ES302, A Novel TL1A/IL-23p19 Bi-specific Antibody Demonstrates Robust Efficacy and Developability for Inflammatory Bowel Disease 2305836

A Novel Dual-targeting PD-1 and TL1A Bispecific Antibody with Synergistic Effect for Immune Disorders Treatment 2255198

Programmed cell death protein 1 (PD-1), an inhibitory immune checkpoint on T cells, maintains immune homeostasis. Dysregulated PD-1 signaling is implicated in autoimmune pathogenesis, whereas insufficient activity may result in uncontrolled T-cell responses. TNF-like ligand 1A (TL1A), a member of the TNF superfamily, engages DR3 to activate NF-κB pathway, thereby amplifying pro-inflammatory cytokine production and contributing to chronic inflammation and fibrosis. We developed a novel bispecific antibody that co-targets PD-1 and TL1A to achieve synergistic inhibition of pathogenic immune activation, with relevance to both PD-1 and TL1A driven immune disorders. Bispecific antibodies were generated by fusing novel PD-1 agonistic and TL1A antagonistic VHH domains in a tetra-valent format. A series of candidates were evaluated through comprehensive in vitro assays including assessment of binding kinetics, PD-1/PD-L1/2 blocking, PD-1 agonism, TL1A-DR3 blocking, ADCC, and T-cell suppression. In vivo efficacy was assessed in a mouse colitis model. The leading bispecific antibody binds to a unique PD-1 epitope, enhances PD-1—PD-L1/2 engagement, and inhibits TL1A—DR3 binding. It demonstrated dose-dependent PD-1 pathway agonism and TL1A antagonism, suppressing T-cell activation, proliferation and cytokine production. Robust ADCC activity against PD-1+ T cells was observed. In vivo, it showed superior efficacy over comparator monotherapies in ameliorating colitis. The anti-PD-1xTL1A bispecific antibody exerts synergistic immunomodulation through three complementary mechanisms: enhancement of PD-1 inhibitory signaling, blockade of the TL1A—DR3 pathway, and selective depletion of PD-1-expressing T cells via ADCC. It significantly mitigates T-cell-driven inflammation in vitro and ameliorates disease activity in vivo, supporting its potential as a novel treatment for autoimmune diseases such as IBD (inflammatory bowel disease). Nanjing Leads Biolabs Co., Ltd Therapeutic Approaches to Autoimmunity (THER)

A Gut-Specific Bispecific Combining MAdCAM-1 Blockade and IL-22 Signaling to Halt T-Cell Inflammation and Promote Mucosal Restoration

Humanized B-hIL4/hIL4RA/hTSLP/hTSLPR plus mice Model for Efficacy and Toxicity Evaluation 2302190

The IL-4 receptor (IL4RA) is a key mediator of the signaling pathways for both IL-4 and IL-13, which play pivotal roles in the pathophysiology of type 2 inflammatory diseases. Thymic stromal lymphopoietin (TSLP) is an alarmin cytokine derived from epithelial cells that has the capacity to initiate both type 2 and non-type 2 inflammatory responses in asthma. TSLP is closely associated with the production of T helper (Th) 2 cytokines, such as IL-4, and is implicated in various inflammatory conditions, including asthma and atopic dermatitis. By simultaneously targeting IL4RA and TSLP, there is significant potential to concurrently suppress both type 2 and non-type 2 inflammation, potentially yielding synergistic effects that inhibit type 2 inflammation more effectively. This therapeutic strategy is anticipated to offer enhanced efficacy in the treatment of type 2 inflammatory diseases. However, TSLP and IL-4 do not cross-react with their receptors between humans and mice. To address this issue, we developed the humanized B-hIL4/hIL4RA/hTSLP/hTSLPR plus mice model for in vivo efficacy evaluation. The humanized mice exhibit characteristics that closely resemble those of wild-type mice, including body weight, blood biochemical indices, and routine blood parameters. The stability of these fundamental physiological indices provides a critical assurance for safety evaluations. In the asthma model developed in B-hIL4/hIL4RA/hTSLP/hTSLPR plus mice, we observed elevated levels of eosinophils, IgE production, and distinct lung pathological features. Notably, the combination of anti-IL4RA and anti-TSLP antibody therapies demonstrated enhanced therapeutic efficacy compared to administering a single antibody drug alone. In conclusion, the humanized B-hIL4/hIL4RA/hTSLP/hTSLPR plus mice model serves as an excellent platform for assessing the efficacy and safety of human IL-4RA and TSLP-related antibodies. N/A Cellular Adhesion, Migration, and Inflammation (CAM)

Anti-inflammatory effect of novel polypeptide WMX-8 through specific blockade of the IL17RA signaling pathway

Interleukin-17 receptor A (IL17RA) acts as a core mediator of pro-inflammatory signaling and contributes crucially to the pathogenesis of autoimmune disorders including psoriasis and rheumatoid arthritis. Monoclonal antibodies against IL17RA have achieved clinical application, yet their clinical utility is restricted by multiple drawbacks: high production cost, complicated manufacturing procedures, mandatory injection delivery, and absent oral bioavailability. To overcome these bottlenecks, this study develops a novel inhibitory peptide WMX-8 intended to specifically disrupt the binding between IL17A and IL17RA. The polypeptide WMX-8 was rationally designed and chemically synthesized, followed by purification to obtain high-purity samples. A series of systematic in vitro biological assessments were conducted using IL17RA-expressing cell models (keratinocytes and monocyte-macrophages), alongside IL17RA-deficient cells as negative control groups. Biochemical and cellular assays verified that WMX-8 binds IL17RA with strong affinity and markedly suppresses the secretion of pro-inflammatory cytokines in IL17RA-positive keratinocytes and monocyte-macrophages. Its anti-inflammatory efficacy is equivalent to that of the reference anti-IL17RA monoclonal antibody. The inhibitory activity fully relies on IL17RA expression, since the anti-inflammatory effect disappears entirely in IL17RA-knockout cells. In addition, WMX-8 displays desirable pharmaceutical features, including low immunogenicity and convenient large-scale synthesis.This study validates the promising druggable properties of WMX-8 targeting the IL17A–IL17RA axis. Our findings lay a solid foundation for further preclinical investigation of peptide therapeutics against IL17A/IL17RA for the treatment of autoimmune diseases.

Abstract B017: CLD-401, a Systemic Gene Medicine for In Situ IL-15 Superagonist Delivery: Driving NK and γδ T Cell-Mediated Tumor Killing

RedTail is a next-generation gene medicine platform based on a tumor-selective extracellular enveloped vaccinia virus (EEV) expressing chimeric CD55 for complement and antibody resistance, enabling systemic delivery. Our lead candidate, CLD-401, delivers an IL-15 superagonist (IL-15[N72D]-IL-15Rα sushi domain), a potent cytokine that induces NK, γδ T and CD8+ T cell responses in the tumor microenvironment (TME), driving robust antitumor immunity. Because IL-15 SA is produced locally within the tumor, it eliminates the need for a stabilizing Fc region, reducing systemic and off-tumor exposure. CLD-401 is currently in IND-enabling studies, with IND submission targeted by end of 2026. CLD-401 was administered systemically in syngeneic tumor-bearing mice. IL-15 SA was quantified by ELISA, immune infiltration by flow cytometry, viral biodistribution by qPCR, and complement resistance using human serum. Tumor selectivity and immune activity were confirmed on human and murine cells. CLD-401 produced EEVs with CD55-mediated resistance to complement and neutralizing antibodies, enabling systemic delivery without immune clearance. CLD-401 selectively amplified in tumor cells with no detectable replication in normal human primary cells or tissues, confirming tumor-restricted amplification. Secreted IL-15 SA demonstrated functional activity on both human and murine immune cells, validating the mouse as a pharmacologically relevant model. Importantly, the viral vector alone induced substantial TME remodeling, including significant T cell infiltration; these changes were further enhanced by IL-15 SA expression, driving marked increases in NK, NKT, and γδ T cell populations and reduction of regulatory T cells. Within tumors, CLD-401 reprogrammed infected cells to produce high levels of IL-15 SA (No Fc) at concentrations comparable to clinically validated IL-15 SA-Fc therapies, with expression confined exclusively to tumor tissue. IL-15 SA and viral expression peaked around day 6 and declined by day 17, coinciding with tumor clearance, ultimately resulting in complete tumor regression in murine breast cancer models. Dose escalation identified an optimal regimen, with a single intravenous dose achieving 80% complete responses in a bilateral EMT6 model. CLD-401 combines tumor-selective amplification with localized in situ cytokine expression, achieving potent antitumor immunity while minimizing systemic toxicity. The self-limiting pharmacokinetic profile supports a favorable safety profile. The tumor-restricted amplification and TME remodeling established by CLD-401 provide the foundation for additional payloads, including tumor-targeted T cell engagers (CLD-501). These findings support IND submission (CLD-401) by end of 2026 and clinical trial initiation in H1 2027, positioning RedTail as a next-generation gene medicine platform. Yunyi Kang, Duong H. Nguyen, Stephanie Songco, Trevor Smith, David Nguyen, Yan Pang, Lina Schulte, Hongli Zhang, Sinje Tigges, Fabian Kortum, Daniela Kleinholz, Susan Tamraz, Ivelina Minev, Robert Porter, Evan Cassavaugh, Thomas Herrmann, G. Travis Clifton, Barbara Haertl, Eric Poma, Antonio F. Santidrian. CLD-401, a Systemic Gene Medicine for In Situ IL-15 Superagonist Delivery: Driving NK and γδ T Cell-Mediated Tumor Killing [abstract]. In: Proceedings of AACR Drug Discovery and Development (AACR D3) Conference; 2026 Jul 21-24; Boston, MA. Philadelphia (PA): AACR; Clin Cancer Res 2026;32(14_Suppl):Abstract nr B017.

A Novel Dual-targeting OX40L and IL-13 Bispecific Antibody with Synergistic Effect for Atopic Dermatitis Treatment 2255160

Atopic dermatitis (AD) is a chronic inflammatory skin disorder. While the immune response in AD is predominantly mediated by T-helper 2 (Th2) cells, contributions from Th1, Th17, and Th22 pathways are also significant. Interleukin-13 (IL-13), a key Th2 cytokine, promotes B-cell proliferation and goblet cell metaplasia. Concurrently, the OX40 ligand (OX40L) and its receptor OX40 function as critical co-stimulatory immune checkpoints regulating T-cell activation. Both the anti-IL-13 antibody lebrikizumab and the anti-OX40L antibody amlitelimab have shown clinical benefits in clinical. Dual targeting of IL-13 and OX40L may thus provide enhanced Th2 suppression and induce broad inhibition across T-helper subsets. Binding affinity was quantified using ForteBio, while functional inhibition of downstream signaling was assessed via STAT6 and NF-κB luciferase reporter assays. Additionally, Mixed lymphocyte reaction (MLR) assay was employed to measure the secretion of IL-2, thymus and activation-regulated chemokine (TARC), IL-17A, and IL-22, serving as indicators of Th1, Th2, Th17, and Th22 activity, respectively. Finally, the in vivo efficacy was evaluated in a murine AD model. The bispecific exhibited high binding affinities to both IL-13 and OX40L. It also potently inhibited both STAT6 and NF-κB pathway activation. In MLR assays, the bispecific and the anti-OX40L antibody similarly suppressed the release of IL-2, IL-17A, and IL-22. Notably, the bispecific agent demonstrated superior inhibition of TARC release compared to either parental antibody alone. In vivo, the bispecific showed the highest therapeutic efficacy. The anti—OX40/IL-13 bispecific exhibited enhanced suppression of Th1, Th2, Th17, and Th22 inflammatory responses both in vitro and in vivo, indicating synergistic immunomodulation through dual target engagement. These findings underscore its strong potential for future clinical development in the treatment of AD. Nanjing Leads Biolabs Co., Ltd Therapeutic Approaches to Autoimmunity (THER)