bims-hummad 2026-08-30 papers

Hum Gene Ther. 2026 Aug 24. 10430342261478743

Engineering Human Hematopoietic Stem and Progenitor Cells for Antigen Expression in Antigen-Presenting Cells.

Clara Heider, Meg Louise Donovan, Carina Walpole, Peter R Murphy, Louisa Alim, Irina Buckle, Liam O'Brien, Maki Nakayama, Simon C Barry, Stuart I Mannering, Kristen J Radford, Raymond J Steptoe.

Gene therapy achieved through genetic manipulation and transfer of hematopoietic stem and progenitor cells (HSPC) is becoming an increasingly attractive option for personalized medicine. In the current clinical scenarios, use is restricted to overcoming genetic disorders, but it is envisioned that more diverse applications will be developed in the future. Immunotherapy of malignant disease already employs non-HSPC-based gene therapies, and there is a body of evidence that HSPC-mediated gene therapy has potential as a powerful immunotherapeutic for some diseases of immune dysregulation such as autoimmune disease and allergies. Administration of HSPC gene-engineered to encode antigen(s) induces antigen-specific immune tolerance in animal models. To translate this technology, we sought to identify whether human dendritic cells (DC) and other antigen-presenting cell populations derived from lentivirally transduced HSPC would express, process, and present antigens of interest. Lentiviral vectors were generated that encoded preproinsulin, a relevant autoantigen implicated in type 1 diabetes, or a control protein carrying a viral epitope along with reporter genes under transcriptional control of ubiquitous or antigen-presenting cell-directed promoters. In vitro, DC were differentiated from transduced HSPC and tested in antigen presentation assays using Jurkat lines carrying relevant type 1 diabetes-associated T cell receptors. In vivo, transduced HSPC were used to generate humanized mice, and the development of a range of antigen-presenting cells and their expression of lentivirus-encoded genes were determined. Antigen-presenting cell progeny of transduced HSPC expressed antigens and reporter genes both in vitro and in vivo, and in vitro-generated DC presented lentivirally encoded antigens. The studies characterize human chimerism and therapeutic gene expression in a new model and provide support for the use of HSPC-based gene therapies for immune dysregulation in humans.

Keywords: T cells; antigen-presenting cells; dendritic cells; hematopoietic stem and progenitor cells; humanized mice; lentivirus

DOI: https://doi.org/10.1177/10430342261478743

Front Immunol. 2026 ;17 1851898

NeoThy™ immune-humanized mice can produce anti-drug antibodies to support immunogenicity assessment for biological drug products.

Sepideh Gharaie, Robyn E Becker, Elizaveta A Svyatova, Megan K Chow, Nicholas A Smith, Adam J Bell, Mohit Pratap Singh, Kathleen L Gabrielson, Katherine I Shea, Janell Richardson, Kristina E Howard.

Introduction: Assessment of immunogenicity for new therapeutic protein products and biosimilars is an important aspect of drug development and the safety evaluation process. Conventional animal models typically do not reliably predict immunogenicity, as the human drug is seen as foreign in the animal model. To address this need, we conducted a proof-of-concept study with neonatal thymus (NeoThy™) immune-humanized mice using drug products known to have higher rates of immunogenicity in patients. NeoThy immune-humanized mice develop a fully engrafted human immune system that includes a human thymus for proper T cell development capable of recognizing human versus foreign proteins.
Objective: This study used infliximab and interferon-beta (IFN-β) as monotherapies and in combination to determine if NeoThy immune-humanized mice could produce specific adaptive immune responses to the drugs.
Methods: NeoThy immune humanized mice were generated at two different locations, creating six experimental groups. Mice received infliximab, IFN-β, a combination of infliximab and IFN-β, positive or negative control with treatment schedule appropriate to the therapeutic. Peripheral blood/serum was collected on day 0, 21, 42, and 63; tissues (bone marrow, spleen, lymph nodes) were harvested at necropsy (day 63). Immune reconstitution and treatment effects were assessed with flow cytometry, proliferation, total IgM/IgG isotyping, anti-drug antibodies (ADA) ELISAs for infliximab and IFN-β, and histopathology.
Results: NeoThy immune-humanized mice showed broad and ample human immune reconstitution with donor-dependent differences noted. We observed immune activation and B cell class switching including IgG1-4 in most donors. In several cases, humanized mouse serum immunoglobulin levels approached or exceeded those from normal human serum, which was evaluated as a control. Binding ADAs to IFN-β and neutralizing ADAs to infliximab, were detected in multiple mice in a donor- and treatment-dependent manner.
Conclusions: NeoThy immune-humanized mice mount human-like, donor-dependent immune responses to biologics, including class switching, antigen-specific proliferation, and ADA formation. These preliminary findings suggest that NeoThy immune-humanized mice have the biological ability to help assess immunogenicity risk, and other immunosafety considerations for biological drug products.

Keywords: IFNβ; anti-drug antibody; immune-humanized mice; immunogenicity; infliximab

DOI: https://doi.org/10.3389/fimmu.2026.1851898

Adv Sci (Weinh). 2026 Aug 25. e77358

Intrasplenic Thymus Organogenesis from Injectable Tissue Fragments Restores Functional T-Cell Immunity.

Shaocong Wang, Zijian Zhang, Fulin Dai, Zhijie Yin, Zhen Xing, Yurong Li, Haochong Lei, Junfeng Zhang, Chunyan Liu, Yan Li, Lei Dong.

Thymic hypofunction due to primary defects, aging, infection, or cytoreductive therapies causes profound restriction of the T-cell receptor (TCR) repertoire and increases rates of morbidity and mortality. Restoring thymic function is therefore critical. Here, the distinctive niche within the spleen has inspired the development of intrasplenic thymus regeneration (ISTR), an approach in which cultured thymic tissue fragments are implanted into the spleens of athymic nude mice, aged mice, thymectomized mice undergoing hematopoietic stem cell transplantation (HSCT), and humanized mice. The spleen's abundant vasculature and supportive stromal milieu enable rapid thymic organogenesis, leading to the reconstitution of phenotypically diverse and functional T-cell compartments, as well as protective responses to viral and tumor challenges. Relative to intramuscular implantation, ISTR drives faster and more complete thymic development, generates greater T-cell output, and is associated with a lower incidence of graft-vs.-host disease. In humanized animals, intrasplenic thymus grafts also promote the rapid emergence of functional human T cells. These results identify the spleen as an optimal ectopic niche for thymus regeneration and provide a promising strategy for clinical immune reconstitution and regenerative immunology.

Keywords: T‐cell immunity; ectopic regeneration; immunodeficiency; spleen; supportive niche; thymus

DOI: https://doi.org/10.1002/advs.77358

Arthritis Rheumatol. 2026 Aug 27.

Efficacy of the Bispecific Anti-BAFF/IL-21 Antibody CZ105 Bis2 in Models of Systemic Lupus Erythematosus.

Xiwei Feng, Di Long, Huiqi Yin, Liming Li, Zijun Wang, Junpeng Zhao, Xinyu Fan, Wei Wu, Haijing Wu, Qianjin Lu.

BACKGROUND: Systemic lupus erythematosus (SLE) is a multi-organ autoimmune disease. B cells play a crucial role in disease initiation and progression. Clinical trial evidence suggests that intensified B-cell depletion can improve SLE therapeutic outcomes. While efficacy and tolerability of belimumab, the first B-cell-targeted agent approved for SLE, have been demonstrated, around 30-40% of patients still show suboptimal treatment response. Interleukin-21 (IL-21), a regulator of B-cell development, is closely associated with disease activity in SLE, underscoring its potential as a therapeutic target. However, monotherapy targeting IL-21 has yielded limited efficacy in clinical trials.
METHODS: We prepared h18B10, a humanized anti-IL-21 monoclonal antibody. Building upon this candidate, we constructed CZ105 Bis2, a bispecific antibody assembled by fusing the variable domains of h18B10 and belimumab, enabling concurrent blockade of IL-21 and BAFF signaling pathways. In vitro functional assays verified that CZ105 Bis2 exhibits binding affinity and cytokine neutralization potency equivalent or superior to its two parent molecules. Compared with selective inhibitors of BAFF or IL-21, CZ105 Bis2 elicited more robust suppression of in vivo B-cell effector functions. In the keyhole limpet hemocyanin (KLH) model, CZ105 Bis2 significantly reduced T-cell-dependent, antigen-specific B-cell responses. In both pristane-induced lupus mouse models and humanized lupus-like models (chronic graft-versus-host disease (GVHD)), CZ105 Bis2 decreased anti-double-stranded DNA (dsDNA) antibody levels, reduced proteinuria, and alleviated renal inflammatory infiltration.
CONCLUSION: Our preclinical data confirm that CZ105 Bis2 achieves superior efficacy over single-target biologics across in vitro and in vivo systems, supporting its translational potential to improve clinical outcomes in SLE.

DOI: https://doi.org/10.1002/art.70310

EMBO Mol Med. 2026 Aug 27.

A synthetic NKG2A engager enables long-term persistence of HLA-deficient allogeneic engineered Tregs.

Tingxi Guo, Kaya R Epstein, Maegan E Hoover, Nathan W Zammit, Jennifer Y Yam, Scott Hussell, Sophia Hernandez, Abigail Doherty, Payam Zarin, Martina Sassone-Corsi, Lindsay Webb, Gene I Uenishi, Thomas Wickham, Christopher L Moore.

Allogeneic cell therapies offer a scalable and off-the-shelf alternative to the autologous approach, but immune rejection, particularly by natural killer (NK) cells following human leukocyte antigen (HLA) ablation, remains a major barrier to their persistence. Here, we report an improved synthetic NKG2A engager to selectively inhibit NKG2A⁺ NK cells while avoiding activation of NKG2C⁺ subsets, thereby overcoming a key limitation of the natural ligand HLA-E. Engineered regulatory T cells (EngTregs) lacking HLA and expressing the engager were protected from in vitro NK cell-mediated cytotoxicity more effectively than previously reported NK inhibitory strategies. In humanized mouse models, EngTregs persisted for up to 12 weeks, whereas unprotected cells were rapidly rejected. Incorporation of the engager into a clinically compatible dual-AAV EngTregs preserved Treg identity and function while conferring resistance to immune rejection. Together, these findings establish the improved NKG2A engager as an effective synthetic immune-evasion strategy and provide a clinically translatable approach to enable durable persistence of off-the-shelf EngTreg therapies.

DOI: https://doi.org/10.1038/s44321-026-00507-4

Immunol Rev. 2026 Sep;342(1): e70165

Protective and Pathogenic Antibodies to Citrullinated Antigens.

Outi Sareila, Yibo He, Zhongwei Xu, Changrong Ge, Erik Lönnblom, Rikard Holmdahl.

Autoimmune diseases start years before clinical onset. In rheumatoid arthritis (RA), autoantibodies to citrullinated proteins (ACPA) and to modified IgG (rheumatoid factors, RF) can be detected many years before the inflammatory attack on cartilaginous joints. It has been assumed that these antibodies are pathogenic. We show here that many of the antibodies produced before disease onset are protective although there are likely also pathogenic clones directed to cartilaginous joints. To determine the function of these antibodies, it is crucial to analyze them in vivo, which is only possible in mouse models. To ease the translation, we have genetically humanized models which will now allow a more accurate analysis of autoimmune mechanisms in human disease. In this review, we will also discuss what we know today regarding the targeted epitopes and the role of pathogenic and protective antibodies. With this knowledge as the basis, we have developed new types of serologic tests for RA.

Keywords: B cells; anti‐citrullinated protein antibodies; autoantibodies; diagnostics; pathogenic mechanisms; protective immunity; rheumatoid arthritis

DOI: https://doi.org/10.1111/imr.70165