PURPOSE Mosunetuzumab is a bispecific antibody targeting CD20 and CD3 that redirects T cells to engage and eliminate malignant B cells and is being developed for relapsed or refractory (R/R) B-cell non-Hodgkin lymphomas (B-NHLs). METHODS This first-in-human trial (ClinicalTrials.gov identifier: NCT02500407 ) evaluated the safety and tolerability and efficacy of mosunetuzumab in patients with R/R B-NHL and established the recommended phase II dose. Data from dose escalation are presented. Single-agent mosunetuzumab was administered intravenously in 3-week cycles, at full dose in cycle 1 day 1 (group A) or with ascending (step-up) doses during cycle 1 on days 1, 8, and 15 (group B), for eight or 17 cycles on the basis of tumor response. RESULTS Two hundred thirty patients were enrolled. Doses up to 2.8 mg and 60 mg were assessed in groups A and B, respectively; maximum tolerated dose was not exceeded. In group B (n = 197), common adverse events (≥ 20% of patients) were neutropenia (28.4%), cytokine release syndrome (27.4%), hypophosphatemia (23.4%), fatigue (22.8%), and diarrhea (21.8%). Cytokine release syndrome was mostly low-grade (grade ≥ 3: 1.0%) and mainly confined to cycle 1. Across the doses investigated (group B), best overall response rates were 34.9% and 66.2% in patients with aggressive and indolent B-NHL, respectively, and complete response rates were 19.4% and 48.5%. Among patients with a complete response, the median duration of response was 22.8 months (95% CI, 7.6 to not estimable) and 20.4 (95% CI, 16 to not estimable) in patients with aggressive and indolent B-NHL, respectively. CONCLUSION Mosunetuzumab, administered with step-up dosing, has a manageable safety profile and induces durable complete responses in R/R B-NHL. The expansion stage of the study is ongoing at the dose level of 1/2/60/60/30 mg selected for further study.

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Approximately 90% of all ophthalmic drug formulations are now applied as eye drops. While eye drops are convenient and well-accepted by patients, ∼95% of the drug contained in the drops is lost due to absorption through the conjunctiva or through the tear drainage. Ophthalmic drug delivery via contact lenses is more effective because it increases the residence time of the drug in the eye and leads to a larger fractional intake of drug by the cornea. In this paper, we model the drug release from the contact lens into the pre- and postlens tear films and the subsequent uptake by the cornea. The motion of the contact lens, which is driven by the eyelid motion during a blink, enhances the mass transfer in the postlens tear film (POLTF). We use regular perturbation methods to obtain the Taylor dispersion coefficient for mass transfer in the POLTF. The diffusion of drug in the gel is assumed to obey Fick's law, and the diffusion in the gel and the mass transfer in the POLTF are combined to yield an integro-differential equation that is solved numerically by finite difference. Two extreme cases are considered in this paper. The first case corresponds to a rapid breakup of the prelens tear film (PLTF) that prevents drug loss from the anterior lens surface into the PLTF. The second case corresponds to a situation in which the prelens tear film exists at all times and, furthermore, the mixing and the tear drainage in the blink ensure that the concentration in this film is zero at all times. These two cases correspond to the minimum and the maximum loss to the prelens tear film and, thus, represent the highest and the lowest estimations for the fraction of the entrapped drug that diffuses into the cornea. Results show that the dispersion coefficient of the drug in the postlens tear film is unaffected by the release of the drug from the gel. Furthermore, simulation results show that drug delivery from a contact lens is more efficient than drug delivery by drops. The fraction of drug that enters the cornea varies from ∼70 to 95% for the first case (no flux to the PLTF) and from 20 to 35% for the second case (zero concentration in the PLTF). The model predicts that delivery of pilocarpine by soaked contact lenses is ∼35 times more efficient than delivery by drops, and this result matches clinical observations.

Approximately 90% of all ophthalmic drug formulations are now applied as eyedrops. Although eyedrops are convenient and well accepted by patients, about 95% of the drug contained in the drops is lost due to absorption through the conjunctiva or through the tear drainage. A major fraction of the drug eventually enters the bloodstream and may cause side effects. To reduce drug loss and side effects, it is proposed to encapsulate the ophthalmic drug formulations in liposomes and to disperse the drug-laden liposomes in the lens material. Upon insertion into the eye, the liposome-laden lens will slowly release the drug into the pre-lens (the film between the air and the lens) and the post-lens (the film between the cornea and the lens) tear films and thus provide drug delivery for extended periods of time. This paper focuses on dispersing dimyristoyl phosphatidylcholine (DMPC) liposomes in poly-2-hydroxyethyl methacrylate (p-HEMA) hydrogels, which are a common contact lens material. The results of this study show that the p-HEMA gels loaded with liposomes are transparent and that these gels release drugs for a period of about 8 days. Contact lenses made of particle-laden gels are expected to deliver drugs at therapeutic levels for a few days. The delivery rates can be tailored by controlling the particle and the drug loading.

Mosunetuzumab, a T-cell dependent bispecific antibody that binds CD3 and CD20 to drive T-cell mediated B-cell killing, is currently being tested in non-Hodgkin lymphoma. However, potent immune stimulation with T-cell directed therapies poses the risk of cytokine release syndrome, potentially limiting dose and utility. To understand mechanisms behind safety and efficacy and explore safety mitigation strategies, we developed a novel mechanistic model of immune and antitumor responses to the T-cell bispecifics (mosunetuzumab and blinatumomab), including the dynamics of Band T-lymphocytes in circulation, lymphoid tissues, and tumor. The model was developed and validated using mosunetuzumab nonclinical and blinatumomab clinical data. Simulations delineated mechanisms contributing to observed cell and cytokine (IL6) dynamics and predicted that initial step-fractionated dosing limits systemic T-cell activation and cytokine release without compromising tumor response. These results supported a change to a step-fractionated treatment schedule of mosunetuzumab in the ongoing Phase I clinical trial, enabling safer administration of higher doses.

ABSTRACT, with a t 1/2 value of 59 min. In vitro autoradiography studies on rhesus monkey brain slices identified the highest level of binding in the cerebellum, brainstem, and meninges. Finally, as an index of central nervous system penetrability, the in vivo cerebrospinal fluid/plasma ratio was determined to be 2 to 3% in cisterna magna-ported rhesus monkeys.Migraine is one of the most prevalent and disabling neurological disorders, with characteristic symptoms that can last for several days. Despite its severity and high prevalence, migraine is not generally recognized as a serious medical condition and the societal burden is not fully appreciated. Migraine often affects people during their most productive years, which in turn burdens families and employers and ultimately affects the quality of life of the migraine sufferer. Migraine is generally agreed to be underdiagnosed and many migraineurs do not receive appropriate therapy, indicating there is significant room for improvement in the diagnosis and management of migraine.An overall improvement in migraine treatment occurred Article, publication date, and citation information can be found at