-cancer therapies. more...- Published
- 2020
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43. A Reduction in B, T, and Natural Killer Cells Expressing CD38 by TAK-079 Inhibits the Induction and Progression of Collagen-Induced Arthritis in Cynomolgus Monkeys.
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Korver W, Carsillo M, Yuan J, Idamakanti N, Wagoner M, Shi P, Xia CQ, Smithson G, McLean L, Zalevsky J, and Fedyk ER
- Subjects
- ADP-ribosyl Cyclase 1 immunology, Animals, Arthritis, Experimental metabolism, Arthritis, Experimental pathology, B-Lymphocytes immunology, CHO Cells, Cricetulus, Disease Progression, Killer Cells, Natural immunology, Macaca fascicularis, T-Lymphocytes immunology, ADP-ribosyl Cyclase 1 metabolism, Antibodies, Monoclonal immunology, Arthritis, Experimental immunology, B-Lymphocytes metabolism, Gene Expression Regulation immunology, Killer Cells, Natural metabolism, T-Lymphocytes metabolism
- Abstract
Ectoenzyme CD38 is increased on lymphocytes in response to an antigenic challenge and it is hypothesized that targeting these activated lymphocytes could ameliorate pathologic activities in autoimmune diseases. The cynomolgus monkey is an appropriate model for assessing potential effects of targeting CD38 in humans because these species exhibit similar expression profiles. TAK-079 is a human monoclonal antibody (IgG
1 λ ) that binds to CD38 and lyses bound cells by complement-dependent cytotoxicity and antibody-dependent cell-mediated cytotoxicity. TAK-079 binds to monkey CD38 with an affinity at EC50 4.5 nM, and the potential activity of TAK-079 was investigated in a monkey collagen-induced arthritis model of autoimmune disease. Prophylactic administration of TAK-079 (3 mg/kg i.v. weekly) was well tolerated and prevented arthritis development compared with vehicle-treated control animals, which exhibited progressive disease with radiographic damage and worsening clinical scores over the study course. Therapeutic treatment of arthritic monkeys with TAK-079 (3 mg/kg i.v. weekly) was also well tolerated and reduced disease progression and symptoms. Arthritis scores and joint swelling were significantly lower than the vehicle control, accompanied by decreases in blood levels of C-reactive protein, alkaline phosphatase, and natural killer, B, and T cells. Histopathology, morphometry, and radiology revealed significantly less joint damage in animals exposed prophylactically to TAK-079 treatment compared with vehicle-treated animals and significantly less damage in animals treated therapeutically with TAK-079 or dexamethasone (0.1 mg/kg oral gavage daily), illustrating potential disease-modifying activity. In conclusion, these data indicate that depletion of CD38-expressing cells could be a therapeutic mechanism for treating autoimmune diseases. SIGNIFICANCE STATEMENT: This study demonstrates that targeting CD38-expressing leukocytes with a cytolytic antibody can ameliorate autoimmune disease in cynomolgus monkeys. The study gives a unique perspective into this therapeutic strategy because the three other anti-CD38 cytolytic antibodies in clinical development (daratumumab, isatuximab, and MOR202) cannot be tested in similar models because they do not crossreact with CD38 expressed by new world primates., (Copyright © 2019 The Author(s).) more...- Published
- 2019
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44. A First-in-Human Study and Biomarker Analysis of NKTR-214, a Novel IL2Rβγ-Biased Cytokine, in Patients with Advanced or Metastatic Solid Tumors.
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Bentebibel SE, Hurwitz ME, Bernatchez C, Haymaker C, Hudgens CW, Kluger HM, Tetzlaff MT, Tagliaferri MA, Zalevsky J, Hoch U, Fanton C, Aung S, Hwu P, Curti BD, Tannir NM, Sznol M, and Diab A
- Subjects
- Antineoplastic Agents pharmacology, Antineoplastic Agents therapeutic use, Biomarkers, CD8-Positive T-Lymphocytes, Cell Line, Tumor, Humans, Interleukin-2 administration & dosage, Interleukin-2 adverse effects, Interleukin-2 pharmacokinetics, Interleukin-2 therapeutic use, Neoplasms etiology, Neoplasms pathology, Polyethylene Glycols administration & dosage, Polyethylene Glycols adverse effects, Polyethylene Glycols pharmacokinetics, Treatment Outcome, Tumor Microenvironment drug effects, Interleukin-2 analogs & derivatives, Interleukin-2 metabolism, Interleukin-2 Receptor alpha Subunit metabolism, Neoplasms drug therapy, Neoplasms metabolism, Polyethylene Glycols therapeutic use, Signal Transduction drug effects
- Abstract
NKTR-214 (bempegaldesleukin) is a novel IL2 pathway agonist, designed to provide sustained signaling through heterodimeric IL2 receptor βγ to drive increased proliferation and activation of CD8 erscript>+ T and natural killer cells without unwanted expansion of T regulatory cells (Treg) in the tumor microenvironment. In this first-in-human multicenter phase I study, NKTR-214 administered as an outpatient regimen was well tolerated and showed clinical activity including tumor shrinkage and durable disease stabilization in heavily pretreated patients. Immune activation and increased numbers of immune cells were observed in the periphery across all doses and cycles with no loss of NKTR-214 activity with repeated administration. On-treatment tumor biopsies demonstrated that NKTR-214 promoted immune cell increase with limited increase of Tregs. Transcriptional analysis of tumor biopsies showed that NKTR-214 engaged the IL2 receptor pathway and significantly increased genes associated with an effector phenotype. Based on safety and pharmacodynamic markers, the recommended phase II dose was determined to be 0.006 mg/kg every three weeks. SIGNIFICANCE: We believe that IL2- and IL2 pathway-targeted agents such as NKTR-214 are key components to an optimal immunotherapy treatment algorithm. Based on its biological activity and tolerability, NKTR-214 is being studied with approved immuno-oncology agents including checkpoint inhibitors. See related commentary by Sullivan, p. 694 . This article is highlighted in the In This Issue feature, p. 681 ., (©2019 American Association for Cancer Research.) more...
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- 2019
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45. NKTR-181: A Novel Mu-Opioid Analgesic with Inherently Low Abuse Potential.
- Author
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Miyazaki T, Choi IY, Rubas W, Anand NK, Ali C, Evans J, Gursahani H, Hennessy M, Kim G, McWeeney D, Pfeiffer J, Quach P, Gauvin D, Riley TA, Riggs JA, Gogas K, Zalevsky J, and Doberstein SK
- Subjects
- Analgesics, Opioid chemistry, Analgesics, Opioid metabolism, Animals, Blood-Brain Barrier drug effects, Blood-Brain Barrier metabolism, Caco-2 Cells, Dose-Response Relationship, Drug, Drug Compounding, Humans, Male, Morphinans chemistry, Morphinans metabolism, Permeability, Rats, Rats, Sprague-Dawley, Receptors, Opioid, mu metabolism, Time Factors, Analgesics, Opioid pharmacology, Morphinans pharmacology, Substance-Related Disorders prevention & control
- Abstract
The increasing availability of prescription opioid analgesics for the treatment of pain has been paralleled by an epidemic of opioid misuse, diversion, and overdose. The development of abuse-deterrent formulations (ADFs) of conventional opioids such as oxycodone and morphine represents an advance in the field and has had a positive but insufficient impact, as most opioids are still prescribed in highly abusable, non-ADF forms, and abusers can tamper with ADF medications to liberate the abusable opioid within. The abuse liability of mu-opioid agonists appears to be dependent on their rapid rate of entry into the central nervous system (CNS), whereas analgesic activity appears to be a function of CNS exposure alone, suggesting that a new opioid agonist with an inherently low rate of influx across the blood-brain barrier could mediate analgesia with low abuse liability, regardless of formulation or route of administration. NKTR-181 is a novel, long-acting, selective mu-opioid agonist with structural properties that reduce its rate of entry across the blood-brain barrier compared with traditional mu-opioid agonists. NKTR-181 demonstrated maximum analgesic activity comparable to that of oxycodone in hot-plate latency and acetic-acid writhing models. NKTR-181 was distinguishable from oxycodone by its reduced abuse potential in self-administration and progressive-ratio break point models, with behavioral effects similar to those of saline, as well as reduced CNS side effects as measured by the modified Irwin test. The in vitro and in vivo studies presented here demonstrate that NKTR-181 is the first selective mu-opioid agonist to combine analgesic efficacy and reduced abuse liability through the alteration of brain-entry kinetics., (Copyright © 2017 by The American Society for Pharmacology and Experimental Therapeutics.) more...
- Published
- 2017
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46. Modeling the receptor pharmacology, pharmacokinetics, and pharmacodynamics of NKTR-214, a kinetically-controlled interleukin-2 (IL2) receptor agonist for cancer immunotherapy.
- Author
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Charych D, Khalili S, Dixit V, Kirk P, Chang T, Langowski J, Rubas W, Doberstein SK, Eldon M, Hoch U, and Zalevsky J
- Subjects
- Algorithms, Animals, CD8-Positive T-Lymphocytes drug effects, CD8-Positive T-Lymphocytes immunology, CD8-Positive T-Lymphocytes metabolism, Cell Line, Tumor, Drug Liberation, Female, Interleukin Receptor Common gamma Subunit agonists, Interleukin Receptor Common gamma Subunit metabolism, Interleukin-2 pharmacokinetics, Interleukin-2 pharmacology, Interleukin-2 Receptor alpha Subunit agonists, Interleukin-2 Receptor alpha Subunit metabolism, Interleukin-2 Receptor beta Subunit agonists, Interleukin-2 Receptor beta Subunit metabolism, Kinetics, Mice, Inbred BALB C, Mice, Inbred C3H, Mice, Inbred C57BL, Models, Theoretical, Neoplasms immunology, Neoplasms metabolism, Phosphorylation drug effects, Polyethylene Glycols pharmacokinetics, Prodrugs pharmacokinetics, Prodrugs pharmacology, Receptors, Interleukin-2 metabolism, STAT5 Transcription Factor metabolism, T-Lymphocytes, Regulatory drug effects, T-Lymphocytes, Regulatory immunology, T-Lymphocytes, Regulatory metabolism, Transplantation, Homologous, Tumor Microenvironment drug effects, Tumor Microenvironment immunology, Immunotherapy methods, Interleukin-2 analogs & derivatives, Neoplasms therapy, Polyethylene Glycols pharmacology, Receptors, Interleukin-2 agonists
- Abstract
Cytokines are potent immune modulating agents but are not ideal medicines in their natural form due to their short half-life and pleiotropic systemic effects. NKTR-214 is a clinical-stage biologic that comprises interleukin-2 (IL2) protein bound by multiple releasable polyethylene glycol (PEG) chains. In this highly PEG-bound form, the IL2 is inactive; therefore, NKTR-214 is a biologic prodrug. When administered in vivo, the PEG chains slowly release, creating a cascade of increasingly active IL2 protein conjugates bound by fewer PEG chains. The 1-PEG-IL2 and 2-PEG-IL2 species derived from NKTR-214 are the most active conjugated-IL2 species. Free-IL2 protein is undetectable in vivo as it is eliminated faster than formed. The PEG chains on NKTR-214 are located at the region of IL2 that contacts the alpha (α) subunit of the heterotrimeric IL2 receptor complex, IL2Rαβγ, reducing its ability to bind and activate the heterotrimer. The IL2Rαβγ complex is constitutively expressed on regulatory T cells (Tregs). Therefore, without the use of mutations, PEGylation reduces the affinity for IL2Rαβγ to a greater extent than for IL2Rβγ, the receptor complex predominant on CD8 T cells. NKTR-214 treatment in vivo favors activation of CD8 T cells over Tregs in the tumor microenvironment to provide anti-tumor efficacy in multiple syngeneic models. Mechanistic modeling based on in vitro and in vivo kinetic data provides insight into the mechanism of NKTR-214 pharmacology. The model reveals that conjugated-IL2 protein derived from NKTR-214 occupy IL-2Rβγ to a greater extent compared to free-IL2 protein. The model accurately describes the sustained in vivo signaling observed after a single dose of NKTR-214 and explains how the properties of NKTR-214 impart a unique kinetically-controlled immunological mechanism of action. more...
- Published
- 2017
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47. Discovery of TAK-659 an orally available investigational inhibitor of Spleen Tyrosine Kinase (SYK).
- Author
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Lam B, Arikawa Y, Cramlett J, Dong Q, de Jong R, Feher V, Grimshaw CE, Farrell PJ, Hoffman ID, Jennings A, Jones B, Matuszkiewicz J, Miura J, Miyake H, Natala SR, Shi L, Takahashi M, Taylor E, Wyrick C, Yano J, Zalevsky J, and Nie Z more...
- Subjects
- Animals, Antineoplastic Agents, Cell Line, Tumor, Cell Proliferation drug effects, Dose-Response Relationship, Drug, Drug Screening Assays, Antitumor, Humans, Mice, Mice, Inbred C57BL, Molecular Structure, Neoplasms, Experimental drug therapy, Neoplasms, Experimental pathology, Protein Kinase Inhibitors administration & dosage, Protein Kinase Inhibitors chemistry, Pyrimidines administration & dosage, Pyrimidines chemistry, Pyrrolidinones administration & dosage, Pyrrolidinones chemistry, Structure-Activity Relationship, Syk Kinase metabolism, Drug Discovery, Protein Kinase Inhibitors pharmacology, Pyrimidines pharmacology, Pyrrolidinones pharmacology, Syk Kinase antagonists & inhibitors
- Abstract
Spleen Tyrosine Kinase (SYK) is a non-receptor cytoplasmic tyrosine kinase that is primarily expressed in hematopoietic cells. SYK is a key mediator for a variety of inflammatory cells, including B cells, mast cells, macrophages and neutrophils and therefore, an attractive approach for treatment of both inflammatory diseases and oncology indications. Using in house co-crystal structure information, and structure-based drug design, we designed and optimized a novel series of heteroaromatic pyrrolidinone SYK inhibitors resulting in the selection of the development candidate TAK-659. TAK-659 is currently undergoing Phase I clinical trials for advanced solid tumor and lymphoma malignancies, a Phase Ib study in advanced solid tumors in combination with nivolumab, and PhIb/II trials for relapsed/refractory AML., (Copyright © 2016 Elsevier Ltd. All rights reserved.) more...
- Published
- 2016
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48. Antibody-dependent cell-mediated cytotoxicity overcomes NK cell resistance in MLL-rearranged leukemia expressing inhibitory KIR ligands but not activating ligands.
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Chan WK, Kung Sutherland M, Li Y, Zalevsky J, Schell S, and Leung W
- Subjects
- Animals, Antibodies, Monoclonal, Humanized pharmacology, Antineoplastic Agents pharmacology, Cell Line, Tumor, Coculture Techniques, Histone-Lysine N-Methyltransferase, Humans, Leukemia immunology, Mice, Mice, Inbred NOD, Mice, SCID, Receptors, IgG genetics, Receptors, KIR metabolism, Translocation, Genetic, Xenograft Model Antitumor Assays, Antibody-Dependent Cell Cytotoxicity, HLA-B Antigens metabolism, Killer Cells, Natural transplantation, Leukemia therapy, Myeloid-Lymphoid Leukemia Protein genetics
- Abstract
Purpose: Leukemias with MLL gene rearrangement are associated with a poor prognosis. Natural killer (NK) cell therapy is a potential treatment, but leukemia cells may be resistant. Here, we sought to determine the susceptibility of MLL-rearranged leukemia cells to NK cell lysis and to develop a novel immunotherapeutic approach to optimize NK cell therapy, including the use of an antibody against leukemia-associated antigen and the elimination of killer-cell immunoglobulin-like receptor (KIR)-mediated inhibition., Experimental Design: Three MLL-rearranged leukemia cell lines (RS4;11, SEM, and MV4-11) and primary leukemia blasts were assessed for surface phenotype and susceptibility to NK cell lysis with or without antibodies against CD19 (XmAb5574), CD33 (lintuzumab), or KIR ligands., Results: All three cell lines were resistant to NK cell lysis, had some inhibitory KIR ligands and protease inhibitor-9, and expressed low levels of NKG2D activating ligands and adhesion molecules. After treatment with XmAb5574 or lintuzumab, MLL-rearranged leukemia cells were efficiently killed by NK cells. The addition of pan-major histocompatibility complex class I antibody, which blocked inhibitory KIR-HLA interaction, further augmented degranulation in all three KIR2DL1, KIR2DL2/3, and KIR3DL1 subsets of NK cells based on the rule of missing-self recognition. A mouse model showed a decreased rate of leukemia progression in vivo as monitored by bioluminescence imaging and longer survival after antibody treatment., Conclusion: Our data support the use of a triple immunotherapy approach, including an antibody directed against tumor-associated antigen, KIR-mismatched NK cell transplantation, and inhibitory KIR blockade, for the treatment of NK cell-resistant MLL-rearranged leukemias., (©2012 AACR.) more...
- Published
- 2012
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49. Antibody-mediated coengagement of FcγRIIb and B cell receptor complex suppresses humoral immunity in systemic lupus erythematosus.
- Author
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Horton HM, Chu SY, Ortiz EC, Pong E, Cemerski S, Leung IW, Jacob N, Zalevsky J, Desjarlais JR, Stohl W, and Szymkowski DE
- Subjects
- Animals, Antigens, CD19 immunology, B-Lymphocyte Subsets immunology, B-Lymphocyte Subsets metabolism, B-Lymphocyte Subsets pathology, Cell Communication genetics, Disease Models, Animal, Female, Gene Amplification immunology, HEK293 Cells, Humans, Leukocytes, Mononuclear immunology, Leukocytes, Mononuclear transplantation, Lupus Erythematosus, Systemic pathology, Lupus Erythematosus, Systemic prevention & control, Lymphocyte Activation genetics, Lymphocyte Activation immunology, Mice, Mice, SCID, Mice, Transgenic, Receptors, Antigen, B-Cell genetics, Receptors, Antigen, B-Cell physiology, Receptors, IgG deficiency, Receptors, IgG physiology, Binding Sites, Antibody, Cell Communication immunology, Immunity, Humoral genetics, Lupus Erythematosus, Systemic immunology, Receptors, Antigen, B-Cell metabolism, Receptors, IgG metabolism
- Abstract
Engagement of the low-affinity Ab receptor FcγRIIb downregulates B cell activation, and its dysfunction is associated with autoimmunity in mice and humans. We engineered the Fc domain of an anti-human CD19 Ab to bind FcγRIIb with high affinity, promoting the coengagement of FcγRIIb with the BCR complex. This Ab (XmAb5871) stimulated phosphorylation of the ITIM of FcγRIIb and suppressed BCR-induced calcium mobilization, proliferation, and costimulatory molecule expression of human B cells from healthy volunteers and systemic lupus erythematosus (SLE) patients, as well as B cell proliferation induced by LPS, IL-4, or BAFF. XmAb5871 suppressed humoral immunity against tetanus toxoid and reduced serum IgM, IgG, and IgE levels in SCID mice engrafted with SLE or healthy human PBMC. XmAb5871 treatment also increased survival of mice engrafted with PBMC from a unique SLE patient. Unlike anti-CD20 Ab, coengagement of FcγRIIb and BCR complex did not promote B cell depletion in human PBMC cultures or in mice. Thus, amplification of the FcγRIIb inhibitory pathway in activated B cells may represent a novel B cell-targeted immunosuppressive therapeutic approach for SLE and other autoimmune diseases that should avoid the complications associated with B cell depletion. more...
- Published
- 2011
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50. Engineering fully human monoclonal antibodies from murine variable regions.
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Bernett MJ, Karki S, Moore GL, Leung IW, Chen H, Pong E, Nguyen DH, Jacinto J, Zalevsky J, Muchhal US, Desjarlais JR, and Lazar GA
- Subjects
- Amino Acid Sequence, Amino Acid Substitution, Animals, Cells, Cultured, Complementarity Determining Regions genetics, Humans, In Vitro Techniques, Interleukin-2 Receptor alpha Subunit antagonists & inhibitors, Mice, Mice, Transgenic, Molecular Sequence Data, Peptide Library, Recombinant Fusion Proteins genetics, Recombinant Fusion Proteins immunology, Sequence Homology, Amino Acid, Species Specificity, T-Lymphocytes immunology, Tumor Necrosis Factor-alpha antagonists & inhibitors, Vascular Endothelial Growth Factor A antagonists & inhibitors, Antibodies, Monoclonal genetics, Immunoglobulin Variable Region genetics, Protein Engineering methods
- Abstract
Fully human monoclonal antibodies (mAbs) derived from transgenic mice or human antibody libraries are the current state of the art for reducing the immunogenicity risk of antibody drugs. Here, we describe a novel method for generating fully human mAbs from nonhuman variable regions using information from the human germline repertoire. Central to our strategy is the rational engineering of residues within and proximal to CDRs and the V(H)/V(L) interface by iteratively exploring substitutions to the closest human germline sequences using semi-automated computational methods. Starting from the parent murine variable regions of three currently marketed mAbs targeting CD25, vascular endothelial growth factor, and tumor necrosis factor alpha, we have generated fully human antibodies with 59, 46, and 45 substitutions, respectively, compared to the parent murine sequences. A large number of these substitutions were in the CDRs, which are typically avoided in humanization methods. Antigen affinities of the fully human variants were comparable to the chimeric mAbs in each case. Furthermore, in vitro functional characterization indicated that all retain potency of the chimeric mAbs and have comparable activity to their respective marketed drugs daclizumab, bevacizumab, and infliximab. Based on local and global sequence identity, the sequences of our engineered mAbs are indistinguishable from those of fully human mAbs isolated from transgenic mice or human antibody libraries. This work establishes a simple rational engineering methodology for generating fully human antibody therapeutics from murine mAbs produced from standard hybridoma technology., (Copyright (c) 2010 Elsevier Ltd. All rights reserved.) more...
- Published
- 2010
- Full Text
- View/download PDF
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