Your browser doesn't support javascript.
loading
Show: 20 | 50 | 100
Results 1 - 10 de 10
Filter
1.
J Transl Autoimmun ; 5: 100152, 2022.
Article in English | MEDLINE | ID: mdl-35517914

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.

2.
J Transl Autoimmun ; 4: 100103, 2021.
Article in English | MEDLINE | ID: mdl-34041473

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 vivo 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-2Rß, and IL-2Rαß 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-Faslpr) 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.

3.
Mol Cancer Ther ; 20(7): 1270-1282, 2021 07.
Article in English | MEDLINE | ID: mdl-33879555

ABSTRACT

The cell surface glycoprotein P-cadherin is highly expressed in a number of malignancies, including those arising in the epithelium of the bladder, breast, esophagus, lung, and upper aerodigestive system. PCA062 is a P-cadherin specific antibody-drug conjugate that utilizes the clinically validated SMCC-DM1 linker payload to mediate potent cytotoxicity in cell lines expressing high levels of P-cadherin in vitro, while displaying no specific activity in P-cadherin-negative cell lines. High cell surface P-cadherin is necessary, but not sufficient, to mediate PCA062 cytotoxicity. In vivo, PCA062 demonstrated high serum stability and a potent ability to induce mitotic arrest. In addition, PCA062 was efficacious in clinically relevant models of P-cadherin-expressing cancers, including breast, esophageal, and head and neck. Preclinical non-human primate toxicology studies demonstrated a favorable safety profile that supports clinical development. Genome-wide CRISPR screens reveal that expression of the multidrug-resistant gene ABCC1 and the lysosomal transporter SLC46A3 differentially impact tumor cell sensitivity to PCA062. The preclinical data presented here suggest that PCA062 may have clinical value for treating patients with multiple cancer types including basal-like breast cancer.


Subject(s)
Antineoplastic Agents, Immunological/pharmacology , Biomarkers, Tumor , Cadherins/genetics , Immunoconjugates/pharmacology , Neoplasms/genetics , Amino Acid Sequence , Animals , Antibody-Dependent Cell Cytotoxicity/immunology , Antineoplastic Agents, Immunological/chemistry , Antineoplastic Agents, Immunological/pharmacokinetics , Binding Sites , Cadherins/chemistry , Cadherins/metabolism , Cell Line, Tumor , Disease Models, Animal , Drug Resistance, Neoplasm , Gene Expression , Humans , Immunoconjugates/chemistry , Immunoconjugates/pharmacokinetics , Immunohistochemistry , Macaca fascicularis , Mice , Models, Molecular , Neoplasms/drug therapy , Neoplasms/metabolism , Neoplasms/pathology , Protein Binding , Protein Transport , Rats , Structure-Activity Relationship , Xenograft Model Antitumor Assays
4.
Cancer Discov ; 10(8): 1158-1173, 2020 08.
Article in English | MEDLINE | ID: mdl-32439653

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.


Subject(s)
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 , 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
5.
Cancer Discov ; 9(6): 711-721, 2019 06.
Article in English | MEDLINE | ID: mdl-30988166

ABSTRACT

NKTR-214 (bempegaldesleukin) is a novel IL2 pathway agonist, designed to provide sustained signaling through heterodimeric IL2 receptor ßγ to drive increased proliferation and activation of CD8+ 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.


Subject(s)
Interleukin-2 Receptor alpha Subunit/metabolism , Interleukin-2/analogs & derivatives , Interleukin-2/metabolism , Neoplasms/drug therapy , Neoplasms/metabolism , Polyethylene Glycols/therapeutic use , Signal Transduction/drug effects , 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
6.
Clin Cancer Res ; 24(17): 4297-4308, 2018 09 01.
Article in English | MEDLINE | ID: mdl-29764854

ABSTRACT

Purpose: c-KIT overexpression is well recognized in cancers such as gastrointestinal stromal tumors (GIST), small cell lung cancer (SCLC), melanoma, non-small cell lung cancer (NSCLC), and acute myelogenous leukemia (AML). Treatment with the small-molecule inhibitors imatinib, sunitinib, and regorafenib resulted in resistance (c-KIT mutant tumors) or limited activity (c-KIT wild-type tumors). We selected an anti-c-KIT ADC approach to evaluate the anticancer activity in multiple disease models.Experimental Design: A humanized anti-c-KIT antibody LMJ729 was conjugated to the microtubule destabilizing maytansinoid, DM1, via a noncleavable linker (SMCC). The activity of the resulting ADC, LOP628, was evaluated in vitro against GIST, SCLC, and AML models and in vivo against GIST and SCLC models.Results: LOP628 exhibited potent antiproliferative activity on c-KIT-positive cell lines, whereas LMJ729 displayed little to no effect. At exposures predicted to be clinically achievable, LOP628 demonstrated single administration regressions or stasis in GIST and SCLC xenograft models in mice. LOP628 also displayed superior efficacy in an imatinib-resistant GIST model. Further, LOP628 was well tolerated in monkeys with an adequate therapeutic index several fold above efficacious exposures. Safety findings were consistent with the pharmacodynamic effect of neutropenia due to c-KIT-directed targeting. Additional toxicities were considered off-target and were consistent with DM1, such as effects in the liver and hematopoietic/lymphatic system.Conclusions: The preclinical findings suggest that the c-KIT-directed ADC may be a promising therapeutic for the treatment of mutant and wild-type c-KIT-positive cancers and supported the clinical evaluation of LOP628 in GIST, AML, and SCLC patients. Clin Cancer Res; 24(17); 4297-308. ©2018 AACR.


Subject(s)
Drug Resistance, Neoplasm/drug effects , Immunoconjugates/pharmacology , Neoplasms/drug therapy , Proto-Oncogene Proteins c-kit/genetics , Animals , Antibodies, Anti-Idiotypic/pharmacology , Cell Line, Tumor , Cell Proliferation/drug effects , Drug Resistance, Neoplasm/immunology , Heterografts , Humans , Imatinib Mesylate/pharmacology , Immunoconjugates/immunology , Mice , Mutation , Neoplasms/classification , Neoplasms/immunology , Neoplasms/pathology , Protein Kinase Inhibitors/pharmacology , Proto-Oncogene Proteins c-kit/immunology
7.
Cancer Biomark ; 15(1): 79-87, 2015.
Article in English | MEDLINE | ID: mdl-25524945

ABSTRACT

BACKGROUND: The JAK-STAT pathway is an important signaling pathway downstream of multiple cytokine and growth factor receptors. Dysregulated JAK-STAT signaling has been implicated in the pathogenesis of multiple human malignancies. OBJECTIVE: Given this pivotal role of JAK-STAT dysregulation, it is important to identify patients with an overactive JAK-STAT pathway for possible treatment with JAK inhibitors. METHODS: We developed a gene signature assay to detect overactive JAK-STAT signaling. The cancer cell line encyclopedia and associated gene-expression data were used to correlate the activation status of STAT5 with the induction of a set of STAT5 target genes. RESULTS: Four target genes were identified (PIM1, CISH, SOCS2, and ID1), the expression of which correlated significantly with pSTAT5 status in 40 hematologic tumor cell lines. In pSTAT5-positive models, the expression of the gene signature genes decreased following ruxolitinib treatment, which corresponded to pSTAT5 downmodulation. In pSTAT5-negative cell lines, neither pSTAT5 modulation nor a change in signature gene expression was observed following ruxolitinib treatment. CONCLUSIONS: The gene signature can potentially be used to stratify or enrich for patient populations with activated JAK-STAT5 signaling that might benefit from treatments targeting JAK-STAT signaling. Furthermore, the 4-gene signature is a predictor of the pharmacodynamic effects of ruxolitinib.


Subject(s)
Hematologic Neoplasms/genetics , Hematologic Neoplasms/metabolism , STAT5 Transcription Factor/genetics , STAT5 Transcription Factor/metabolism , Animals , Cell Line, Tumor , Female , Hematologic Neoplasms/drug therapy , Heterografts , Humans , Janus Kinases/metabolism , Mice , Mice, Inbred NOD , Mice, SCID , Nitriles , Pyrazoles/pharmacology , Pyrimidines , Signal Transduction/drug effects
8.
Clin Cancer Res ; 20(7): 1834-45, 2014 Apr 01.
Article in English | MEDLINE | ID: mdl-24474669

ABSTRACT

PURPOSE: PIM kinases have been shown to act as oncogenes in mice, with each family member being able to drive progression of hematologic cancers. Consistent with this, we found that PIMs are highly expressed in human hematologic cancers and show that each isoform has a distinct expression pattern among disease subtypes. This suggests that inhibitors of all three PIMs would be effective in treating multiple hematologic malignancies. EXPERIMENTAL DESIGN: Pan-PIM inhibitors have proven difficult to develop because PIM2 has a low Km for ATP and, thus, requires a very potent inhibitor to effectively block the kinase activity at the ATP levels in cells. We developed a potent and specific pan-PIM inhibitor, LGB321, which is active on PIM2 in the cellular context. RESULTS: LGB321 is active on PIM2-dependent multiple myeloma cell lines, where it inhibits proliferation, mTOR-C1 signaling and phosphorylation of BAD. Broad cancer cell line profiling of LGB321 demonstrates limited activity in cell lines derived from solid tumors. In contrast, significant activity in cell lines derived from diverse hematological lineages was observed, including acute lymphoblastic leukemia (ALL), acute myelogenous leukemia (AML), multiple myeloma and non-Hodgkin lymphoma (NHL). Furthermore, we demonstrate LGB321 activity in the KG-1 AML xenograft model, in which modulation of pharmacodynamics markers is predictive of efficacy. Finally, we demonstrate that LGB321 synergizes with cytarabine in this model. CONCLUSIONS: We have developed a potent and selective pan-PIM inhibitor with single-agent antiproliferative activity and show that it synergizes with cytarabine in an AML xenograft model. Our results strongly support the development of Pan-PIM inhibitors to treat hematologic malignancies.


Subject(s)
Hematologic Neoplasms/therapy , Protein Serine-Threonine Kinases/genetics , Proto-Oncogene Proteins c-pim-1/genetics , Proto-Oncogene Proteins/genetics , Animals , Cell Line, Tumor , Hematologic Neoplasms/genetics , Hematologic Neoplasms/pathology , Humans , Mice , Phosphorylation , Protein Kinase Inhibitors/therapeutic use , Protein Serine-Threonine Kinases/antagonists & inhibitors , Proto-Oncogene Proteins/antagonists & inhibitors , Proto-Oncogene Proteins c-pim-1/antagonists & inhibitors , Signal Transduction/genetics , TOR Serine-Threonine Kinases/genetics , Xenograft Model Antitumor Assays
9.
J Biomol Screen ; 11(7): 792-806, 2006 Oct.
Article in English | MEDLINE | ID: mdl-17035625

ABSTRACT

Chk1 is a key regulator of the S and G2/M checkpoints and is activated following DNA damage by agents such as the topoisomerase I inhibitor camptothecin (CPT). It has been proposed that Chk1 inhibitors used in combination with such a DNA damaging agent to treat tumors would potentiate cytotoxicity and increase the therapeutic index, particularly in tumors lacking functional p53. The aim of this study was to determine whether gene expression analysis could be used to inform lead optimization of a novel series of Chk1 inhibitors. The candidate small-molecule Chk1 inhibitors were used in combination with CPT to identify potential markers of functional Chk1 inhibition, as well as resulting cell cycle progression, using cDNA-based microarrays. Differential expression of several of these putative marker genes was further validated by RT-PCR for use as a medium-throughput assay. In the presence of DNA damage, Chk1 inhibitors altered CPT-dependent effects on the expression of cell cycle and DNA repair genes in a manner consistent with a Chk1-specific mechanism of action. Furthermore, differential expression of selected marker genes, cyclin E2, EGR1, and DDIT3, was dose dependent for Chk1 inhibition. RT-PCR results for these genes following treatment with a panel of Chk1 inhibitors showed a strong correlation between marker gene response and the ability of each compound to abrogate cell cycle arrest in situ following CPT-induced DNA damage. These results demonstrate the utility of global expression analysis to identify surrogate markers, providing an alternative method for rapid compound characterization to support advancement decisions in early drug discovery.


Subject(s)
Cell Cycle/drug effects , Gene Expression Profiling/methods , Protein Kinase Inhibitors/pharmacology , Protein Kinases/metabolism , Transcription, Genetic/drug effects , Biomarkers/analysis , Camptothecin/pharmacology , Cell Cycle/genetics , Checkpoint Kinase 1 , DNA Damage/genetics , Dose-Response Relationship, Drug , Humans , Protein Kinase Inhibitors/chemistry , Reverse Transcriptase Polymerase Chain Reaction
10.
Exp Cell Res ; 273(1): 21-33, 2002 Feb 01.
Article in English | MEDLINE | ID: mdl-11795943

ABSTRACT

To facilitate the study of human endothelial cells we have used a replication defective retrovirus encoding the catalytic subunit of telomerase (hTERT) to derive populations of telomerase-immortalized human microvascular endothelial (TIME) cells. Whereas parental HMVECs became senescent on average within 35-45 population doublings (PDs), TIME cells have continued to proliferate for at least 200 PDs. TIME cells express readily detectable telomerase activity but display only a modest increase in telomere length. Karyotypic analysis reveals the cells to have a normal complement of human chromosomes with no evidence of gross genetic abnormalities. Furthermore, TIME cells retain many of the characteristics of the primary endothelial cells from which they were derived. For example, they express a panel of characteristic endothelial cell surface marker proteins such as CD31/PECAM-1 and alpha(v)beta3-integrin. In addition, TIME cells express receptors for low-density lipoprotein (LDL) receptor as they are competent for receptor-mediated endocytosis of fluorescent acetylated LDL. Importantly, when plated on matrigel, TIME cells undergo tubule formation. Moreover, when cocultured in the presence of human glioma cells, but not primary human astrocytes, TIME cells are induced to form stable tubules. Detachment of TIME cells from extracellular matrix leads to a form of programmed cell death known as anoikis. Conditional activation of the protein kinase Akt (Akt:ER*) significantly inhibited the onset of TIME cell anoikis under these conditions. We believe that the ability of hTERT to immortalize primary human endothelial cells, and the fact that such cells retain the endothelial characteristics of the cells from which they were derived, will greatly facilitate the analysis of human endothelial cell biology in vitro.


Subject(s)
Brain Neoplasms/blood supply , Endothelium, Vascular/pathology , Glioblastoma/blood supply , Neovascularization, Pathologic/pathology , Protein Serine-Threonine Kinases , Telomerase/metabolism , Apoptosis , Blotting, Western , Brain Neoplasms/pathology , Cells, Cultured , Coculture Techniques , DNA-Binding Proteins , Endothelium, Vascular/enzymology , Glioblastoma/pathology , Humans , In Situ Hybridization, Fluorescence , Karyotyping , Lipoproteins, LDL , Neovascularization, Pathologic/metabolism , Platelet Endothelial Cell Adhesion Molecule-1/metabolism , Proto-Oncogene Proteins/metabolism , Proto-Oncogene Proteins c-akt , RNA, Messenger/metabolism , Receptors, LDL/metabolism , Receptors, Vitronectin/metabolism , Retroviridae/genetics , Telomerase/genetics , Telomere/metabolism
SELECTION OF CITATIONS
SEARCH DETAIL
...