Synergism between IL7R and CXCR4 drives BCR-ABL induced transformation in Philadelphia chromosome-positive acute lymphoblastic leukemia.

Ph+ acute lymphoblastic leukemia (ALL) is characterized by the expression of an oncogenic fusion kinase termed BCR-ABL1. Here, we show that interleukin 7 receptor (IL7R) interacts with the chemokine receptor CXCR4 to recruit BCR-ABL1 and JAK kinases in close proximity. Treatment with BCR-ABL1 kinase inhibitors results in elevated expression of IL7R which enables the survival of transformed cells when IL7 was added together with the kinase inhibitors. Importantly, treatment with anti-IL7R antibodies prevents leukemia development in xenotransplantation models using patient-derived Ph+ ALL cells. Our results suggest that the association between IL7R and CXCR4 serves as molecular platform for BCR-ABL1-induced transformation and development of Ph+ ALL. Targeting this platform with anti-IL7R antibody eliminates Ph+ ALL cells including those with resistance to commonly used ABL1 kinase inhibitors. Thus, anti-IL7R antibodies may provide alternative treatment options for ALL in general and may suppress incurable drug-resistant leukemia forms.

Targeting the interleukin-7 receptor alpha by an anti-CD127 monoclonal antibody improves allergic airway inflammation in mice.

BACKGROUND: Interleukin-7 (IL-7) is the most important cytokine for T-cell homeostasis. IL-7 signals through the IL-7 receptor (IL-7R) which is composed of an alpha chain (IL-7Rα), also called CD127 and a common gamma chain. T lymphocytes, especially T helper type 2, play a crucial role in the pathobiology of allergic asthma. OBJECTIVE: To study the effects of an anti-CD127 monoclonal antibody (mAb) in a murine model of allergic airway inflammation induced by house dust mite (HDM). METHODS: Allergic airway inflammation was induced in mice using a protocol comprising 4 weekly percutaneous sensitizations followed by 2 weekly intranasal challenges with total HDM extracts and treated by intraperitoneal injections of an anti-CD127 mAb. Because CD127 is shared by both IL-7R and the receptor for thymic stromal lymphopoietin (TSLP), a group of mice was also treated with an anti-IL-7 mAb to block only the IL-7 signalling pathway. RESULTS: Anti-CD127 mAb-treated mice showed significantly lower airway resistance in response to methacholine and improvement in lung histology compared with isotype mAb-treated animals. Anti-CD127 mAb treatment significantly decreased the mRNA expression of Th2 cytokines (IL-4, IL-5, and IL-13) and chemokines (CCL5/RANTES) in lung tissue, decreased the secretion of Th2 cytokines (IL-4, IL-5, and IL-13) and chemokines (CXCL1 and CCL11/eotaxin) in bronchoalveolar lavage fluid (BALF), decreased serum HDM-specific IgE, and reduced the number of total leucocytes and leucocyte subpopulations such as eosinophils, macrophages, lymphocytes, T lymphocytes, and ILC2 in BALF and lung tissue. Mice treated with anti-IL-7 mAb also showed less allergic airway inflammation as evidenced by significantly lower airway resistance and fewer leucocytes in BALF and lung tissue compared to mice treated with the corresponding isotype control mAb. CONCLUSION AND CLINICAL RELEVANCE: Targeting the IL-7Rα by an anti-CD127 mAb improves allergic airway inflammation in mice and presents as a potential therapeutic approach for allergic asthma.

Immunomodulatory activity of humanized anti-IL-7R monoclonal antibody RN168 in subjects with type 1 diabetes.

BACKGROUND: The cytokine IL-7 is critical for T cell development and function. We performed a Phase Ib study in patients with type 1 diabetes (T1D) to evaluate how blockade of IL-7 would affect immune cells and relevant clinical responses. METHODS: Thirty-seven subjects with T1D received s.c. RN168, a monoclonal antibody that blocks the IL -7 receptor α (IL7Rα) in a dose-escalating study. RESULTS: Between 90% and 100% IL-7R occupancy and near-complete inhibition of pSTAT5 was observed at doses of RN168 1 mg/kg every other week (Q2wk) and greater. There was a significant decline in CD4+ and CD8+ effector and central memory T cells and CD4+ naive cells, but there were fewer effects on CD8+ naive T cells. The ratios of Tregs to CD4+ or CD8+ effector and central memory T cells versus baseline were increased. RNA sequencing analysis showed downmodulation of genes associated with activation, survival, and differentiation of T cells. Expression of the antiapoptotic protein Bcl-2 was reduced. The majority of treatment-emergent adverse events (TEAEs) were mild and not treatment related. Four subjects became anti-EBV IgG+ after RN168, and 2 had symptoms of active infection. The immunologic response to tetanus toxoid was preserved at doses of 1 and 3 mg/kg Q2wk but reduced at higher doses. CONCLUSIONS: This trial shows that, at dosages of 1-3 mg/kg, RN168 selectively inhibits the survival and activity of memory T cells while preserving naive T cells and Tregs. These immunologic effects may serve to eliminate pathologic T cells in autoimmune diseases. TRIAL REGISTRATION: NCT02038764. FUNDING: Pfizer Inc.

Anti-IL-7 receptor α monoclonal antibody (GSK2618960) in healthy subjects - a randomized, double-blind, placebo-controlled study.

AIM: Interleukin (IL)-7 signalling modulates T cell activity and is implicated in numerous autoimmune diseases. The present study investigated the safety, pharmacokinetics, target engagement, pharmacodynamics and immunogenicity of GSK2618960, an IL-7 receptor-α subunit (CD127) monoclonal antibody. METHODS: A double-blind (sponsor-unblind) study of a single intravenous infusion of either GSK2618960 (0.6 mg kg-1 or 2.0 mg kg-1 ) or placebo was carried out in 18 healthy subjects over 24 weeks. RESULTS: GSK2618960 was well tolerated; there were no serious or significant adverse events. The observed half-life was 5 (±1) days (2.0 mg kg-1 ), with nonlinear pharmacokinetics. Full receptor occupancy (>95%) was observed until day 8 (0.6 mg kg-1 ) and day 22 (2.0 mg kg-1 ). Maximal inhibition of IL-7-mediated signal transducer and activator of transcription 5 (STAT5) phosphorylation was observed in 5/6 subjects until day 22 (2.0 mg kg-1 ). Mean circulating IL-7 and soluble receptor (CD127) levels were increased above baseline during days 2 and 15 (0.6 mg kg-1 ) and days 2 and 22 (2.0 mg kg-1 ). No meaningful changes were observed in absolute numbers or proportions of immune cell populations or inflammatory cytokine profiles (IL-6, tumour necrosis factor-α, interferon-γ, IL-2). Persistent antidrug antibodies (ADAs) were detected in 5/6 subjects administered a dose of 0.6 mg kg-1 (neutralizing in 2/6) and in 6/6 subjects administered 2.0 mg kg-1 (neutralizing in 5/6). CONCLUSION: GSK2618960 was well tolerated and blocked IL-7 receptor signalling upon full target engagement. Although there was no discernible impact on peripheral T cell subsets in healthy subjects, GSK2618960 may effectively modulate the autoinflammatory activity of pathogenic T cells in diseased tissue. A relatively short half-life is likely the result of target-mediated rather than ADA-mediated clearance.

Blockade of CD127 Exerts a Dichotomous Clinical Effect in Marmoset Experimental Autoimmune Encephalomyelitis.

Non-human primate models of human disease have an important role in the translation of a new scientific finding in lower species into an effective treatment. In this study, we tested a new therapeutic antibody against the IL-7 receptor α chain (CD127), which in a C57BL/6 mouse model of experimental autoimmune encephalomyelitis (EAE) ameliorates disease, demonstrating an important pathogenic function of IL-7. We observed that while the treatment was effective in 100 % of the mice, it was only partially effective in the EAE model in common marmosets (Callithrix jacchus), a small-bodied Neotropical primate. EAE was induced in seven female marmoset twins and treatment with the anti-CD127 mAb or PBS as control was started 21 days after immunization followed by weekly intravenous administration. The anti-CD127 mAb caused functional blockade of IL-7 signaling through its receptor as shown by reduced phosphorylation of STAT5 in lymphocytes upon stimulation with IL-7. Group-wise analysis showed no significant effects on the clinical course and neuropathology. However, paired twin analysis revealed a delayed disease onset in three twins, which were high responders to the immunization. In addition, we observed markedly opposite effects of the antibody on pathological changes in the spinal cord in high versus low responder twins. In conclusion, promising clinical effect of CD127 blockade observed in a standard inbred/SPF mouse EAE model could only be partially replicated in an outbred/non-SPF non-human primate EAE model. Only in high responders to the immunization we found a positive response to the treatment. The mechanism underpinning this dichotomous response will be discussed.

Blockade of the interleukin-7 receptor inhibits collagen-induced arthritis and is associated with reduction of T cell activity and proinflammatory mediators.

OBJECTIVE: To study the effects of interleukin-7 receptor α-chain (IL-7Rα) blockade on collagen-induced arthritis (CIA) and to investigate the effects on T cell numbers, T cell activity, and levels of proinflammatory mediators. METHODS: We studied the effect of anti-IL-7Rα antibody treatment on inflammation and joint destruction in CIA in mice. Numbers of thymocytes, splenocytes, T cell subsets, B cells, macrophages, and dendritic cells were assessed. Cytokines indicative of Th1, Th2, and Th17 activity and several proinflammatory mediators were assessed by multianalyte profiling in paw lysates. In addition, T cell-associated cytokines were measured in supernatants of lymph node cell cultures. RESULTS: Anti-IL-7Rα treatment significantly reduced clinical arthritis severity in association with reduced radiographic joint damage. Both thymic and splenic cellularity were reduced after treatment with anti-IL-7Rα. IL-7Rα blockade specifically reduced the total number of cells as well as numbers of naive, memory, CD4+, and CD8+ T cells from the spleen and significantly reduced T cell-associated cytokines (interferon-γ, IL-5, and IL-17). IL-7Rα blockade also decreased local levels of proinflammatory cytokines and factors associated with tissue destruction, including tumor necrosis factor α, IL-1ß, IL-6, matrix metalloproteinase 9, and RANKL. IL-7Rα blockade did not significantly affect B cells, macrophages, and dendritic cells. B cell activity, indicated by serum anticollagen IgG antibodies, was not significantly altered. CONCLUSION: Blockade of IL-7Rα potently inhibited joint inflammation and destruction in association with specific reductions of T cell numbers, T cell-associated cytokines, and numerous mediators that induce inflammation and tissue destruction. This study demonstrates an important role of IL-7R-driven immunity in experimental arthritis and indicates the therapeutic potential of IL-7Rα blockade in human arthritic conditions.