Antibody drug conjugates (ADC) are a promising class of oncology therapeutics consisting of an antibody conjugated to a payload via a linker. DYP688 is a novel ADC comprising of a signaling protein inhibitor payload (FR900359) that undergoes unique on-antibody inactivation in plasma, resulting in complex pharmacology. To assess the impact of FR inactivation on DYP688 pharmacology and clinical developability, we performed translational modeling of preclinical PK and tumor growth inhibition (TGI) data, accompanied by mechanistic Krogh cylinder tumor modeling.
View Article and Find Full Text PDFAntibody-drug conjugates (ADCs) are a class of biopharmaceuticals that combine the specificity of monoclonal antibodies (mAbs) with the cytotoxicity of small molecule drugs. 15 ADCs have been approved by regulatory authorities up to now, mainly for indications in oncology, however, this review paper will only focus on the 13 ADCs that have been approved by either the FDA or EMA.ADME (Absorption, Distribution, Metabolism, and Excretion) studies are essential for the development of small molecule drugs to evaluate their disposition properties.
View Article and Find Full Text PDFAccess to the cyclic depsipeptide FR900359 (FR), a selective G protein inhibitor of high pharmacological interest and a potential lead molecule for targeted therapy of cancers with oncogenic GNAQ or GNA11 mutations (encoding G and G respectively), has been challenging ever since its initial discovery more than three decades ago. The recent discovery of Chromobacterium vaccinii as a cultivable FR producer enables the development of approaches leading to a high-yielding, scalable and sustainable biotechnological process for production of FR, thereby removing this bottleneck. Here we characterize different promoters in exchange of the native promoter of the FR assembly line, resulting in an overexpression mutant with significantly increased production of FR.
View Article and Find Full Text PDFAntibody-drug conjugates (ADCs) represent a rapidly evolving area of drug development and hold significant promise. To date, nine ADCs have been approved by the US Food and Drug Administration (FDA). These conjugates combine the target specificity of monoclonal antibodies with the anticancer activity of small-molecule therapeutics (also referred to as payload).
View Article and Find Full Text PDFThe recent development of successful CAR (chimeric antigen receptor) T cell therapies has been accompanied by a need to better control potentially fatal toxicities that can arise from adverse immune reactions. Here we present a ligand-controlled CAR system, based on the IKZF3 ZF2 β-hairpin IMiD-inducible degron, which allows for the reversible control of expression levels of type I membrane proteins, including CARs. Testing this system in an established mouse xenotransplantation model for acute lymphoblastic leukemia, we validate the ability of the CAR19-degron to target and kill CD19-positive cells displaying complete control/clearance of the tumor.
View Article and Find Full Text PDFThe pharmacokinetics (PK) of the anti-CD20 monoclonal antibody obinutuzumab was assessed after single intravenous dosing to cynomolgus monkeys. In addition, the pharmacokinetic-pharmacodynamic (PKPD) relationship for B-cell depletion was characterized. The PKPD model was used to estimate the B-cell repopulation during the recovery phase of chronic toxicology studies, thereby supporting the study design, in particular planning the recovery phase duration.
View Article and Find Full Text PDFBackground/aims: Cortisol is involved in the regulation of intraocular pressure (IOP). This study aimed to assess the effect of 11β-hydroxysteroid-dehydrogenase type 1 (11βHSD1) inhibition by oral administration of RO5093151 on IOP.
Methods: The exposure of key ocular compartments following oral administration was assessed in rabbits.
Background: During development of biologics, safety and efficacy assessments are often hampered by immune responses to the treatment. To assess active exposure of a drug peptide in a toxicology study, we developed an ex vivo potency assay which complemented the total drug quantification assay.
Methodology: Compound activity was assessed in samples of treated monkeys by cell-based cAMP measurements.
Objective: To assess the effect of strong and moderate cytochrome P450 (CYP) 3A4 inhibition on exposure of bitopertin, a glycine reuptake inhibitor primarily metabolized by CYP3A4, and to compare the results with predictions based on physiologically based pharmacokinetic (PBPK) modelling.
Methods: The effects of ketoconazole and erythromycin were assessed in two male volunteer studies with open-label, two-period, fixed-sequence designs. Twelve subjects were enrolled in each of the studies.
Bitopertin (RG1678) is a glycine reuptake inhibitor in phase 3 trials for treatment of schizophrenia. Its clinical oral pharmacokinetics is sensitive to changes in drug substance particle size and dosage form. Physiologically based pharmacokinetic (PBPK) absorption model simulations of the impact of changes in particle size and dosage form (either capsules, tablets, or an aqueous suspension) on oral pharmacokinetics was verified by comparison to measured plasma concentrations.
View Article and Find Full Text PDFRecombinant human serum albumin (HSA) conjugates of a 15-amino-acid truncated peptide YY (PYY) analogue were prepared using three heterobifunctional linkers [succinimidyl 4-[N-maleimidomethyl]cyclohexane-1-carboxylate (SMCC), 6-maleimidohexanoic acid N-hydroxysuccinimide ester (MHS), and N-[γ-maleimidobutyryloxy]sulfosuccinimide ester (GMBS)] in 2 synthetic steps involving (1) reaction of succinimidyl ester on linker with ε-amine of Lys2 on the peptide and (2) reaction of maleimide on peptide linker with free thiol of Cysteine 34 (Cys34) on albumin. In-process controls using ESI LC-MS were used to follow reactions and identify reaction products. Proteolytic digests of the conjugate revealed that peptide conjugation occurs at Cys34 on HSA.
View Article and Find Full Text PDFBackground: Bitopertin (RG1678) is a glycine reuptake inhibitor currently in phase 3 trials for treatment of schizophrenia. This paper describes the use of physiologically based pharmacokinetic (PBPK) modelling and preclinical data to gain insights into and predict bitopertin clinical pharmacokinetics.
Methods: Simulations of pharmacokinetics were initiated early in the drug discovery stage by integrating physicochemical properties and in vitro measurements into a PBPK rat model.
A specific positron emission tomography (PET) radiotracer for the glycine transporter type 1 (GlyT1) would constitute an imaging biomarker to investigate the distribution of GlyT1 in normal individuals and those with neuropsychiatric disorders. In addition it could demonstrate the ability of a novel drug to reach its target in the brain and enable receptor occupancy studies, thus facilitating drug development. In this article we describe the evaluation in non-human primates of two candidate PET radiotracers ([(11)C]RO5013852 and [(11)C]RO5013853) previously characterized in the rat.
View Article and Find Full Text PDFDysfunctional N-methyl-d-aspartate (NMDA) receptor neurotransmission has been implicated in the pathophysiology of schizophrenia. It is thought that this abnormal functioning can be corrected by increasing availability of the NMDA co-agonist glycine through inhibition of glycine transporter type 1 (GlyT1). Herein is described the pharmacologic profile of RG1678, a potent and noncompetitive glycine reuptake inhibitor.
View Article and Find Full Text PDFBenzoylisoindolines were discovered as a novel structural class of GlyT1 inhibitors. SAR studies and subsequent lead optimization efforts focused primarily on addressing hERG liability and on improving in vivo efficacy resulted in the identification of potent GlyT1 inhibitors displaying excellent selectivity and in vivo PD and PK profiles.
View Article and Find Full Text PDFPyrido pyrimidinones are selective agonists of the human high affinity niacin receptor GPR109A (HM74A). They show no activity on the highly homologous low affinity receptor GPR109B (HM74). Starting from a high throughput screening hit the in vitro activity of the pyrido pyrimidinones was significantly improved providing lead compounds suitable for further optimization.
View Article and Find Full Text PDFThe GlyT1 transporter has emerged as a key novel target for the treatment of schizophrenia. Herein, we report on the optimization of the 2-alkoxy-5-methylsulfonebenzoylpiperazine class of GlyT1 inhibitors to improve hERG channel selectivity and brain penetration. This effort culminated in the discovery of compound 10a (RG1678), the first potent and selective GlyT1 inhibitor to have a beneficial effect in schizophrenic patients in a phase II clinical trial.
View Article and Find Full Text PDFSeveral novel classes of potent and small amide-type inhibitors of glycine transport (GlyT1) were developed through sequential simplification of a benzodiazepinone-lead structure identified from a high-throughput screening. The most potent compounds of these structurally simple classes show low nanomolar inhibition at the GlyT1 target.
View Article and Find Full Text PDFScreening of the Roche compound library led to the identification of the benzoylpiperazine 7 as a structurally novel GlyT1 inhibitor. The SAR which was developed in this series resulted in the discovery of highly potent compounds displaying excellent selectivity against the GlyT2 isoform, drug-like properties, and in vivo efficacy after oral administration.
View Article and Find Full Text PDFA novel class of 4-substituted-8-(1-phenyl-cyclohexyl)-2,8-diaza-spiro[4.5]decan-1-ones have been discovered and developed as potent and selective GlyT1 inhibitors. The molecules are devoid of activity at the GlyT2 isoform and display excellent selectivities against the mu opioid receptor as well as the nociceptin/orphanin FQ peptide (NOP) receptor.
View Article and Find Full Text PDFA novel class of 4-aryl-8-(2-hydroxy-2-phenyl-cyclohexyl)-2,8-diaza-spiro[4.5]decan-1- ones have been discovered and developed as potent and selective GlyT1 inhibitors. The molecules are devoid of activity at the GlyT2 isoform and display excellent selectivities against the mu-opioid receptor as well as the Nociceptin/Orphanin FQ peptide (NOP) receptor.
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