Background/Purpose: Blood dendritic cell antigen 2 (BDCA2) is specifically expressed on pDCs whose uncontrolled production of type I IFN play a crucial role in the pathogenesis of autoimmune disorders. Litifilimab, an anti-BDCA2 antibody, has demonstrated promising preliminary efficacy and excellent safety profile in patients with cutaneous lupus erythematosus. Meanwhile B-cell activating factor (BAFF) and a proliferation-inducing ligand (APRIL) bind to the transmembrane activator and CAML interactor (TACI) on B cells, facilitating B cell proliferation and differentiation. Targeting this pathway, two TACI based recombinant fusion proteins, such as Povetacicept and Telitacicept, have shown clinical benefits and favorable safety profile in autoimmune disease trials. Therefore, we have developed LBL-047, which simultaneously targets BDCA2 on pDCs and block TACI-mediated signaling on B cells. This dual-targeting approach may hold promise for the treatment of autoimmune diseases.

Methods: LBL-047 was obtained by fusing CRD2 domain of TACI to the N-terminal of the humanized, afucosylated anti-BDCA2 antibody, and the YTE mutation was introduced to extend its half-life. The potency of LBL-047-induced pDCs depletion and pro-inflammatory cytokines inhibition were evaluated in human peripheral blood mononuclear cells (PBMCs). The internalization assay was performed using the BDCA2 overexpressed cell line and measured by flow cytometry. The inhibition of human primary B cells’ proliferation and differentiation induced by LBL-047 was evaluated by flow cytometry. The keyhole limpet hemocyanin (KLH)-immunized human CD34+ hematopoietic stem cells- engrafted immunodeficient NCG mouse model (huHSC-NCG model) was used to test the efficacy of LBL-047 in inhibiting the function of pDCs and B cells. The pharmacokinetics (PK), pharmacodynamics (PD) and toxicity of LBL-047 were evaluated in cynomolgus monkeys.

Results: LBL-047 robustly depleted pDCs and activated BDCA2 downstream signaling pathways, thereby suppressing pDCs produced IFN-α, TNF-α and IL-6. Additionally, LBL-047 mediated potent inhibition of B cells’ proliferation and differentiation. When co-bound to BAFF and cell-surface-expressed BDCA2, both LBL-047 and BAFF protein were rapidly internalized into the cells. In KLH immunized huHSC-NCG mouse model, LBL-047 effectively inhibited the function of both pDCs and B cells. LBL-047 also exhibited a linear PK characteristic following single S.C administration in cyno monkeys across 0.3-10 mg/kg, and serum IgM, IgA, and IgG levels were significantly decreased up to 6 weeks in a dose-dependent manner. In a 4-week GLP toxicology study, LBL-047 was shown a favorable safety profile with a NOAEL of 100 mg/kg.

Conclusion: LBL-047 has shown dual immunosuppressive effects, inhibiting simultaneously the function of pDCs and B cells both in vitro and in vivo. In addition, it has demonstrated excellent PK and PD profile, coupled with good safety profile and tolerability in cynomolgus monkeys. Taken together, these findings support the clinical development of LBL-047 and highlight its promise as a therapeutic candidate for autoimmune diseases.

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ACR Meeting Abstracts - https://acrabstracts.org/abstract/lbl-047-a-first-in-class-anti-bdca2-taci-fusion-protein-inhibits-the-function-of-both-pdcs-and-b-cells/