BAFF and APRIL: Key Targets in Autoimmune Diseases and a Review of Dual- and Single-Target Inhibitors

On June 25, 2025, Remegen announced a global licensing agreement with the American biotechnology company Vor Bio for its core product, Telitacicept. Under the agreement, Remegen will receive an upfront payment of $45 million and warrants valued at $80 million from Vor Bio. Additionally, Vor Bio will pay Remegen up to $4.105 billion in milestone payments. The product, Telitacicept, is a dual BAFF and APRIL inhibitor, which demonstrates the potential of BAFF and APRIL as cornerstone targets for treating autoimmune diseases.These diseases are highly prevalent, impacting ~24 million Americans, and the global autoimmune disease therapeutics market is estimated to reach 200$ billion by 2031. 

As critical switches for B cells survival, the interaction between BAFF and APRIL with their receptors (BAFF-R, TACI, BCMA) plays a crucial role in immune homeostasis. Abnormal expression of BAFF, APRIL, or their receptors can disrupt immune tolerance and promote tumor progression. When over-activated, it allows pathological B cells to survive and produce auto-antibodies that attack the body's own tissues, potentially leading to autoimmune diseases like systemic lupus erythematosus (SLE), myasthenia gravis (MG), IgA nephropathy (IgAN), lupus nephritis (LN), rheumatoid arthritis (RA), primary Sjögren's syndrome, and neuromyelitis optica spectrum disorders (NMOSD). In addition to autoimmune diseases, the BAFF system also plays an important role in blood cancers, infections, organ transplantation, allergies, and immunodeficiencies.

BAFF and APRIL are both members of the tumor necrosis factor (TNF) family, which primarily regulates the differentiation, survival, and function of B cells. BAFF (B cell activating factor), also known as BLyS (B lymphocyte stimulator), TNFSF13B, or CD257, is mainly involved in the early maturation of B cells and maintaining the number of mature B cells. APRIL is an essential factor for the long-term survival of antibody-producing plasma cells

 

BAFF and APRIL are both type II homotrimeric proteins. They can exist in stable, soluble forms after protease cleavage. The soluble BAFF and APRIL can be either homo- or heterotrimeric molecules. In the case of BAFF, these trimers can form 60-mers as well in a pH-dependent manner. While BAFF and APRIL preferentially bind to their distinct primary receptors, BAFF-R and BCMA respectively, both cytokines can also engage the shared receptor TACI (transmembrane activator and CAML interactor; TNFRSF13B). APRIL can also bind to the polysaccharide side chains of heparan sulfate proteoglycans (HSPG) without interfering with its interaction with BCMA and TACI.

 

Interaction between BAFF/APRIL and their corresponding receptors [1] 

Dual-Target BAFF-APRIL Inhibitors

By simultaneously blocking both BAFF and APRIL signals, the dual-target inhibitors can comprehensively suppress B-cell and plasma-cell activation, which is suitable for systemic autoimmune diseases and antibody-mediated kidney diseases. Representative drugs include:

Telitacicept:

Telitacicept is a TACI-Fc fusion protein owned by RemeGen that can bind to both soluble and membrane-bound forms of BAFF and APRIL. It prevents BAFF and APRIL from interacting with B cell membrane receptors (TACI, BCMA, BAFF-R), impeding B cell maturation, and B cell-to-plasma cell conversion, which can effectively reduce the production of pathogenic antibodies.

Structure of Telitacicept [2]

In November 2023, Telitacicept received full approval in China as the first dual-target biologic for treating systemic lupus erythematosus. In July 2024, that approval was expanded to the treatment of rheumatoid arthritis. In early 2024, the US FDA granted Telitacicept Fast Track Designation for the treatment of Primary Sjögren’s Syndrome. On May 27, 2025, the NMPA approved its label expansion in combination with conventional treatments for adult patients with anti-acetylcholine receptor (AChR) antibody-positive generalized myasthenia gravis.

Atacicept:

Atacicept, developed by Vera Therapeutics, is currently in the clinical stage. A Phase 2 clinical trial for IgAN showed a significant reduction in the urine protein-to-creatinine ratio (uPCR) at week 24 (25%) and week 36 (35%), while the estimated glomerular filtration rate (eGFR) remained stable at week 36. Atacicept has now advanced to Phase 3.

Povetacicept:

Povetacicept (also known as ALPN-303, Pove) was developed by Alpine Immune Sciences and acquired by Vertex Pharmaceuticals. Currently in Phase 3 clinical trials, it is an engineered TACI-Fc variant with a 6- to 10-fold higher affinity for BAFF-APRIL. The indication focuses on IgAN, with a complete remission rate of 63% (uPCR <0.5 g/g + no hematuria), which is significantly better than existing approved drugs. Compared to the weekly subcutaneous injections of Telitacicept and Atacicept, Povetacicept's extended dosing to once a month improves patient comfort and compliance. On January 10, 2025, Zai Lab and Vertex reached an exclusive collaboration and licensing agreement, granting Zai Lab the development and commercialization rights for Povetacicept in Greater China and Singapore.

CS2013:

CS2013 is a bispecific antibody targeting BAFF and APRIL, first disclosed by CStone Pharmaceuticals on July 3, 2025. Preclinical studies showed that it can trigger a high synergistic effect with better pharmacokinetic characteristics than fusion proteins, including longer half-life, potentially longer dosing intervals, and support for subcutaneous administration. The proposed indications include various B cell-related autoimmune diseases such as SLE, RA, and IgAN. CS2013 is currently in the preclinical candidate confirmation stage, with IND filing to be initiated in the second half of 2025.

APRIL Monoclonal Antibodies

APRIL is a key driver of galactose-deficient IgA1 (Gd-IgA1) production, which is a core pathogenic factor in IgA nephropathy. APRIL promotes pathogenic IgA production by stimulating B cell differentiation and plasma cell survival. So far, drugs targeting APRIL are mostly targeting IgAN. Representative drugs include:

Sibeprenlimab:

Sibeprenlimab (VIS649 by Otsuka) is the first humanized IgG2 monoclonal antibody that targets APRIL. In February 2024, sibeprenlimab received Breakthrough Therapy designation by the US FDA. The mid-term results of the Phase 3 clinical trial for IgA nephropathy met the primary endpoint. Its advantage lies in a significant reduction in proteinuria (over 50% decrease) and good drug safety. On March 31, 2025, Otsuka submitted a BLA application to the FDA, aiming to be the first-in-class drug for an IgAN indication.

Zigakibart:

Zigakibart (BION-1301 by Novartis) is a humanized IgG4 monoclonal antibody. A 100-week long-term study showed that Zigakibart can significantly reduce Gd-IgA1 levels, decrease the frequency of hematuria, substantially reduce proteinuria, and stabilize patient renal function throughout the observation period. In week 100, proteinuria was reduced by 60% from baseline, with over half of the patients achieving <500 mg/24 hours and 31% reaching <300 mg/24 hours, while eGFR remained stable in all subgroups. Zigakibart has initiated a global Phase 3 multi-center clinical study sponsored by Novartis.

MIL116:

Mabwork’s MIL116 is currently in the preclinical stage. MIL116 was engineered for a prolonged half-life, and preclinical results showed it is more effective at blocking and degrading APRIL. On January 10, 2025, Mabworks granted Climb Bio a $9 million license to obtain MIL116-related patents and proprietary technology, as well as the global rights to develop, manufacture, and commercialize outside the Greater China region.

BAFF-R Monoclonal Antibodies ESG206:

ESG206 from Escugen is currently in Phase I/II clinical trials for the treatment of primary immune thrombocytopenia (ITP). Its advantages fall in high target selectivity, potentially better safety, and a convenient dosing schedule of once every four weeks. 

Recombinant Protein Product Portfolio for the BAFF-APRIL Pathway

The dual-target, multi-pathway inhibition for autoimmune diseases has become the primary approach for long-lasting effects. The giant patient population for autoimmune diseases is expanding, and traditional treatments cannot prevent irreversible organ damage (such as kidney failure). The fact that these innovative drugs can significantly reduce the rates of disability/death and decrease steroid dependence makes their clinical and economic value more substantial.

KACTUS supplies high-quality recombinant protein products for the BAFF and APRIL pathways to fulfill the demand for autoimmune disease drug development. Our product portfolio covers various forms of ligands and receptors expressed in mammalian cells with rigorously validated biological activity. Our recombinant proteins products are suitable for various application scenarios, including animal immunization, ELISA, SPR, and BLI.

Product Validation:

Human BAFF protein trimer (BAF-HM112)

Human BAFF trimer (BAF-HM213)

Human BAFFR with Human BAFF trimer on SPR assay

Product List:

 

References:

[1] Transmembrane Activator and CAML Interactor (TACI): Another Potential Target for Immunotherapy of Multiple Myeloma? doi: 10.3390/cancers12041045

[2] Telitacicept, a novel humanized, recombinant TACI-Fc fusion protein, for the treatment of systemic lupus erythematosus. doi: 10.1358/dot.2022.58.1.3352743.

[3] A Phase 2 Trial of Sibeprenlimab in Patients with IgA Nephropathy. doi: 10.1056/NEJMoa2305635.

[4] The BAFF/APRIL system: Emerging functions beyond B cell biology and autoimmunity. doi: 10.1016/j.cytogfr.2013.04.003.

[5] The BAFF-APRIL System in Cancer. doi: 10.3390/cancers15061791.

[6] B-cell activating factor in the pathophysiology of multiple myeloma: A target for therapy? doi: 10.1038/bcj.2015.3.

[7]BAFF, APRIL and their receptors: Structure, function and signaling doi: 10.1016/j.smim.2006.04.006.

[8] TACI Isoforms Regulate Ligand Binding and Receptor Function doi: 10.3389/fimmu.2018.02125.

[9] Selectivity of BAFF/BLyS and APRIL for Binding to the TNF Family Receptors BAFFR/BR3 and BCMA doi: 10.1021/bi048227k.

[10] The TNFSF Members APRIL and BAFF and Their Receptors TACI, BCMA, and BAFFR in Oncology, With a Special Focus in Breast Cancer doi: 10.3389/fonc.2020.00827.