Correlation of FCGRT genomic structure with serum immunoglobulin, albumin and farletuzumab pharmacokinetics in patients with first relapsed ovarian cancer.

Farletuzumab (FAR) is a humanized monoclonal antibody (mAb) that binds to folate receptor alpha. A Ph3 trial in ovarian cancer patients treated with carboplatin/taxane plus FAR or placebo did not meet the primary statistical endpoint. Subgroup analysis demonstrated that subjects with high FAR exposure levels (Cmin>57.6µg/mL) showed statistically significant improvements in PFS and OS. The neonatal Fc receptor (fcgrt) plays a central role in albumin/IgG stasis and mAb pharmacokinetics (PK). Here we evaluated fcgrt sequence and association of its promoter variable number tandem repeats (VNTR) and coding single nucleotide variants (SNV) with albumin/IgG levels and FAR PK in the Ph3 patients. A statistical correlation existed between high FAR Cmin and AUC in patients with the highest quartile of albumin and lowest quartile of IgG1. Analysis of fcgrt identified 5 different VNTRs in the promoter region and 9 SNVs within the coding region, 4 which are novel.

Population pharmacokinetics and exposure-response relationship of amatuximab, an anti-mesothelin monoclonal antibody, in patients with malignant pleural mesothelioma and its application in dose selection.

PURPOSE: To characterize amatuximab pharmacokinetics (PK) and the relationship of amatuximab exposure with response in patients with unresectable malignant pleural mesothelioma (MPM) receiving amatuximab with pemetrexed and cisplatin. METHODS: A nonlinear mixed effects PK model was built using data from all of the amatuximab studies conducted to date. Patients received amatuximab alone or in combination with chemotherapy. The influence of demographic, laboratory and disease characteristics on PK parameters was assessed. Exposure-response analyses explored relationships between amatuximab exposure and overall survival (OS), progression-free survival (PFS) and safety. Alternative amatuximab dosing regimens were explored with simulations using population PK and parametric survival models. RESULTS: Amatuximab PK was best described by a two-compartment model with parallel linear and nonlinear elimination pathways. Body weight and an antidrug antibodies reaction with the titer >64 affected volume of distribution and clearance, respectively. Exposure-response analyses demonstrated that the amatuximab exposure (C min) showed a significant effect on OS (log-rank test, P = 0.0202). For patients with amatuximab C min above the median (38.2 µg/mL), the median OS was 583 days (90 % CI 418 -NE). For patients with C min ≤ 38.2 µg/mL, the median OS was 375 days (90 % CI 325-486). The amatuximab exposure showed similar significant effect on PFS. Exposure-response analysis for adverse events did not reveal any relationship. CONCLUSIONS: In patients with MPM, higher amatuximab exposure in combination with chemotherapy was shown to be associated with longer OS, supporting evaluation of more frequent dosing in future trials to achieve higher exposure and subsequently longer OS.

Targeting endosialin/CD248 through antibody-mediated internalization results in impaired pericyte maturation and dysfunctional tumor microvasculature.

Over-expression of endosialin/CD248 (herein referred to as CD248) has been associated with increased tumor microvasculature in various tissue origins which makes it an attractive anti-angiogenic target. In an effort to target CD248, we have generated a human CD248 knock-in mouse line and MORAb-004, the humanized version of the mouse anti-human CD248 antibody Fb5. Here, we report that MORAb-004 treatment significantly impacted syngeneic tumor growth and tumor metastasis in the human CD248 knock-in mice. In comparison with untreated tumors, MORAb-004 treated tumors displayed overall shortened and distorted blood vessels. Immunofluorescent staining of tumor sections revealed drastically more small and dysfunctional vessels in the treated tumors. The CD248 levels on cell surfaces of neovasculature pericytes were significantly reduced due to its internalization. This reduction of CD248 was also accompanied by reduced α-SMA expression, depolarization of pericytes and endothelium, and ultimately dysfunctional microvessels. These results suggest that MORAb-004 reduced CD248 on pericytes, impaired tumor microvasculature maturation and ultimately suppressed tumor development.

A first-in-human phase I study of MORAb-004, a monoclonal antibody to endosialin in patients with advanced solid tumors.

PURPOSE: Endosialin (TEM-1, CD248) is a protein expressed on the surface of activated mesenchymal cells, including certain subsets of tumors. Preclinical models suppressing endosialin function have shown antitumor activity. A humanized monoclonal antibody, MORAb-004, was engineered to target endosialin and is the first agent in clinical development for this mesenchymal cell target. EXPERIMENTAL DESIGN: This first-in-human, open-label, phase I study recruited patients with treatment-refractory solid tumors. MORAb-004 was administered intravenously once weekly in 4-week cycles. Objectives included determination of the safety of multiple infusions of MORAb-004, identification of the maximum tolerated dose (MTD), pharmacokinetic modeling, detection of any anti-human antibody response, and assessment of objective radiographic response to therapy. RESULTS: Thirty-six patients were treated at 10 dose levels of MORAb-004, ranging from 0.0625 to 16 mg/kg. Drug-related adverse events were primarily grade 1-2 infusion toxicities. Dose-limiting toxicity of grade 3 vomiting was observed at 16 mg/kg. Eighteen of 32 evaluable patients across all doses achieved disease stability, with minor radiographic responses observed in 4 patients (pancreatic neuroendocrine, hepatocellular, and sarcoma tumor types). Pharmacokinetics showed MORAb-004 accumulation beginning at 4 mg/kg and saturable elimination beginning at 0.25 mg/kg. Exposure increased in a greater-than-dose-proportional manner with terminal half-life increasing proportionally with dose. The MTD was identified as 12 mg/kg. CONCLUSIONS: Preliminary antitumor activity was observed. Safety profile, pharmacokinetics, and early antitumor activity suggest that MORAb-004 is safe at doses up to 12 mg/kg and should be studied further for efficacy.

Population pharmacokinetics of farletuzumab, a humanized monoclonal antibody against folate receptor alpha, in epithelial ovarian cancer.

PURPOSE: The purpose of this analysis was to develop a population pharmacokinetic model for farletuzumab, a humanized immunoglobulin (Ig)G(1) monoclonal antibody (mAb) to the folate receptor alpha, which is a receptor over-expressed in ovarian cancer, but largely absent from normal tissue. METHODS: In total, 2,472 samples were included in the building of the pharmacokinetic model. Farletuzumab 12.5-400 mg/m(2) had been administered via intravenous infusion to 79 patients with advanced ovarian cancer enrolled in one of the two clinical studies. Data were analyzed by a nonlinear mixed-effects modeling approach. RESULTS: Farletuzumab pharmacokinetics was best described by a two-compartment model with first-order (linear) elimination. In the final model, estimated values of clearance and volume of distribution of the central compartment were 0.00784 l/h and 3.00 l, respectively. Body weight was the only covariate investigated that explained inter-patient variability in clearance and the central volume of distribution. There was no effect of age, human anti-human antibodies, or concomitant chemotherapy on the pharmacokinetics of farletuzumab. Simulations showed that, when the mg/kg/week dose was maintained, steady-state exposure to farletuzumab was similar with dosing every week or every 3 weeks. CONCLUSIONS: The pharmacokinetic parameters of farletuzumab are similar to those of other IgG mAbs. The results support weight-based dosing of farletuzumab on a weekly or 3-weekly schedule.

Production of recombinant adeno-associated type 5 (rAAV5) vectors using recombinant herpes simplex viruses containing rep and cap.

We developed a scaleable production system for adeno-associated virus type 5 (AAV5)-based vectors using a replication-defective recombinant herpes simplex type 1 virus (rHSV) containing the rep and cap genes of AAV5. Multiple rHSV isolates containing AAV5 rep and cap with normal or altered p5 promoter elements were constructed and tested in vector production. Compared with rAAV5 vector yields obtained by plasmid transfection, yields of rAAV5 using any of the rHSV isolates were low. Evidence suggests that the low vector yields are a consequence of the extensive and early cytopathology induced by the rHSV isolates. In addition, we found a correlation between the amount of Rep52 or Rep40 proteins and the amount of vector produced by each rHSV isolate, suggesting that packaging of vector DNA into virus particles is rate-limiting when using rHSV to generate rAAV5 vectors.