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Other new emerging monoclonal antibodies exploit a range of targets involved in immune system function, including CD20, a protein that appears on the surface of B-cells and helps them to function in the immune response, the cytokines B-cell-activating factor (BAFF) (also known as B lymphocyte stimulator [BLyS], which is involved in supporting B-cell functions, and the granulocyte macrophage colony-stimulating factor (GM-CSF) receptor (GM-CSF is a immune system protein that stimulates the production of a range white blood cells. However, it requires its receptor to function. Ofatumumab (Arzerra) is a new CD20-targeted monoclonal antibody, tabalumab is a BAFF-targeted agent, belimumab is a BLyS-targeted agent, and mavrilimumab is a GM-CSF receptor-targeted agent.1-3
Emerging monoclonal antibodies with various targetsAgent
Sponsor
Target
Phase
Ofatumumab (Arzerra)
GlaxoSmithKline
CD20
Phase III
Tabalumab (LY2127399)
Eli Lilly and Co
BAFF
Phase III
Belimumab (Benlysta)
GlaxoSmithKline
BLyS
Phase II
Mavrilimumab (CAM-3001)
MedImmune
GM-CSF receptor-α
Phase II
BAFF=B-cell-activating factor; BLyS=B lymphocyte stimulator; CM-CSF=granulocyte macrophage colony-stimulating factor.
OfatumumabOfatumumab (Arzerra) is a monoclonal antibody that targets CD20 being developed by GlaxoSmithKline. It is a fully human monoclonal antibody, which is potentially important in terms of the risk of side effects. Unlike monoclonal antibodies that are derived from animals (such as mice), fully human antibodies have less risk for certain side effects. Arzerra is formulated for both intravenous (IV) infusion and subcutaneous (SC) injection and is already approved for chronic lymphocytic leukemia (CLL) in Europe and the US. Arzerra is also being studied for the treatment of relapsing-remitting multiple sclerosis (RRMS). Arzerra targets the antigen CD20, a type of protein located on the surface of B-cells that is responsible for activating the B-cell so that it can take part in the immune response.3,4 Ofatumumab is currently in Phase 3 development for RA. In a completed Phase 1/2 randomized, controlled trial evaluating ofatumumab given as an IV infusion, it resulted in significant benefit versus placebo in patients with active RA who had experienced an inadequate response to conventional disease-modifying anti-rheumatic drug (DMARD) treatment. Another Phase 1/2 study was conducted to evaluate ofatumumab given as a SC injection. In this study, SC ofatumumab resulted in significant and durable reductions of B-cells in the blood.4 Two Phase 3 studies of ofatumumab are ongoing. One is evaluating ofatumumab in patients with RA who had an inadequate response to methotrexate and the other in patients who had an inadequate response to tumor necrosis factor-alpha (TNF-α) inhibitor therapy. Results from the first of these Phase 3 studies has been published and showed that ofatumumab + methotrexate significantly improved all clinical outcomes versus placebo + methotrexate, including rates of ACR20 responses at 24 weeks (50% versus 27%, respectively; P<0.001) and good or moderate responses by European League Against Rheumatism (EULAR) criteria (67% versus 41%; P<0.001). The most common adverse effects associated with ofatumumab were rash and urticaria (hives) and serious adverse effects occurred in 5% of patients who received ofatumumab + methotrexate and 3% of patients who received placebo + methotrexate.2,5
TabalumabTabalumab (LY2127399) is a monoclonal antibody that targets BAFF being developed by Eli Lilly and Company. It is a fully human monoclonal antibody. It is formulated for SC administration. BAFF, a type of protein present on a range of white blood cells, plays an important role in the production and maintenance of B-cells. By neutralizing BAFF, tabalumab can inhibit the production and function of B-cells in the immune response. In published results from a Phase 2 randomized, controlled trial conducted in patients with RA who had an inadequate response to methotrexate, tabalumab significantly reduced the signs and symptoms of RA versus placebo (all patients in the study received methotrexate), with similar safety to placebo (or methotrexate alone). Rates of ACR20 responses for different tabalumab dosing groups ranged from 51.5% to 67.6% compared with 29% for placebo (P<0.05 tabalumab versus placebo).6 Several Phase 3 studies of tabalumab are currently underway. These include the FLEX V study, in patients who had an inadequate response to one or more TNF-α inhibitor treatments, the FLEX M study, in patients with an inadequate response to methotrexate, and the FLEX O study, in patients with and without background DMARD treatment, as well as an open-label study designed to evaluated long-term treatment with tabalumab. Tabalumab administration using an autoinjector system is also being evaluated in a Phase 3 study.2
BelimumabBelimumab (Benlysta) is a monoclonal antibody that targets BLyS being developed by GlaxoSmithKline. Benlysta is a fully human monoclonal antibody already approved to treat systemic lupus erythematosus (SLE). BLyS is a protein (also known as BAFF, a member of the TNF family) present on B-cells that supports the production and function of B-cells. In a Phase 2 study conducted in RA patients with an inadequate response to conventional DMARD treatment, belimumab 1 mg/kg resulted in a rate of ACR20 response at 24 weeks of 34.7% versus 15.9% for placebo (P=0.01). Differences in ACR20 responses between higher doses of belimumab (4 mg/kg and 10 mg/kg) and placebo did not reach significance.7 Based on results from Phase 2 studies, the Phase 3 program for belimumab in RA has been discontinued.2
MavrilimumabMavrilimumab (CAM-3001) is a monoclonal antibody that targets the GM-CSF receptor being developed by MedImmune. Mavrilimumab is a fully human monoclonal antibody that is formulated for SC administration. GM-CSF plays a key role in the activation and function of white blood cells including macrophages and neutrophils. Macrophages have been shown to promote synovitis and levels of macrophages in joint tissue has been correlated with progression of joint destruction. By blocking the GM-CSF receptor and inhibiting GM-CSF, mavrilimumab can reduce disease activity in RA and provide benefits for patients. In the randomized, placebo-controlled Phase 2 EARTH study, mavrilimumab (given with methotrexate) resulted in rapid decreases in disease activity. The rate of ACR20 response at week 12 with mavrilimumab + methotrexate (across all mavrilimumab dosing groups) was 55.7% versus 34.7% for placebo + methotrexate (P=0.003). Adverse effects with mavrilimumab were mostly mild-to-moderate in intensity.8 Mavrilimumab is currently being evaluated in two Phase 2 studies, one assessing the long-term safety of mavrilimumab and the other comparing mavrilimumab with the TNF-α inhibitor golimumab (Simponi) in patients who have had an inadequate response to one or two TNF-α inhibitor treatments.2 |
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