ABSTRACT
BACKGROUND: Diffuse-type tenosynovial giant cell tumour (dt-GCT) of the soft tissue (alternatively known as pigmented villonodular synovitis), an orphan disease with unmet medical need, is characterised by an overexpression of colony-stimulating factor 1 (CSF1), and is usually caused by a chromosomal translocation involving CSF1. CSF1 receptor (CSF1R) activation leads to the recruitment of CSF1R-expressing cells of the mononuclear phagocyte lineage that constitute the tumor mass in dt-GCT. Emactuzumab (RG7155) is a novel monoclonal antibody that inhibits CSF1R activation. We have assessed the safety, tolerability and activity of emactuzumab in patients with Dt-GCT of the soft tissue. METHODS: In this phase 1, first-in-human dose-escalation and dose-expansion study, eligible patients were aged 18 years or older with dt-GCT of the soft tissue with locally advanced disease or resectable tumours requiring extensive surgery, an Eastern Cooperative Oncology Group performance status of 1 or less, measurable disease according to Response Evaluation Criteria In Solid Tumors version 1.1, and adequate end-organ function. Patients with GCT of the bone were not eligible. Patients received intravenous emactuzumab at 900 mg, 1350 mg, or 2000 mg every 2 weeks in the dose-escalation phase and at the optimal biological dose in a dose-expansion phase. The primary objective was to evaluate the safety and tolerability of emactuzumab, and to determine the maximum tolerated dose or optimal biological dose. All treated patients were included in the analyses. Expansion cohorts are currently ongoing. This study is registered with ClinicalTrials.gov, number NCT01494688. FINDINGS: Between July 26, 2012, and Oct 21, 2013, 12 patients were enrolled in the dose-escalation phase. No dose-limiting toxicities were noted in the dose-escalation cohort; on the basis of pharmacokinetic, pharmacodynamic, and safety information, we chose a dose of 1000 mg every 2 week for the dose-expansion cohort, into which 17 patients were enrolled. Owing to different cutoff dates for safety and efficacy readouts, the safety population comprised 25 patients. Common adverse events after emactuzumab treatment were facial oedema (16 [64%] of 25 patients), asthenia (14 [56%]), and pruritus (14 [56%]). Five serious adverse events (periorbital oedema, lupus erythematosus [occurring twice], erythema, and dermohypodermitis all experienced by one [4%] patient each) were reported in five patients. Three of the five serious adverse events-periorbital oedema (one [4%]), lupus erythematosus (one [4%]), and dermohypodermitis (one [4%])-were assessed as grade 3. Two other grade 3 events were reported: mucositis (one [4%]) and fatigue (one [4%]). 24 (86%) of 28 patients achieved an objective response; two (7%) patients achieved a complete response. INTERPRETATION: Further study of dt-GCT is warranted and different possibilities, such as an international collaboration with cooperative groups to assure appropriate recruitment in this rare disease, are currently being assessed. FUNDING: F Hoffmann-La Roche.
Subject(s)
Antibodies, Monoclonal/administration & dosage , Antineoplastic Agents/administration & dosage , Giant Cell Tumors/drug therapy , Receptor, Macrophage Colony-Stimulating Factor/antagonists & inhibitors , Soft Tissue Neoplasms/drug therapy , Synovitis, Pigmented Villonodular/drug therapy , Adolescent , Adult , Aged , Aged, 80 and over , Antibodies, Monoclonal/adverse effects , Antibodies, Monoclonal, Humanized , Antineoplastic Agents/adverse effects , Drug Administration Schedule , Female , Giant Cell Tumors/immunology , Giant Cell Tumors/metabolism , Giant Cell Tumors/pathology , Humans , Infusions, Intravenous , Male , Middle Aged , Receptor, Macrophage Colony-Stimulating Factor/immunology , Receptor, Macrophage Colony-Stimulating Factor/metabolism , Signal Transduction/drug effects , Soft Tissue Neoplasms/immunology , Soft Tissue Neoplasms/metabolism , Soft Tissue Neoplasms/pathology , Synovitis, Pigmented Villonodular/immunology , Synovitis, Pigmented Villonodular/metabolism , Synovitis, Pigmented Villonodular/pathology , Time Factors , Treatment Outcome , Young AdultABSTRACT
Targeted biological therapies may achieve maximal therapeutic efficacy at doses below the maximum tolerated dose (MTD); therefore, the search for the MTD in clinical studies may not be ideal for these agents. Emactuzumab is an investigational monoclonal antibody that binds to and inhibits the activation of the cell surface colony-stimulating factor-1 receptor. Here, we show how modeling target-mediated drug disposition coupled with pharmacodynamic end points was used to optimize the dose of emactuzumab without defining an MTD. The model could be used to recommend doses across different disease indications. The approach recommended an optimal biological dose of emactuzumab for dosing every 2 weeks (q2w) ≥ 900 mg, approximately three-fold lower than the highest dose tested clinically. The model predicted that emactuzumab doses ≥ 900 mg q2w would achieve target saturation in excess of 90% over the entire dosing cycle. Subsequently, a dose of 1,000 mg q2w was used in the extension phase of a phase I study of emactuzumab in patients with advanced solid tumors or diffuse-type tenosynovial giant cell tumor. Clinical data from this study were consistent with model predictions. The model was also used to predict the optimum dose of emactuzumab for use with dosing every 3 weeks, enabling dosing flexibility with respect to comedications. In summary, this work demonstrates the value of quantitative clinical pharmacology approaches to dose selection in oncology as opposed to traditional MTD methods.
Subject(s)
Antibodies, Monoclonal, Humanized/pharmacokinetics , Antineoplastic Agents, Immunological/pharmacokinetics , Giant Cell Tumor of Tendon Sheath/drug therapy , Receptors, Granulocyte-Macrophage Colony-Stimulating Factor/antagonists & inhibitors , Antibodies, Monoclonal, Humanized/administration & dosage , Antineoplastic Agents, Immunological/administration & dosage , Clinical Trials, Phase I as Topic , Drug Administration Schedule , Drug Dosage Calculations , Giant Cell Tumor of Tendon Sheath/metabolism , Giant Cell Tumor of Tendon Sheath/pathology , Humans , Models, Biological , Molecular Targeted Therapy , Receptors, Granulocyte-Macrophage Colony-Stimulating Factor/metabolism , Signal Transduction , Treatment OutcomeABSTRACT
To identify monoclonal antibodies (mAbs) with high potency and novel recognition sites, more than 25,000 of mouse hybridomas were screened and 4 novel anti-human CCR5 mAbs ROAb12, ROAb13, ROAb14, and ROAb18 showing potent activity in cell-cell fusion (CCF) assay were identified. These mAbs demonstrated potent antiviral activities in both single-cycle HIV infection (IC(50) range: 0.16-4.3 microg/ml) and PBMC viral replication (IC(50) range: 0.02-0.04 microg/ml) assays. These potent antiviral effects were donor-independent. All 4 mAbs were also highly potent in the PhenoSense assay against 29 HIV isolates covering clade A through G. In all antiviral assays, these mAbs showed potency superior to the previously reported mAb 2D7 in side-by-side comparison studies. All 4 mAbs were also fully active against viruses resistant to HIV fusion inhibitor enfuvirtide and CCR5 antagonist maraviroc. Although ROAb12, ROAb14, and ROAb18 inhibited RANTES, MIP1alpha and MIP1beta binding and cell activation, the other novel mAb ROAb13 was inactive in inhibiting cell activation by these three ligands. Furthermore, highly synergistic antiviral effects were found between mAb ROAb13 and 2D7 or ROAb12. In addition, none of these mAbs showed agonist activity or caused internalization of the CCR5 receptor.
Subject(s)
Anti-HIV Agents/pharmacology , Antibodies, Monoclonal/immunology , Antibodies, Monoclonal/pharmacology , HIV/drug effects , HIV/physiology , Receptors, CCR5/immunology , Adaptor Proteins, Signal Transducing/metabolism , Animals , CCR5 Receptor Antagonists , Cell Fusion , Cell Line , Chemokine CCL5/metabolism , Cricetinae , Drug Synergism , Female , Humans , Mice , Mice, Inbred BALB C , Receptors, CCR5/metabolismABSTRACT
Vascular endothelial growth factor (VEGF)-A blockade has been validated clinically as a treatment for human cancers. Angiopoietin-2 (Ang-2) is a key regulator of blood vessel remodeling and maturation. In tumors, Ang-2 is up-regulated and an unfavorable prognostic factor. Recent data demonstrated that Ang-2 inhibition mediates anti-tumoral effects. We generated a tetravalent bispecific antibody (Ang-2-VEGF-TAvi6) targeting VEGF-A with 2 arms based on bevacizumab (Avastin®), and targeting Ang-2 with 2 arms based on a novel anti-Ang-2 antibody (LC06). The two Ang-2-targeting single-chain variable fragments are disulfide-stabilized and fused to the C-terminus of the heavy chain of bevacizumab. Treatment with Ang-2-VEGF-A-TAvi6 led to a complete abrogation of angiogenesis in the cornea micropocket assay. Metastatic spread and tumor growth of subcutaneous, orthotopic and anti-VEGF-A resistant tumors were also efficiently inhibited. These data further establish Ang-2-VEGF bispecific antibodies as a promising anti-angiogenic, anti-metastatic and anti-tumor agent for the treatment of cancer.
Subject(s)
Angiopoietin-2/antagonists & inhibitors , Antibodies, Bispecific , Antibodies, Neoplasm , Neoplasm Proteins/antagonists & inhibitors , Neoplasms, Experimental , Neovascularization, Pathologic , Vascular Endothelial Growth Factor A/antagonists & inhibitors , Animals , Antibodies, Bispecific/immunology , Antibodies, Bispecific/pharmacology , Antibodies, Neoplasm/immunology , Antibodies, Neoplasm/pharmacology , CHO Cells , Cricetinae , Cricetulus , HEK293 Cells , Human Umbilical Vein Endothelial Cells , Humans , Mice , Neoplasm Metastasis , Neoplasms, Experimental/drug therapy , Neoplasms, Experimental/immunology , Neoplasms, Experimental/pathology , Neovascularization, Pathologic/drug therapy , Neovascularization, Pathologic/immunology , Neovascularization, Pathologic/pathology , Xenograft Model Antitumor AssaysABSTRACT
RG7356, a recombinant anti-CD44 immunoglobulin G1 humanized monoclonal antibody, inhibits cell adhesion and has been associated with macrophage activation in preclinical models. We report results of a phase I dose-escalation study of RG7356 in relapsed/refractory acute myeloid leukemia (AML).Eligible patients with refractory AML, relapsed AML after induction chemotherapy, or previously untreated AML not eligible for intensive chemotherapy were enrolled and received intravenous RG7356 at dosages ≤ 2400 mg every other week or ≤ 1200 mg weekly or twice weekly; dose escalation started at 300 mg.Forty-four patients (median age, 69 years) were enrolled. One dose-limiting toxicity occurred (grade 3 hemolysis exacerbation) after one 1200 mg dose (twice-weekly cohort). The majority of adverse events were mild/moderate. Infusion-related reactions occurred in 64% of patients mainly during cycle 1. Two patients experienced grade 3 drug-induced aseptic meningitis. Pharmacokinetics increased supraproportionally, suggesting a target-mediated drug disposition (TMDD) at ≥ 1200 mg. Two patients achieved complete response with incomplete platelet recovery or partial response, respectively. One patient had stable disease with hematologic improvement.RG7356 was generally safe and well tolerated. Maximum tolerated dose was not reached, but saturation of TMDD was achieved. The recommended dose for future AML evaluations is 2400 mg every other week.
Subject(s)
Antibodies, Monoclonal, Humanized/administration & dosage , Antibodies, Monoclonal, Humanized/adverse effects , Leukemia, Myeloid, Acute/drug therapy , Adult , Aged , Aged, 80 and over , Dose-Response Relationship, Drug , Female , Humans , Leukemia, Myeloid, Acute/pathology , Male , Middle Aged , Young AdultABSTRACT
The tumor necrosis factor-like weak inducer of apoptosis (TWEAK) is a multifunctional cytokine playing a key role in tissue regeneration and remodeling. Dysregulation of TWEAK signaling is involved in various pathological processes like autoimmune diseases and cancer. The unique interaction with its cognate receptor Fn14 makes both ligand and receptor promising targets for novel therapeutics. To gain insights into this important signaling pathway, we determined the structure of soluble human TWEAK in complex with the Fab fragment of an antibody selected for inhibition of receptor binding. In the crystallized complex TWEAK is bound by three Fab fragments of the neutralizing antibody. Homology modeling shows that Fab binding overlaps with the putative Fn14 binding site of TWEAK. Docking of the Fn14 cysteine rich domain (CRD) to that site generates a highly complementary interface with perfectly opposing charged and hydrophobic residues. Taken together the presented structure provides new insights into the biology of TWEAK and the TWEAK/Fn14 pathway, which will help to optimize the therapeutic strategy for treatment of related cancer types and autoimmune diseases.