Journal: Molecular Therapy

Authors: Romain Hardet, Shu-Hung Wang, Sandrine Delignat, Marine Blandin, Reinaldo Digigow, Cornelia Gottwick, Markus Heine, Lígia Margarida Marques Mesquita, Marco Fanzutti, Anna-Lisa Vocaturo, Disha Mungalpara,  Olivier Boyer, Sébastien Lacroix-Desmazes, Sabine Fleischer, Sahil Adriouch

Summary

Liver sinusoidal endothelial cells (LSECs) naturally cross-present antigens and induce T cell tolerance. Targeting LSECs with peptide-coupled nanoparticles offers an efficient strategy to induce antigen-specific immune tolerance. Previous preclinical and clinical studies have shown that peptide-coupled nanoparticles can effectively inhibit T cell responses to the selected cognate peptide epitopes. However, clinical situations such as viral-vector-mediated gene therapy would benefit from simultaneous tolerance induction to multiple epitopes/antigens, posing a significant challenge. In this study, we used mouse models of adeno-associated virus (AAV)-mediated gene transfer to assess the in vivo effects of peptide-loaded nanoparticles designed to tolerize immune responses to transgene- or/and capsid-derived epitopes. We report here for the first time that LSEC-targeting nanoparticles coupled to a single peptide epitope promoted extension of tolerance to multiple relevant epitopes/antigens and simultaneously tolerized both CD4+ and CD8+ T cell responses. This tolerance spreading, which we termed “Tspread,” remained specific to the transgene- and capsid-derived antigens conveyed by the administered AAV vector and did not impair immune responses to an unrelated vaccine antigen. These findings delineate a novel LSEC-mediated tolerance spreading with important clinical implications for viral-vector gene therapy, where tolerance to multiple epitopes/antigens is essential for long-term expression of therapeutic genes.

Journal: Journal of Hepatology

Authors: Antonella Carambia, Barbara Freund, Dorothee Schwinge, Oliver T Bruns, Sunhild C Salmen, Harald Ittrich, Rudolph Reimer, Markus Heine, Samuel Huber, Christian Waurisch, Alexander Eychmüller, David C Wraith, Thomas Korn, Peter Nielsen, Horst Weller, Christoph Schramm, Stefan Lüth, Ansgar W Lohse, Joerg Heeren, Johannes Herkel

Summary

It is well-known that the liver can induce immune tolerance, yet this knowledge could, thus far, not be translated into effective treatments for autoimmune diseases. We have previously shown that liver sinusoidal endothelial cells (LSECs) could substantially contribute to hepatic tolerance through their ability to induce CD4+ Foxp3+ regulatory T cells (Tregs). Here, we explored whether the Treg-inducing potential of LSECs could be harnessed for the treatment of autoimmune disease.

We engineered a polymeric nanoparticle (NP) carrier for the selective delivery of autoantigen peptides to LSECs in vivo. In the well-characterized autoimmune disease model of experimental autoimmune encephalomyelitis (EAE), we investigated whether administration of LSEC-targeting autoantigen peptide-loaded NPs could protect mice from autoimmune disease.

We demonstrate that NP-based autoantigen delivery to LSECs could completely and permanently prevent the onset of clinical EAE. More importantly, in a therapeutic approach, mice with already established EAE improved rapidly and substantially following administration of a single dose of autoantigen peptide-loaded NPs, whereas the control group deteriorated. Treatment efficacy seemed to depend on Tregs. The Treg frequencies in the spleens of mice treated with autoantigen peptide-loaded NPs were significantly higher than those in vehicle-treated mice. Moreover, NP-mediated disease control was abrogated after Treg depletion by repeated administration of Treg-depleting antibody.

Our findings provide proof of principle that the selective delivery of autoantigen peptides to LSECs by NPs can induce antigen-specific Tregs and enable effective treatment of autoimmune disease. These findings highlight the importance of Treg induction by LSECs for immune tolerance.

Journal: Frontiers of Immunology

Authors: Shu-Hung Wang, Isabelle Serr, Reinaldo Digigow, Barbara Metzler, Alexey Surnov, Cornelia Gottwick, Muhammad Alsamman, Daria Krzikalla, Markus Heine, Miriam Zahlten, Agata Widera, Disha Mungalpara, Muharrem Şeleci, Marco Fanzutti, Lígia Margarida Marques Mesquita, Anna-Lisa Vocaturo, Johannes Herkel, Antonella Carambia, Christian Schröter, Dikran Sarko, Johannes Pohlner, Carolin Daniel, Cristina de Min, Sabine Fleischer

Summary

Journal: Immunology

Authors: Antonella Carambia, Cornelia Gottwick, Dorothee Schwinge, Stephanie Stein, Reinaldo Digigow, Muharrem Şeleci, Disha Mungalpara, Markus Heine, Fenja A Schuran, Carlotta Corban, Ansgar W Lohse, Christoph Schramm, Joerg Heeren, Johannes Herkel

Summary

Autoimmune diseases are caused by adaptive immune responses to self‐antigens. The development of antigen‐specific therapies that suppress disease‐related, but not unrelated immune responses in general, is an important goal of biomedical research. We have previously shown that delivery of myelin peptides to liver sinusoidal endothelial cells (LSECs) using LSEC‐targeting nanoparticles provides effective protection from CD4 T‐cell‐driven autoimmune encephalomyelitis. Here, we investigated whether this methodology might also serve antigen‐specific treatment of a CD8 T‐cell‐driven autoimmune disease. As a model for CD8 T‐cell‐mediated autoimmunity, we used OT‐1 T‐cell‐driven cholangitis in K14‐OVAp mice expressing the cognate MHC I‐restricted SIINFEKL peptide in cholangiocytes. To study whether peptide delivery to LSECs could modulate cholangitis, SIINFEKL peptide‐conjugated nanoparticles were administered intravenously one day before transfer of OT‐1 T cells; five days after cell transfer, liver pathology and hepatic infiltrates were analysed. SIINFEKL peptide‐conjugated nanoparticles were rapidly taken up by LSECs in vivo, which effectively cross‐presented the delivered peptide on MHC I molecules. Intriguingly, K14‐OVAp mice receiving SIINFEKL‐loaded nanoparticles manifested significantly reduced liver damage compared with vehicle‐treated K14‐OVAp mice. Mechanistically, treatment with LSEC‐targeting SIINFEKL‐loaded nanoparticles significantly reduced the number of liver‐infiltrating OT‐1 T cells, which up‐regulated expression of the co‐inhibitory receptor PD‐1 and down‐regulated cytotoxic effector function and inflammatory cytokine production. These findings show that tolerogenic LSECs can effectively internalize circulating nanoparticles and cross‐present nanoparticle‐bound peptides on MHC I molecules. Therefore, nanoparticle‐mediated autoantigen peptide delivery to LSECs might serve the antigen‐specific treatment of CD8 T‐cell‐driven autoimmune disease.

Journal: British Journal of Dermatology

Hamburg, Germany, May 6, 2025 – Topas Therapeutics presented positive clinical proof-of-concept data demonstrating gluten-specific tolerance induction in celiac disease (CeD) patients. Data from a Phase 2a clinical trial evaluating TPM502, the company’s lead candidate, demonstrated a positive safety and tolerability profile, a significant reduction of the inflammatory responses to gluten and long-lasting phenotypic changes to gliadin-specific T cells. In addition, TPM502-treated patients reported a beneficial impact on symptoms post a gluten challenge. Developed using Topas’ proprietary platform, TPM502 consists of nanoparticles coupled with CeD disease-relevant antigens. The study findings were presented at Digestive Disease Week® (DDW) 2025 on Monday, May 5, 2025, in an oral presentation and were selected for the American Gastroenterological Association Presidential Plenary

“The data presented at DDW represent a significant validation of TPM502 as a potential treatment for celiac disease. The observed safety profile, combined with the clear, dose-dependent reduction of IL-2 and IFN-γ release by gluten-specific T cells as well as phenotypic changes in antigen-specific CD4+ T cells, reinforces TPM502’s ability to precisely and durably modulate the underlying autoimmune response to gluten,” stated Knut E. A. Lundin, MD, PhD, Principal Investigator of the Phase 2a study and Professor and Head of Clinical Education at the Institute of Clinical Medicine, University of Oslo.

“By directly addressing the pathogenic T-cell activation central to celiac disease, TPM502 could redefine the treatment paradigm and provide a much-needed therapeutic option for patients who currently have no approved alternatives to a lifelong gluten-free diet. Indeed, the gluten-free diet does not meet the medical needs of many celiac disease patients,” added Cristina de Min, MD, CMO of Topas Therapeutics.  “Our Phase 2a trial data also support the application of our nanoparticle platform for a range of autoimmune disease indications for which tolerance induction could be a transformative therapeutic approach.”

The multi-center, double-blind, randomized, placebo-controlled Phase 2a study evaluated TPM502 in HLA-DQ2.5 positive adults with confirmed CeD on a gluten-free diet (NCT05660109). HLA-DQ2.5 is a very common genetic variant among CeD patients, representing approximately 90% of the total disease population.[1] A total of 38 patients that achieved a predefined IL-2 response to bolus gluten challenge (6 g gluten) were randomized and assigned to placebo or 1 of 4 dose cohorts, receiving 2 intravenous infusions of TPM502 (from 0.72 μmol to 7.2 μmol total peptide dose) on day 1 and day 15. A total of 26 patients received TPM502 and 12 received placebo. The gluten challenge was repeated 7 days after the second administration of TPM502 or placebo. As reported in the DDW presentation, TPM502 demonstrated a favorable safety profile. Treatment-related adverse events (TAEs) were reported in 27 patients, including 8 on placebo, with the majority being Grade 1 or 2 events such as nausea, headache, and vomiting; only a single patient experienced four Grade 3 TAEs.

Importantly, a significant and dose-related reduction of IL-2 and IFN-γ release by gluten-specific T cells was observed after TPM502 treatment at the highest dose, which was maintained throughout the study period of 1 month following the last TPM502 administration. In addition, immunomodulation was demonstrated by post-treatment phenotypic changes in gluten-specific CD4+ T cells consistent with T cell anergy or exhaustion and a significant increase in gluten-specific regulatory CD4+ T cells at the highest TPM502 dose, suggesting the induction of regulatory status in these T cells. Patient-reported outcomes using a Celiac Disease Patient‐Reported Outcome (CeD PRO®) tool, indicated a dose-dependent reduction in gastrointestinal symptoms in TPM502-treated patients compared to placebo, following the post treatment gluten challenge.

“Topas Therapeutics is committed to advancing TPM502 as a much-needed treatment option for celiac disease patients, building on data that represent a breakthrough for this and potentially other immune-mediated diseases,” said Hugo Fry, CEO of Topas Therapeutics. “With this validation of our technology and its ability to modulate immune responses in a precise and durable manner, we look forward to the next clinical steps for TPM502 and our pipeline.”

The abstract was selected for presentation in two sessions at DDW. Further details are listed below and available for registered attendees on the DDW conference website.

Session Title: American Gastroenterological Association (AGA) Clinical Science Plenary
Session Date & Time: Monday, May 5^th, 08:00 – 9:30 am PDT
Abstract Title: 621: Safety, Tolerability and Pharmacodynamic Effects of TPM502, a Mixture of Tolerizing Nanoparticles for Treatment of Celiac Disease (CeD)
Presenter: Knut Lundin, MD, PhD, Principal Investigator of the Phase 2a study and Professor and Head of Clinical Education at the Institute of Clinical Medicine, University of Oslo

Session Title: AGA Presidential Plenary: AGA at its Best and the Best of AGA
Session Date & Time: Monday, May 5^th, 10:00 – 11:30 am PDT
Abstract Title: Sp832: Safety, Tolerability and Pharmacodynamic Effects of TPM502, a Mixture of Tolerizing Nanoparticles for Treatment of Celiac Disease (CeD)
Presenter: Knut Lundin, MD, PhD, Principal Investigator of the Phase 2a study and Professor and Head of Clinical Education at the Institute of Clinical Medicine, University of Oslo

Hamburg, Germany, March 17, 2025 – Topas Therapeutics today announced the publication of data highlighting the ability of its proprietary antigen-coupled nanoparticles’ to achieve tolerance induction in relevant autoimmune disease models, under the title “Nanoparticle Platform Preferentially Targeting Liver Sinusoidal Endothelial Cells Induces Tolerance in CD4+ T Cell-Mediated Disease Models” in the journal Frontiers in Immunology. The Topas platform consists of Topas Particles (TPs), that serve as a highly flexible scaffold for coupling with disease-relevant antigens to generate Topas Particle Conjugates (TPCs) that preferentially harness liver sinusoidal endothelial cells (LSECs) to generate antigen-specific tolerance. The publication describes the ability of TPCs to specifically reach LSECs and to generate tolerance in well-established animal disease models of Type 1 Diabetes (T1D) and Multiple Sclerosis (MS). In addition to the proof-of-concept data from the Phase 2a trial evaluating Topas’ lead candidate TPM502 in adults with celiac disease, the preclinical data reported in the publication underscores the broad potential of this innovative platform approach.

In vivo data included in the publication show that intravenous administration of TPCs resulted in predominant uptake by LSECs with negligible uptake by other non-parenchymal liver cells, confirming its cellular targeting specificity. LSECs are lining the liver sinusoids, a position that puts them in direct contact with antigens in the blood. This location, combined with their extraordinary clearance and tolerogenic function, facilitate LSECs’ rapid uptake of nanosized peptide carriers for antigen-specific tolerance induction in various CD4+ T cell-dependent disease models. In a translational mouse model of T1D, a Topas particle mixture comprising five different peptide-coupled TPCs, significantly reduced the frequency of hyperglycemia onsets compared to control, suggesting that even for complex diseases such as T1D, induction of immune tolerance is possible. In a mouse model of multiple sclerosis (MS), administration of TPCs both prior to disease induction and during disease onset, significantly attenuated disease severity and mitigated demyelination within spinal cords as compared to the control, highlighting the TPCs’ ability to induce tolerance prophylactically and therapeutically.

“These published results, coupled with the efficacy data we have established in celiac disease, further support our broad development strategy of advancing TPM502 into a Phase 2b study in celiac disease patients while expanding our pipeline with TPC candidates in highly prevalent autoimmune diseases,” said Cristina de Min, MD, CMO of Topas Therapeutics. “We look forward to presenting the full data analysis of our Phase 2a study during the Digestive Disease Week in San Diego in May, as a further clinical demonstration of what we believe can be transformative approach in promoting immune tolerance.”

“The publication in Frontiers in Immunology underscores the potential of the innovative Topas platform for reinstating antigen-specific tolerance in many autoimmune diseases, while avoiding the complications of broad immunosuppression,” said Hugo Fry, CEO of Topas Therapeutics. “The data pave the way for exploring our TPCs in indications like type 1 diabetes and serves as a foundation to realize the significant potential across autoimmune and immune-mediated diseases.”

The open access article is available via this link.

Hamburg, Germany, October 15^th, 2024 – Topas Therapeutics today announced positive topline results from its Phase 2a trial evaluating lead candidate, TPM502, in patients with celiac disease. The study data serves as the first clinical proof of concept for Topas’ proprietary nanoparticle platform and its potential to induce targeted, antigen-specific tolerogenic effects.

The international, multi-center, double-blind, randomized, placebo-controlled Phase 2a trial (NCT05660109) was initiated in 2023 to investigate the safety, tolerability and pharmacodynamics of two infusions of TPM502 in adult patients with celiac disease.  Pharmacodynamic parameters were assessed through a gluten challenge after patients received treatment with TPM502 or placebo. Initial analysis showed that antigen-specific markers of tolerance induction exhibited a clear dose-response that reached statistical significance. Further, these antigen-specific effects persisted throughout the study’s follow-up period. TPM502 was safe at all doses investigated. Topas intends to submit the full data and analysis for presentation at an upcoming scientific conference and for publication in a peer-reviewed journal.

“This first look at the TPM502 Phase 2a data is an important milestone for the Topas team and our mission to demonstrate that our platform induces antigen-specific tolerogenic effects. The data generated in this study underscore the potential of this versatile, novel modality in a broad spectrum of autoimmune and immune-mediated diseases,” said Hugo Fry, CEO of Topas Therapeutics. “We believe these results provide a valuable springboard to the next stage of development for Topas and position the company extremely well in the immune-tolerance space.”

Topas’ lead candidate, TPM502, leverages the company’s proprietary platform, a nanotechnology-based modality designed to induce targeted, antigen-specific immune tolerance. TPM502 is comprised of a mixture of nanoparticles that carry the major gluten epitopes for HLA-DQ2.5, present in the majority of celiac disease patients. TPM502 has been developed to establish long-term immune tolerance that will offer significant therapeutic benefit to celiac patients, who currently have no treatment options.

The initiation of the Phase 2a study for TPM502 builds on promising preclinical data and the excellent safety profile demonstrated in the Phase 1 study assessing Topas’ TPM203 in pemphigus vulgaris patients. The company’s next development steps for TPM502 will be based on the full data analysis.

Hamburg, Germany, May 7th, 2024 – Topas Therapeutics, a clinical-stage biotech company developing novel antigen-specific immune tolerance therapies to treat autoimmune disorders, announced today the appointment of Hugo Fry as its new Chief Executive Officer. Bringing three decades of experience including senior management and executive roles at both large pharmaceutical and innovative biotechnology companies, Hugo has a significant track record in leading companies from early research and development through product commercialization.

“Hugo joins Topas at the right time to provide his broad expertise and strategic direction as we advance our mission of developing novel, disease-modifying treatment options for a range of autoimmune and inflammatory diseases,” commented Erich F. Greiner, Executive Chairman of Topas Therapeutics. “With data from a Phase 2a trial of lead candidate TPM502 in celiac disease expected later this year, we believe Hugo’s leadership will drive value for the company and fully leverage the potential of its innovative approach.”

“Topas is at the forefront of tolerance induction therapy with a cutting-edge nanoparticle technology platform designed to elicit immune tolerization in T-cell-mediated diseases,” said Hugo Fry, CEO of Topas Therapeutics. “As I take the helm, I am excited to advance the work of this talented team and look forward to leading Topas’ strategic efforts to progress our corporate and clinical development.”

Hugo Fry has an extensive and diverse career spanning three decades within the pharmaceutical and biotechnology sectors, characterized by strategic and leadership roles, including Chief Commercial Officer at Imbria Pharmaceuticals and Chief Business Officer and Managing Director at 20Med Therapeutics as well as CEO of RQ Biotechnology. With a focus on guiding companies toward success, Hugo has previously led R&D, Industrial Affairs as well as Commercial teams and is experienced in licensing, fundraising and forging strategic partnerships. He has also held several executive positions spanning multiple countries, including Managing Director of Sanofi UK and Ireland, and Vice President and Chief Marketing Officer for the Sanofi Pasteur MSD joint venture, along with being the Vice-President of the Association of the British Pharmaceutical Industry. Hugo holds a B.Sc. in Chemistry from the University of Salford and has completed further studies in Finance at London Business School and Leadership at Duke University.