Combining mathematical modeling, data and clinical target expression to support bispecific antibody binding affinity selection: a case example with FAP-4-1BBL.

The majority of bispecific costimulatory antibodies in cancer immunotherapy are capable of exerting tumor-specific T-cell activation by simultaneously engaging both tumor-associated targets and costimulatory receptors expressed by T cells. The amount of trimeric complex formed when the bispecific antibody is bound simultaneously to the T cell receptor and the tumor-associated target follows a bell-shaped curve with increasing bispecific antibody exposure/dose. The shape of the curve is determined by the binding affinities of the bispecific antibody to its two targets and target expression.

Sex differences in sensitivity to dopamine receptor manipulations of risk-based decision making in rats.

Risky decision making involves the ability to weigh risks and rewards associated with different options to make adaptive choices. Previous work has established a necessary role for the basolateral amygdala (BLA) in mediating effective decision making under risk of punishment, but the mechanisms by which the BLA mediates this process are less clear. Because this form of decision making is profoundly sensitive to dopaminergic (DA) manipulations, we hypothesized that DA receptors in the BLA may be involved in risk-taking behavior.

A model-based approach leveraging in vitro data to support dose selection from the outset: A framework for bispecific antibodies in immuno-oncology.

FAP-4-1BBL is a bispecific antibody exerting 4-1BB-associated T-cell activation only while simultaneously bound to the fibroblast activation protein (FAP) receptor, expressed on the surface of cancer-associated fibroblasts. The trimeric complex formed when FAP-4-1BBL is simultaneously bound to FAP and 4-1BB represents a promising mechanism to achieve tumor-specific 4-1BB stimulation. We integrated in vitro data with mathematical modeling to characterize the pharmacology of FAP-4-1BBL as a function of trimeric complex formation when combined with the T-cell engager cibisatamab.

Symptoms and impacts of ambulatory nonsense mutation Duchenne muscular dystrophy: a qualitative study and the development of a patient-centred conceptual model.

Background: Duchenne muscular dystrophy is a rare genetic neuromuscular disorder, which can result in early death due to disease progression. Ataluren is indicated for the treatment of nonsense mutation Duchenne muscular dystrophy, in ambulatory individuals aged two years and older. This study explored the symptoms and impacts of nonsense mutation Duchenne muscular dystrophy and experience with ataluren.

Quantitative Clinical Pharmacology Supports the Bridging From i.v. Dosing and Approval of s.c. Rituximab in B-Cell Hematological Malignancies.

A fixed-dose subcutaneous (s.c.) formulation of the anti-CD20 antibody, rituximab, has been developed to address safety, infusion time, and patient comfort concerns relating to intravenous (i.

Rituximab dosing in hematological malignancies: an old question, revisited.

Rituximab is the standard of care for most B-cell malignancies. Its rapid clinical development enabled patients to receive this life-prolonging medicine sooner; however, it precluded a thorough assessment of dose selection. Extensive clinical pharmacology data collected from the recent subcutaneous development program enabled re-examination of this old question and support that the approved rituximab dosing regimens in non-Hodgkin's lymphoma and chronic lymphocytic leukemia appear to maximize the clinical benefit in the majority of patients.

Large magneto-Seebeck effect in magnetic tunnel junctions with half-metallic Heusler electrodes.

Spin caloritronics studies the interplay between charge-, heat- and spin-currents, which are initiated by temperature gradients in magnetic nanostructures. A plethora of new phenomena has been discovered that promises, e.g.

Subcutaneous Rituximab for the Treatment of B-Cell Hematologic Malignancies: A Review of the Scientific Rationale and Clinical Development.

Unlabelled: Rituximab (MabThera/Rituxan), a chimeric murine/human monoclonal antibody that binds specifically to the transmembrane antigen CD20, was the first therapeutic antibody to enter clinical practice for the treatment of cancer. As monotherapy and in combination with chemotherapy, rituximab has been shown to prolong progression-free survival and, in some indications overall survival, in patients with various B-cell malignancies, while having a well-established and manageable safety profile and a wide therapeutic window. As a result, rituximab is considered to have revolutionized treatment practices for patients with B-cell malignancies.

Efficacy and safety of subcutaneous rituximab versus intravenous rituximab for first-line treatment of follicular lymphoma (SABRINA): a randomised, open-label, phase 3 trial.

Background: Intravenous rituximab is the standard of care in B-cell non-Hodgkin lymphoma, and is administered over 1·5-6 h. A subcutaneous formulation could reduce patients' treatment burden and improve resource utilisation in health care. We aimed to show the pharmacokinetic non-inferiority of subcutaneous rituximab to intravenous rituximab in follicular lymphoma and to provide efficacy and safety data.

On/off switching of bit readout in bias-enhanced tunnel magneto-Seebeck effect.

Thermoelectric effects in magnetic tunnel junctions are promising to serve as the basis for logic devices or memories in a "green" information technology. However, up to now the readout contrast achieved with Seebeck effects was magnitudes smaller compared to the well-established tunnel magnetoresistance effect. Here, we resolve this problem by demonstrating that the tunnel magneto-Seebeck effect (TMS) in CoFeB/MgO/CoFeB tunnel junctions can be switched on to a logic "1" state and off to "0" by simply changing the magnetic state of the CoFeB electrodes.

Pharmacokinetics and safety of subcutaneous rituximab in follicular lymphoma (SABRINA): stage 1 analysis of a randomised phase 3 study.

Background: Intravenous rituximab is a mainstay of treatment for follicular lymphoma. A subcutaneous formulation that achieves equivalent rituximab serum concentrations might improve convenience and save health-care resources without sacrificing clinical activity. We aimed to assess pharmacokinetic non-inferiority of 3 week cycles of fixed-dose subcutaneous rituximab versus standard intravenous rituximab.

Time-resolved measurement of the tunnel magneto-Seebeck effect in a single magnetic tunnel junction.

Recently, several groups have reported spin-dependent thermoelectric effects in magnetic tunnel junctions. In this paper, we present a setup for time-resolved measurements of thermovoltages and thermocurrents of a single micro- to nanometer-scaled tunnel junction. An electrically modulated diode laser is used to create a temperature gradient across the tunnel junction layer stack.

Health-economic comparison of paricalcitol, calcitriol and alfacalcidol for the treatment of secondary hyperparathyroidism during haemodialysis.

This study evaluated the health-economic consequences of use of intravenous paricalcitol (Zemplar), oral calcitriol or oral and intravenous alfacalcidol for the treatment of patients with secondary hyperparathyroidism, focusing on a third-party payer perspective through inclusion of medication and hospital costs, survival rates and utilities. Cost values were based on German treatment recommendations and prices. Reference values for survival rates and utilities were based on the results of a MEDLINE search.

CD45 monoclonal antibody-mediated cytolysis of human NK and T lymphoma cells.

Background And Objectives: The CD45 rat monoclonal IgG2b antibodies YTH24.5 and YTH54.12 act synergistically to produce cytolysis of normal lymphocytes and have been safely given to patients in conditioning regimens for allogeneic stem cell transplantation.