ABSTRACT
Purpose To investigate the safety and clinical activity of comprehensive human epidermal growth factor receptor (HER) family receptor inhibition using lumretuzumab (anti-HER3) and pertuzumab (anti-HER2) in combination with paclitaxel in patients with metastatic breast cancer (MBC). Methods This phase Ib study enrolled 35 MBC patients (first line or higher) with HER3-positive and HER2-low (immunohistochemistry 1+ to 2+ and in-situ hybridization negative) tumors. Patients received lumretuzumab (1000 mg in Cohort 1; 500 mg in Cohorts 2 and 3) plus pertuzumab (840 mg loading dose [LD] followed by 420 mg in Cohorts 1 and 2; 420 mg without LD in Cohort 3) every 3 weeks, plus paclitaxel (80 mg/m2 weekly in all cohorts). Patients in Cohort 3 received prophylactic loperamide treatment. Results Diarrhea grade 3 was a dose-limiting toxicity of Cohort 1 defining the maximum tolerated dose of lumretuzumab when given in combination with pertuzumab and paclitaxel at 500 mg every three weeks. Grade 3 diarrhea decreased from 50% (Cohort 2) to 30.8% (Cohort 3) with prophylactic loperamide administration and omission of the pertuzumab LD, nonetheless, all patients still experienced diarrhea. In first-line MBC patients, the objective response rate in Cohorts 2 and 3 was 55% and 38.5%, respectively. No relationship between HER2 and HER3 expression or somatic mutations and clinical response was observed. Conclusions Combination treatment with lumretuzumab, pertuzumab and paclitaxel was associated with a high incidence of diarrhea. Despite the efforts to alter dosing, the therapeutic window remained too narrow to warrant further clinical development. TRIAL REGISTRATION: on ClinicalTrials.gov with the identifier NCT01918254 first registered on 3rd July 2013.
Subject(s)
Antibodies, Monoclonal, Humanized/administration & dosage , Antineoplastic Combined Chemotherapy Protocols/administration & dosage , Breast Neoplasms/drug therapy , Paclitaxel/administration & dosage , Receptor, ErbB-2/antagonists & inhibitors , Adult , Aged , Antibodies, Monoclonal, Humanized/adverse effects , Antibodies, Monoclonal, Humanized/pharmacokinetics , Antineoplastic Agents/administration & dosage , Antineoplastic Agents/adverse effects , Antineoplastic Agents/pharmacokinetics , Antineoplastic Combined Chemotherapy Protocols/adverse effects , Breast Neoplasms/genetics , Breast Neoplasms/metabolism , Diarrhea/chemically induced , Female , Humans , Hypokalemia/chemically induced , Male , Middle Aged , Paclitaxel/adverse effects , Polymorphism, Single Nucleotide , Receptor, ErbB-2/genetics , Receptor, ErbB-2/metabolism , Receptor, ErbB-3/antagonists & inhibitors , Receptor, ErbB-3/genetics , Receptor, ErbB-3/metabolismABSTRACT
The cannabinoid receptor type 1 (CB1) is abundantly expressed in the central nervous system where it negatively controls the release of several neurotransmitters. CB1 activity plays a crucial role in learning and memory and in synaptic plasticity. In the present study, the role of CB1 was investigated in three different hippocampus-dependent memory tasks and in in vivo hippocampal synaptic plasticity in knockout (CB1-ko) and wildtype mice. There was no difference in short-term and long-term social and object recognition memory between CB1-ko and wildtype mice. In contrast, in background contextual fear conditioning CB1-ko mice showed enhanced freezing levels in the conditioning context and increased generalised contextual fear after a high-intensity conditioning foot shock of 1.5 mA, but not after 0.7 mA. In in vivo field potential recordings in the dentate gyrus, CB1-ko mice displayed a decreased paired-pulse facilitation of the populations spikes, suggesting an altered inhibitory synaptic drive onto hippocampal granule cells. Furthermore, CB1-ko mice displayed significantly higher levels of in vivo long-term potentiation (LTP) in the dentate gyrus. In conclusion, CB1 deficiency leads to enhanced contextual fear memory and altered synaptic plasticity in the hippocampus, supporting the key role of endocannabinoid signalling in learning and memory, in particular following highly aversive encounters.
Subject(s)
Association , Fear/physiology , Hippocampus/physiology , Memory/physiology , Receptor, Cannabinoid, CB1/genetics , Animals , Behavior, Animal/physiology , Conditioning, Psychological/physiology , Cues , Long-Term Potentiation/physiology , Mice , Mice, Knockout , Neurons/physiology , Receptor, Cannabinoid, CB1/metabolism , Recognition, Psychology/physiologyABSTRACT
BACKGROUND: This phase 1b study (NCT02323191) evaluated the safety, antitumor activity, pharmacokinetics, and pharmacodynamics of colony-stimulating factor-1 receptor-blocking monoclonal antibody (mAb) emactuzumab in combination with the programmed cell death-1 ligand (PD-L1)-blocking mAb atezolizumab in patients with advanced solid tumors naïve or experienced for immune checkpoint blockers (ICBs). METHODS: Emactuzumab (500-1350 mg flat) and atezolizumab (1200 mg flat) were administered intravenously every 3 weeks. Dose escalation of emactuzumab was conducted using the 3+3 design up to the maximum tolerated dose (MTD) or optimal biological dose (OBD). Extension cohorts to evaluate pharmacodynamics and clinical activity were conducted in metastatic ICB-naive urothelial bladder cancer (UBC) and ICB-pretreated melanoma (MEL), non-small cell lung cancer (NSCLC) and UBC patients. RESULTS: Overall, 221 patients were treated. No MTD was reached and the OBD was determined at 1000 mg of emactuzumab in combination with 1200 mg of atezolizumab. Grade ≥3 treatment-related adverse events occurred in 25 (11.3%) patients of which fatigue and rash were the most common (14 patients (6.3%) each). The confirmed objective response rate (ORR) was 9.8% for ICB-naïve UBC, 12.5% for ICB-experienced NSCLC, 8.3% for ICB-experienced UBC and 5.6% for ICB-experienced MEL patients, respectively. Tumor biopsy analyses demonstrated increased activated CD8 +tumor infiltrating T lymphocytes (TILs) associated with clinical benefit in ICB-naïve UBC patients and less tumor-associated macrophage (TAM) reduction in ICB-experienced compared with ICB-naïve patients. CONCLUSION: Emactuzumab in combination with atezolizumab demonstrated a manageable safety profile with increased fatigue and skin rash over usual atezolizumab monotherapy. A considerable ORR was particularly seen in ICB-experienced NSCLC patients. Increase ofCD8 +TILs under therapy appeared to be associated with persistence of a TAM subpopulation.
Subject(s)
Carcinoma, Non-Small-Cell Lung , Lung Neoplasms , Melanoma , Urinary Bladder Neoplasms , Antibodies, Monoclonal/adverse effects , Antibodies, Monoclonal, Humanized , Carcinoma, Non-Small-Cell Lung/drug therapy , Carcinoma, Non-Small-Cell Lung/pathology , Fatigue/chemically induced , Humans , Immune Checkpoint Inhibitors , Ligands , Lung Neoplasms/drug therapy , Melanoma/drug therapy , Receptor Protein-Tyrosine Kinases , Urinary Bladder Neoplasms/drug therapyABSTRACT
Balanced control of neuronal activity is central in maintaining function and viability of neuronal circuits. The endocannabinoid system tightly controls neuronal excitability. Here, we show that endocannabinoids directly target hippocampal glutamatergic neurons to provide protection against acute epileptiform seizures in mice. Functional CB1 cannabinoid receptors are present on glutamatergic terminals of the hippocampal formation, colocalizing with vesicular glutamate transporter 1 (VGluT1). Conditional deletion of the CB1 gene either in cortical glutamatergic neurons or in forebrain GABAergic neurons, as well as virally induced deletion of the CB1 gene in the hippocampus, demonstrate that the presence of CB1 receptors in glutamatergic hippocampal neurons is both necessary and sufficient to provide substantial endogenous protection against kainic acid (KA)-induced seizures. The direct endocannabinoid-mediated control of hippocampal glutamatergic neurotransmission may constitute a promising therapeutic target for the treatment of disorders associated with excessive excitatory neuronal activity.
Subject(s)
Cannabinoid Receptor Modulators/physiology , Endocannabinoids , Epilepsy/pathology , Epilepsy/physiopathology , Hippocampus/pathology , Nerve Net/pathology , Analysis of Variance , Animals , Behavior, Animal/drug effects , Benzoxazines , Calcium Channel Blockers/pharmacology , Calcium-Calmodulin-Dependent Protein Kinase Type 2 , Calcium-Calmodulin-Dependent Protein Kinases/genetics , Epilepsy/chemically induced , Epilepsy/genetics , Gene Expression/physiology , Glutamic Acid/genetics , Glutamic Acid/metabolism , Hippocampus/drug effects , Hippocampus/physiopathology , Kainic Acid/toxicity , Male , Membrane Potentials/drug effects , Membrane Potentials/genetics , Membrane Potentials/radiation effects , Mice , Mice, Inbred C57BL , Mice, Transgenic , Morpholines/pharmacology , Naphthalenes/pharmacology , Nerve Net/drug effects , Nerve Net/physiopathology , Pyramidal Cells/physiology , Pyramidal Cells/radiation effects , Receptor, Cannabinoid, CB1/deficiency , Reverse Transcriptase Polymerase Chain Reaction/methods , Vesicular Glutamate Transport Protein 1/metabolism , gamma-Aminobutyric Acid/geneticsABSTRACT
BACKGROUND: This phase Ib study evaluated the safety, clinical activity, pharmacokinetics, and pharmacodynamics (PD) of emactuzumab (anti-colony stimulating factor 1 receptor monoclonal antibody (mAb)) in combination with selicrelumab (agonistic cluster of differentiation 40 mAb) in patients with advanced solid tumors. METHODS: Both emactuzumab and selicrelumab were administered intravenously every 3 weeks and doses were concomitantly escalated (emactuzumab: 500 to 1000 mg flat; selicrelumab: 2 to 16 mg flat). Dose escalation was conducted using the product of independent beta probabilities dose-escalation design. PD analyzes were performed on peripheral blood samples and tumor/skin biopsies at baseline and on treatment. Clinical activity was evaluated using investigator-based and Response Evaluation Criteria In Solid Tumors V.1.1-based tumor assessments. RESULTS: Three dose-limiting toxicities (all infusion-related reactions (IRRs)) were observed at 8, 12 and 16 mg of selicrelumab together with 1000 mg of emactuzumab. The maximum tolerated dose was not reached at the predefined top doses of emactuzumab (1000 mg) and selicrelumab (16 mg). The most common adverse events were IRRs (75.7%), fatigue (54.1%), facial edema (37.8%), and increase in aspartate aminotransferase and creatinine phosphokinase (35.1% both). PD analyzes demonstrated an increase of Ki67+-activated CD8+ T cells accompanied by a decrease of B cells and the reduction of CD14Dim CD16bright monocytes in peripheral blood. The best objective clinical response was stable disease in 40.5% of patients. CONCLUSION: Emactuzumab in combination with selicrelumab demonstrated a manageable safety profile and evidence of PD activity but did not translate into objective clinical responses. TRIALREGISTRATION NUMBER: NCT02760797.
Subject(s)
Antibodies, Monoclonal, Humanized/therapeutic use , Antineoplastic Combined Chemotherapy Protocols/therapeutic use , CD40 Antigens/metabolism , Neoplasms/drug therapy , Receptor, Macrophage Colony-Stimulating Factor/antagonists & inhibitors , Antibodies, Monoclonal, Humanized/pharmacology , Antineoplastic Combined Chemotherapy Protocols/pharmacology , Female , Humans , Male , Neoplasms/immunology , Receptor, Macrophage Colony-Stimulating Factor/metabolismABSTRACT
OBJECTIVES: This study investigated the safety, clinical activity and patient-reported outcomes of patients with diffuse-type tenosynovial giant-cell tumour (dTGCT) of the soft tissue who were treated with emactuzumab, a humanised anti-colony stimulating factor 1 receptor (CSF1R) monoclonal antibody and were followed up for up to 2 years after the start of treatment. METHODS: In this open-label phase 1 study (ClinicalTrials.govNCT01494688), patients received intravenous (IV) emactuzumab from 900 to 2000 mg every two weeks in the dose-escalation phase and at the optimal biological dose of 1000 mg with different schedules in the dose-expansion phase. Adverse event (AE) rates and biomarker assessments from tumour biopsies were analysed. Quality of life was assessed using a standard questionnaire (EuroQol-5D-3L) and the WOMAC® 3.1 Osteoarthritis Index. Tumour responses were determined with magnetic resonance imaging. RESULTS: Altogether, 63 patients were enrolled into the study. The most frequently reported AEs were pruritus, asthenia and oedema. In 36 patients for whom biopsy tissue was available a substantial decrease of CSF1R-positive and CD68/CD163-positive macrophages was detected. The independently reviewed best overall objective response rate (ORR) (Response Evaluation Criteria in Solid Tumors version 1.1) was 71%. Responses were durable, and an ORR of 70% and 64% was determined after one or two years after enrolment into the study. Clinical activity was accompanied by an improvement in EuroQol-5D-3L and particularly the joint disorder-specific WOMAC score. CONCLUSIONS: Systemic therapy of dTGCT patients with emactuzumab resulted in pronounced and durable responses associated with symptomatic improvement and a manageable safety profile.
Subject(s)
Antibodies, Monoclonal, Humanized/therapeutic use , Antineoplastic Agents, Immunological/therapeutic use , Quality of Life , Synovitis, Pigmented Villonodular/drug therapy , Adolescent , Adult , Aged , Aged, 80 and over , Female , Humans , Male , Middle Aged , Young AdultABSTRACT
PURPOSE: This study investigated the safety and clinical activity of lumretuzumab, a humanised antihuman epidermal growth factor receptor 3 (HER3) monoclonal antibody, in combination with carboplatin and paclitaxel in first-line treatment of patients with squamous non-small cell lung cancer (sqNSCLC). HER3 ligand heregulin and HER3 protein expression were evaluated as potential biomarkers of clinical activity. PATIENTS AND METHODS: This open-label, phase Ib/II study enrolled patients receiving lumretuzumab at 800 mg (flat) in combination with carboplatin (area under the curve (AUC) 6 mg/mL×min) and paclitaxel (200 mg/m2) administered intravenously on a every 3-week schedule. Adverse event (AE) rates and tumour responses were determined. Heregulin messenger RNA (mRNA) and HER3 protein expression were investigated in archival tumour biopsies. RESULTS: Altogether, 12 patients received lumretuzumab in combination with carboplatin and paclitaxel. The most frequent AEs were gastrointestinal, haematological and nervous system toxicities, which were generally mild and manageable. Partial responses were observed in 3 of 12 patients lasting 81, 177 and 207 days. All responses were achieved in tumours expressing higher heregulin mRNA levels. CONCLUSION: Lumretuzumab in combination with carboplatin and paclitaxel was well tolerated. Objective responses were enriched in tumours expressing higher heregulin mRNA levels.
ABSTRACT
The human epidermal growth factor receptor (HER) family consists of four transmembrane receptor tyrosine kinases: epidermal growth factor receptor (EGFR), HER2, HER3, and HER4. They are part of a complex signalling network and stimulate intracellular pathways regulating cell growth and differentiation. So far, monoclonal antibodies (mAbs) and small molecule tyrosine kinase inhibitors targeting EGFR and HER2 have been developed and approved. Recently, focus has turned to HER3 as it may play an important role in resistance to EGFR- and HER2-targeting therapies. HER3-targeting agents have been undergoing clinical evaluation for the last 10â¯years and currently thirteen mAbs are in phase 1 or 2 clinical studies. Single agent activity has proven to be limited, however, the tolerability was favourable. Thus, combinations of HER3-binding mAbs with other HER-targeting therapies or chemotherapies have been pursued in various solid tumor entities. Data indicate that the HER3-binding ligand heregulin may serve as a response prediction marker for HER3-targeting therapy. Within this review the current status of clinical development of HER3-targeting compounds is described.
Subject(s)
Antibodies, Monoclonal/therapeutic use , Neoplasms/therapy , Protein Kinase Inhibitors/therapeutic use , Receptor, ErbB-3/immunology , Antibodies, Monoclonal/immunology , ErbB Receptors/antagonists & inhibitors , ErbB Receptors/immunology , Humans , Molecular Targeted Therapy , Neoplasms/enzymology , Neoplasms/immunology , Receptor, ErbB-3/antagonists & inhibitorsABSTRACT
Rearrangements of NRG1 have been identified in invasive mucinous adenocarcinoma of the lung (IMA), formerly referred to as mucinous bronchioloalveolar carcinoma. NRG1 ligand signals through induction of HER2-HER3 heterodimers, thus leading to PI3K-AKT pathway activation. Therefore, targeting HER2, HER3 and the downstream pathway may be a hypothesis-driven strategy for IMA with NRG1 fusion. Herein we reported two patients who benefited from lumretuzumab, a monoclonal anti-HER3 antibody, in combination of erlotinib during a clinical trial (NCT01482377). At least sixteen weeks of progression-free survival were achieved without any unacceptable toxicity.
Subject(s)
Adenocarcinoma, Mucinous/drug therapy , Antibodies, Monoclonal, Humanized/therapeutic use , Antineoplastic Agents/therapeutic use , Lung Neoplasms/drug therapy , Neuregulin-1/genetics , Oncogene Proteins, Fusion/genetics , Adenocarcinoma, Mucinous/genetics , Adult , Clinical Trials as Topic , ErbB Receptors/genetics , ErbB Receptors/metabolism , Erlotinib Hydrochloride/therapeutic use , Female , Humans , Lung Neoplasms/genetics , Middle Aged , Molecular Targeted Therapy , Neoplasm Staging , Phosphatidylinositol 3-Kinases/metabolism , Progression-Free Survival , Proto-Oncogene Proteins c-akt/metabolism , Receptor, ErbB-3/immunology , Receptor, ErbB-3/metabolism , Signal Transduction/drug effectsABSTRACT
Combination of targeted therapies is expected to provide superior efficacy in the treatment of cancer either by enhanced antitumor activity or by preventing or delaying the development of resistance. Common challenges in developing combination therapies include the potential of additive and aggravated toxicities associated with pharmacologically related adverse effects. We have recently reported that combination of anti-HER2 and anti-HER3 antibodies, pertuzumab and lumretuzumab, along with paclitaxel chemotherapy in metastatic breast cancer, resulted in a high incidence of diarrhea that ultimately limited further clinical development of this combination. Here, we further dissected the diarrhea profile of the various patient dose cohorts and carried out in vitro investigations in human colon cell lines and explants to decipher the contribution and the mechanism of anti-HER2/3 therapeutic antibodies to intestinal epithelium malfunction. Our clinical investigations in patients revealed that while dose reduction of lumretuzumab, omission of pertuzumab loading dose, and introduction of a prophylactic antidiarrheal treatment reduced most severe adverse events, patients still suffered from persistent diarrhea during the treatment. Our in vitro investigations showed that pertuzumab and lumretuzumab combination treatment resulted in upregulation of chloride channel activity without indication of intestinal barrier disruption. Overall, our findings provide a mechanistic rationale to explore alternative of conventional antigut motility using medication targeting chloride channel activity to mitigate diarrhea of HER combination therapies. Mol Cancer Ther; 17(7); 1464-74. ©2018 AACR.
Subject(s)
Antibodies, Anti-Idiotypic/administration & dosage , Colonic Neoplasms/drug therapy , Diarrhea/genetics , Receptor, ErbB-2/genetics , Receptor, ErbB-3/genetics , Adult , Aged , Antibodies, Anti-Idiotypic/adverse effects , Antibodies, Monoclonal, Humanized/administration & dosage , Antibodies, Monoclonal, Humanized/adverse effects , Antineoplastic Combined Chemotherapy Protocols/administration & dosage , Antineoplastic Combined Chemotherapy Protocols/adverse effects , Breast Neoplasms/drug therapy , Breast Neoplasms/genetics , Breast Neoplasms/pathology , Caco-2 Cells , Cell Proliferation/drug effects , Colonic Neoplasms/genetics , Colonic Neoplasms/pathology , Combined Modality Therapy , Diarrhea/chemically induced , Diarrhea/pathology , Dose-Response Relationship, Drug , Drug-Related Side Effects and Adverse Reactions/drug therapy , Drug-Related Side Effects and Adverse Reactions/pathology , Female , Humans , Intestinal Mucosa/drug effects , Intestinal Mucosa/pathology , Middle Aged , Neoplasm Metastasis , Paclitaxel/administration & dosage , Paclitaxel/adverse effects , Receptor, ErbB-2/antagonists & inhibitors , Receptor, ErbB-3/antagonists & inhibitorsABSTRACT
PURPOSE: This study aimed at evaluating if pharmacokinetic and pharmacodynamic data from the first few patients treated with an investigational monoclonal antibody in a dose-escalation study can be used to guide the early initiation of potentially more efficacious combination regimens. METHODS: Emerging pharmacokinetic and pharmacodynamic data from the first nine patients treated with lumretuzumab (a glycoengineered anti-HER3 monoclonal antibody) monotherapy at doses from 100 to 400 mg q2w were used along with a pharmacokinetic model that incorporated target-mediated drug disposition to guide the selection of the starting dose for use in combination regimens. RESULTS: The dose-escalation study investigated lumretuzumab doses up to 2000 mg q2w and a maximum tolerated dose was not reached. However, the model described in this report predicted linear lumretuzumab pharmacokinetics and >95% target saturation at doses ≥400 mg q2w. These data, along with safety data, contributed to the decision to begin dose-escalation studies in combination with cetuximab and erlotinib using a starting dose of 400 mg lumretuzumab. Pharmacokinetic data from patients treated with lumretuzumab 400-2000 mg q2w in combination regimens were consistent with the model predictions. CONCLUSION: PK/PD modelling of emerging clinical data might accelerate development programs by enabling additional parts of a trial to commence before completion of the monotherapy part. The dose and schedule of lumretuzumab were optimised for concomitant therapy at doses substantially below the highest dose investigated.
Subject(s)
Antibodies, Monoclonal, Humanized/pharmacology , Antibodies, Monoclonal, Humanized/pharmacokinetics , Antineoplastic Agents/pharmacology , Antineoplastic Agents/pharmacokinetics , Adult , Antibodies, Monoclonal, Humanized/adverse effects , Antineoplastic Agents/administration & dosage , Antineoplastic Agents/adverse effects , Antineoplastic Combined Chemotherapy Protocols/therapeutic use , Cohort Studies , Dose-Response Relationship, Drug , Erlotinib Hydrochloride/administration & dosage , Female , Humans , Male , Maximum Tolerated Dose , Middle Aged , Models, Statistical , Receptor, ErbB-2/antagonists & inhibitors , Research DesignABSTRACT
The tumor-permissive and immunosuppressive characteristics of tumor-associated macrophages (TAM) have fueled interest in therapeutically targeting these cells. In this context, the colony-stimulating factor 1 (CSF1)/colony-stimulating factor 1 receptor (CSF1R) axis has gained the most attention, and various approaches targeting either the ligands or the receptor are currently in clinical development. Emerging data on the tolerability of CSF1/CSF1R-targeting agents suggest a favorable safety profile, making them attractive combination partners for both standard treatment modalities and immunotherapeutic agents. The specificity of these agents and their potent blocking activity has been substantiated by impressive response rates in diffuse-type tenosynovial giant cell tumors, a benign connective tissue disorder driven by CSF1 in an autocrine fashion. In the malignant disease setting, data on the clinical activity of immunotherapy combinations with CSF1/CSF1R-targeting agents are pending. As our knowledge of macrophage biology expands, it becomes apparent that the complex phenotypic and functional properties of macrophages are heavily influenced by a continuum of survival, differentiation, recruitment, and polarization signals within their specific tissue environment. Thus, the role of macrophages in regulating tumorigenesis and the impact of depleting and/or reprogramming TAM as therapeutic approaches for cancer patients may vary greatly depending on organ-specific characteristics of these cells. We review the currently available clinical safety and efficacy data with CSF1/CSF1R-targeting agents and provide a comprehensive overview of ongoing clinical studies. Furthermore, we discuss the local tissue macrophage and tumor-type specificities and their potential impact on CSF1/CSF1R-targeting treatment strategies for the future.
Subject(s)
Antineoplastic Agents, Immunological/therapeutic use , Immunotherapy/methods , Neoplasms/therapy , Receptors, Granulocyte-Macrophage Colony-Stimulating Factor/antagonists & inhibitors , Antineoplastic Combined Chemotherapy Protocols/therapeutic use , Clinical Trials as Topic , Humans , Macrophages/drug effects , Patient SafetyABSTRACT
Bidirectional cross talk between members of the human epidermal growth factor family of receptors (HER) and the estrogen receptor (ER) is believed to underlie resistance mechanisms that develop in response to treatment with anti-HER agents and endocrine therapy. We investigated the interaction between HER2, HER3 and the ER in vitro using human embryonic kidney cells transfected with human HER2, HER3, and ERα. We also investigated the additive efficacy of combination regimens consisting of anti-HER3 (lumretuzumab), anti-HER2 (pertuzumab), and endocrine (fulvestrant) therapy in vivo. Our data show that both HER2 and HER3 can directly complex with the ER and can mediate phosphorylation of the ER. Phosphorylation of the ER was only observed in cells that expressed both HER2 and ERα or in heregulin-stimulated cells that expressed both HER3 and ERα. Using a mouse xenograft model of ER+/HER2-low (HER2 immunohistochemistry 1+ or 2+ without gene amplification) human breast cancer we show that the combination of lumretuzumab and pertuzumab is highly efficacious and induces long-lasting tumor regression in vivo and adding endocrine therapy (fulvestrant) to this combination further improved efficacy. In addition, a prolonged clinical response was observed with the combination of lumretuzumab and pertuzumab in a patient with ER+/HER2-low breast cancer who had failed endocrine therapy. These preclinical data confirm that direct cross talk exists between HER2/HER3 and ER which may explain the resistance mechanisms to endocrine therapy and monoclonal antibodies that target HER2 and HER3. Our data also indicate that the triplet of anti-HER2, anti-HER3, and endocrine therapy might be an efficacious combination for treating patients with ER+/HER2-low breast cancer, which is an area of significant unmet medical need.
Subject(s)
Antibodies, Monoclonal, Humanized/therapeutic use , Breast Neoplasms/drug therapy , Receptor Cross-Talk , Receptor, ErbB-2/metabolism , Receptor, ErbB-3/metabolism , Receptors, Estrogen/metabolism , Adult , Animals , Antibodies, Monoclonal, Humanized/pharmacology , Antineoplastic Combined Chemotherapy Protocols/pharmacology , Antineoplastic Combined Chemotherapy Protocols/therapeutic use , Breast Neoplasms/metabolism , Cell Line, Tumor , Female , Humans , Immunoprecipitation , Mice , Paclitaxel/pharmacology , Paclitaxel/therapeutic use , Remission Induction , Signal Transduction/drug effects , Treatment Outcome , Xenograft Model Antitumor AssaysABSTRACT
Purpose: We evaluated biodistribution and tumor targeting of 89Zr-lumretuzumab before and during treatment with lumretuzumab, a human epidermal growth factor receptor 3 (HER3)-targeting monoclonal antibody.Experimental Design: Twenty patients with histologically confirmed HER3-expressing tumors received 89Zr-lumretuzumab and underwent positron emission tomography (PET). In part A, 89Zr-lumretuzumab was given with additional, escalating doses of unlabeled lumretuzumab, and scans were performed 2, 4, and 7 days after injection to determine optimal imaging conditions. In part B, patients were scanned following tracer injection before (baseline) and after a pharmacodynamic (PD)-active lumretuzumab dose for saturation analysis. HER3 expression was determined immunohistochemically in skin biopsies. Tracer uptake was calculated as standardized uptake value (SUV).Results: Optimal PET conditions were found to be 4 and 7 days after administration of 89Zr-lumretuzumab with 100-mg unlabeled lumretuzumab. At baseline using 100-mg unlabeled lumretuzumab, the tumor SUVmax was 3.4 (±1.9) at 4 days after injection. SUVmean values for normal blood, liver, lung, and brain tissues were 4.9, 6.4, 0.9 and 0.2, respectively. Saturation analysis (n = 7) showed that 4 days after lumretuzumab administration, tumor uptake decreased by 11.9% (±8.2), 10.0% (±16.5), and 24.6% (±20.9) at PD-active doses of 400, 800, and 1,600 mg, respectively, when compared with baseline. Membranous HER3 was completely downregulated in paired skin biopsies already at and above 400-mg lumretuzumab.Conclusions: PET imaging showed biodistribution and tumor-specific 89Zr-lumretuzumab uptake. Although, PD-active lumretuzumab doses decreased 89Zr-lumretuzumab uptake, there was no clear evidence of tumor saturation by PET imaging as the tumor SUV did not plateau with increasing doses. Clin Cancer Res; 23(20); 6128-37. ©2017 AACR.
Subject(s)
Antibodies, Monoclonal, Humanized/therapeutic use , Antineoplastic Agents, Immunological/therapeutic use , Neoplasms/diagnosis , Neoplasms/drug therapy , Positron-Emission Tomography , Radiopharmaceuticals , Zirconium , Aged , Antibodies, Monoclonal, Humanized/administration & dosage , Antibodies, Monoclonal, Humanized/adverse effects , Antibodies, Monoclonal, Humanized/pharmacokinetics , Antineoplastic Agents, Immunological/administration & dosage , Antineoplastic Agents, Immunological/adverse effects , Antineoplastic Agents, Immunological/pharmacokinetics , Drug Monitoring , Female , Gene Expression , Humans , Male , Middle Aged , Molecular Targeted Therapy , Neoplasms/metabolism , Receptor, ErbB-3/antagonists & inhibitors , Receptor, ErbB-3/genetics , Receptor, ErbB-3/metabolism , Treatment OutcomeABSTRACT
Purpose: This study investigated the safety, clinical activity, and target-associated biomarkers of lumretuzumab, a humanized, glycoengineered, anti-HER3 monoclonal antibody (mAb), in combination with the EGFR-blocking agents erlotinib or cetuximab in patients with advanced HER3-positive carcinomas.Experimental Design: The study included two parts: dose escalation and dose extension phases with lumretuzumab in combination with either cetuximab or erlotinib, respectively. In both parts, patients received lumretuzumab doses from 400 to 2,000 mg plus cetuximab or erlotinib according to standard posology, respectively. The effect of HRG mRNA and HER3 mRNA and protein expression were investigated in a dedicated extension cohort of squamous non-small cell lung cancer (sqNSCLC) patients treated with lumretuzumab and erlotinib.Results: Altogether, 120 patients were treated. One dose-limiting toxicity (DLT) in the cetuximab part and two DLTs in the erlotinib part were reported. The most frequent adverse events were gastrointestinal and skin toxicities, which were manageable. The objective response rate (ORR) was 6.1% in the cetuximab part and 4.2% in the erlotinib part. In the sqNSCLC extension cohort of the erlotinib part, higher tumor HRG and HER3 mRNA levels were associated with a numerically higher disease control rate but not ORR.Conclusions: The toxicity profile of lumretuzumab in combination with cetuximab and erlotinib was manageable, but only modest clinical activity was observed across tumor types. In the sqNSCLC cohort, there was no evidence of meaningful clinical benefit despite enriching for tumors with higher HRG mRNA expression levels. Clin Cancer Res; 23(18); 5406-15. ©2017 AACR.
Subject(s)
Antineoplastic Combined Chemotherapy Protocols/therapeutic use , Biomarkers, Tumor , Neoplasms/drug therapy , Neoplasms/metabolism , Neuregulin-1/metabolism , Receptor, ErbB-3/metabolism , Antibodies, Monoclonal, Humanized/administration & dosage , Antineoplastic Combined Chemotherapy Protocols/adverse effects , Cetuximab/administration & dosage , Erlotinib Hydrochloride/administration & dosage , Female , Gene Expression Regulation, Neoplastic , Humans , Male , Neoplasms/mortality , Neoplasms/pathology , Neuregulin-1/genetics , Receptor, ErbB-3/genetics , Survival Analysis , Treatment OutcomeABSTRACT
In depressed patients as well as healthy controls, a positive relationship between hippocampal volume and trait anxiety has been reported. This study sought to explore the possible inter-relation between hippocampal volume and trait anxiety further. Magnetic resonance imaging at 7 T was used to measure hippocampal volumes in a rat model of extremes in trait anxiety (experiment 1) and in a Wistar population with normal anxiety-related behavior (experiment 2). In addition to anxiety-related behavior, potentially confounding factors (depression-like, exploratory, and locomotor behavior) were assessed. Experiment 1 globally supported the hypothesis of a positive relationship between hippocampus volume and trait anxiety but did not allow for ruling out possible confounds arising from cosegregation of other behavioral traits. Experiment 2 yielded strong evidence for a negative relationship which was specific for trait anxiety. Thus, the relationship between hippocampal volume and anxiety may be more complex than expected. Interestingly, anxiety-related behavior in experiment 2 had a stronger influence on hippocampal volume than depression-like behavior. In the light of hippocampal volume loss in anxiety disorder and frequent comorbidity of anxiety and depression, this finding suggests that further research into the relationship between anxiety and hippocampal volume may be critical for understanding hippocampal contributions to normal and pathological behavior.
Subject(s)
Anxiety Disorders/diagnosis , Anxiety Disorders/physiopathology , Atrophy/diagnosis , Atrophy/physiopathology , Hippocampus/pathology , Hippocampus/physiopathology , Animals , Anxiety Disorders/complications , Atrophy/etiology , Depressive Disorder/complications , Depressive Disorder/diagnosis , Depressive Disorder/physiopathology , Disease Models, Animal , Magnetic Resonance Imaging , Male , Neural Pathways/pathology , Neural Pathways/physiopathology , RatsABSTRACT
PURPOSE: A first-in-human phase I study was conducted to characterize safety, efficacy, and pharmacokinetic (PK) and pharmacodynamic (PD) properties of lumretuzumab, a humanized and glycoengineered anti-HER3 monoclonal antibody, in patients with advanced cancer. EXPERIMENTAL DESIGN: Twenty-five patients with histologically confirmed HER3-expressing tumors received lumretuzumab (100, 200, 400, 800, 1,600, and 2,000 mg) every two weeks (q2w) in 3+3 dose-escalation phase. In addition, 22 patients were enrolled into an extension cohort at 2,000 mg q2w. RESULTS: There were no dose-limiting toxicities. Common adverse events (any grade) included diarrhea (22 patients, 46.8%), fatigue (21 patients, 44.7%), decreased appetite (15 patients, 31.9%), infusion-related reactions (13 patients, 27.7%), and constipation (10 patients, 21.3%). The peak concentration (Cmax) and area under the concentration-time curve up to the last measurable concentration (AUClast) of lumretuzumab increased more than dose proportionally from 100 mg up to 400 mg. Linear PK was observed with doses ≥ 400 mg q2w indicating target-mediated drug disposition saturation. Downregulation of HER3 membranous protein was observed in on-treatment tumor biopsies from 200 mg, and was maximal at and above 400 mg. An ex vivo assay demonstrated increased activation potential of peripheral NK lymphocytes with lumretuzumab compared with a non-glycoengineered anti-HER3 antibody. Ten patients (21.3%) had stable disease and remained on study at a median of 111 days (range, 80-225 days). CONCLUSIONS: Lumretuzumab was well tolerated and showed evidence of clinical activity. Linear serum PK properties and plateauing of PD effects in serial tumor biopsies indicate optimal biologically active doses of lumretuzumab from 400 mg onwards.
Subject(s)
Analgesics/therapeutic use , Antibodies, Monoclonal, Humanized/therapeutic use , Colorectal Neoplasms/drug therapy , Adult , Aged , Analgesics/pharmacology , Antibodies, Monoclonal, Humanized/pharmacology , Colorectal Neoplasms/metabolism , Female , Humans , Male , Maximum Tolerated Dose , Middle Aged , Receptor, ErbB-3/antagonists & inhibitors , Receptor, ErbB-3/metabolism , Treatment OutcomeABSTRACT
In the hippocampus of freely moving rats, neurons have been recorded that fire predominantly when the animal travels through a particular area while exploring the environment (so-called 'place cells'). This study investigates if the neuronal firing characteristics of such cells are modulated by attention, expectation of reward or memory load. A total of 16 electrodes were implanted in the CA1 region of the hippocampus of 3-month-old Long-Evans rats. Using a tetrode recording system, single neurons were recorded while a rat explored an 8-arm maze and retrieved pellets at the end of each arm. It was found that 31 out of 67 neurons showed place cell characteristics, while the other cells either fired in more than one place or fired along whole arms of the maze. Interestingly, 11 of the 31 neurons showed enhanced firing activity when the animal entered a baited arm but did not fire when the arm was visited again after the bait had been retrieved. In a second experiment, only four out of eight arms were baited. Firing rates of 46 neurons were analysed, and all cells (spatial or non-spatial) fired more in baited arms than in non-baited ones (P<0.001). In a reversal task in which the previously unbaited four arms were subsequently baited, neuronal activity was increased in the newly baited arms (42 cells analysed, P<0.001). Since no alterations to the maze or cues have been made, we interpret the increased firing probability of neurons in baited arms compared to unbaited arms as a correlate for 'attention' or 'expectation'.
Subject(s)
Attention/physiology , Hippocampus/physiology , Maze Learning/physiology , Reinforcement, Psychology , Animals , Electrophysiology , Hippocampus/cytology , Male , Neurons/physiology , Rats , Rats, Long-EvansABSTRACT
Fenobam [N-(3-chlorophenyl)-N'-(4,5-dihydro-1-methyl-4-oxo-1H-imidazole-2-yl)urea] was suggested to possess anxiolytic actions 30 years ago. Hoffmann-La Roche researchers recently reported that it is a selective and potent mGlu5 receptor antagonist, acting as a negative allosteric modulator. In the present study, we show that fenobam readily penetrates to the brain, reaching concentrations over 600 nM, clearly above the affinity for mGluR5 receptors. Fenobam (at 10, 30, and 100 mg/kg) did not affect horizontal locomotor activity in the open field test. Anxiolytic-like activity in the context freezing test was seen at 30 mg/kg, while fenobam was not active in the elevated plus maze test at the tested concentrations. Fenobam had antinociceptive actions in the formalin test at 10 and 30 mg/kg, but failed to attenuate mechanical allodynia in the chronic constriction injury model. Impairment of learning was revealed in the passive avoidance test at 30 mg/kg. Fenobam also impaired performance in both the Morris water maze and in the contextual fear conditioning test at the doses of 30 and 10 mg/kg, respectively. Prepulse inhibition, used as a model of psychomimetic activity, was not affected by fenobam at doses of up to 60 mg/kg. Our results indicate that the beneficial effects of fenobam occur in a similar dose range as the potential side-effects.
Subject(s)
Analgesics, Non-Narcotic/pharmacology , Anti-Anxiety Agents/pharmacology , Brain/drug effects , Imidazoles/pharmacology , Learning/drug effects , Receptors, Metabotropic Glutamate/antagonists & inhibitors , Animals , Avoidance Learning/drug effects , Conditioning, Classical/drug effects , Dose-Response Relationship, Drug , Fear , Freezing Reaction, Cataleptic/drug effects , Locomotion/drug effects , Male , Maze Learning/drug effects , Pain/drug therapy , Pain Measurement , Physical Stimulation , Random Allocation , Rats , Rats, Sprague-Dawley , Receptor, Metabotropic Glutamate 5ABSTRACT
Following secretion from the posterior pituitary, the neuropeptide vasopressin (AVP) stimulates the kidney to retain water, and when released centrally it can contribute to anxiety- and depression-like behaviours. We hypothesized that CD1 mice bred for low trait anxiety (LAB) suffer from a deficit in AVP. Both osmotically stimulated peripheral secretion and intra-paraventricular nucleus (PVN) release of AVP were found decreased in LAB animals compared with normal anxiety (NAB) or high anxiety (HAB) controls. Consequently, in addition to their extreme non-anxiety, LAB mice showed signs of central diabetes insipidus (cDI), including increased fluid intake and reduced urine osmolality, as well as a pathological increase in plasma osmolality upon water deprivation. These cDI symptoms were attenuated by administration of a selective AVP V2 receptor agonist. A single nucleotide polymorphism (SNP) in exon 1 (C(+40)T) of the Avp gene of LAB animals causes an amino acid substitution in the signal peptide of the AVP precursor, and is likely to impair processing and trafficking of the precursor, as suggested by reduced axonal transport of AVP from the hypothalamic PVN, finally contributing to cDI symptoms and low trait anxiety. In an F2 panel, this SNP co-segregated with fluid intake and showed a partial contribution to low anxiety-related behaviour, indicated by its co-segregation with time spent on the open arms of the elevated plus-maze in a subset of F2 mice. Thus, the SNP-associated deficit in plasma and central AVP contributes to signs of cDI and, at least partially, to low trait anxiety, both features being typical of LAB animals.