A Novel Antigen Design Strategy to Isolate Single-Domain Antibodies that Target Human Nav1.7 and Reduce Pain in Animal Models.

Genetic studies have identified the voltage-gated sodium channel 1.7 (Na1.7) as pain target.

Pharmacokinetics and Pharmacodynamic Effect of a Blood-Brain Barrier-Crossing Fusion Protein Therapeutic for Alzheimer's Disease in Rat and Dog.

Purpose: We have recently demonstrated the brain-delivery of an Amyloid-ß oligomer (Aßo)-binding peptide-therapeutic fused to the BBB-crossing single domain antibody FC5. The bi-functional fusion protein, FC5-mFc-ABP (KG207-M) lowered both CSF and brain Aß levels after systemic dosing in transgenic mouse and rat models of Alzheimer's disease (AD). For development as a human therapeutic, we have humanized and further engineered the fusion protein named KG207-H.

Preclinical longitudinal assessment of KG207-M as a disease-modifying Alzheimer's disease therapeutic.

biomarker abnormalities provide measures to monitor therapeutic interventions targeting amyloid-β pathology as well as its effects on downstream processes associated with Alzheimer's disease pathophysiology. Here, we applied an longitudinal study design combined with imaging and cerebrospinal fluid biomarkers, mirroring those used in human clinical trials to assess the efficacy of a novel brain-penetrating anti-amyloid fusion protein treatment in the McGill-R-Thy1-APP transgenic rat model. The bi-functional fusion protein consisted of a blood-brain barrier crossing single domain antibody (FC5) fused to an amyloid-β oligomer-binding peptide (ABP) via Fc fragment of mouse IgG (FC5-mFc2a-ABP).

7-Fluorosialyl Glycosides Are Hydrolysis Resistant but Readily Assembled by Sialyltransferases Providing Easy Access to More Metabolically Stable Glycoproteins.

The maintenance of therapeutic glycoproteins within the circulatory system is associated, in large part, with the integrity of sialic acids as terminal sugars on the glycans. Glycoprotein desialylation, either by spontaneous cleavage or through host sialidases, leads to protein clearance, mainly through the liver. Thus, the installation of minimally modified sialic acids that are hydrolysis-resistant yet biologically equivalent should lead to increased circulatory half-lives and improved pharmacokinetic profiles.

Enhanced anti-metastatic bioactivity of an IGF-TRAP re-engineered to improve physicochemical properties.

The insulin-like growth factor (IGF) axis has been implicated in the progression of malignant disease and identified as a clinically important therapeutic target. Several IGF-1 receptor (IGF-1R) targeting drugs including humanized monoclonal antibodies have advanced to phase II/III clinical trials, but to date, have not progressed to clinical use, due, at least in part, to interference with insulin receptor signalling. We previously reported on the production of a soluble fusion protein consisting of the extracellular domain of human IGF-1R fused to the Fc portion of human IgG (first generation IGF-TRAP) that bound human IGF-1 and IGF-2 with a 3 log higher affinity than insulin.

Enhanced Delivery of Galanin Conjugates to the Brain through Bioengineering of the Anti-Transferrin Receptor Antibody OX26.

The blood-brain barrier (BBB) is a formidable obstacle for brain delivery of therapeutic antibodies. However, antibodies against the transferrin receptor (TfR), enriched in brain endothelial cells, have been developed as delivery carriers of therapeutic cargoes into the brain via a receptor-mediated transcytosis pathway. In vitro and in vivo studies demonstrated that either a low-affinity or monovalent binding of these antibodies to the TfR improves their release on the abluminal side of the BBB and target engagement in brain parenchyma.

Feasibility of real-time motion management with helical tomotherapy.

Purpose: This study investigates the potential application of image-based motion tracking and real-time motion correction to a helical tomotherapy system.

Methods: A kV x-ray imaging system was added to a helical tomotherapy system, mounted 90 degrees offset from the MV treatment beam, and an optical camera system was mounted above the foot of the couch. This experimental system tracks target motion by acquiring an x-ray image every few seconds during gantry rotation.

Investigating the clinical advantages of a robotic linac equipped with a multileaf collimator in the treatment of brain and prostate cancer patients.

The purpose of this study was to evaluate the performance of a commercially avail-able CyberKnife system with a multileaf collimator (CK-MLC) for stereotactic body radiotherapy (SBRT) and standard fractionated intensity-modulated radiotherapy (IMRT) applications. Ten prostate and ten intracranial cases were planned for the CK-MLC. Half of these cases were compared with clinically approved SBRT plans generated for the CyberKnife with circular collimators, and the other half were compared with clinically approved standard fractionated IMRT plans generated for conventional linacs.

Evaluation of an innovative population pharmacokinetic-based design for behavioral pharmacodynamic endpoints.

Pre-clinical behavioral pharmacology studies supporting indications like analgesia typically consist of at least three different studies; dose-finding, duration of effect, and tolerance-development studies. Pharmacokinetic (PK) plasma samples are generally taken from a parallel group of animals to avoid disruption of the behavioral pharmacodynamic (PD) endpoint. Our objective was to investigate if pre-clinical behavioral pharmacology studies in rats could be performed effectively by combining three studies into a single experimental design and using sparse PK sampling in the same animals as for PD.

N-Methyl-3-(tetrahydro-2H-pyran-4-yl)-2,3,4,9-tetrahydro-1H-carbazole-6-carboxamides as a novel class of cannabinoid receptors agonists with low CNS penetration.

Cannabinoid CB(1) receptor agonists exhibit potent analgesic effects in rodents and humans, but their clinical utility as analgesic drugs is often limited by centrally mediated side effects. We report herein the preparation of N-methyl-3-(tetrahydro-2H-pyran-4-yl)-2,3,4,9-tetrahydro-1H-carbazole-6-carboxamides as a novel class of hCB(1)/hCB(2) dual agonists with attractive physicochemical properties. More specifically, (R)-N,9-dimethyl-N-(4-(methylamino)-4-oxobutyl)-3-(tetrahydro-2H-pyran-4-yl)-2,3,4,9-tetrahydro-1H-carbazole-6-carboxamide, displayed an extremely low level of CNS penetration (Rat Cbr/Cplasma=0.

γ-Carbolines: a novel class of cannabinoid agonists with high aqueous solubility and restricted CNS penetration.

An oral, peripherally restricted CB1/CB2 agonist could provide an interesting approach to treat chronic pain by harnessing the analgesic properties of cannabinoids but without the well-known central side effects. γ-Carbolines are a novel class of potent mixed CB1/CB2 agonists characterized by attractive physicochemical properties including high aqueous solubility. Optimization of the series has led to the discovery of 29, which has oral activity in a rat inflammatory pain model and limited brain exposure at analgesic doses, consistent with a lower risk of CNS-mediated tolerability issues.

Blocking spinal CCR2 with AZ889 reversed hyperalgesia in a model of neuropathic pain.

Background: The CCR2/CCL2 system has been identified as a regulator in the pathogenesis of neuropathy-induced pain. However, CCR2 target validation in analgesia and the mechanism underlying antinociception produced by CCR2 antagonists remains poorly understood. In this study, in vitro and in vivo pharmacological approaches using a novel CCR2 antagonist, AZ889, strengthened the hypothesis of a CCR2 contribution to neuropathic pain and provided confidence over the possibilities to treat neuropathic pain with CCR2 antagonists.

A peripherally restricted cannabinoid receptor agonist produces robust anti-nociceptive effects in rodent models of inflammatory and neuropathic pain.

Cannabinoids are analgesic in man, but their use is limited by their psychoactive properties. One way to avoid cannabinoid receptor subtype 1 (CB1R)-mediated central side-effects is to develop CB1R agonists with limited CNS penetration. Activation of peripheral CB1Rs has been proposed to be analgesic, but the relative contribution of peripheral CB1Rs to the analgesic effects of systemic cannabinoids remains unclear.

Relationship between isotope half-life and prostatic edema for optimal prostate dose coverage in permanent seed implants.

The robustness of treatment planning to prostatic edema for three different isotopes (125I, 103Pd, and 131Cs) is explored using dynamical dose calculations on 25 different clinical prostate cases. The treatment plans were made using the inverse planning by simulated annealing (IPSA) algorithm. The prescription was 144, 127, and 125 Gy for 125I, 131Cs, and 103Pd, respectively.

Inverse planning simulated annealing for magnetic resonance imaging-based intracavitary high-dose-rate brachytherapy for cervical cancer.

Purpose: To develop a technique using exclusively magnetic resonance imaging (MRI) to perform dwell position identification, targets and organs at risk delineation, and to apply inverse planning dose optimization to high-dose-rate brachytherapy for cervical cancer.

Methods And Materials: We included 15 consecutive women treated with high-dose-rate (HDR) brachytherapy for cervical cancer. All patients underwent MRI after placement of tandem and ring applicator containing a gadodiamide-filled dummy marker.

Class solution in inverse planned HDR prostate brachytherapy for dose escalation of DIL defined by combined MRI/MRSI.

Purpose: To establish an inverse planning set of parameters (class solution) to boost dominant intra-prostatic lesion (DIL) defined by MRI/MRSI.

Methods: For 15 patients, DIL were contoured on CT or MR images and a class solution was developed to boost the DIL under the dosimetric requirements of the RTOG-0321 protocol. To determine the maximum attainable level of boost for each patient, 5 different levels were considered, at least 110%, 120%, 130%, 140% and 150% of the prescribed dose.

Optimization of HDR brachytherapy dose distributions using linear programming with penalty costs.

Prostate cancer is increasingly treated with high-dose-rate (HDR) brachytherapy, a type of radiotherapy in which a radioactive source is guided through catheters temporarily implanted in the prostate. Clinicians must set dwell times for the source inside the catheters so the resulting dose distribution minimizes deviation from dose prescriptions that conform to patient-specific anatomy. The primary contribution of this paper is to take the well-established dwell times optimization problem defined by Inverse Planning by Simulated Annealing (IPSA) developed at UCSF and exactly formulate it as a linear programming (LP) problem.

Class solution for inversely planned permanent prostate implants to mimic an experienced dosimetrist.

The purpose of this paper is to present a method for the selection of inverse planning parameters and to establish a set of inverse planning parameters (class solution) for the inverse planning included in a commercial permanent prostate implant treatment planning system. The manual planning of more than 750 patients since 1996 led to the establishment of general treatment planning rules. A class solution is tuned to fulfill the treatment planning rules and generate equivalent implants.

Optimization of dose distribution for HDR brachytherapy of the prostate using Attraction-Repulsion Model.

Purpose: To optimize dose distribution for high-dose-rate brachytherapy for prostate cancer, we have developed a new algorithm named Attraction-Repulsion Model (ARM). In this study, we compared the ARM with geometric optimization (GO).

Methods And Materials: The ARM was used to optimize the dose distribution by finding the best dwell time combination.

3D inverse treatment planning for the tandem and ovoid applicator in cervical cancer.

Purpose: Three-dimensional treatment planning systems and inverse planning optimization for brachytherapy are becoming commercially available. Guidelines for target delineation and dose constrictions have not been established using this new software. In this study we describe a method of target delineation for the tandem and ovoids applicator.

Anatomy-based inverse planning dose optimization in HDR prostate implant: a toxicity study.

Background And Purpose: The aim of this study is to evaluate the acute and late complications in patients who have received HDR implant boost using inverse planning, and to determine dose volume correlations.

Patients And Methods: Between September 1999 and October 2002, 44 patients with locally advanced prostate cancer (PSA>/=10 ng/ml, and/or Gleason score>/=7, and/or Stage T2c or higher) were treated with 40-45 Gy external pelvic field followed by 2--3 fraction of inverse-planned HDR implant boost (6--9.5 Gy /fraction).

Inverse treatment planning based on MRI for HDR prostate brachytherapy.

Purpose: To develop and optimize a technique for inverse treatment planning based solely on magnetic resonance imaging (MRI) during high-dose-rate brachytherapy for prostate cancer.

Methods And Materials: Phantom studies were performed to verify the spatial integrity of treatment planning based on MRI. Data were evaluated from 10 patients with clinically localized prostate cancer who had undergone two high-dose-rate prostate brachytherapy boosts under MRI guidance before and after pelvic radiotherapy.

Comparison of inverse planning simulated annealing and geometrical optimization for prostate high-dose-rate brachytherapy.

Purpose: An inverse planning simulated annealing (IPSA) algorithm for optimization of high-dose-rate (HDR) brachytherapy has been previously described. In this study, IPSA is compared with geometrical optimization (GO) for prostate brachytherapy.

Methods And Materials: Using CT data collected from 10 patients, treatment plans were prepared using GO and IPSA.

Dose uncertainty due to computed tomography (CT) slice thickness in CT-based high dose rate brachytherapy of the prostate cancer.

In computed tomography (CT)-based high dose rate (HDR) brachytherapy, the uncertainty in the localization of the longitudinal catheter-tip positions due to the discrete CT slice thickness, results in a delivered dose uncertainty. Catheter coordinates were extracted from five patients treated for prostate cancer, and three simulation scenarios were followed to mimic the longitudinal imprecision of the catheter tips, hence the dwell positions. All catheters were displaced (1) forward, (2) backward, or (3) randomly distributed within the space defined by one CT slice thickness, for thicknesses ranging from 2 to 5 mm.

MRI-guided HDR prostate brachytherapy in standard 1.5T scanner.

Purpose: Magnetic resonance imaging (MRI) provides superior visualization of the prostate and surrounding anatomy, making it the modality of choice for imaging the prostate gland. This pilot study was performed to determine the feasibility and dosimetric quality achieved when placing high-dose-rate prostate brachytherapy catheters under MRI guidance in a standard "closed-bore" 1.5T scanner.