Genentech, Inc., is an American biotechnology corporation which became a subsidiary of Roche in 2009. Genentech Research and Early Development operates as an independent center within Roche.As of February 2020, Genentech employed 13,638 people.
Dysregulated microglia are intimately involved in neurodegeneration, including Alzheimer's disease (AD) pathogenesis, but the mechanisms controlling pathogenic microglial gene expression remain poorly understood. The transcription factor CCAAT/enhancer binding protein beta (c/EBPβ) regulates pro-inflammatory genes in microglia and is upregulated in AD. We show expression of c/EBPβ in microglia is regulated post-translationally by the ubiquitin ligase COP1 (also called RFWD2). In the absence of COP1, c/EBPβ accumulates rapidly and drives a potent pro-inflammatory and neurodegeneration-related gene program, evidenced by increased neurotoxicity in microglia-neuronal co-cultures. Antibody blocking studies reveal that neurotoxicity is almost entirely attributable to complement. Remarkably, loss of a single allele of Cebpb prevented the pro-inflammatory phenotype. COP1-deficient microglia markedly accelerated tau-mediated neurodegeneration in a mouse model where activated microglia play a deleterious role. Thus, COP1 is an important suppressor of pathogenic c/EBPβ-dependent gene expression programs in microglia.
Abstract There is a growing demand in the subcutaneous delivery of monoclonal antibodies (mAbs) to reduce treatment burden for both patients and healthcare systems when compared to intravenous administration. However, it poses significant challenges in formulation development primarily due to high viscosities in highly concentrated solutions of mAbs for subcutaneous injection, which impacts injectability and effective dosing. Advances in protein spray drying have enabled the production of solid protein powders with enhanced stability. When suspended in non-aqueous media, these spray-dried powders facilitate the achievement of protein concentrations far exceeding 200 mg/mL to overcome challenges associated with high-concentration formulations for biologics such as solubility, viscosity, and aggregation. This perspective aims to discuss recent studies showcasing the successful application of spray-dried proteins to achieve high protein concentrations; key formulation aspects of protein spray drying with respect to subvisible particles; formulation considerations for spray-dried protein suspensions in non-aqueous media; technical and regulatory challenges for subcutaneous delivery of non-aqueous suspensions for mAbs; their knowledge gaps in clinical translation; and the need for patient-centric studies to enhance patient experience, providing insights into how future research can better balance quality and compliance. Finally, with the growing exploration of drying technologies, this article discusses the future outlook for high-concentration suspensions of therapeutic proteins.
Productivity losses from illness, treatment, and informal caregiving impose a substantial economic burden on patients, caregivers, employers, and society in the United States (US), but measurement remains inconsistent and often omits key domains, such as presenteeism and unpaid non-market work productivity. These gaps limit the integration of productivity into economic evaluations and policy and may lead to undervaluation of interventions that improve health and reduce disease burden. The aim was to identify evidence priorities and methodological improvements for measuring and valuing productivity in US economic evaluations. A targeted literature review (TLR) of US-based studies published from 2020 to 2024 was conducted to evaluate measurement of absenteeism, presenteeism, or unpaid non-market work productivity. Definitions, instruments, valuation methods, and reporting practices were extracted. Findings informed a virtual workshop with eight stakeholders, who completed prioritization exercises and participated in facilitated discussions to refine evidence priorities and methodological recommendations. Thirty studies met the TLR inclusion criteria. Absenteeism was assessed in 77
QuestionWhat are the safety, tolerability, and effects associated with intravitreal vamikibart (anti-interleukin 6 antibody) in uveitic macular edema (UME)?FindingsIn this open-label, multiple-ascending-dose, phase 1, nonrandomized clinical trial, 37 patients with UME secondary to noninfectious uveitis (NIU) received intravitreal vamikibart. Across all doses (0.25 mg, 1 mg, 2.5 mg) from baseline to 12 weeks, vamikibart was tolerated and associated with improved best-corrected visual acuity and central subfield thickness.MeaningThis evidence supports short-term safety and tolerability, as well as visual acuity and macular central subfield thickness improvement, of intravitreal vamikibart in cases of UME secondary to NIU. ImportanceEffective nonsteroidal therapies are needed for uveitic macular edema (UME).ObjectiveTo assess the safety, tolerability, and effects associated with intravitreal (IVT) vamikibart in UME.Design, Setting, and ParticipantsThis multipart, multicenter, open-label, multiple-ascending-dose nonrandomized clinical trial of vamikibart (RO7200220), a novel IVT anti-interleukin 6 monoclonal antibody, included monotherapy in participants with UME secondary to noninfectious uveitis (NIU). DOVETAIL was conducted from July 2019 to November 2023 at 18 sites in the US. Adults with UME secondary to NIU (optical coherence tomography central subfield thickness [CST] >= 325 & micro;m) were eligible for inclusion. Data were analyzed from February 2024 to May 2024.InterventionsParticipants were enrolled into 3 dose groups (0.25, 1, or 2.5 mg) and received IVT vamikibart at day 1, week 4, and week 8, followed by observation not receiving treatment until weeks 20 (2.5 mg) or 36 (0.25 or 1 mg).Main Outcomes and MeasuresThe primary outcomes were safety and tolerability; exploratory outcomes included best-corrected visual acuity (BCVA) and CST.ResultsIn this nonrandomized study, vamikibart was associated with improvements in BCVA and CST across all doses. A total of 37 participants with UME were enrolled (0.25 mg: n = 12; 1 mg: n = 12; 2.5 mg: n = 13); 22 of 37 patients (59.5%) were female, and the mean (SD) age was 63.5 (15.4) years. At week 12, mean (SD) change from baseline in BCVA letter score was +9.9 (8.9), an approximate 2-line improvement (improvements in letter scores of +11.1 [8.1], +10.3 [8.0], and +8.4 [10.8] for the 0.25-mg, 1-mg, and 2.5-mg groups, respectively), and mean (SD) CST reduction was -165.1 (147.5) & micro;m (-125.0 [135.0] & micro;m, -188.1 [152.4] & micro;m, and -183.6 [159.4] & micro;m for the 3 dose groups, respectively). Of 37 participants, 36 continued vamikibart throughout the 12 weeks. Ocular adverse events (AEs) in the study eye were reported in 19 participants (51.4%), including 1 serious AE (uveitis worsening, unrelated to study drug) and 1 treatment-related AE (VA reduced transiently). No cases of retinal vasculitis (occlusive or nonocclusive) were reported.Conclusions and RelevanceThese results from the phase 1 DOVETAIL nonrandomized clinical trial provide preliminary evidence supporting safety, tolerability, and potential effects of vamikibart for UME secondary to NIU. Two phase 3 clinical trials (MEERKAT [NCT05642312] and SANDCAT [NCT05642325]) are underway to further evaluate vamikibart in UME.Trial RegistrationClinicalTrials.gov Identifier: NCT06771271 The phase 1 DOVETAIL nonrandomized clinical trial assesses the safety, tolerability, and effects associated with intravitreal vamikibart in uveitic macular edema.
Recent advances in large language models (LLMs) have shown great potential to accelerate drug discovery. However, the specialized nature of biochemical data often necessitates costly domain-specific fine-tuning, posing critical challenges. First, it hinders the application of more flexible general-purpose LLMs in cutting-edge drug discovery tasks. More importantly, it limits the rapid integration of the vast amounts of scientific data continuously generated through experiments and research. Compounding these challenges is the fact that real-world scientific questions are typically complex and open-ended, requiring reasoning beyond pattern matching or static knowledge retrieval. To address these challenges, we propose CLADD, a retrieval-augmented generation (RAG)-empowered agentic system tailored to drug discovery tasks. Through the collaboration of multiple LLM agents, CLADD dynamically retrieves information from biomedical knowledge bases, contextualizes query molecules, and integrates relevant evidence to generate responses - all without the need for domain-specific fine-tuning. Crucially, we tackle key obstacles in applying RAG workflows to biochemical data, including data heterogeneity, ambiguity, and multi-source integration. We demonstrate the flexibility and effectiveness of this framework across a variety of drug discovery tasks, showing that it outperforms general-purpose and domain-specific LLMs as well as traditional deep learning approaches.
