Recombinant adenoassociated virus (rAAV) type 2 vectors have been used to transduce a wide variety of cell types, including hematopoietic progenitor cells. For in vivo gene transfer, it is desirable to have an rAAV vector that specifically transduces selected target cells. As a first step toward generating an rAAV vector capable of targeting delivery in vivo, we have engineered a chimeric protein combining the AAV capsid protein and the variable region of a single-chain antibody against human CD34 molecules, a cell surface marker for hematopoietic stem/progenitor cells. Inclusion of the chimeric CD34 single-chain antibody-AAV capsid proteins within an rAAV virion significantly increased the preferential infectivity of rAAV for the CD34+ human myoleukemia cell line KG-1, which is normally refractory to rAAV transduction. Antibodies against the single-chain antibody and the CD34 protein blocked this transduction. This chimeric vector represents a significant improvement in the host range of rAAV and the first step toward specific gene delivery by rAAV vectors to cells of choice, in this case, hematopoietic progenitor cells, for the treatment of human disease.
PURPOSE Six-transmembrane epithelial antigen of the prostate 1 (STEAP1) is highly expressed in prostate cancers. DSTP3086S is a humanized immunoglobulin G1 anti-STEAP1 monoclonal antibody linked to the potent antimitotic agent monomethyl auristatin E. This study evaluated the safety and activity of DSTP3086S in patients with metastatic castration-resistant prostate cancer. METHODS Patients were enrolled in a 3 + 3 dose escalation study to evaluate DSTP3086S (0.3 to 2.8 mg/kg intravenously) given once every 3 weeks followed by cohort expansion at the recommended phase II dose or weekly (0.8 to 1.0 mg/kg). RESULTS Seventy-seven patients were given DSTP3086S once every 3 weeks, and seven were treated weekly. Two patients in the once-every-3-weeks dose escalation had dose-limiting grade 3 transaminitis. Grade 3 hyperglycemia and grade 4 hypophosphatemia were dose-limiting toxicities in one patient treated at 1.0 mg/kg weekly. Initial cohort expansion evaluated dosing at 2.8 mg/kg once every 3 weeks (n = 10), but frequent dose reductions led to testing of 2.4 mg/kg (n = 39) in the expansion phase. Common related adverse events (> 20%) across doses (once every 3 weeks) were fatigue, peripheral neuropathy, nausea, constipation, anorexia, diarrhea, and vomiting. DSTP3086S pharmacokinetics were linear. Among 62 patients who received > 2 mg/kg DSTP3086S once every 3 weeks, 11 (18%) demonstrated a ≥ 50% decline in prostate-specific antigen; two (6%) of 36 with measurable disease at baseline achieved a radiographic partial response; and of 27 patients with informative unfavorable baseline circulating tumor cells ≥ 5/7.5 mL of blood, 16 (59%) showed conversions to favorable circulating tumor cells < 5. No prostate-specific antigen or RECIST responses were seen with weekly dosing. CONCLUSION DSTP3086S has acceptable safety at the recommended phase II dose level of 2.4 mg/kg once every 3 weeks. Antitumor activity at doses between 2.25 and 2.8 mg/kg once every 3 weeks supports the potential benefit of treating STEAP1-expressing metastatic castration-resistant prostate cancer with an STEAP1-targeting antibody-drug conjugate.
The application of modeling and simulation techniques is increasingly common in the preclinical stages of the drug development process.is a potent second-generation antagonist of inhibitor of apoptosis (IAP) proteins that is being developed for the treatment of various cancers. GDC-0917 has low to moderate clearance in the mouse (12.0 ml/min/ kg), rat (27.0 ml/min/kg), and dog (15.3 ml/min/kg), and high clearance in the monkey (67.6 ml/min/kg). Accordingly, oral bioavailability was lowest in monkeys compared with other species. Based on our experience with a prototype molecule with similar structure, in vitroin vivo extrapolation was used to predict a moderate clearance (11.5 ml/min/kg) in humans. The predicted human volume of distribution was estimated using simple allometry at 6.69 l/kg. Translational pharmacokinetic-pharmacodynamic (PK-PD) analysis using results from MDA-MB-231-X1.1 breast cancer xenograft studies and predicted human pharmacokinetics suggests that ED 50 and ED 90 targets can be achieved in humans using acceptable doses (72 mg and 660 mg, respectively) and under an acceptable time frame. The relationship between GDC-0917 concentrations and pharmacodynamic response (cIAP1 degradation) was characterized using an in vitro peripheral blood mononuclear cell immunoassay. Simulations of human GDC-0917 plasma concentration-time profile and cIAP1 degradation at the 5-mg starting dose in the phase 1 clinical trial agreed well with observations. This work shows the importance of leveraging information from prototype molecules and illustrates how modeling and simulation can be used to add value to preclinical studies in the early stages of the drug development process.
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