Efficient drug delivery to lymph nodes by intradermal administration and enhancement of anti-tumor effects of immune checkpoint inhibitors.

Immune checkpoint inhibitors are novel immunotherapy drugs that have improved cancer treatments. Yet only a small percentage of patients experience durable responses to immune checkpoint inhibitors. Recently, it has been suggested that lymph nodes are important for the efficacy of immunotherapy. However, it is still unclear whether the efficient anti-PD-L1 antibody delivery to tumor-draining lymph nodes improves drug efficacy. In this study, we first characterized lymphatic drug delivery by intradermal administration compared with conventional subcutaneous and systemic administration in rodents and non-human primates. The results confirmed that intradermal administration of immune checkpoint inhibitors is suitable for efficient delivery to the tumor-draining lymph node. In FM3A and EMT6 tumor mice models with different PD-L1 expressions in tumor, efficient delivery of anti-PD-L1 antibody to tumor-draining lymph node by intradermal administration resulted in efficient inhibition of tumor growth in both models. The intradermal administration of low-dose anti-PD-L1 antibody also significantly suppressed tumor growth compared to intraperitoneal administration. It also suppressed tumor growth regardless of PD-L1 expression in tumors, suggesting the importance of blocking PD-L1 in tumor-draining lymph nodes. Hence, efficient delivery by intradermal administration of anti-PD-L1 antibody to tumor-draining lymph node might to be helpful to enhance drug efficacy and potentially reduce adverse events.

Development of a novel Poly (I:C)-induced murine model with accelerated lupus nephritis and examination of the therapeutic effects of mycophenolate mofetil and a cathepsin S inhibitor.

Systemic lupus erythematosus (SLE) is an autoimmune disease involving multi-organ systems with a widely heterogeneous clinical presentation. Renal involvement, observed mainly in lupus nephritis (LN), is the most common organ lesion associated with SLE and a determinant of prognosis. However, treatment of LN remains controversial and challenging, prompting the need for novel therapeutic approaches. In particular, development of a clinically relevant LN animal model would greatly facilitate the development of new treatments. Here, we report a novel murine model for LN established by administering polyinosinic-polycytidylic acid (Poly (I:C)) to NZB/W F1 mice. We investigated the effectiveness of administering Poly (I:C) to NZB/W F1 mice for accelerating nephritis onset and explored the optimal conditions under which to enroll mice with nephritis with similar pathology for studying treatment candidates. Gene-expression analysis revealed that activation of macrophages, which are reported to be involved in the progression of LN in patients, was a unique characteristic in this accelerated nephritis model. Evaluation of the therapeutic effect of mycophenolate mofetil (MMF), a recommended first-choice agent for LN, in this novel LN model showed that MMF significantly reduced proteinuria. The cathepsin S (CatS) inhibitor ASP1617, which has been reported to prevent development of lupus-like glomerulonephritis in the spontaneous NZB/W F1 mouse model, also showed marked therapeutic effect in this model. Our novel Poly (I:C) accelerated LN model would thus be very useful for screening clinical candidates for LN, and CatS may be an attractive therapeutic target for the treatment of LN.

Potential benefit of the cathepsin S inhibitor, ASP1617, as a treatment for systemic lupus erythematosus.

Systemic lupus erythematosus (SLE) is an autoimmune disease characterized by the dysregulation of various cell types and immunological pathways. Autoantibodies play an important role in its pathogenesis. The presence of autoantibodies suggests that self-antigen presentation through major histocompatibility complex (MHC) class II on antigen presenting cells is involved in the pathogenesis of autoimmune diseases, including SLE. Cathepsin S (CatS) is a key protease for antigen peptide loading onto lysosomal/endosomal MHC class II molecules through invariant chain degradation to promote antigen presentation. Inhibition of CatS is therefore expected to suppress antigen presentation via MHC class II, T and B cell activation, and antibody production from B cells. Here, we report the pharmacological profile of ASP1617, a novel CatS inhibitor. ASP1617 induced invariant chain accumulation and decreased the expression level of MHC class ΙΙ on the cell surface in both mouse and human B cells. Further, ASP1617 prevented DO11.10 mice T cell proliferation to ovalbumin antigen. We investigated the effects of ASP1617 and mycophenolate mofetil (MMF) on the development of lupus-like nephritis in NZB/W F1 mice, a widely used SLE mouse model. Oral administration of ASP1617 suppressed anti-dsDNA IgG, prevented progression of lupus-like glomerulonephritis, and significantly prevented proteinuria excretion. In contrast, MMF did not suppress anti-dsDNA IgG. Further, we found that plasma and/or urine CatS levels were increased in specimens from NZB/W F1 mice and several SLE patients. These results indicate that CatS may be an attractive therapeutic target for the treatment of SLE.