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1.
Clin Cancer Res ; 30(7): 1264-1272, 2024 Apr 01.
Article in English | MEDLINE | ID: mdl-38295160

ABSTRACT

PURPOSE: E7389-LF is a liposomal formulation of the microtubule dynamics inhibitor eribulin and has shown preliminary efficacy in the treatment of gastric cancer. Study 120, a phase Ib/II open-label study, assessed efficacy and safety of E7389-LF in combination with nivolumab, a programmed cell death (PD)-1 inhibitor. This report focuses on the gastric cancer cohort within the expansion phase. PATIENTS AND METHODS: Eligible patients had unresectable, measurable gastric cancer, progression following a platinum drug plus fluoropyrimidine (1L), and a taxane-containing regimen (2L). The primary objective of the expansion phase was objective response rate, secondary objectives included safety and PFS, and exploratory objectives included overall survival and biomarker evaluation. Patients received E7389-LF 2.1 mg/m2 in combination with nivolumab 360 mg every 3 weeks, both as intravenous infusions. Tumor responses were assessed every 6 weeks by the investigators per RECIST v1.1. Plasma and tumor biomarkers were assessed. RESULTS: In the 31 patients who received E7389-LF in combination with nivolumab, the objective response rate was 25.8% [confidence interval (CI), 11.9-44.6]. The median progression-free survival was 2.69 months (95% CI, 1.91-2.99) and median overall survival was 7.85 months (95% CI, 4.47-not estimable). The most common treatment-related TEAE of any grade were neutropenia (77.4%), leukopenia (74.2%), and decreased appetite (51.6%). E7389-LF in combination with nivolumab significantly increased CD8-positive cells at C2D1 (P = 0.039), and six of seven vascular markers and four IFNγ-related markers showed increases from C1D1. CONCLUSIONS: Promising antitumor activity was observed with E7389-LF in combination with nivolumab in patients with gastric cancer, and no new safety signals were observed, compared with either monotherapy.


Subject(s)
Nivolumab , Polyether Polyketides , Stomach Neoplasms , Humans , Stomach Neoplasms/drug therapy , Furans/adverse effects , Ketones/adverse effects , Tubulin Modulators , Antineoplastic Combined Chemotherapy Protocols/adverse effects
2.
Cancer Res Commun ; 4(1): 226-235, 2024 01 29.
Article in English | MEDLINE | ID: mdl-38181055

ABSTRACT

PURPOSE: E7389-LF is a liposomal formulation of eribulin that contributes to tumor vascular remodeling. The phase II part of this phase Ib/II study assessed the efficacy/safety of E7389-LF in combination with nivolumab in several disease cohorts; herein, we report results from the small cell lung cancer (SCLC) cohort. EXPERIMENTAL DESIGN: Patients with unresectable/measurable SCLC and disease progression with first-line platinum-based chemotherapy with/without an immune checkpoint inhibitor (ICI) were enrolled to receive E7389-LF 2.1 mg/m2 plus nivolumab 360 mg intravenously every 3 weeks. The primary objective of this part was to assess the objective response rate (ORR). Secondary objectives included assessments of safety and progression-free survival (PFS); exploratory assessments included overall survival (OS) and biomarkers. RESULTS: Thirty-four patients were enrolled. By the data cut-off date (May 31, 2022), 29 (85.3%) had discontinued. Efficacy/biomarker analyses included 33 patients (1 had their diagnosis changed postenrollment); the ORR of E7389-LF plus nivolumab was 24.2% [95% confidence interval (CI): 11.1-42.3], the median PFS was 3.98 months (95% CI: 2.63-4.40), and, at a median follow-up of 10.6 months, the median OS was not reached (95% CI: not estimable). Notably, 27 of 33 patients (81.8%) had received an ICI as their prior first-line therapy. Treatment-related, treatment-emergent adverse events occurred in 97.1% (any grade) and 82.4% (grade ≥3) of enrolled patients; the most common event was neutropenia. Changes in vascular and immune-related plasma markers were observed. CONCLUSIONS: E7389-LF 2.1 mg/m2 in combination with nivolumab 360 mg every 3 weeks showed notable antitumor activity as second-line therapy for SCLC; no new safety signals were observed compared with either agent as monotherapy. SIGNIFICANCE: This phase II part of a phase Ib/II study assessed liposomal eribulin (E7389-LF) plus nivolumab in 34 patients with pretreated SCLC; 8 of 33 evaluable patients (including 6/27 pretreated with ICIs) had objective responses. The combination was tolerable; increases in vasculature-related biomarkers tended to correlate with responses.


Subject(s)
Furans , Ketones , Lung Neoplasms , Polyether Polyketides , Small Cell Lung Carcinoma , Vinca Alkaloids , Humans , Nivolumab/adverse effects , Small Cell Lung Carcinoma/drug therapy , Lung Neoplasms/drug therapy , Vinca Alkaloids/therapeutic use , Biomarkers
3.
Cancer Res Commun ; 3(7): 1189-1199, 2023 07.
Article in English | MEDLINE | ID: mdl-37435605

ABSTRACT

Purpose: To determine a recommended dose of liposomal eribulin (E7389-LF) in combination with nivolumab in patients with advanced solid tumors, and to evaluate the safety, efficacy, pharmacokinetics, and biomarker impact of this regimen. Experimental Design: Japanese patients with advanced, nonresectable, or recurrent solid tumors and no existing alternative standard/effective therapy (except nivolumab monotherapy) were assigned to either E7389-LF 1.7 mg/m2 plus nivolumab 360 mg every 3 weeks, E7389-LF 2.1 mg/m2 plus nivolumab 360 mg every 3 weeks, E7389-LF 1.1 mg/m2 plus nivolumab 240 mg every 2 weeks, or E7389-LF 1.4 mg/m2 plus nivolumab 240 mg every 2 weeks. Primary objectives were to evaluate the safety/tolerability of each dose cohort and to determine the recommended phase II dose (RP2D). Secondary/exploratory objectives, including safety [dose-limiting toxicities (DLT) and adverse events (AE)], pharmacokinetics, efficacy [including objective response rate (ORR)], and biomarker results were used in determining the RP2D. Results: Twenty-five patients were enrolled to treatment [E7389-LF 1.7 mg/mg2 every 3 weeks (n = 6), E7389-LF 2.1 mg/m2 every 3 weeks (n = 6), E7389-LF 1.1 mg/m2 every 2 weeks (n = 7), E7389-LF 1.4 mg/m2 every 2 weeks (n = 6)]. Twenty-four patients were evaluated for DLTs, of whom 3 had DLTs (1 at E7389-LF 1.7 mg/m2 every 3 weeks, 1 at 1.1 mg/m2 every 2 weeks, and 1 at 1.4 mg/m2 every 2 weeks). All patients had ≥1 treatment-related treatment-emergent AE (TEAE); 68.0% had ≥1 grade 3-4 treatment-related TEAE. Changes in vasculature and IFN-related biomarkers were seen in each cohort. The overall ORR was 16%. Conclusions: E7389-LF plus nivolumab was tolerable overall; the recommended dose for future study was 2.1 mg/m2 plus nivolumab 360 mg every 3 weeks. Significance: This phase Ib part of a phase Ib/II study assessed the tolerability and activity of a liposomal formulation of eribulin (E7389-LF) plus nivolumab in 25 patients with advanced solid tumors. The combination was tolerable overall; 4 patients had a partial response. Vasculature and immune-related biomarker levels increased, suggesting vascular remodeling.


Subject(s)
Neoplasms , Vinca Alkaloids , Humans , Furans/adverse effects , Ketones/adverse effects , Liposomes , Neoplasms/drug therapy , Nivolumab/adverse effects
4.
Bioorg Med Chem ; 26(9): 2291-2301, 2018 05 15.
Article in English | MEDLINE | ID: mdl-29580851

ABSTRACT

Prostate-specific membrane antigen (PSMA), which is overexpressed in malignant prostate cancer (PCa), is an ideal target for imaging and therapy of PCa. We previously reported a PSMA imaging probe, 800CW-SCE, based on succinimidyl-Cys-C(O)-Glu (SCE) for optical imaging of PCa. In this study, we investigated the structure-activity relationships of novel SCE derivatives with five different near-infrared (NIR) fluorophores (IRDye 680LT, IRDye 750, Indocyanine Green, Cyanine 5.5, and Cyanine 7) as optical imaging probes targeting PSMA. An in vitro binding assay revealed that 800CW-SCE, 680LT-SCE, and 750-SCE exhibited higher binding affinity than 2-PMPA, which is known as a PSMA inhibitor. These three SCE derivatives were internalized into PSMA-positive cells (LNCaP cells) but not into PSMA-negative cells (PC-3 cells). In the in vivo imaging study, 800CW-SCE and 750-SCE were highly accumulated in LNCaP tumors but not in PC-3 tumors, and the ratio of LNCaP/PC-3 accumulation of 800CW-SCE was higher than that of 750-SCE. The present study may provide valuable molecular design information for the future development of new PSMA imaging probes based on the SCE scaffold.


Subject(s)
Dipeptides/pharmacology , Fluorescent Dyes/pharmacology , Glutamate Carboxypeptidase II/metabolism , Indoles/pharmacology , Membrane Glycoproteins/metabolism , Urea/analogs & derivatives , Urea/pharmacology , Animals , Binding Sites , Cell Line, Tumor , Dipeptides/chemistry , Dipeptides/metabolism , Dipeptides/pharmacokinetics , Fluorescent Dyes/chemistry , Fluorescent Dyes/metabolism , Fluorescent Dyes/pharmacokinetics , Glutamate Carboxypeptidase II/chemistry , Humans , Indoles/chemistry , Indoles/metabolism , Indoles/pharmacokinetics , Male , Membrane Glycoproteins/chemistry , Mice, SCID , Optical Imaging/methods , Protein Binding , Structure-Activity Relationship , Tissue Distribution , Urea/chemistry , Urea/metabolism
5.
Bioorg Med Chem Lett ; 27(21): 4876-4880, 2017 11 01.
Article in English | MEDLINE | ID: mdl-28964633

ABSTRACT

Prostate-specific membrane antigen (PSMA), which is highly expressed in both localized and metastatic prostate cancer (PCa), is an ideal target for imaging and therapy of PCa. We previously reported radiolabeled asymmetric urea derivatives asa PSMA-targeting radiotracer for single-photon emission computed tomography (SPECT) and positron emission tomography (PET) imaging. Here, based on these radiopharmaceutical probes, we designed a novel near-infrared (NIR) fluorescent imaging probe (800CW-SCE) by chemical conjugation between IRDye 800CW-Maleimide and an asymmetric urea compound, known as PSMA inhibitor, for optical imaging. In the in vitro cellular uptake study, 800CW-SCE was internalized into PSMA-positive PCa cells (LNCaP cells) but not into PSMA-negative PCa cells (PC-3 cells). Moreover, in the in vivo imaging study, the probe was highly accumulated in LNCaP tumors but not in PC-3 tumors, and remained in LNCaP tumors until 24h after intravenous administration. These results suggest that the potent NIR conjugate may contribute to clinical intraoperative optical imaging.


Subject(s)
Fluorescent Dyes/chemistry , Prostate-Specific Antigen/metabolism , Radiopharmaceuticals/chemical synthesis , Animals , Cell Line, Tumor , Fluorescent Dyes/chemical synthesis , Fluorescent Dyes/metabolism , Humans , Iodine Radioisotopes/chemistry , Male , Maleimides/chemistry , Mice , Positron-Emission Tomography , Prostate-Specific Antigen/antagonists & inhibitors , Prostatic Neoplasms/metabolism , Prostatic Neoplasms/pathology , Radiopharmaceuticals/chemistry , Radiopharmaceuticals/metabolism , Succinimides/chemistry , Tomography, Emission-Computed, Single-Photon , Transplantation, Heterologous , Urea/chemistry
6.
J Nucl Med ; 57(12): 1978-1984, 2016 Dec.
Article in English | MEDLINE | ID: mdl-27417647

ABSTRACT

Prostate-specific membrane antigen (PSMA) is a membrane protein highly expressed on prostate cancer cells and a potential imaging target for diagnosis. 18F-DCFPyL has been recently developed as an effective probe with high diagnostic accuracy for prostate cancer imaging. However, its radiochemical yield is low. We developed new PSMA probes using succinimidyl 4-18F-fluorobenzoate (18F-SFB), a rapid and effective 18F-labeling agent, taking advantage of the high radiochemical yield of this compound. We evaluated the probes as PET probes for PSMA imaging. METHODS: Four 18F-labeled probes, 18F-8a, 18F-8b, 18F-10a, and 18F-10b, were synthesized using 18F-SFB, and their affinity for PSMA and partition coefficients (log D) were evaluated in vitro. Biodistribution studies were performed in human prostate cancer xenograft-bearing mice. PET images were obtained using 2 compounds, 18F-8a and 18F-10a, and a toxicologic study of 18F-10a was performed. RESULTS: Four 18F-labeled asymmetric urea compounds, conjugated with 18F-SFB, were synthesized at a radiochemical yield of 30%-50% (decay-corrected), with a radiochemical purity greater than 95%. The radiochemical yield was 10-15 times higher than that of 18F-DCFPyL, the probe currently used in clinical studies. All 4 compounds showed high affinity for PSMA. 18F-8a and 18F-10a had a particularly high binding affinity (Ki values of 3.35 and 2.23 nM, respectively). In the biodistribution study, the accumulation of 18F-8a (13.3 ± 2.2 percentage injected dose per gram [%ID/g]) and 18F-10a (14.0 ± 3.1 %ID/g) in PSMA-positive human prostate (LNCaP) tumors was higher than that of the other 2 compounds and similar to that of 18F-DCFPyL (16.0 ± 2.9 %ID/g). 18F-10a showed the lowest hepatic and intestinal accumulation among the 4 compounds and slightly slower blood clearance than others. In the PET imaging studies, 18F-8a and 18F-10a were clearly visualized in LNCaP in xenograft-bearing mice. 18F-10a showed higher LNCaP-to-liver ratios than 18F-8a. We confirmed the safety profiles of 18F-10a; the no-observed-adverse-effects level was larger than 13.2 µg/kg. CONCLUSION: A novel 18F-labeled asymmetric urea compound, 18F-10a, had a high radiochemical yield, high binding affinity for PSMA, and pharmacokinetic profiles suitable for a PSMA imaging probe. We believe that 18F-10a can be effectively and safely used in this type of imaging.


Subject(s)
Antigens, Surface/metabolism , Benzoates/chemical synthesis , Benzoates/metabolism , Glutamate Carboxypeptidase II/metabolism , Positron-Emission Tomography/methods , Prostatic Neoplasms/diagnostic imaging , Prostatic Neoplasms/metabolism , Animals , Benzoates/chemistry , Benzoates/pharmacokinetics , Cell Line, Tumor , Cell Transformation, Neoplastic , Chemistry Techniques, Synthetic , Humans , Male , Mice , Molecular Probes/chemical synthesis , Molecular Probes/chemistry , Molecular Probes/metabolism , Molecular Probes/pharmacokinetics , Organophosphorus Compounds/pharmacology , Prostatic Neoplasms/pathology , Protein Binding/drug effects , Radiochemistry , Tissue Distribution
7.
Bioorg Med Chem ; 24(10): 2251-6, 2016 05 15.
Article in English | MEDLINE | ID: mdl-27073053

ABSTRACT

Prostate-specific membrane antigen (PSMA) is expressed strongly in prostate cancers and is, therefore, an attractive diagnostic and radioimmunotherapeutic target. In contrast to previous reports of PMSA-targeting (99m)Tc-tricarbonyl complexes that are cationic or lack a charge, no anionic (99m)Tc-tricarbonyl complexes have been reported. Notably, the hydrophilicity conferred by both cationic and anionic charges leads to rapid hepatobiliary clearance, whereas an anionic charge might better enhance renal clearance relative to a cationic charge. Therefore, an improvement in rapid clearance would be expected with either cationic or anionic charges, particularly anionic charges. In this study, we designed and synthesized a novel anionic (99m)Tc-tricarbonyl complex ([(99m)Tc]TMCE) and evaluated its use as a single-photon emission computed tomography (SPECT) imaging probe for PSMA detection. Direct synthesis of [(99m)Tc]TMCE from dimethyl iminodiacetate, which contains both the asymmetric urea and succinimidyl moiety important for PSMA binding, was performed using our microwave-assisted one-pot procedure. The chelate formation was successfully achieved even though the precursor included a complicated bioactive moiety. The radiochemical yield of [(99m)Tc]TMCE was 12-17%, with a radiochemical purity greater than 98% after HPLC purification. [(99m)Tc]TMCE showed high affinity in vitro, with high accumulation in LNCaP tumors and low hepatic retention in biodistribution and SPECT/CT studies. These findings warrant further evaluation of [(99m)Tc]TMCE as an imaging agent and support the benefit of this strategy for the design of other PSMA imaging probes.


Subject(s)
Antigens, Surface/analysis , Glutamate Carboxypeptidase II/analysis , Organotechnetium Compounds/chemistry , Prostatic Neoplasms/diagnostic imaging , Technetium/chemistry , Tomography, Emission-Computed, Single-Photon/methods , Urea/analogs & derivatives , Animals , Drug Design , Male , Mice , Organotechnetium Compounds/pharmacokinetics , Technetium/pharmacokinetics , Urea/pharmacokinetics
8.
Immunol Lett ; 161(1): 149-56, 2014 Sep.
Article in English | MEDLINE | ID: mdl-24954639

ABSTRACT

Fab fragments (Fabs) have the ability to bind to specific antigens but lack the Fc portion for binding to receptors on immune and inflammatory cells that play a critical role in allergic diseases. In the present study, we investigated whether Fabs of an allergen-specific IgG1 monoclonal antibody (mAb) inhibited allergic rhinitis in mice. BALB/c mice sensitized by intraperitoneal injections of ovalbumin (OVA) plus alum on days 0 and 14 were intranasally challenged with OVA on days 28-30, and 35. Fabs prepared by the digestion of an anti-OVA IgG1 mAb (O1-10) with papain were also intranasally administered 15min before each OVA challenge. The results showed that treatment with O1-10 Fabs significantly suppressed the sneezing frequency, associated with decrease of OVA-specific IgE in the serum and infiltration by mast cells in the nasal mucosa seen following the fourth antigenic challenge; additionally, the level of mouse mast cell protease-1, a marker of mast cell activation, in serum was decreased. Furthermore, infiltration of eosinophils and goblet cell hyperplasia in the nasal mucosa at the fourth challenge were inhibited by treatment with O1-10 Fabs. In conclusion, these results suggest that intranasal exposure to Fabs of a pathogenic antigen-specific IgG1 mAb may be effective in regulating allergic rhinitis through allergen capture by Fabs in the nasal mucosa before the interaction of the intact antibody and allergen.


Subject(s)
Allergens/immunology , Immunoglobulin Fab Fragments/immunology , Immunoglobulin G/immunology , Immunomodulation , Rhinitis, Allergic/immunology , Administration, Intranasal , Allergens/metabolism , Animals , Chemokine CCL2/biosynthesis , Disease Models, Animal , Immunoglobulin E/immunology , Immunoglobulin Fab Fragments/administration & dosage , Immunoglobulin Fab Fragments/metabolism , Immunoglobulin G/metabolism , Male , Mast Cells/immunology , Mast Cells/metabolism , Mice , Nasal Mucosa/immunology , Nasal Mucosa/metabolism , Nasal Mucosa/pathology , Ovalbumin/adverse effects , Ovalbumin/immunology
9.
Immunology ; 141(4): 617-27, 2014 Apr.
Article in English | MEDLINE | ID: mdl-24303921

ABSTRACT

Fab fragments (Fabs) maintain the ability to bind to specific antigens but lack effector functions due to the absence of the Fc portion. In the present study, we tested whether Fabs of an allergen-specific monoclonal antibody (mAb) were able to regulate asthmatic responses in mice. Asthmatic responses were induced in BALB/c mice by passive sensitization with anti-ovalbumin (OVA) polyclonal antibodies (pAbs) (day 0) and by active sensitization with OVA (days 0 and 14), followed by intratracheal (i.t.) challenge with OVA on day 1 and days 28, 29, 30 and 35. Fabs prepared by the digestion of an anti-OVA IgG1 (O1-10) mAb with papain were i.t. administered only once 30 min before antigenic challenge on day 1 or day 35. The results showed that i.t. administration of O1-10 Fabs with OVA markedly suppressed the early and/or late phases of asthmatic responses caused by passive and active sensitization. Similar results were obtained when Fabs of anti-OVA IgG2b mAb (O2B-3) were i.t. administered. In contrast, neither i.t. injection of intact 01-10/O2B-3 nor systemic injection of O1-10 Fabs suppressed the asthmatic responses. In vitro studies revealed that the capture of OVA by O1-10 Fabs prevented the subsequent binding of intact anti-OVA pAbs to the captured OVA. These results suggest that asthmatic responses may be down-regulated by the i.t. exposure to Fabs of an allergen-specific mAb via a mechanism involving the capture of allergen by Fabs in the respiratory tract before the interaction of intact antibody and allergen essential for the induction of asthmatic responses.


Subject(s)
Allergens/immunology , Anti-Allergic Agents/administration & dosage , Antibodies, Monoclonal/administration & dosage , Asthma/drug therapy , Immunoglobulin Fab Fragments/administration & dosage , Lung/drug effects , Ovalbumin/immunology , Administration, Inhalation , Airway Resistance/drug effects , Animals , Antigen-Antibody Reactions/drug effects , Asthma/immunology , Asthma/physiopathology , Disease Models, Animal , Lung/immunology , Lung/physiopathology , Male , Mice , Mice, Inbred BALB C , Time Factors
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