Preclinical Investigations Of Genetic Correlates Of Alcohol Use Disorder

Alcohol use disorder (AUD) is a common neuropsychiatric condition characterized by uncontrolled alcohol use that has serious medical and social consequences. AUD is heritable and intense work has been done to characterize its genetic basis. Preclinical studies have been critical in describing the functional significance of genes associated with AUD and have advanced our understanding of the neurobiological underpinnings of this disorder. This dissertation presents a collection of mouse studies that describe behavioral and neurochemical consequences of genetic or pharmacological manipulations of three systems genetically implicated in AUD: (i) the ZIP8 transporter, (ii) the GluK1-containing kainate receptors, and (iii) the α5-containing nicotinic acetylcholine receptors (nAChR). First, we describe disturbances in baseline behavior and increased volitional alcohol intake in animals lacking the ZIP8 transporter. We then report the effects of selective inhibition of GluK1-containing kainate receptors using LY466195 on ethanol consumption, reinforcement, and withdrawal. In the third study, we describe how disruption of α5-containing nAChR function influences adolescent ethanol and nicotine consumption, as well as adult drug intake in a sex-specific manner. Finally, we propose a framework to investigate the spontaneous manifestation of ethanol withdrawal in mice voluntarily drinking alcohol in a model with high face validity. Altogether, this body of work contributes to the current understanding of the etiology of AUD

Teclistamab: Mechanism of action, clinical, and translational science

Abstract Multiple myeloma (MM) remains incurable despite improvements in treatment options. B‐cell maturation antigen (BCMA) is predominantly expressed in B‐lineage cells and represents a promising new target for MM. Teclistamab (TECVAYLITM) is the first T‐cell redirecting bispecific antibody approved for patients with MM. Targeting both CD3 receptor complex on T cells and BCMA on myeloma cells, teclistamab leads to T‐cell activation and subsequent lysis of BCMA+ cells. The recommended dose of teclistamab is 1.5 mg/kg subcutaneous weekly after two step‐up doses of 0.06 and 0.3 mg/kg, which was selected after review of safety, efficacy, pharmacokinetic, and pharmacodynamic data. Exposure‐response analyses of efficacy and safety data were also used to confirm the teclistamab dose. Teclistamab resulted in a high rate of deep and durable responses (63% overall response, 45.5% complete response or better, with 22 months median duration of response) in patients with triple‐exposed relapsed/refractory MM. Common adverse reactions included cytokine release syndrome, hematologic abnormalities, and infections. Teclistamab is currently being investigated as monotherapy as well as combination therapy across different MM indications