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Telitacicept (Tai'ai ® ) is fusion protein comprising a recombinant transmembrane activator and calcium modulator and cyclophilin ligand interactor (TACI) receptor fused to the fragment crystallizable (Fc) domain of human immunoglobulin G (IgG). Telitacicept is being developed by Yantai Rongchang Pharmaceutical through its subsidiary RemeGen for the treatment of B cell-mediated autoimmune diseases, such as systemic lupus erythematosus (SLE), rheumatoid arthritis (RA) and multiple sclerosis (MS). Telitacicept binds to and neutralizes the activity of two cell-signalling molecules, B-lymphocyte stimulator (BLyS) and a proliferation-inducing ligand (APRIL), thereby suppressing the development and survival of plasma cells and mature B cells. In March 2021, telitacicept received its first approval in China for the treatment of patients with active SLE. Clinical studies of telitacicept in several other indications, including IgA nephropathy, MS, myasthenia gravis, neuromyelitis optica spectrum disorders, RA and Sjögren's syndrome are underway in China. This article summarizes the milestones in the development of telitacicept leading to this first approval for SLE.

The recent understanding of plasma cell (PC) biology has been obtained mainly from murine models. The current concept is that plasmablasts home to the BM and further differentiate into long-lived PCs (LLPCs). These LLPCs survive for months in contact with a complex niche comprising stromal cells (SCs) and hematopoietic cells, both producing recruitment and survival factors. Using a multi-step culture system, we show here the possibility to differentiate human memory B cells into LLPCs surviving for at least 4 months in vitro and producing immunoglobulins continuously. A remarkable feature is that IL-6 is mandatory to generate LLPCs in vitro together with either APRIL or soluble factors produced by SCs, unrelated to APRIL/BAFF, SDF-1, or IGF-1. These LLPCs are out of the cell cycle, express highly PC transcription factors and surface markers. This model shows a remarkable robustness of human LLPCs, which can survive and produce highly immunoglobulins for months in vitro without the contact with niche cells, providing the presence of a minimal cocktail of growth factors and nutrients. This model should be useful to understand further normal PC biology and its deregulation in premalignant or malignant PC disorders.

The costimulation of immune cells using first-generation anti-4-1BB monoclonal antibodies (mAbs) has demonstrated anti-tumor activity in human trials. Further clinical development, however, is restricted by significant off-tumor toxicities associated with FcγR interactions. Here, we have designed an Fc-free tumor-targeted 4-1BB-agonistic trimerbody, 1D8 N/C EGa1, consisting of three anti-4-1BB single-chain variable fragments and three anti-EGFR single-domain antibodies positioned in an extended hexagonal conformation around the collagen XVIII homotrimerization domain. The1D8 N/C EGa1 trimerbody demonstrated high-avidity binding to 4-1BB and EGFR and a potent in vitro costimulatory capacity in the presence of EGFR. The trimerbody rapidly accumulates in EGFR-positive tumors and exhibits anti-tumor activity similar to IgG-based 4-1BB-agonistic mAbs. Importantly, treatment with 1D8 N/C EGa1 does not induce systemic inflammatory cytokine production or hepatotoxicity associated with IgG-based 4-1BB agonists. These results implicate FcγR interactions in the 4-1BB-agonist-associated immune abnormalities, and promote the use of the non-canonical antibody presented in this work for safe and effective costimulatory strategies in cancer immunotherapy. Cancer therapy using systemically administrated 4-1BB-targeting antibodies is often associated with severe toxicity due to the nonspecific activation of autoreactive T cells. Here, the authors have developed a trimeric antibody targeting both 4-1BB and EGFR, which activates T cells effectively and shows negligible cytotoxicity.

Ganss and colleagues show that targeting the inflammatory cytokine LIGHT to tumor vessels via a vascular targeting peptide induces tertiary lymphoid structures and enables the influx of endogenous T cells and tumor killing. The tumor microenvironment confers profound resistance to anti-cancer immunotherapy. By targeting LIGHT, a member of the TNF superfamily of cytokines, to tumor vessels via a vascular targeting peptide (VTP), we developed a reagent with the dual ability to modulate the angiogenic vasculature and to induce tertiary lymphoid structures (TLSs). LIGHT-VTP triggered the influx of endogenous T cells into autochthonous or syngeneic tumors, which are resistant to immunotherapy. LIGHT-VTP in combination with checkpoint inhibition generated a large number of intratumoral effector and memory T cells with ensuing survival benefits, while the addition of anti-tumor vaccination achieved maximal therapeutic efficacy. Thus, the combination treatments stimulated the trafficking of pre-existing endogenous effector T cells as well as their intratumoral activation and were more successful than current immunotherapies, which fail due to tumor-intrinsic resistance mechanisms.

A proliferation-inducing ligand (APRIL) is a member of the tumor necrosis factor (TNF) superfamily. Despite advances in clinical and genetic studies, the details of the pathological roles of APRIL in IgA nephropathy (IgAN) remain to be fully defined. The present study aimed to further assess the pathological role of APRIL using a mouse model of IgAN. Mice with IgAN designated \"grouped ddY\" (gddY) were intraperitoneally administered an anti-APRIL monoclonal antibody (anti-APRIL Ab) or control IgG (Control Ab) twice each week for 2 weeks starting during the early stage of IgAN (6-7 weeks of age). Urinary albumin, serum IgA, and glomerular IgA deposition were evaluated. We further assessed the inflammatory responses during treatment by measuring the levels of the chemokine fractalkine (FKN) and its receptor CX3CR1 as well as the level of peripheral blood monocytosis. Anti-APRIL Ab treatment significantly decreased albuminuria and tissue damage combined with decreases in serum IgA levels and deposition of glomerular IgA. In contrast, the abundance of IgA+/B220+ or CD138+/B220+ B cells in the spleen and bone marrow, respectively, was unchanged. Treating gddY mice with anti-April Ab reduced the overexpression of FKN/CX3CR1 in the kidney and the increase in the population of circulating Gr1-/CD115+ monocytes. The size of the population of Gr1-/CD115+ monocytes correlated with renal FKN and urinary albumin levels. Moreover, mice treated with anti-APRIL Ab exhibited reduced progression of IgAN, serum IgA levels, and glomerular IgA deposition as well as an attenuated inflammatory process mediated by FKN-associated activation of monocytes. To the best of our knowledge, this is the first study to implicate the APRIL signal transduction pathway in the pathogenesis of nephrogenic IgA production. Moreover, our findings identify APRIL as a potential target of therapy.

In this trial involving patients with IgA nephropathy, sibeprenlimab, a humanized IgG2 monoclonal antibody that blocks a proliferation-inducing ligand, resulted in a greater decrease in proteinuria than placebo.

Background A Proliferation-Inducing Ligand (APRIL) is a tumour necrosis factor superfamily member with multiple effector roles in the peripheral and central nervous system (CNS). In the CNS, APRIL helps maintain immune homeostasis and supports neuronal survival, yet whether it can therapeutically modulate acute neuro-inflammatory and neurodegenerative processes is unclear. To investigate this in a severe neuro-inflammatory context, we tested whether local APRIL delivery can influence microglial/astrocytic responses and demyelination in the cuprizone (CPZ) mouse model of neuro-inflammation and demyelination. Methods We applied adeno-associated virus (AAV)–mediated gene transfer to drive APRIL expression by cortical neurons positioned directly above the splenium of the corpus callosum. Following CPZ intoxication, we evaluated microglial and astrocytic activation and myelin content by in vivo T2 and diffusion magnetic resonance imaging (MRI), and validated them by post-mortem quantitative immunohistochemistry (IHC) and bulk transcriptomic and proteomic profiling. Results T2 and diffusion MRI, corroborated by quantitative IHC, demonstrated that secretion of APRIL by cortical neurons attenuated CPZ-induced microglial recruitment and demyelination in the splenium, but not in the cortex. Integrated transcriptome-proteome analysis of splenium and cortex, further supported by IHC, highlighted astroglial lipid-metabolic circuitry - marked by the astrocytic fatty-acid-binding protein 7 (Fabp7) - as a candidate axis underlying APRIL’s effects to reduce inflammatory cell recruitment and myelin preservation. Conclusions AAV-mediated expression of APRIL by cortical neuron counteracted microglial recruitment and demyelination in the splenium of CPZ-treated mice. Our multi-omics integration analysis nominated several pathways, including Fabp7-linked astrocytic lipid metabolism, to elucidate APRIL’s mechanism of action. Together, these findings provide a framework for the mechanistic dissection of APRIL’s therapeutic potential and further translational evaluation in CNS pathologies characterised by acute neuro-inflammatory responses.

We investigate here how APRIL impacts immune regulatory T cells and directly contributes to the immunosuppressive multiple myeloma (MM) bone marrow (BM) microenvironment. First, APRIL receptor TACI expression is significantly higher in regulatory T cells (Tregs) than conventional T cells (Tcons) from the same patient, confirmed by upregulated Treg markers, i.e., Foxp3, CTLA-4. APRIL significantly stimulates proliferation and survival of Tregs, whereas neutralizing anti-APRIL monoclonal antibodies (mAbs) inhibit these effects. Besides TACI-dependent induction of cell cycle progression and anti-apoptosis genes, APRIL specifically augments Foxp3, IL-10, TGFβ1, and PD-L1 in Tregs to further enhance Treg-inhibited Tcon proliferation. APRIL further increases MM cell-driven Treg (iTreg) via TACI-dependent proliferation associated with upregulated IL-10, TGFβ1, and CD15s in iTreg, which further inhibits Tcons. Osteoclasts producing APRIL and PD-L1 significantly block Tcon expansion by iTreg generation, which is overcome by combined treatment with anti-APRIL and anti-PD1/PD-L1 mAbs. Finally, APRIL increases IL-10-producing B regulatory cells (Bregs) via TACI on BM Bregs of MM patients. Taken together, these results define novel APRIL actions via TACI on Tregs and Bregs to promote MM cell survival, providing the rationale for targeting APRIL/TACI system to alleviate the immunosuppressive BM milieu and improve patient outcome in MM.

Autoimmunity arises when the immune system erroneously attacks self-antigens, potentially resulting in organ dysfunction. This review focuses on the proliferation-inducing ligand, APRIL, and its critical role in regulating antibody-producing B cells. We explore the implications of APRIL in autoimmune diseases such as systemic lupus erythematosus, rheumatoid arthritis, and Sjögren’s syndrome. Emerging evidence indicates that APRIL may modulate autoimmune pathology and influence B cell survival, particularly through its interactions with receptors like B-cell maturation antigen (BCMA) and transmembrane activator and CAML interactor (TACI). We emphasize the contrasting roles of APRIL and BAFF in autoimmunity, highlighting the conflicting data regarding their contributions to disease progression and activity levels. Furthermore, we evaluate therapeutic strategies aimed at inhibiting APRIL and compare them with existing B-cell-targeted therapies, such as rituximab and belimumab. The potential benefits of specific APRIL antagonism are discussed, especially for patients with antibody-driven autoimmune disorders. This highlights the necessity for further research into APRIL-targeted therapies in clinical practice. Ultimately, this review seeks to provide a comprehensive overview of the current understanding of APRIL’s role in autoimmunity and outline future directions for targeting this ligand in the treatment of autoimmune diseases.

The BAFF-APRIL system is crucial for the pathogenesis of systemic lupus erythematosus (SLE) by promoting B cell survival, differentiation and the maintenance of humoral autoimmunity. Here, we investigated the relationship of BCMA expression on B cell subsets with its ligands BAFF and APRIL, together with soluble BCMA, and with clinical and serologic variables in a cohort of 100 SLE patients (86 under conventional and 14 under belimumab therapy) and 30 healthy controls (HCs) using multicolor flow cytometry and ELISA. We found that BCMA expression in SLE patients was significantly increased on all B cell subsets compared to HCs, with all examined components of the BAFF-APRIL system being upregulated. BCMA expression was significantly increased on switched and unswitched memory B cells compared to naïve B cells, both in HCs and SLE. BCMA expression on B cells correlated with plasmablast frequencies, serum anti-dsDNA antibodies and complement consumption, while soluble BCMA correlated with plasmablast frequency, highlighting its potential as a clinical biomarker. Belimumab treatment significantly reduced BCMA expression on most B cell subsets and soluble TACI and contributed to the inhibition of almost the entire BAFF-APRIL system and restoration of B cell homeostasis. These results provide insights into the complex dysregulation of the BAFF-APRIL system in SLE and highlight the therapeutic potential of targeting its components, particularly BCMA, in addition to its use as a biomarker for disease activity.