Aimmune Therapeutics (United Kingdom)

ABSTRACTRenal ischemia–reperfusion injury (IRI) is a key driver of the progression from acute kidney injury (AKI) to chronic kidney disease (CKD), primarily through mechanisms involving oxidative stress, ferroptosis, and inflammation that promote fibrotic remodelling. This study investigates the therapeutic potential of MIT‐001, a mitochondria‐targeted reactive oxygen species (ROS) scavenger, in mitigating renal IRI. In vitro, MIT‐001 attenuated ferroptotic cell death and fibrotic responses in HK‐2 cells challenged with TGF‐β or RSL3. MIT‐001 restored GPX4 expression and activity, activated Nrf2 signalling, reduced lipid ROS and suppressed fibrogenic markers (α‐SMA, Snail, collagen IV), while preserving E‐cadherin levels. In a bilateral renal IRI mouse model, administration of MIT‐001 significantly improved renal function and histology. Oxidative stress (DHE staining), apoptosis (TUNEL) and ferroptosis (4‐HNE, xCT, GPX4) were markedly reduced. Additionally, MIT‐001 inhibited the NF‐κB/HMGB1 inflammatory axis and enhanced antioxidant defence via the Nrf2/HO‐1 pathway, resulting in decreased immune infiltration and fibrosis. These findings demonstrate that MIT‐001 confers renal protection by concurrently targeting oxidative stress, ferroptosis and inflammation, underscoring its promise as a therapeutic strategy to prevent AKI‐to‐CKD progression.

Abstract Antibody-drug conjugates (ADCs) are a therapeutic modality that combines the targeting precision of monoclonal antibodies with the potent cytotoxicity of small-molecule drugs. Despite recent progress of ADC technology in treatment of cancer, efficacy and safety profile of ADCs is often limited by the characteristics of the payloads, highlighting the need for continued innovation in payload selection strategies. To address the unmet needs, we developed a novel class of ADC payload platform employing a novel payload class that disrupts proteostasis by inhibiting a critical component of the cellular protein degradation machinery. Upon internalization, the proteasome inhibitor (PI) payload can block tumor specific protein degradation pathway such as inhibitor of kappa B (IkB) degradation in hematologic malignancies or can induce the accumulation of misfolded and damaged proteins, leading to apoptotic cell death- particularly effective in tumor cells with high protein turnover. Various antibodies were conjugated with PI payload using different conjugation technologies, generating PI-ADCs for the treatment of solid tumors or hematologic malignancies. The resulting ADCs demonstrated efficient intracellular delivery and payload-dependent activity. Strong in vitro cytotoxicity and robust in vivo anti-tumor efficacy were observed across multiple preclinical tumor models, including those with limited sensitivity to existing ADC therapies. These findings highlight the potential of a new broad spectrum payload class to overcome resistance mechanisms and expand the therapeutic landscape of ADCs across diverse malignancies. Citation Format: Won-Gyun Ahn, Jaehee Jang, Seung-Joo Lee, Yong Soo Kim, Jaeseung Kim, Robert Huber, Uwe Koch, Johannes Bange, Martin Huber, Bert Klebl, Kiyean Nam. Proteasome inhibitor (PI) ADC: A novel broad spectrum payload platform [abstract]. In: Proceedings of the AACR-NCI-EORTC International Conference on Molecular Targets and Cancer Therapeutics; 2025 Oct 22-26; Boston, MA. Philadelphia (PA): AACR; Mol Cancer Ther 2025;24(10 Suppl):Abstract nr A110.

Background: Machine learning models trained on paratope-similarity networks have shown superior accuracy compared with clonotype-based models in binary disease classification. However, the computational demands of paratope networks hinder their use on large datasets and multi-disease classification. Methods: We reanalyzed publicly available T cell receptor (TCR) repertoire data from 1,421 donors across 15 disease groups and a large control group, encompassing approximately 81 million TCR sequences. To address computational bottlenecks, we replaced the paratope-similarity network approach (Paratope Cluster Occupancy or PCO) with a new pipeline Fast Approximate Clustering Techniques (FACTS) which comprises of four main steps: (1) high-dimensional vector encoding of sequences; (2) efficient clustering of vectors; (3) donor-level feature construction from cluster distributions; and (4) gradient-boosted decision tree classification for multi-class disease prediction. Findings: FACTS processed 10⁷ sequences in under 120 CPU hours. Using only TCR data, and evaluated with 3-fold cross-validation, it achieved a mean ROC AUC of 0.99 across 16 disease classes. Compared with the recently reported Mal-ID model, FACTS achieved higher donor-level classification accuracy for BCR (0.840 vs. 0.740), TCR (0.862 vs. 0.751), and combined BCR+TCR datasets (0.898 vs. 0.853). FACTS also preserved biologically meaningful signals, as shown by unsupervised t-SNE projections revealing distinct disease-associated and age-associated clusters. Interpretation: Paratope-based encoding with FACTS-derived features provides a scalable and biologically grounded approach for adaptive immune receptor (AIR) repertoire classification. The resulting classifier achieves superior multi-disease diagnostic performance while maintaining interpretability, supporting its potential for clinical and population-scale health profiling. Funding: This study was supported by the Japan Society for the Promotion of Science (JSPS) KAKENHI [JA23H034980] and by the Japan Agency for Medical Research and Development (AMED) [JP21am0101001].

BackgroundOral immunotherapy containing peanut (Arachis hypogaea) allergen powder-dnfp (PTAH) (Palforzia [Aimmune Therapeutics, Brisbane, Calif]) for 9 to 12 months resulted in higher tolerated amounts of peanut protein in PTAH-treated individuals aged 4 to 17 years with peanut allergy than in placebo-treated participants.ObjectiveWe aimed to describe additional long-term pooled safety data and changes in peanut sensitization markers from baseline through approximately 5 years of treatment.MethodsThe results from 6 clinical trials of PTAH (3 controlled and 3 open-label extension studies [N = 1227]) were pooled, and analysis of safety outcomes and immunologic data was performed. The PTAH doses were administered sequentially as follows: initial dose escalation (dose increased to 6 mg over 2 days), updosing (dose increased every 2 weeks to 300 mg for a minimum of 6 months), and maintenance dosing (300 mg per day).ResultsThere was a trend toward decreased adverse events (AEs) at years 1 and 2 that was maintained up to 5 years, with 94% of patients experiencing mild or moderate AEs and only 13% discontinuing PTAH use because of AEs overall. Gastrointestinal symptoms were the most commonly reported treatment-related AEs. A downward trend in systemic allergic reactions was also reported. PTAH treatment resulted in reduced levels of peanut-specific IgE after the first year and increased levels of peanut-specific IgG4, with a lowered peanut-specific IgE:IgG4 ratio. A reduction in median peanut skin prick test wheal diameter was observed (11.50 mm at baseline vs 5.75 mm at year 5).ConclusionLong-term immunomodulation without any new safety signals was reported with PTAH immunotherapy in the largest safety data set and longest treatment duration for oral immunotherapy published to date.

Abstract Adenosine deaminase acting on RNA (ADAR1) catalyzes the hydrolytic deamination of adenosine (A) to inosine (I) in double-stranded RNA (dsRNA). There are 2 isoforms of ADAR1 (p110 in the nucleus; p150 in cytoplasm) and both modify self dsRNA in coding and non-coding regions. The ADAR1 p150 isoform is expressed from an interferon (IFN)-responsive promoter and has a Z-DNA/Z-RNA binding domain at the N-terminus. Previous reports have provided a strong rationale for the development of ADAR1 p150 inhibitors for cancer immunotherapy. Here, we describe AVA-ADR-001, a potential first-in-class small molecule inhibitor of ADAR1 p150 targeting the Zα domain. AVA-ADR-001 binds specifically to the Zα domain of ADAR1 p150 as confirmed by fluorescence spectroscopy and showed significant interferon induction in THP1 macrophages, which have high ADAR1 p150 expression compared with monocytes. Proteomics and transcriptomics analysis revealed significant upregulation of interferon signaling upon treatment with AVA-ADR − 001. Interestingly, activation of interferon signaling resulted in AVA-ADR-001 induced cell killing in ADAR1-independent cell lines. In addition, treatment with AVA-ADR − 001 resulted in significant activation of PKR, which may explain the decreased cell proliferation. Finally, AVA-ADR-001 showed superior anti-tumor efficacy compared to anti-PD1 in an in vivo tumor efficacy study and has a moderately synergistic effect when combined. Overall, this study reveals that ADAR1 p150 inhibition by AVA-ADR-001 exerts a multipronged impact on anti-tumor efficacy mediated by immune cells, accumulation of interferons and activation of PKR, resulting in protein translation inhibition and cell proliferation arrest.

The Allergy to Peanuts imPacting Emotions And Life study (APPEAL) explored the psychosocial burden of living with self-reported peanut allergy experienced by children, teenagers, adults and caregivers in the UK and Ireland. A two-stage (quantitative survey and qualitative interview [APPEAL-1]), cross-sectional study of the psychosocial burden of peanut allergy (APPEAL-2) was conducted. Quantitative data were evaluated using descriptive statistics and qualitative data were analysed using MAXQDA software. A conceptual model specific to UK and Ireland was developed using the concepts identified during the analysis. A total of 284 adults in the UK and Ireland completed the APPEAL-1 survey and 42 individuals participated in APPEAL-2. Respondents reported that peanut allergy restricts their choices in various situations, especially with regard to choosing food when eating out (87% moderately or severely restricted), choosing where to eat (82%), special occasions (76%) and when buying food from a shop (71%). Fifty-two percent of survey participants and 40% of interview participants reported being bullied because of PA. Psychological impact of peanut allergy included feeling at least moderate levels of frustration (70%), uncertainty (79%), and stress (71%). The qualitative analysis identified three different types of coping strategies (daily monitoring or vigilance, communication and planning) and four main areas of individuals' lives that are impacted by peanut allergy (social activities, relationships, emotions and work [adults and caregivers only]). The extent of the impact reported varied substantially between participants, with some reporting many negative consequences of living with peanut allergy and others feeling it has minimal impact on their health-related quality of life. This large survey and interview study highlight the psychosocial burden of peanut allergy for adults, teenagers, children and caregivers in the UK and Ireland. The analysis demonstrates the wide variation in level of impact of peanut allergy and the unmet need for those individuals who experience a substantial burden from living with peanut allergy.

Peanut (Arachis hypogaea) allergen powder-dnfp (PTAH; previously known as AR101) is a daily oral immunotherapy approved to mitigate allergic reactions after accidental peanut exposure in peanut-allergic individuals aged 4-17 years. We sought to comprehensively summarize the PTAH safety profile for up to ∼2 years of treatment. Safety and adverse event (AE) data from participants aged 4-17 years from 3 controlled, phase 3 and 2 open-label extension trials were pooled and assessed. Of the 944 individuals receiving ≥1 PTAH dose, median exposure was ∼49 weeks; most participants experienced ≥1 treatment-related AE (TRAE; n= 853; 90.4%). Atotal of 829 participants experienced TRAEs with a maximum severity of mild (497, 52.6%) or moderate (332, 35.2%); 24 participants (2.5%) experienced TRAEs graded as severe. Overall, 80 participants (9.5%) discontinued as a result of AEs; most experienced gastrointestinal symptoms and discontinued during the first 6 months. When adjusted for exposure, AEs and TRAEs occurred at a rate of 76.4 and 58.7 events per participant-year of exposure (PYE), respectively, during updosing; AEs and TRAEs decreased to 23.0 and 14.2, respectively, during 300 mg maintenance. Overall, exposure-adjusted rates of systemic allergic reactions were 0.12 events/PYE (mild), 0.11 events/PYE (moderate), and 0.01 events/PYE (severe [anaphylaxis]). The safety profile of PTAH was consistent across trials, manageable, and improved over time. AEs were predominantly mild to moderate, and all grades declined in frequency with continued treatment. These data can be used to facilitate shared decision-making discussions with patients and families considering treatment with PTAH.