Quantitative Measurement of Rate of Targeted Protein Degradation.

Targeted protein degradation (TPD) is a therapeutic approach that leverages the cell's natural machinery to degrade targets instead of inhibiting them. This is accomplished by using mono- or bifunctional small molecules designed to induce the proximity of target proteins and E3 ubiquitin ligases, leading to ubiquitination and subsequent proteasome-dependent degradation of the target. One of the most significant attributes of the TPD approach is its proposed catalytic mechanism of action, which permits substoichiometric exposure to achieve the desired pharmacological effects.

Assumptions Underlying Hepatic Clearance Models: Recognizing the Influence of Saturable Protein Binding on Driving Force Concentration and Discrimination Between Models of Hepatic Clearance.

One underlying assumption of hepatic clearance models is often underappreciated. Namely, plasma protein binding is assumed to be nonsaturable within a given drug concentration range, dependent only on protein concentration and equilibrium dissociation constant. However, in vitro hepatic clearance experiments often use low albumin concentrations that may be prone to saturation effects, especially for high-clearance compounds, where the drug concentration changes rapidly.

Industry Perspective on the Pharmacokinetic and Absorption, Distribution, Metabolism, and Excretion Characterization of Heterobifunctional Protein Degraders.

Targeted protein degraders (TPDs), specifically the bifunctional protein degraders discussed in this manuscript, consist of two linked ligands for a protein of interest and an E3 ligase, resulting in molecules that largely violate accepted physicochemical limits (e.g., Lipinski's Rule of Five) for oral bioavailability.

PBPK model for antibody disposition in mouse brain: validation using large-pore microdialysis data.

The objective of this manuscript was to validate a physiologically-based pharmacokinetic (PBPK) model developed to characterize brain pharmacokinetics (PK) of monoclonal antibodies (mAbs) using novel large-pore microdialysis data generated in mice. To support this objective, brain, CSF, and ISF PK of a human anti-tetanus toxin (TeTx) antibody was measured in mice following intraperitoneal (IP) administration. This antibody has no binding in mice.

Antibody-drug conjugates as targeted therapies: Are we there yet? A critical review of the current clinical landscape.

Antibody-drug conjugates (ADCs) are targeted therapies with the expectation of broadened therapeutic window due to tumor-specific drug delivery. Recent approvals, including ADCs with a novel payload class, topoisomerase-1 inhibitors, generated renewed excitement in the field. We provide a critical review of approved and late-stage molecules, discuss strategies in solid tumors and ADCs outside oncology.

High-dose methotrexate is effective for prevention of isolated CNS relapse in diffuse large B cell lymphoma.

The role of central nervous system (CNS) prophylaxis with high-dose methotrexate (HDMTX) in DLBCL is controversial. In this retrospective study, we evaluated the efficacy of prophylactic HDMTX on isolated CNS relapse, concomitant CNS and systemic relapse, systemic relapse, and survival outcomes in 226 patients with newly diagnosed DLBCL and high-risk CNS International Prognostic Index (CNS-IPI) score treated with RCHOP. The three-year risk of isolated CNS relapse was significantly lower in patients who received HDMTX, at 3.

Harnessing cerebrospinal fluid circulation for drug delivery to brain tissues.

Initially thought to be useful only to reach tissues in the immediate vicinity of the CSF circulatory system, CSF circulation is now increasingly viewed as a viable pathway to deliver certain therapeutics deeper into brain tissues. There is emerging evidence that this goal is achievable in the case of large therapeutic proteins, provided conditions are met that are described herein. We show how fluid dynamic modeling helps predict infusion rate and duration to overcome high CSF turnover.

Mechanistic Modeling of Antibody-Drug Conjugate Internalization at the Cellular Level Reveals Inefficient Processing Steps.

Antibody-drug conjugates (ADC) offer an avenue for specific drug delivery to target cells. Here, parameters with important roles in the cellular processing of ADCs were quantitatively measured for Ab033, an antibody against EGFR. In EGFR-overexpressing cancer cell lines, Ab033 internalized at rates of 0.

Mathematical and Experimental Validation of Flux Dialysis Method: An Improved Approach to Measure Unbound Fraction for Compounds with High Protein Binding and Other Challenging Properties.

A flux dialysis method to measure unbound fraction () of compounds with high protein binding and other challenging properties was tested and validated. This method is based on the principle that the initial flux rate of a compound through a size-excluding dialysis membrane is proportional to the product of the compound initial concentration, , and unbound dialysis membrane permeability (). Therefore, can be determined from the initial concentration and flux rate, assuming membrane is known.

The impact of time from diagnosis to treatment in diffuse large B-cell lymphoma.

Diffuse large B-cell lymphoma (DLBCL) is a high-grade lymphoma that requires treatment. We retrospectively analyzed the impact of time from diagnosis-to-treatment (TDT) on progression-free survival (PFS) and overall survival (OS) in 581 R-CHOP-treated patients. TDT was defined as the interval between diagnostic biopsy date and day 1 R-CHOP.

Pharmacokinetic Considerations for Antibody-Drug Conjugates against Cancer.

Antibody-drug conjugates (ADCs) are ushering in the next era of targeted therapy against cancer. An ADC for cancer therapy consists of a potent cytotoxic payload that is attached to a tumour-targeted antibody by a chemical linker, usually with an average drug-to-antibody ratio (DAR) of 3.5-4.

Quantifying the effects of antiangiogenic and chemotherapy drug combinations on drug delivery and treatment efficacy.

Tumor-induced angiogenesis leads to the development of leaky tumor vessels devoid of structural and morphological integrity. Due to angiogenesis, elevated interstitial fluid pressure (IFP) and low blood perfusion emerge as common properties of the tumor microenvironment that act as barriers for drug delivery. In order to overcome these barriers, normalization of vasculature is considered to be a viable option.

Clinicopathological features and outcome of chronic lymphocytic leukaemia in Chinese patients.

Chronic lymphocytic leukaemia (CLL) is uncommon in Chinese population and its biology, genetics and treatment outcome in Chinese patients have not been comprehensively investigated. In this study, we studied the clinicopathological features and outcome of 212 Chinese patients with newly diagnosed CLL in Hong Kong and Singapore. The median age at diagnosis was 64 years.

Population PBPK modelling of trastuzumab: a framework for quantifying and predicting inter-individual variability.

In this work we proposed a population physiologically-based pharmacokinetic (popPBPK) framework for quantifying and predicting inter-individual pharmacokinetic variability using the anti-HER2 monoclonal antibody (mAb) trastuzumab as an example. First, a PBPK model was developed to account for the possible mechanistic sources of variability. Within the model, five key factors that contribute to variability were identified and the nature of their contribution was quantified with local and global sensitivity analyses.

PD1 blockade with pembrolizumab is highly effective in relapsed or refractory NK/T-cell lymphoma failing l-asparaginase.

Natural killer (NK)/T-cell lymphomas failing L-asparaginse regimens have no known salvage and are almost invariably fatal. Seven male patients with NK/T-cell lymphoma (median age, 49 years; range, 31-68 years) for whom a median of 2 (range, 1-5) regimens (including l-asparaginase regimens and allogeneic hematopoietic stem-cell transplantation [HSCT] in 2 cases) failed were treated with the anti-programmed death 1 (PD1) antibody pembrolizumab. All patients responded, according to various clinical, radiologic (positron emission tomography), morphologic, and molecular (circulating Epstein-Barr virus [EBV] DNA) criteria.

Drug-induced reactive oxygen species (ROS) rely on cell membrane properties to exert anticancer effects.

Pharmacological concentrations of small molecule natural products, such as ascorbic acid, have exhibited distinct cell killing outcomes between cancer and normal cells whereby cancer cells undergo apoptosis or necrosis while normal cells are not adversely affected. Here, we develop a mathematical model for ascorbic acid that can be utilized as a tool to understand the dynamics of reactive oxygen species (ROS) induced cell death. We determine that not only do endogenous antioxidants such as catalase contribute to ROS-induced cell death, but also cell membrane properties play a critical role in the efficacy of ROS as a cytotoxic mechanism against cancer cells vs.