Safety, Pharmacokinetics, and Activity of Pateclizumab
Safety, Pharmacokinetics, and Activity of Pateclizumab
Introduction Pateclizumab (MLTA3698A) is a humanized mAb against lymphotoxin α (LTα), a transiently expressed cytokine on activated B and T cells (Th1, Th17), which are implicated in rheumatoid arthritis (RA) pathogenesis. This study was conducted to assess the safety, tolerability, and biologic activity of single and multiple doses of intravenous (IV) or subcutaneous (SC) pateclizumab in RA patients.
Methods The single ascending dose (SAD) phase in patients with stable RA consisted of six cohorts (4:1 active:placebo at 0.3 mg/kg IV, 1.0 mg/kg IV, 1.0 mg/kg SC, 3.0 mg/kg IV, 3.0 mg/kg SC, and 5.0 mg/kg IV; n = 5/cohort). In the multiple ascending dose (MAD) phase, patients with prespecified RA disease activity received three doses of pateclizumab or placebo (4:1) every 2 weeks (1.0 mg/kg SC, n = 10; 3.0 mg/kg SC, n = 20; or 5.0 mg/kg IV, n = 5). Safety and tolerability were assessed throughout, and clinical activity was determined after three doses (Week 6).
Results We observed no serious adverse events (AEs) or dose-limiting toxicities, and the majority of AEs were mild to moderate. The pharmacokinetic profiles were linear, and clearance was independent of dose. Reductions in levels of serum CXCL13 were observed, supporting the biologic activity of pateclizumab on the LTα pathway. Patients receiving pateclizumab in the 3.0 mg/kg MAD group (3.0 mg/kg SC) demonstrated ACR20, ACR50, and ACR70 response rates at week 6 of 75%, 56% and 25%, respectively, compared with 57%, 29%, and 0% in the placebo group. The median Disease Activity Score in 28 joints, C-reactive protein, reduction was 28% for pateclizumab, versus 8.4% for placebo.
Conclusions Pateclizumabwas generally well-tolerated in RA patients. Preliminary evidence of clinical activity was observed in active RA patients at the dose level targeted for clinical effect.
Rheumatoid arthritis (RA) is a systemic autoimmune inflammatory disease associated with progressive joint damage, pain, fatigue, and disability. Despite advances in the treatment of RA, a significant proportion of patients do not achieve an adequate clinical response upon treatment with available therapies, and less than half of patients who do respond to therapy achieve complete remission. Current biologic treatment options for the management of RA often target the proinflammatory cytokine TNF-α; however, these agents are associated with safety concerns, such as increased risk of serious infection. In addition, intolerance to or contraindication of an existing therapy may further limit a patient's therapeutic alternatives.
Depletion of cellular subsets implicated in RA immunopathogenesis has demonstrated significant clinical efficacy. Novel therapies that both target the cellular source of multiple proinflammatory cytokines and interrupt the autoimmune inflammatory cycle perpetuated in RA could lead to improved outcomes compared to existing treatments.
Lymphotoxin α (LTα), a member of the TNF superfamily, is both secreted (as the homotrimer LTα3) and transiently expressed on the cell surface of activated B, Th1 and Th17 cells, where it forms a complex with LTβ as LTα1β2 heterotrimers (Figure 1). Soluble LTα3 binds TNF receptor (TNFR) types I and II, whereas cell-bound LTα1β2 heterotrimers bind LTβ receptors (LTβR), resulting in the downstream secretion of proinflammatory cytokines and chemokines, such as chemokine (C-X-C motif) ligand 13 (CXCL13). In addition, signaling through the LTβR pathway is required for the normal development of secondary lymph nodes and orchestration of robust germinal center architecture, and is also implicated in the development of ectopic lymphoid structures in chronically inflamed tissue.
(Enlarge Image)
Figure 1.
Mechanism of action of MLTA3698A. Lymphotoxin α (LTα) is a cytokine that is transiently expressed (as a secreted homotrimer or expressed together with LTβ on the cell surface) by subsets of activated T cells (Th1, Th17) and activated B cells (B) that are implicated in the pathogenesis of rheumatoid arthritis autoimmunity. Pateclizumabbinding to LTα expressed on the cell surface results in both the specific depletion of the activated cells and inhibition of immune cell trafficking and/or recruitment to inflammatory sites while leaving non-LTα-expressing cells such as Th2 unaffected. TNFR = tumor necrosis factor receptor; LTβR = lymphotoxin β receptor.
LTα expression is also associated with the pathogenesis of RA. Ectopic lymphoid structures are present in synovial tissue from patients with RA, and both trimeric forms (LTα3 and LTα1β2) are elevated in the synovial fluid of patients with RA. Furthermore, LTα, LTβ and LTβR transcripts are elevated in RA synovium.
A mouse-specific depleting mAb targeting surface LTα has been shown to ameliorate inflammation and arthritis in murine models of disease. In the collagen-induced arthritis (CIA) model, mouse anti-LTα efficacy has been attributed to depletion of Th1 and Th17 cells, which are T-cell subsets that express LTα and are pathogenic drivers of disease. To date there are no therapies that specifically target these T-cell subsets.
Pateclizumab (MLTA3698A), a humanized mAb, specifically binds LTα in both the soluble LTα3 homotrimeric form and the surface-expressed LTα1β2 heterotrimer. Pateclizumab interferes with binding of LT trimers to its cognate receptors LTβR and TNFR and has the potential to deplete subsets of LTα-expressing cells. In this randomized, double-blind, placebo-controlled phase I study of 65 patients with active RA, we show the safety and activity of pateclizumab.
Abstract and Introduction
Abstract
Introduction Pateclizumab (MLTA3698A) is a humanized mAb against lymphotoxin α (LTα), a transiently expressed cytokine on activated B and T cells (Th1, Th17), which are implicated in rheumatoid arthritis (RA) pathogenesis. This study was conducted to assess the safety, tolerability, and biologic activity of single and multiple doses of intravenous (IV) or subcutaneous (SC) pateclizumab in RA patients.
Methods The single ascending dose (SAD) phase in patients with stable RA consisted of six cohorts (4:1 active:placebo at 0.3 mg/kg IV, 1.0 mg/kg IV, 1.0 mg/kg SC, 3.0 mg/kg IV, 3.0 mg/kg SC, and 5.0 mg/kg IV; n = 5/cohort). In the multiple ascending dose (MAD) phase, patients with prespecified RA disease activity received three doses of pateclizumab or placebo (4:1) every 2 weeks (1.0 mg/kg SC, n = 10; 3.0 mg/kg SC, n = 20; or 5.0 mg/kg IV, n = 5). Safety and tolerability were assessed throughout, and clinical activity was determined after three doses (Week 6).
Results We observed no serious adverse events (AEs) or dose-limiting toxicities, and the majority of AEs were mild to moderate. The pharmacokinetic profiles were linear, and clearance was independent of dose. Reductions in levels of serum CXCL13 were observed, supporting the biologic activity of pateclizumab on the LTα pathway. Patients receiving pateclizumab in the 3.0 mg/kg MAD group (3.0 mg/kg SC) demonstrated ACR20, ACR50, and ACR70 response rates at week 6 of 75%, 56% and 25%, respectively, compared with 57%, 29%, and 0% in the placebo group. The median Disease Activity Score in 28 joints, C-reactive protein, reduction was 28% for pateclizumab, versus 8.4% for placebo.
Conclusions Pateclizumabwas generally well-tolerated in RA patients. Preliminary evidence of clinical activity was observed in active RA patients at the dose level targeted for clinical effect.
Introduction
Rheumatoid arthritis (RA) is a systemic autoimmune inflammatory disease associated with progressive joint damage, pain, fatigue, and disability. Despite advances in the treatment of RA, a significant proportion of patients do not achieve an adequate clinical response upon treatment with available therapies, and less than half of patients who do respond to therapy achieve complete remission. Current biologic treatment options for the management of RA often target the proinflammatory cytokine TNF-α; however, these agents are associated with safety concerns, such as increased risk of serious infection. In addition, intolerance to or contraindication of an existing therapy may further limit a patient's therapeutic alternatives.
Depletion of cellular subsets implicated in RA immunopathogenesis has demonstrated significant clinical efficacy. Novel therapies that both target the cellular source of multiple proinflammatory cytokines and interrupt the autoimmune inflammatory cycle perpetuated in RA could lead to improved outcomes compared to existing treatments.
Lymphotoxin α (LTα), a member of the TNF superfamily, is both secreted (as the homotrimer LTα3) and transiently expressed on the cell surface of activated B, Th1 and Th17 cells, where it forms a complex with LTβ as LTα1β2 heterotrimers (Figure 1). Soluble LTα3 binds TNF receptor (TNFR) types I and II, whereas cell-bound LTα1β2 heterotrimers bind LTβ receptors (LTβR), resulting in the downstream secretion of proinflammatory cytokines and chemokines, such as chemokine (C-X-C motif) ligand 13 (CXCL13). In addition, signaling through the LTβR pathway is required for the normal development of secondary lymph nodes and orchestration of robust germinal center architecture, and is also implicated in the development of ectopic lymphoid structures in chronically inflamed tissue.
(Enlarge Image)
Figure 1.
Mechanism of action of MLTA3698A. Lymphotoxin α (LTα) is a cytokine that is transiently expressed (as a secreted homotrimer or expressed together with LTβ on the cell surface) by subsets of activated T cells (Th1, Th17) and activated B cells (B) that are implicated in the pathogenesis of rheumatoid arthritis autoimmunity. Pateclizumabbinding to LTα expressed on the cell surface results in both the specific depletion of the activated cells and inhibition of immune cell trafficking and/or recruitment to inflammatory sites while leaving non-LTα-expressing cells such as Th2 unaffected. TNFR = tumor necrosis factor receptor; LTβR = lymphotoxin β receptor.
LTα expression is also associated with the pathogenesis of RA. Ectopic lymphoid structures are present in synovial tissue from patients with RA, and both trimeric forms (LTα3 and LTα1β2) are elevated in the synovial fluid of patients with RA. Furthermore, LTα, LTβ and LTβR transcripts are elevated in RA synovium.
A mouse-specific depleting mAb targeting surface LTα has been shown to ameliorate inflammation and arthritis in murine models of disease. In the collagen-induced arthritis (CIA) model, mouse anti-LTα efficacy has been attributed to depletion of Th1 and Th17 cells, which are T-cell subsets that express LTα and are pathogenic drivers of disease. To date there are no therapies that specifically target these T-cell subsets.
Pateclizumab (MLTA3698A), a humanized mAb, specifically binds LTα in both the soluble LTα3 homotrimeric form and the surface-expressed LTα1β2 heterotrimer. Pateclizumab interferes with binding of LT trimers to its cognate receptors LTβR and TNFR and has the potential to deplete subsets of LTα-expressing cells. In this randomized, double-blind, placebo-controlled phase I study of 65 patients with active RA, we show the safety and activity of pateclizumab.