Safety, pharmacokinetics, and biologic activity of pateclizumab, a novel monoclonal antibody targeting lymphotoxin α: results of a phase I randomized, placebo-controlled trial

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 [1]. 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 [2]. 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 [3]. 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 [4‐6] (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) [7]. 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 [8].

LTα expression is also associated with the pathogenesis of RA. Ectopic lymphoid structures are present in synovial tissue from patients with RA [9], and both trimeric forms (LTα3 and LTα1β2) are elevated in the synovial fluid of patients with RA [10]. Furthermore, LTα, LTβ and LTβR transcripts are elevated in RA synovium [11‐13].

A mouse-specific depleting mAb targeting surface LTα has been shown to ameliorate inflammation and arthritis in murine models of disease [6]. 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.

We designed this randomized, double-blind, placebo-controlled trial to evaluate the safety, tolerability, pharmacokinetics (PK), pharmacodynamics (PD), and preliminary evidence of biologic activity of pateclizumab in patients with RA. Study participants were recruited from 26 centers in the United States and Hungary. The institutional review boards at each study site approved the protocol, and all subjects provided their written informed consent. The trial was registered under US National Institutes of Health ClinicalTrials.gov identifier NCT00888745.

In this phase I study, pateclizumab, a humanized mAb that specifically binds LTα, was well-tolerated in patients with active RA. Using an expanded cohort approach, preliminary evidence of clinical activity was observed at the prespecified target dose of 3 mg/kg SC as measured by reduction in DAS28-CRP scores, reduction of CRP values, and achievement of ACR20, ACR50, and ACR70 responses. PK data revealed linear biphasic kinetics with dose proportionality. CXCL13 reduction as a PD marker was observed, supporting the anticipated effect of pateclizumabon downstream signaling via the LTα pathway.

Pateclizumabis a humanized mAb against the cytokine LTα. It is thought to act both by selectively depleting a specific subset of LTα-expressing activated T and B cells and by blocking LTα-mediated signaling (Figure 1). LTα is expressed on subsets of Th1 and Th17 T cells, as well as on activated B cells, but is absent from other subsets, such as Th2 [6]. Pateclizumablikely exerts its effects farther upstream than TNF inhibitors by targeting the cellular source of multiple proinflammatory cytokines. In a preclinical model of CIA, a murine antibody targeting LTα showed clinical efficacy by specifically depleting LTα-expressing lymphocytes, resulting in decreased joint pathology and rapid reduction of TNF-α, IL-1β and IL-6 levels within the hindpaw [6]. Importantly, the murine antibody had no effect in a Th2-driven model of asthma, demonstrating selectivity of anti-LTα for Th1 and Th17 cells.

This phase I study of patients with moderate to severe RA was designed to assess the safety and tolerability of pateclizumaband to evaluate preliminary evidence of clinical activity. pateclizumabwas well-tolerated in patients receiving IV or SC administration of either single or multiple doses. The majority of AEs were grade 1 or 2, with no serious AEs and no withdrawal of the study drug due to AEs. Importantly, no serious infections were reported during the study, and no increased rate of infections was reported in patients receiving pateclizumabcompared with placebo. PK analysis revealed that exposure to pateclizumabwas approximately dose-proportional. Anti-pateclizumabantibodies were detected in 7 of 52 pateclizumab-treated patients, but without any clinical sequelae.

CXCL13 is a chemokine induced downstream of LTβR signaling which has been implicated in the formation of ectopic lymphoid structures [11, 12, 16]. Elevated CXCL13 serum levels have been associated with synovitis in RA [17], and serum CXCL13 is decreased following treatment of RA patients with TNF-α inhibitors and anti-CD20 rituximab [17‐19], thus implicating CXCL13 as a robust biomarker of RA disease activity. In our PD evaluations, pateclizumabadministration maximally decreased CXCL13 levels in all dose cohorts ≥ 1.0 mg/kg SC or IV. The reduction in CXCL13 most likely reflects an effect on downstream events following interruption of the LTα pathway.

The 3.0 mg/kg SC cohort in the MAD phase of the study consisted of an expanded cohort designed to evaluate clinical activity of pateclizumabat the target dose. Clinical response variables were assessed at week 6 (2 weeks after the last dose of drug). ACR20, ACR50, and ACR70 response rates were seen in 75%, 55%, and 25% of patients. In addition to ACR20, ACR50, and ACR70 responses achieved in this patient cohort, these patients showed substantial decreases in DAS28-CRP scores and CRP levels compared to placebo-treated subjects. Overall, for all measures evaluated, there was preliminary evidence of clinical activity in patients receiving pateclizumabcompared to placebo. Furthermore, evidence of sustained clinical activity was observed, with 50% of patients maintaining an ACR50 score up to 6 weeks after receiving their last dose of the study drug. The concomitant use of methotrexate did not affect clinical activity results. None of the three patients who had previously received TNF blockade achieved an ACR50 score. However, the small number of these patients limits the interpretation of activity in these subpopulations of patients who may be receiving (or may have received) other medications targeting RA disease.

The limitations of this study include the small sample size, which restricts interpretation of the study results. Regarding clinical activity, the other MAD dose cohorts (1.0 mg/kg SC and 5.0 mg/kg IV) were not designed as expanded cohorts, thus the ability to detect a dose response was limited by the small number of patients within these cohorts. In addition, patients were recruited from only two countries for this study (the United States and Hungary). Larger global studies will allow the evaluation of the effect of pateclizumabacross a broader RA patient population. Baminercept (a human LTβR-human immunoglobulin G1 (IgG1) fusion protein) failed to show clinical benefit in a phase II trial in patients with RA [20, 21]. Although both pateclizumaband baminercept block LTαβ-induced signaling (via the LTβ receptor) [7], it is important to note that pateclizumabis distinct in its potential to selectively deplete LTα-expressing cells. In a preclinical murine model of established arthritis, a depleting murine anti-LTα antibody had efficacy comparable to that of anti-TNF-α antibodies, whereas an LTβR/Ig blocker had no effect [6]. In addition, this murine antibody demonstrated efficacy in mice that were refractory to anti-TNF administration [22]. Together these data suggest that the depleting anti-LTα mAb pateclizumabhas great potential for clinical activity in RA.

Inhibition of the LTα pathway provides a unique approach by which to abrogate proinflammatory responses in RA pathology. By blocking signaling through the LTα pathway, as well as by depleting LTα-expressing cells, which are dominant sources of TNF-α and IL-6, pateclizumabis likely to work upstream of TNF-α blockade. This mechanism may provide an attractive alternative therapeutic approach for patients with moderate to severe RA. In this phase I study, pateclizumabwas well-tolerated and provided a linear PK profile when delivered subcutaneously. Given preliminary evidence of biologic and clinical activity, further evaluation of its clinical efficacy is warranted in larger clinical trials. To further characterize the safety, PK, PD and clinical activity of pateclizumab, a phase II study of RA patients without an adequate response to DMARDs is in progress.