Kymera Therapeutics

The autoimmune disease systemic lupus erythematosus (SLE) is associated with genetic variants in the X-linked gene CXORF21, which encodes the protein TASL. TASL acts as an adaptor in the IRF5 pathway and is necessary for the phosphorylation of IRF5 in response to TLR7 or TLR9 stimulation. Here, we investigate the role of TASL in the humoral immune response, and in the development of lupus in the B6.MRLlpr murine model of SLE. We find that while TASL is dispensable for their development, it is required for the full activation of B cells via TLR9 stimulation, and consequent interferon signaling and inflammatory cytokine expression. Additionally, TASL is crucial for the emergence of age-associated B cells (ABCs), a B cell population derived from the extrafollicular response that increases with age and is expanded in autoimmune disease, and the production of IgG2c antibodies. We also find that deletion of TASL prevents the onset of autoimmunity in the genetically-determined B6.MRLlpr model of lupus.

Atherosclerotic macrophages predominantly exhibit a pro-inflammatory phenotype, driving chronic inflammatory and accelerating atherosclerotic progression. Interferon regulatory factor 5 (IRF5) is highly expressed in lesional macrophages within advanced atherosclerotic plaques, where it promotes the secretion of pro-inflammatory cytokines. However, current approaches lack an effective therapeutic strategy to specifically silence this gene in lesional macrophages for atherosclerosis treatment. This study aims to develop and evaluate a dual-targeted, siRNA-based nanotherapeutic platform that selectively acts on atherosclerosis-promoting genes in plaque macrophages, offering a potential strategy for treating atherosclerosis by reprogramming lesional macrophages. Here we designed and developed dual-targeted liposome-based nano-immunotherapeutics encapsulating small interfering RNA (siRNA) against IRF5 (siIRF5) to reprogram macrophage phenotypes within advanced plaques. In high-fat diet-fed ApoE-/- mice with advanced atherosclerotic plaques, dual-targeted siIRF5-loaded liposomes effectively accumulate within lesional macrophages, downregulate IRF5 expression, and promote anti-inflammatory macrophage polarization. Moreover, this siIRF5-based nanoimmunotherapy significantly reduces plaque burden and enhances plaque stability in two independent murine models of atherosclerosis. Furthermore, this siIRF5 nanoimmunotherapy exhibits biocompatibility even after long-term administration, underscoring its translational potential for clinical application in atherosclerosis treatment. This study introduces an innovative dual-targeted siRNA-based nanotherapeutic strategy that acts on atherosclerosis-promoting genes in plaque macrophages, offering a promising therapeutic avenue for atherosclerosis and other macrophage-driven inflammatory diseases.

Hidradenitis suppurativa (HS) is a chronic, recurrent inflammatory skin disease characterized by painful nodules, abscesses, and epithelialized tunnels, predominantly affecting flexural regions. With a global prevalence of approximately 1%, HS has a significant negative impact on quality of life. Multi-omics and histopathology studies have revealed a complex interplay between innate and adaptive immunity in HS, with neutrophils emerging as important drivers of inflammation. While therapies targeting TNF-α and IL-17 isoforms offer a degree of benefit, significant unmet need remains. Neutrophil signatures in HS lesions and the circulation underscore the rationale for selective modulation of neutrophil function. Strategies advancing through clinical trials include inhibition of chemokine-mediated trafficking, neutrophil serine protease inactivation and suppression of neutrophil extracellular traps (NETs), which amplify inflammatory and autoimmune responses. These emerging therapies mark a significant shift toward targeted neutrophil modulation, offering new opportunities to improve outcomes for patients with HS.

Alopecia areata (AA) is an autoimmune hair loss disorder characterized by follicular destruction. While bulk transcriptomic studies have identified contributory inflammatory axes, specific cell pathways remain underexplored. We characterized the single-cell transcriptomic landscape underpinning AA scalp compared to healthy controls. We performed single-cell RNA sequencing on lesional (LS) and nonlesional scalp biopsy samples from 13 patients with moderate-to-severe AA (5 with alopecia totalis/universalis) and 11 healthy controls. Overall, we profiled 41,067 high-quality cells. LS AA samples demonstrated robust TH1 activation and cytotoxicity, with upregulated IFNG, GZMH/K, and XCL1/2. Concurrently, TH2 skewing (IL13, IL13RA1, IL4R) and TNFRSF4/OX40 elevations in LS CD4+ and regulatory T-cells were also observed. IL15, JAK2/3, and STAT1 levels were increased in distinct LS dendritic cell subsets, with JAK/STAT genes also upregulated in fibroblasts and keratinocytes. Fibroblasts and smooth muscle cells exhibited enriched proinflammatory and profibrotic markers (CXCL9, CCL26, POSTN, COL5A3, COL6A6). LS keratinocytes further demonstrated downregulated hair keratins and increased interferon signaling. AA endothelial cells showed increased angiogenic and interferon signatures. Compared to patchy AA and controls, alopecia totalis/universalis demonstrated higher expression of multiple cytotoxic, TH1, TH2, and JAK/STAT markers in immune cells, and proliferative and inflammatory signatures in nonimmune cells. This comprehensive high-resolution single-cell map uncovers potential communication networks between immune and nonimmune cell populations in AA scalp, possibly disrupting immune privilege at the hair follicle and driving disease progression and/or severity.

Belimumab is a biologic therapy for active, autoantibody-positive systemic lupus erythematosus (SLE) that has been shown to reduce disease activity, flare frequency, and glucocorticoid use, thereby preventing organ damage. Belimumab is typically reserved for refractory disease, but emerging evidence suggests earlier initiation may lead to higher response rates, greater achievement of remission or low disease activity, and further reduction in glucocorticoid use. To evaluate the economic and health-related outcomes of early vs delayed belimumab initiation for biologic-naive patients with clinically active SLE, comparing medical costs and quality-adjusted life-years (QALYs). This economic evaluation using cost-utility analysis from a US payer perspective was conducted with a Markov model with monthly cycles over a 15-year horizon and was informed by studies published from 2013 to 2025, identified through a targeted literature review. Biologic-naive adult SLE patients with active disease (SLE Disease Activity Index 2000 score >0) were included. Patients began in a pretreatment state and transitioned monthly between 5 health states: complete response (per SLE Responder Index-4 [SRI-4]), partial response, nonresponse (failure to meet SRI-4 accompanied by flare or treatment-emergent adverse event), no treatment (standard of care), and death. Early (≤2 years of disease duration) or delayed (after failure of standard therapy) initiation of intravenous belimumab. Primary outcomes included total direct medical costs, QALYs, incremental cost-effectiveness ratio (ICER), and incremental net monetary benefit (INMB). The 95% uncertainty intervals (UIs) for incremental costs, QALYs, and INMB were calculated from the 2.5 and 97.5 percentiles of the probabilistic sensitivity analyses. The modeled cohort included 1000 adults (912 female [91.2%]) with a mean (SD) age of 41 (11) years at belimumab initiation. Early initiation provided an additional 0.30 (95% UI, -0.42 to 1.39) QALYs at an incremental cost of -$126 337.12 (95% UI, -$910 010.39 to $168 383.94) per patient relative to delayed initiation, yielding a favorable ICER of -$421 123.73 per QALY. At a $50 000 per QALY threshold, the mean INMB was $141 337.12 (95% UI, -$157 997.53 to $925 019.51), with early initiation preferred in 81.3% of simulations (8125 of 10 000 simulations). Deterministic sensitivity analyses identified time horizon (INMB range, $6351.07 for a 1-year horizon to $156 497.12 for a lifetime horizon) and SRI-4 response odds ratio (INMB range, $69 741.68 for an odds ratio of 1.08 to $209 591.09 for an odds ratio of 3.47) as the most influential parameters. In this economic evaluation of early vs delayed belimumab in biologic-naive patients with active SLE, early initiation was associated with improved health outcomes and reduced costs. These findings support earlier clinical adoption and reconsideration of reimbursement criteria to reflect long-term value.

Cancer cells activate the integrated stress response (ISR) to adapt to stress and resist therapy1. ISR signals converge on activating transcription factor 4 (ATF4), which controls cell-intrinsic transcriptional programs that are involved in metabolic adaptation, survival and growth2,3. However, whether the ISR-ATF4 axis influences anti-tumour immune responses remains mostly unknown. Here we show that loss of ATF4 decreases tumour progression considerably in immunocompetent mice, but not in immunocompromised ones, by enhancing T cell-dependent anti-cancer immune responses. An unbiased genetic screen of ATF4-regulated genes identifies lipocalin 2 (LCN2) as the principal ATF4-dependent effector that impairs anti-tumour immunity by favouring infiltration with immunosuppressive interstitial macrophages. Furthermore, we find that LCN2 promotes T cell exclusion and immune evasion in preclinical mouse models, and correlates with decreased T cell infiltration in patients with lung and pancreatic adenocarcinomas. Anti-LCN2 antibodies promote robust anti-tumour T cell responses in mouse models of aggressive solid tumours. Our study shows that the ATF4-LCN2 axis has a cell-extrinsic role in suppressing anti-cancer immunity, and could pave the way for an immunotherapy approach that targets LCN2.

Acute myeloid leukemia (AML) is an aggressive myeloid malignancy with a poor prognosis. Venetoclax (Ven), a BCL2 inhibitor, has shown promising results but often leads to relapse due to mitochondrial dysregulation, particularly due to upregulation of the anti-apoptotic protein MCL1. Overexpression of the transcription factor STAT3 has been linked to poor survival in AML patients. Overexpression of STAT3 in a transgenic murine model induces a myeloid malignancy with a short latency period and inflammatory upregulation. The current study identifies STAT3 upregulation as a key mechanism of Ven resistance. A clinically relevant STAT3 degrader effectively reduces both total and phosphorylated STAT3, corrects mitochondrial structural and functional dysregulation, and induces apoptosis in Ven-resistant AML cell lines. KT-333 significantly decreases STAT3 and MCL1 protein levels and improves survival in Ven-resistant (Ven-Res) AML murine models. In summary, STAT3 hyperactivation is leukemogenic, is further potentiated in Ven-resistance and can be clinically targeted with a novel and specific STAT3 degrader. Pictorial representation depicting upregulation of STAT3 and MCL1 in venetoclax resistant myeloid malignancies such as MDS and AML causing mitochondrial structural abnormalities and dysfunction. By using specific STAT3 degrader, STAT3 inhibition, and thereby indirect downregulation of MCL1 can be a promising therapeutic intervention to target drug resistant clones in MDS and AML.