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1.
Future Oncol ; 18(27): 3011-3020, 2022 Sep.
Article in English | MEDLINE | ID: mdl-35920133

ABSTRACT

Aim: This phase II study investigated safety and efficacy of dilpacimab or bevacizumab plus FOLFIRI in patients with previously treated metastatic colorectal cancer (mCRC). Materials & methods: Overall, 66 patients were treated (n = 34 dilpacimab + FOLFIRI; n = 32 bevacizumab + FOLFIRI). Progression-free survival, overall survival, response rates and tolerability were assessed. Results: Median progression-free survival for dilpacimab + FOLFIRI compared with bevacizumab + FOLFIRI was 3.78 months (95% CI: 2.07-7.20) versus 7.36 months (95% CI: 5.68-10.55) (hazard ratio: 3.57; 95% CI: 1.57-8.11; stratified). Median overall survival: 7.95 months for dilpacimab + FOLFIRI; not reached for bevacizumab + FOLFIRI. Objective response rates: 5.6% for dilpacimab + FOLFIRI and 14.7% for bevacizumab + FOLFIRI. Patients treated with dilpacimab + FOLFIRI experienced serious treatment-related adverse events (n = 4; 11.8%), including one case of intestinal perforation leading to death; none were reported for bevacizumab + FOLFIRI. Conclusion: Treatment with dilpacimab + FOLFIRI was not well tolerated and did not provide clinical benefit to patients with mCRC compared with bevacizumab + FOLFIRI. Clinical Trial Registration: NCT03368859 (Clinicaltrials.gov).


Subject(s)
Antineoplastic Agents , Colonic Neoplasms , Colorectal Neoplasms , Rectal Neoplasms , Antineoplastic Agents/therapeutic use , Antineoplastic Combined Chemotherapy Protocols/adverse effects , Bevacizumab , Camptothecin/therapeutic use , Colonic Neoplasms/drug therapy , Colorectal Neoplasms/pathology , Disease-Free Survival , Fluorouracil , Humans , Leucovorin , Rectal Neoplasms/drug therapy
2.
Mol Cancer Ther ; 20(10): 1988-1995, 2021 10.
Article in English | MEDLINE | ID: mdl-34315767

ABSTRACT

Dilpacimab (formerly ABT-165), a novel dual-variable domain immunoglobulin, targets both delta-like ligand 4 (DLL4) and VEGF pathways. Here, we present safety, pharmacokinetic (PK), pharmacodynamic (PD), and preliminary efficacy data from a phase I study (trial registration ID: NCT01946074) of dilpacimab in patients with advanced solid tumors. Eligible patients (≥18 years) received dilpacimab intravenously on days 1 and 15 in 28-day cycles at escalating dose levels (range, 1.25-7.5 mg/kg) until progressive disease or unacceptable toxicity. As of August 2018, 55 patients with solid tumors were enrolled in the dilpacimab monotherapy dose-escalation and dose-expansion cohorts. The most common treatment-related adverse events (TRAE) included hypertension (60.0%), headache (30.9%), and fatigue (21.8%). A TRAE of special interest was gastrointestinal perforation, occurring in 2 patients (3.6%; 1 with ovarian and 1 with prostate cancer) and resulting in 1 death. The PK of dilpacimab showed a half-life ranging from 4.9 to 9.5 days, and biomarker analysis demonstrated that the drug bound to both VEGF and DLL4 targets. The recommended phase II dose for dilpacimab monotherapy was established as 3.75 mg/kg, primarily on the basis of tolerability through multiple cycles. A partial response was achieved in 10.9% of patients (including 4 of 16 patients with ovarian cancer). The remaining patients had either stable disease (52.7%), progressive disease (23.6%), or were deemed unevaluable (12.7%). These results demonstrate that dilpacimab monotherapy has an acceptable safety profile, with clinical activity observed in patients with advanced solid tumors.


Subject(s)
Adaptor Proteins, Signal Transducing/immunology , Antibodies, Bispecific/pharmacology , Antineoplastic Agents/pharmacology , Calcium-Binding Proteins/immunology , Neoplasms/drug therapy , Vascular Endothelial Growth Factor A/immunology , Adaptor Proteins, Signal Transducing/blood , Adult , Aged , Antibodies, Bispecific/pharmacokinetics , Antineoplastic Agents/pharmacokinetics , Calcium-Binding Proteins/blood , Female , Follow-Up Studies , Humans , Male , Maximum Tolerated Dose , Middle Aged , Neoplasms/immunology , Neoplasms/pathology , Prognosis , Tissue Distribution , Vascular Endothelial Growth Factor A/blood
3.
Clin Cancer Res ; 27(13): 3556-3566, 2021 07 01.
Article in English | MEDLINE | ID: mdl-33820780

ABSTRACT

PURPOSE: Leucine-rich repeat containing 15 (LRRC15) is expressed on stromal fibroblasts in the tumor microenvironment of multiple solid tumor types and may represent an interesting target for therapy, particularly in patients with sarcomas where LRRC15 is also expressed by malignant cells. ABBV-085 is a monomethyl auristatin-E antibody-drug conjugate that targets LRRC15 and showed antineoplastic efficacy in preclinical experiments. Herein, we report findings of ABBV-085 monotherapy or combination therapy in adult patients with sarcomas and other advanced solid tumors. PATIENTS AND METHODS: This first-in-human phase I study (NCT02565758) assessed ABBV-085 safety, pharmacokinetics/pharmacodynamics, and preliminary antitumor activity. The study consisted of two parts: dose escalation and dose expansion. ABBV-085 was administered by intravenous infusion at 0.3 to 6.0 mg/kg every 14 days. RESULTS: In total, 85 patients were enrolled; 45 patients received the recommended expansion dose of 3.6 mg/kg ABBV-085 monotherapy, including 10 with osteosarcoma and 10 with undifferentiated pleomorphic sarcoma (UPS). Most common treatment-related adverse events were fatigue, nausea, and decreased appetite. The overall response rate for patients with osteosarcoma/UPS treated at 3.6 mg/kg was 20%, including four confirmed partial responses. No monotherapy responses were observed for other advanced cancers treated at 3.6 mg/kg. One patient treated with ABBV-085 plus gemcitabine achieved partial response. CONCLUSIONS: ABBV-085 appeared safe and tolerable at a dose of 3.6 mg/kg every 14 days, with preliminary antitumor activity noted in patients with osteosarcoma and UPS. Given the high unmet need in these orphan malignancies, further investigation into targeting LRRC15 in these sarcomas may be warranted.


Subject(s)
Antineoplastic Agents , Bone Neoplasms , Immunoconjugates , Neoplasms , Sarcoma , Adult , Antineoplastic Agents/adverse effects , Bone Neoplasms/drug therapy , Humans , Immunoconjugates/adverse effects , Membrane Proteins/genetics , Neoplasms/pathology , Sarcoma/drug therapy , Sarcoma/genetics , Tumor Microenvironment
4.
Invest New Drugs ; 38(6): 1815-1825, 2020 12.
Article in English | MEDLINE | ID: mdl-32524319

ABSTRACT

ABBV-176 is an antibody-drug conjugate composed of the humanized antibody h16f (PR-1594804) conjugated to a highly potent, cytotoxic cross-linking pyrrolobenzodiazepine dimer (PBD; SGD-1882) targeting the prolactin receptor (PRLR), which is overexpressed in several solid tumor types. This phase 1, dose-escalation study (NCT03145909) evaluated the safety, pharmacokinetics, and preliminary activity of ABBV-176 in patients with advanced solid tumors likely to exhibit elevated levels of PRLR. Patients received ABBV-176 once every 3 weeks. Dose escalation was by an exposure-adjusted, continual reassessment method. Dose-limiting toxicities (DLTs) were assessed from the first day of dosing until the next dose of ABBV-176 to determine the maximum tolerated dose (MTD) and recommended phase 2 dose (RP2D). Nineteen patients received ABBV-176 at doses from 2.7-109.35 µg/kg. Patients enrolled had colorectal cancer (n = 11), breast cancer (n = 6), or adrenocortical carcinoma (n = 2). DLTs occurred in 4 patients and included thrombocytopenia (n = 2; both at 99.9-µg/kg dose level), neutropenia (n = 2; 78.3-µg/kg and 99.9-µg/kg dose levels), and pancytopenia (n = 1; 109.35-µg/kg dose level). The most common treatment-emergent adverse events related to ABBV-176 were thrombocytopenia, neutropenia, increased aspartate aminotransferase, nausea, fatigue, and pleural effusions. Effusions and edema were common, and timing of onset suggested possible cumulative ABBV-176 toxicity. Tumor expression of PRLR varied among patients enrolled and analyzed. No patient had an objective response. MTD was not formally determined, as identification of a tolerable dose was confounded by late-onset toxicities. ABBV-176 was associated with significant toxicity in this phase 1, dose-escalation study. Although cytopenias were often dose limiting, effusions and edema were also common and had late onset that suggested cumulative toxicity. No responses were observed, although data were available from a small number of patients with variable tumor PRLR expression. This study was terminated after the dosing of 19 patients.


Subject(s)
Antineoplastic Agents/administration & dosage , Immunoconjugates/administration & dosage , Neoplasms/drug therapy , Receptors, Prolactin/antagonists & inhibitors , Adult , Aged , Antineoplastic Agents/adverse effects , Antineoplastic Agents/pharmacokinetics , Female , Humans , Immunoconjugates/adverse effects , Immunoconjugates/pharmacokinetics , Male , Middle Aged , Neoplasms/metabolism , Receptors, Prolactin/metabolism , Treatment Outcome
5.
Mol Cancer Ther ; 19(5): 1210-1217, 2020 05.
Article in English | MEDLINE | ID: mdl-32127466

ABSTRACT

This first-in-human phase I study evaluated the pharmacokinetics, safety, and preliminary efficacy of telisotuzumab, formerly called ABT-700, an antagonistic antibody directed against c-Met. For dose escalation (3+3 design), 3 to 6 patients with advanced solid tumors were enrolled into four dose cohorts (5-25 mg/kg). In the dose-expansion phase, a subset of patients was prospectively selected for MET amplification (FISH screening). Patients received telisotuzumab intravenously on day 1 every 21 days. For dose expansion, 15 mg/kg was chosen as the dose on the basis of safety, pharmacokinetics, and other data from the escalation cohorts. Forty-five patients were enrolled and received at least one dose of telisotuzumab (dose escalation, n = 15; dose expansion, n = 30). Telisotuzumab showed a linear pharmacokinetics profile; peak plasma concentration was proportional to dose level. There were no acute infusion reactions and no dose-limiting toxicities were observed. The most common treatment-related adverse events included hypoalbuminemia (n = 9, 20.0%) and fatigue (n = 5, 11.1%). By Response Evaluation Criteria In Solid Tumors (RECIST), 4 of 10 (40.0%) patients with MET-amplified tumors had confirmed partial response in target lesions (one ovarian, two gastric, and one esophageal), two (20.0%) had stable disease, three (30.0%) had progressive disease; one patient was unable to be evaluated. Among patients with nonamplified tumors (n = 35), no objective responses were observed; however, 11 patients had stable disease per RECIST criteria. In conclusion, telisotuzumab has an acceptable safety profile with clinical activity observed in patients with MET-amplified advanced solid tumors.


Subject(s)
Antibodies, Monoclonal/therapeutic use , Neoplasms/drug therapy , Proto-Oncogene Proteins c-met/antagonists & inhibitors , Adult , Aged , Aged, 80 and over , Female , Follow-Up Studies , Humans , Male , Maximum Tolerated Dose , Middle Aged , Neoplasms/immunology , Neoplasms/pathology , Prognosis , Prospective Studies , Proto-Oncogene Proteins c-met/immunology , Retrospective Studies , Tissue Distribution
6.
J Clin Oncol ; 36(33): 3298-3306, 2018 11 20.
Article in English | MEDLINE | ID: mdl-30285518

ABSTRACT

PURPOSE: This first-in-human study evaluated telisotuzumab vedotin (Teliso-V), formerly called ABBV-399, an antibody-drug conjugate of the anti-c-Met monoclonal antibody ABT-700 and monomethyl auristatin E. MATERIALS AND METHODS: For dose escalation, three to six patients with advanced solid tumors were enrolled in eight cohorts (0.15 to 3.3 mg/kg). The dose-expansion phase enrolled patients with non-small-cell lung cancer (NSCLC) with c-Met-overexpressing tumors (c-Met positive; immunohistochemistry membrane H-score ≥ 150). Patients received Teliso-V monotherapy intravenously on day 1 once every 3 weeks. Safety, tolerability, pharmacokinetics, and maximum tolerated dose were determined. RESULTS: Forty-eight patients were enrolled (median age, 65 years; 35.4% NSCLC; median four prior therapies). One patient each in the 3.0-mg/kg (n = 9) and 3.3-mg/kg (n = 3) cohorts experienced dose-limiting toxicities. Although the maximum tolerated dose was not formally identified, the recommended phase II dose was defined as 2.7 mg/kg on the basis of overall safety and tolerability. The most frequent treatment-emergent adverse events (any grade) were fatigue (42%), nausea (27%), constipation (27%), decreased appetite (23%), vomiting (21%), dyspnea (21%), diarrhea (19%), peripheral edema (19%), and neuropathy (17%). The most frequent Teliso-V-related grade ≥ 3 adverse events were fatigue, anemia, neutropenia, and hypoalbuminemia (4% each). Teliso-V and total antibody pharmacokinetics were approximately dose proportional, with a mean harmonic half-life of 2 to 4 days each. Prospective screening identified 35 (60%) of 58 patients with c-Met-positive NSCLC. Of 16 patients with c-Met-positive NSCLC who were treated with Teliso-V 2.4 to 3.0 mg/kg, three (18.8%; 95% CI, 4.1% to 45.7%) achieved a partial response (median response duration, 4.8 months; median progression-free survival, 5.7 months; 95% CI, 1.2 months to 15.4 months). No other patients experienced a response. CONCLUSION: Teliso-V monotherapy demonstrated favorable safety and tolerability profiles, with encouraging evidence of antitumor activity in patients with c-Met-positive NSCLC.


Subject(s)
Antibodies, Monoclonal/administration & dosage , Antineoplastic Agents/administration & dosage , Neoplasms/drug therapy , Adult , Aged , Aged, 80 and over , Antibodies, Monoclonal/adverse effects , Antibodies, Monoclonal/pharmacokinetics , Antineoplastic Agents/adverse effects , Antineoplastic Agents/pharmacokinetics , Dose-Response Relationship, Drug , Female , Humans , Male , Maximum Tolerated Dose , Middle Aged , Proto-Oncogene Proteins c-met/antagonists & inhibitors
7.
Mol Cancer Ther ; 17(5): 1039-1050, 2018 05.
Article in English | MEDLINE | ID: mdl-29592882

ABSTRACT

Antiangiogenic therapy is a clinically validated modality in cancer treatment. To date, all approved antiangiogenic drugs primarily inhibit the VEGF pathway. Delta-like ligand 4 (DLL4) has been identified as a potential drug target in VEGF-independent angiogenesis and tumor-initiating cell (TIC) survival. A dual-specific biologic targeting both VEGF and DLL4 could be an attractive strategy to improve the effectiveness of anti-VEGF therapy. ABT-165 was uniquely engineered using a proprietary dual-variable domain immunoglobulin (DVD-Ig) technology based on its ability to bind and inhibit both DLL4 and VEGF. In vivo, ABT-165 induced significant tumor growth inhibition compared with either parental antibody treatment alone, due, in part, to the disruption of functional tumor vasculature. In combination with chemotherapy agents, ABT-165 also induced greater antitumor response and outperformed anti-VEGF treatment. ABT-165 displayed nonlinear pharmacokinetic profiles in cynomolgus monkeys, with an apparent terminal half-life > 5 days at a target saturation dose. In a GLP monkey toxicity study, ABT-165 was well-tolerated at doses up to 200 mg/kg with non-adverse treatment-related histopathology findings limited to the liver and thymus. In summary, ABT-165 represents a novel antiangiogenic strategy that potently inhibits both DLL4 and VEGF, demonstrating favorable in vivo efficacy, pharmacokinetic, and safety profiles in preclinical models. Given these preclinical attributes, ABT-165 has progressed to a phase I study. Mol Cancer Ther; 17(5); 1039-50. ©2018 AACR.


Subject(s)
Antineoplastic Combined Chemotherapy Protocols/pharmacology , Glioblastoma/drug therapy , Immunoglobulins/pharmacology , Intracellular Signaling Peptides and Proteins/antagonists & inhibitors , Membrane Proteins/antagonists & inhibitors , Vascular Endothelial Growth Factor A/antagonists & inhibitors , Xenograft Model Antitumor Assays , Animals , Antineoplastic Combined Chemotherapy Protocols/metabolism , Antineoplastic Combined Chemotherapy Protocols/pharmacokinetics , Cell Line, Tumor , Drug Screening Assays, Antitumor/methods , Glioblastoma/metabolism , Glioblastoma/pathology , HT29 Cells , Humans , Immunoglobulins/metabolism , Immunologic Factors/metabolism , Immunologic Factors/pharmacokinetics , Immunologic Factors/pharmacology , Intracellular Signaling Peptides and Proteins/metabolism , Macaca fascicularis/metabolism , Membrane Proteins/metabolism , Treatment Outcome , Vascular Endothelial Growth Factor A/metabolism
8.
Clin Cancer Res ; 23(4): 992-1000, 2017 Feb 15.
Article in English | MEDLINE | ID: mdl-27573171

ABSTRACT

Purpose: Despite the importance of the MET oncogene in many malignancies, clinical strategies targeting c-Met have benefitted only small subsets of patients with tumors driven by signaling through the c-Met pathway, thereby necessitating selection of patients with MET amplification and/or c-Met activation most likely to respond. An ADC targeting c-Met could overcome these limitations with potential as a broad-acting therapeutic.Experimental Design: ADC ABBV-399 was generated with the c-Met-targeting antibody, ABT-700. Antitumor activity was evaluated in cancer cells with overexpressed c-Met or amplified MET and in xenografts including patient-derived xenograft (PDX) models and those refractory to other c-Met inhibitors. The correlation between c-Met expression and sensitivity to ABBV-399 in tumor and normal cell lines was assessed to evaluate the risk of on-target toxicity.Results: A threshold level of c-Met expressed by sensitive tumor but not normal cells is required for significant ABBV-399-mediated killing of tumor cells. Activity extends to c-Met or amplified MET cell line and PDX models where significant tumor growth inhibition and regressions are observed. ABBV-399 inhibits growth of xenograft tumors refractory to other c-Met inhibitors and provides significant therapeutic benefit in combination with standard-of-care chemotherapy.Conclusions: ABBV-399 represents a novel therapeutic strategy to deliver a potent cytotoxin to c-Met-overexpressing tumor cells enabling cell killing regardless of reliance on MET signaling. ABBV-399 has progressed to a phase I study where it has been well tolerated and has produced objective responses in c-Met-expressing non-small cell lung cancer (NSCLC) patients. Clin Cancer Res; 23(4); 992-1000. ©2016 AACR.


Subject(s)
Antibodies, Monoclonal/administration & dosage , Neoplasms/drug therapy , Neoplasms/genetics , Proto-Oncogene Proteins c-met/genetics , Animals , Antibodies, Monoclonal/adverse effects , Cell Proliferation/drug effects , Gene Expression Regulation, Neoplastic/drug effects , Humans , MCF-7 Cells , Mice , Neoplasms/immunology , Neoplasms/pathology , Proto-Oncogene Proteins c-met/antagonists & inhibitors , Signal Transduction/drug effects , Xenograft Model Antitumor Assays
9.
BMC Cancer ; 16: 105, 2016 Feb 16.
Article in English | MEDLINE | ID: mdl-26879245

ABSTRACT

BACKGROUND: c-Met is the receptor tyrosine kinase for hepatocyte growth factor (HGF) encoded by the MET proto-oncogene. Aberrant activation of c-Met resulting from MET amplification and c-Met overexpression is associated with poor clinical outcome in multiple malignancies underscoring the importance of c-Met signaling in cancer progression. Several c-Met inhibitors have advanced to the clinic; however, the development of inhibitory c-Met-directed therapeutic antibodies has been hampered by inherent agonistic activity. METHOD: We generated and tested a bivalent anti-c-Met monoclonal antibody ABT-700 in vitro for binding potency and antagonistic activity and in vivo for antitumor efficacy in human tumor xenografts. Human cancer cell lines and gastric cancer tissue microarrays were examined for MET amplification by fluorescence in situ hybridization (FISH). RESULTS: ABT-700 exhibits a distinctive ability to block both HGF-independent constitutive c-Met signaling and HGF-dependent activation of c-Met. Cancer cells addicted to the constitutively activated c-Met signaling driven by MET amplification undergo apoptosis upon exposure to ABT-700. ABT-700 induces tumor regression and tumor growth delay in preclinical tumor models of gastric and lung cancers harboring amplified MET. ABT-700 in combination with chemotherapeutics also shows additive antitumor effect. Amplification of MET in human cancer tissues can be identified by FISH. CONCLUSIONS: The preclinical attributes of ABT-700 in blocking c-Met signaling, inducing apoptosis and suppressing tumor growth in cancers with amplified MET provide rationale for examining its potential clinical utility for the treatment of cancers harboring MET amplification.


Subject(s)
Antibodies, Monoclonal/pharmacology , Antineoplastic Agents/pharmacology , Proto-Oncogene Proteins c-met/drug effects , Proto-Oncogene Proteins c-met/genetics , Animals , Antibodies, Monoclonal/metabolism , Antibodies, Monoclonal/therapeutic use , Antineoplastic Agents/metabolism , Antineoplastic Agents/therapeutic use , Cell Line, Tumor , Gene Amplification , Humans , Male , Mice , Mice, SCID , Neoplasms, Experimental/drug therapy , Neoplasms, Experimental/genetics , Neoplasms, Experimental/metabolism , Neoplasms, Experimental/pathology , Protein Binding , Proto-Oncogene Mas , Proto-Oncogene Proteins c-met/antagonists & inhibitors , Xenograft Model Antitumor Assays
10.
J Clin Invest ; 123(9): 3997-4009, 2013 Sep.
Article in English | MEDLINE | ID: mdl-23945239

ABSTRACT

Many oncology drugs are administered at their maximally tolerated dose without the knowledge of their optimal efficacious dose range. In this study, we describe a multifaceted approach that integrated preclinical and clinical data to identify the optimal dose for an antiangiogenesis agent, anti-EGFL7. EGFL7 is an extracellular matrix-associated protein expressed in activated endothelium. Recombinant EGFL7 protein supported EC adhesion and protected ECs from stress-induced apoptosis. Anti-EGFL7 antibodies inhibited both of these key processes and augmented anti-VEGF-mediated vascular damage in various murine tumor models. In a genetically engineered mouse model of advanced non-small cell lung cancer, we found that anti-EGFL7 enhanced both the progression-free and overall survival benefits derived from anti-VEGF therapy in a dose-dependent manner. In addition, we identified a circulating progenitor cell type that was regulated by EGFL7 and evaluated the response of these cells to anti-EGFL7 treatment in both tumor-bearing mice and cancer patients from a phase I clinical trial. Importantly, these preclinical efficacy and clinical biomarker results enabled rational selection of the anti-EGFL7 dose currently being tested in phase II clinical trials.


Subject(s)
Angiogenesis Inhibitors/pharmacology , Antibodies/pharmacology , Apoptosis , Endothelial Growth Factors/immunology , Human Umbilical Vein Endothelial Cells/drug effects , Vascular Endothelial Growth Factor A/antagonists & inhibitors , Animals , Antibodies, Monoclonal, Humanized/pharmacology , Bevacizumab , Calcium-Binding Proteins , Carcinoma, Non-Small-Cell Lung/drug therapy , Carcinoma, Non-Small-Cell Lung/pathology , Clinical Trials, Phase I as Topic , EGF Family of Proteins , Human Umbilical Vein Endothelial Cells/physiology , Humans , Insulinoma/blood supply , Insulinoma/drug therapy , Insulinoma/metabolism , Lung Neoplasms/drug therapy , Lung Neoplasms/pathology , Mice , Mice, Nude , Mice, Transgenic , Neoplastic Cells, Circulating/drug effects , Neoplastic Cells, Circulating/metabolism , Neoplastic Stem Cells/drug effects , Neoplastic Stem Cells/metabolism , Pancreatic Neoplasms/blood supply , Pancreatic Neoplasms/drug therapy , Pancreatic Neoplasms/metabolism , Tumor Burden/drug effects , Tumor Cells, Cultured , Vascular Endothelial Growth Factor A/physiology , Xenograft Model Antitumor Assays
11.
Curr Opin Mol Ther ; 12(2): 248-57, 2010 Apr.
Article in English | MEDLINE | ID: mdl-20373269

ABSTRACT

Glembatumumab vedotin (CR-011-vc-MMAE) is a mAb-drug conjugate being developed by Celldex Therapeutics Inc for the treatment of glycoprotein non-metastatic melanoma protein B (GPNMB)-expressing cancers. Glembatumumab is a fully human mAb directed against an extracellular domain of GPNMB expressed in human breast cancers and melanomas. Glembatumumab is conjugated to the potent microtubule inhibitor monomethyl auristatin E using a cathepsin cleavable valine-citrulline (vc) dipeptide linker. Glembatumumab vedotin has demonstrated potent antitumor activity in preclinical studies, including in GPNMB-expressing cell lines. In human melanoma xenograft mice, intravenous glembatumumab vedotin was associated with complete tumor regression without significant toxicity. In two phase I/II clinical trials, intravenous glembatumumab vedotin demonstrated antitumor activity in patients with breast cancer or melanoma. Skin rash was the most common toxicity reported, which may have been caused by the expression of GPNMB in healthy skin. Glembatumumab vedotin had a relatively short t(1/2) , prompting the evaluation of more frequent dosing schedules. Prospective, randomized clinical trials will likely be required to determine the therapeutic potential of glembatumumab vedotin in the treatment of breast cancer and melanoma.


Subject(s)
Antibodies, Monoclonal/therapeutic use , Breast Neoplasms/drug therapy , Melanoma/drug therapy , Membrane Glycoproteins/immunology , Oligopeptides/therapeutic use , Animals , Antibodies, Monoclonal/chemistry , Cell Line , Clinical Trials as Topic , Drug Screening Assays, Antitumor , Female , Humans , Membrane Glycoproteins/chemistry , Mice , Oligopeptides/chemistry , Transplantation, Heterologous
12.
Clin Cancer Res ; 15(20): 6462-71, 2009 Oct 15.
Article in English | MEDLINE | ID: mdl-19825958

ABSTRACT

PURPOSE: Therapeutic strategies to enhance the efficacy of radioimmunotherapy have not been explored. Motexafin gadolinium is a novel anticancer agent that targets redox-dependent pathways and enhances sensitivity of tumor cells to ionizing radiation. EXPERIMENTAL DESIGN: We did preclinical studies examining motexafin gadolinium combined with rituximab and/or radiation in lymphoma cells. We subsequently completed a phase I clinical trial combining escalating doses of motexafin gadolinium concurrently with standard [(90)Y]ibritumomab tiuxetan for patients with relapsed/refractory non-Hodgkin's lymphoma. RESULTS: In HF1 lymphoma cells, motexafin gadolinium and rituximab resulted in synergistic cytotoxicity (combination index, 0.757) through a mitochondrial-mediated caspase-dependent pathway, whereas cell death in Ramos and SUDHL4 cells was additive. Motexafin gadolinium/rituximab combined with radiation (1-3 Gy) resulted in additive apoptosis. Twenty-eight of 30 patients were evaluable on the phase I clinical trial. Median age was 65 years (47-87 years), and histologies were marginal-zone (n = 1), mantle-cell (n = 3), diffuse large cell (n = 6), and follicular lymphoma (n = 18). Of all patients, 86% were rituximab refractory. Therapy was well tolerated, and no dose-limiting toxicity was seen. Overall response rate was 57% [complete remission (CR), 43%], with median time-to-treatment failure of 10 months (1-48+ months) and median duration-of-response of 17 months. Of note, all responses were documented at 4 weeks. Furthermore, in rituximab-refractory follicular lymphoma (n = 14), overall response rate was 86% (CR, 64%), with a median time-to-treatment failure of 14 months (2-48+ months). CONCLUSIONS: This represents the first report of a novel agent to be combined safely concurrently with radioimmunotherapy. Furthermore, tumor responses with [(90)Y]ibritumomab tiuxetan/motexafin gadolinium were prompt with a high rate of CRs, especially in rituximab-refractory follicular lymphoma.


Subject(s)
Antibodies, Monoclonal/administration & dosage , Antineoplastic Combined Chemotherapy Protocols/therapeutic use , Lymphoma, Non-Hodgkin/drug therapy , Lymphoma, Non-Hodgkin/radiotherapy , Metalloporphyrins/administration & dosage , Radiation-Sensitizing Agents/administration & dosage , Yttrium Radioisotopes/administration & dosage , Aged , Aged, 80 and over , Antibodies, Monoclonal/adverse effects , Antineoplastic Combined Chemotherapy Protocols/adverse effects , Cell Line, Tumor , Combined Modality Therapy , Drug Administration Schedule , Female , Humans , Male , Metalloporphyrins/adverse effects , Middle Aged , Porphyrins , Radioimmunotherapy , Recurrence , Treatment Outcome
13.
Leuk Lymphoma ; 50(12): 1977-82, 2009 Dec.
Article in English | MEDLINE | ID: mdl-19860624

ABSTRACT

Chronic lymphocytic leukemia (CLL) cells are susceptible to oxidative stress. The expanded porphyrin, motexafin gadolinium (MGd), reacts with intracellular reducing metabolites and protein thiols to generate reactive oxygen species (ROS). A phase II trial administered MGd 5 mg/kg/day IV for 5 days every 3 weeks until disease progression to patients with previously treated CLL and small lymphocytic lymphoma. Thirteen patients (median age 66 years) with a median of four prior therapies (range 2-9) were enrolled. Modest anti-tumor activity was seen in three patients, with improvement in lymphocytosis, lymphadenopathy and/or splenomegaly, but no patient achieved a partial or complete response by NCI 96 criteria. Flow cytometry confirmed tumor uptake of MGd. Serial increase in AKT phosphorylation in patient samples following MGd treatment was not observed, suggesting intracellular generation of ROS was not optimal. Therefore, this schedule of administration achieved MGd uptake into primary tumor cells in vivo, but clinical activity was modest.


Subject(s)
Leukemia, Lymphocytic, Chronic, B-Cell/drug therapy , Metalloporphyrins/therapeutic use , Aged , Aged, 80 and over , Antineoplastic Agents/adverse effects , Antineoplastic Agents/pharmacokinetics , Antineoplastic Agents/therapeutic use , Chromosome Deletion , Chromosomes, Human, Pair 11/genetics , Chromosomes, Human, Pair 17/genetics , Drug Administration Schedule , Drug Resistance, Neoplasm , Female , Flow Cytometry , Humans , Immunoblotting , In Situ Hybridization, Fluorescence , Leukemia, Lymphocytic, Chronic, B-Cell/genetics , Leukemia, Lymphocytic, Chronic, B-Cell/metabolism , Male , Metalloporphyrins/adverse effects , Metalloporphyrins/pharmacokinetics , Middle Aged , Phosphorylation/drug effects , Proto-Oncogene Proteins c-akt/metabolism , Treatment Outcome
14.
Proc Natl Acad Sci U S A ; 106(11): 4390-5, 2009 Mar 17.
Article in English | MEDLINE | ID: mdl-19251665

ABSTRACT

The expression of ASPP2 (53BP2L), a proapoptotic member of a family of p53-binding proteins, is frequently suppressed in many human cancers. Accumulating evidence suggests that ASPP2 inhibits tumor growth; however, the mechanisms by which ASPP2 suppresses tumor formation remain to be clarified. To study this, we targeted the ASPP2 allele in a mouse by replacing exons 10-17 with a neoR gene. ASPP2(-/-) mice were not viable because of an early embryonic lethal event. Although ASPP2(+/-) mice appeared developmentally normal, they displayed an increased incidence of a variety of spontaneous tumors as they aged. Moreover, gamma-irradiated 6-week-old ASPP2(+/-) mice developed an increased incidence of high-grade T cell lymphomas of thymic origin compared with ASPP2(+/+) mice. Primary thymocytes derived from ASPP2(+/-) mice exhibited an attenuated apoptotic response to gamma-irradiation compared with ASPP2(+/+) thymocytes. Additionally, ASPP2(+/-) primary mouse embryonic fibroblasts demonstrated a defective G(0)/G(1) cell cycle checkpoint after gamma-irradiation. Our results demonstrate that ASPP2 is a haploinsufficient tumor suppressor and, importantly, open new avenues for investigation into the mechanisms by which disruption of ASPP2 pathways could play a role in tumorigenesis and response to therapy.


Subject(s)
Apoptosis Regulatory Proteins/genetics , Tumor Suppressor Proteins/genetics , Animals , Apoptosis/radiation effects , Cell Cycle/radiation effects , Gamma Rays , Genetic Predisposition to Disease , Heterozygote , Lymphoma, T-Cell/etiology , Lymphoma, T-Cell/genetics , Mice , Mice, Mutant Strains , Neoplasms/etiology , Neoplasms/genetics , Thymus Gland
15.
Mol Cancer ; 6: 9, 2007 Jan 19.
Article in English | MEDLINE | ID: mdl-17233922

ABSTRACT

BACKGROUND: Sapphyrin analogues and related porphyrin-like species have attracted attention as anticancer agents due to their selective localization in various cancers, including hematologic malignancies, relative to surrounding tissues. Sapphyrins are electron affinic compounds that generate high yields of singlet oxygen formation. Although initially explored in the context of photodynamic therapy, sapphyrins have intrinsic anticancer activity that is independent of their photosensitizing properties. However, the mechanisms for their anticancer activity have not been fully elucidated. RESULTS: We have prepared a series of hydrophilic sapphyrins and evaluated their effect on proliferation, uptake, and cell death in adherent human lung (A549) and prostate (PC3) cancer cell lines and in an A549 xenograft tumor model. PCI-2050, the sapphyrin derivative with the highest in vitro growth inhibitory activity, significantly lowered 5-bromo-2'-deoxyuridine incorporation in S-phase A549 cells by 60% within eight hours and increased levels of reactive oxygen species within four hours. The growth inhibition pattern of PCI-2050 in the National Cancer Institute 60 cell line screen correlated most closely using the COMPARE algorithm with known transcriptional or translational inhibitors. Gene expression analyses conducted on A549 plateau phase cultures treated with PCI-2050 uncovered wide-spread decreases in mRNA levels, which especially affected short-lived transcripts. Intriguingly, PCI-2050 increased the levels of transcripts involved in RNA processing and trafficking, transcriptional regulation, and chromatin remodeling. We propose that these changes reflect the activation of cellular processes aimed at countering the observed wide-spread reductions in transcript levels. In our A549 xenograft model, the two lead compounds, PCI-2050 and PCI-2022, showed similar tumor distributions despite differences in plasma and kidney level profiles. This provides a possible explanation for the better tolerance of PCI-2022 relative to PCI-2050. CONCLUSION: Hydrophilic sapphyrins were found to display promise as novel agents that localize to tumors, generate oxidative stress, and inhibit gene expression.


Subject(s)
Hydrophobic and Hydrophilic Interactions , Oligonucleotide Array Sequence Analysis , Porphyrins/pharmacokinetics , Porphyrins/toxicity , Cell Line, Tumor , Cell Proliferation , Cluster Analysis , Gene Expression Profiling , Humans , Molecular Structure , Reactive Oxygen Species/metabolism , Xenograft Model Antitumor Assays
16.
Mol Pharmacol ; 71(1): 193-200, 2007 Jan.
Article in English | MEDLINE | ID: mdl-17018578

ABSTRACT

Heme oxygenase-1 (HO1), which oxidizes heme to biliverdin, CO, and free iron, conveys protection against oxidative stress and is antiapoptotic. Under stress conditions, some porphyrin derivatives can inhibit HO1 and trigger cell death. Motexafin gadolinium (MGd) is an expanded porphyrin that selectively targets cancer cells through a process of futile redox cycling that decreases intracellular reducing metabolites and protein thiols. Here, we report that hematopoietic-derived cell lines that constitutively express HO1 are more susceptible to MGd-induced apoptosis than those that do not. MGd used in combination with tin protoporphyrin IX, an inhibitor of HO1, resulted in synergistic cell killing. Consistent with these cell culture observations, we found that MGd is an inhibitor of heme oxygenase-1 activity in vitro. We demonstrate that inhibition of HO1 reflects an interaction of MGd with NADPH-cytochrome P450 reductase, the electron donor for HO1, that results in diversion of reducing equivalents from heme oxidation to oxygen reduction. In accord with this mechanism, MGd is also an in vitro inhibitor of CYP2C9, CYP3A4, and CYP4A1. Inhibition of HO1 by MGd may contribute to its anticancer activity, whereas its in vitro inhibition of a broad spectrum of P450 enzymes indicates that a potential exists for drug-drug interactions.


Subject(s)
Cell Division/drug effects , Heme Oxygenase-1/genetics , Metalloporphyrins/pharmacology , NADPH-Ferrihemoprotein Reductase/antagonists & inhibitors , Antineoplastic Agents/pharmacology , Cell Line, Tumor , Chromatography, High Pressure Liquid , Gene Expression Regulation, Enzymologic/drug effects , Humans , Kinetics , Oxidoreductases Acting on CH-CH Group Donors/metabolism , Oxygen Consumption/drug effects , Spectrophotometry
17.
Mol Cancer Ther ; 5(11): 2798-805, 2006 Nov.
Article in English | MEDLINE | ID: mdl-17121926

ABSTRACT

Sapphyrins are pentapyrrolic metal-free expanded porphyrins with potential medical use as anticancer agents. The novel sapphyrin derivative, PCI-2050, functionalized with 2-[2-(2-methoxyethoxy)ethoxy]ethoxy groups to enhance solubility and a modified bipyrrole moiety was found to be more potent in inducing apoptosis than the previously described sapphyrin PCI-2000. Because some sapphyrins may localize to tumors, we took advantage of the intrinsic fluorescence of these compounds to develop a flow cytometry-based assay to track sapphyrin biodistribution in tumor-bearing mice. Ex vivo analysis of sapphyrin-injected animals revealed that PCI-2050 preferentially localized to tumor, whereas PCI-2000 distributed into normal tissues rather than tumor. PCI-2050 uptake in xenograft tumor cells and resultant tumor cell cytotoxicity was dose dependent. To investigate structure-activity relationships, we focused on PCI-2050 and three derivatives that differ by their alkyl substituents on the bipyrrole moiety: PCI-2051, PCI-2052, and PCI-2053. Treatment of Ramos cells in culture or treatment of Ramos xenograft-bearing animals with each of the sapphyrins followed by ex vivo growth of tumor cells revealed the same pattern of cytotoxicity: PCI-2050 > PCI-2052 > PCI-2051 > PCI-2053. Thus, subtle changes in the alkyl substituents on the bipyrrole moiety result in significant changes in antitumor activity. PCI-2050 displayed significant antitumor efficacy in both Ramos and RKO xenograft models without hematologic, hepatic, or renal abnormalities as assessed by complete blood counts and serum chemistries. On the basis of these findings, it is concluded that the sapphyrin PCI-2050 warrants further evaluation as a potential anticancer agent due to its intrinsic proapoptotic activity and tumor localization ability.


Subject(s)
Antineoplastic Agents/pharmacology , Porphyrins/pharmacology , Animals , Antineoplastic Agents/chemistry , Antineoplastic Agents/pharmacokinetics , Apoptosis/drug effects , Cell Line, Tumor , Female , Flow Cytometry , Mice , Neoplasms/metabolism , Porphyrins/chemical synthesis , Porphyrins/chemistry , Porphyrins/pharmacokinetics , Xenograft Model Antitumor Assays
18.
Mol Cancer Ther ; 5(5): 1176-82, 2006 May.
Article in English | MEDLINE | ID: mdl-16731749

ABSTRACT

Motexafin gadolinium (MGd, Xcytrin) is a tumor-selective expanded porphyrin that targets oxidative stress-related proteins. MGd treatment of the follicular lymphoma-derived cell line HF-1 resulted in growth suppression and apoptosis whereas MGd treatment of the Burkitt's lymphoma-derived cell line Ramos resulted in growth suppression but not apoptosis. Because phosphorylation status of Akt/protein kinase B is regulated by oxidative stress, we monitored total and phosphorylated Akt (pAkt) in MGd-treated HF-1 and Ramos cells. Levels of pAkt increased within 30 minutes after MGd treatment of HF-1 but after 4 hours began to show a progressive decline to below baseline levels before cells underwent apoptosis. In MGd-treated Ramos cells, pAkt increased approximately 2-fold within 4 hours and remained persistently elevated. Because pAkt activates survival pathways, we determined if MGd-induced cell death could be enhanced by inhibiting phosphorylation of Akt. The addition of specific inhibitors of Akt phosphorylation (Akt inhibitor 1 or SH-5) reduced pAkt levels in MGd-treated HF-1 and Ramos cells and synergistically enhanced MGd-induced cell death. MGd was also evaluated in combination with celecoxib, an inhibitor of Akt phosphorylation, or docetaxel, a microtubule inhibitor that can decrease Akt phosphorylation. The combination of MGd/celecoxib or MGd/docetaxel resulted in decreased Akt phosphorylation and in synergistic cytotoxicity compared with either agent alone. These data point to a potential protective role for pAkt in MGd-induced apoptosis and suggest that MGd activity may be enhanced by combining it with agents that inhibit Akt phosphorylation.


Subject(s)
Antineoplastic Agents/pharmacology , Metalloporphyrins/pharmacology , Proto-Oncogene Proteins c-akt/metabolism , Antineoplastic Agents/metabolism , Apoptosis/drug effects , Celecoxib , Cell Line, Tumor , Cyclooxygenase Inhibitors/metabolism , Cyclooxygenase Inhibitors/pharmacology , Docetaxel , Drug Synergism , Humans , Lymphoma/metabolism , Metalloporphyrins/metabolism , Phosphorylation/drug effects , Proto-Oncogene Proteins c-akt/antagonists & inhibitors , Pyrazoles/metabolism , Pyrazoles/pharmacology , Pyrazoles/toxicity , Sulfonamides/metabolism , Sulfonamides/pharmacology , Sulfonamides/toxicity , Taxoids/metabolism , Taxoids/pharmacology
19.
Dalton Trans ; (16): 1934-42, 2006 Apr 28.
Article in English | MEDLINE | ID: mdl-16609763

ABSTRACT

The synthesis of four new analogues of motexafin gadolinium (MGd), a gadolinium(III) texaphyrin complex in clinical trials for its anticancer properties, is described. These new derivatives contain either 1,2-diaminobenzene or 2,3-diaminonaphthalene subunits as the source of the imine nitrogens and bear multiple 2-[2-(2-methoxyethoxy)ethoxy]ethoxy (PEG) groups, on either meso aryl or beta-pyrrolic substituents, to increase their water solubility. All four analogues were found to be more active in vitro than the parent system MGd as judged from cell proliferation assays using the PC3 and A549 cell lines.


Subject(s)
Antineoplastic Agents/chemical synthesis , Antineoplastic Agents/pharmacology , Porphyrins/chemical synthesis , Porphyrins/pharmacology , Antineoplastic Agents/chemistry , Cell Line, Tumor , Cell Proliferation/drug effects , Crystallography, X-Ray , Drug Screening Assays, Antitumor , Electrochemistry , Humans , Models, Molecular , Molecular Structure , Porphyrins/chemistry , Structure-Activity Relationship
20.
Cancer Res ; 65(24): 11676-88, 2005 Dec 15.
Article in English | MEDLINE | ID: mdl-16357179

ABSTRACT

There is an emerging appreciation of the importance of zinc in regulating cancer cell growth and proliferation. Recently, we showed that the anticancer agent motexafin gadolinium (MGd) disrupted zinc metabolism in A549 lung cancer cells, leading, in the presence of exogenous zinc, to cell death. Here, we report the effect of MGd and exogenous zinc on intracellular levels of free zinc, oxidative stress, proliferation, and cell death in exponential phase human B-cell lymphoma and other hematologic cell lines. We find that increased levels of oxidative stress and intracellular free zinc precede and correlate with cell cycle arrest and apoptosis. To better understand the molecular basis of these cellular responses, gene expression profiling analyses were conducted on Ramos cell cultures treated with MGd and/or zinc acetate. Cultures treated with MGd or zinc acetate alone elicited transcriptional responses characterized by induction of metal response element-binding transcription factor-1 (MTF-1)-regulated and hypoxia-inducible transcription factor-1 (HIF-1)-regulated genes. Cultures cotreated with MGd and zinc acetate displayed further increases in the levels of MTF-1- and HIF-1-regulated transcripts as well as additional transcripts regulated by NF-E2-related transcription factor 2. These data provide insights into the molecular changes that accompany the disruption of intracellular zinc homeostasis and support a role for MGd in treatment of B-cell hematologic malignancies.


Subject(s)
Antineoplastic Agents/pharmacology , Apoptosis/drug effects , Lymphoma, B-Cell/drug therapy , Metalloporphyrins/pharmacology , Oxidative Stress/drug effects , Zinc/metabolism , DNA-Binding Proteins/genetics , DNA-Binding Proteins/metabolism , Gene Expression Profiling , Humans , Hypoxia-Inducible Factor 1, alpha Subunit/genetics , Hypoxia-Inducible Factor 1, alpha Subunit/metabolism , Lymphoma, B-Cell/metabolism , Lymphoma, B-Cell/pathology , NF-E2-Related Factor 2/genetics , NF-E2-Related Factor 2/metabolism , Oligonucleotide Array Sequence Analysis , Response Elements , S Phase/drug effects , Transcription Factors/genetics , Transcription Factors/metabolism , Tumor Cells, Cultured , Transcription Factor MTF-1
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