Human Anti-Peanut Ara h 2 Monoclonal Antibody, clone 27B9

Introduction Methotrexate intoxication following high-dose methotrexate-induced acute kidney injury is a life-threatening complication. Glucarpidase can quickly reduce extracellular methotrexate to safe levels, but the effectiveness and safety of its use in different episodes of nephrotoxicity remain an unknown area. Case Report A 30-year-old male diagnosed with acute lymphoblastic T-cell lymphoma received methotrexate 5 g/m2 intravenous (IV) as part of the first consolidation cycle. On Consolidation 3, he restarted methotrexate at a dose of 3 g/m2 IV showing slow methotrexate elimination, associated myelosuppression, and hepatic toxicity. Glucarpidase was administered (total dose of 2000 International Units (IU)). No adverse events were observed, and his renal function returned to normal. One hundred and six days later, he was diagnosed with leptomeningeal and cerebellar relapse and treatment with methotrexate 3,5 g/m2 IV day 1 and cytosine arabinoside (Ara-C) 2 g/m2 IV twice per day days 1, 3, and 5 was started. At 36 h from methotrexate infusion, serum creatinine increased up to 1.89 mg/dL and methotrexate concentration was 100 mu mol/L. Management and Outcome:Ara-C was suspended, and a second administration of glucarpidase (2000 IU) was dispensed. No adverse events were noticed, methotrexate levels decreased and renal function progressively improved, recovering completely three weeks later. Discussion The effectiveness and safety of the use of glucarpidase in different episodes of nephrotoxicity remain an unknown area, and the rate and consequences of antiglucarpidase antibody formation remain poorly understood. This case report is, to our knowledge, the first case of a second administration of glucarpidase in a different cycle of high-dose methotrexate in an adult patient.

Proteasome inhibitors are used as research tools and to treat multiple myeloma, and proteasome activity is diminished in several neurodegenerative diseases. We therefore studied how cells compensate for proteasome inhibition. In 4 h, proteasome inhibitor treatment caused dramatic and selective induction of GAB ARA PL1 (but not other autophagy genes) and p62, which binds ubiquitinated proteins and GAB ARA PL1 on autophagosomes. Knockdown of p62 or GAB ARA PL1 reduced cell survival upon proteasome inhibition. p62 induction requires the transcription factor nuclear factor (erythroid-derived 2)-like 1 (Nrf1), which simultaneously induces proteasome genes. After 20-h exposure to proteasome inhibitors, cells activated autophagy and expression of most autophagy genes by an Nrf1-independent mechanism. Although p62 facilitates the association of ubiquitinated proteins with autophagosomes, its knockdown in neuroblastoma cells blocked the buildup of ubiquitin conjugates in perinuclear aggresomes and of sumoylated proteins in nuclear inclusions but did not reduce the degradation of ubiquitinated proteins. Thus, upon proteasome inhibition, cells rapidly induce p62 expression, which enhances survival primarily by sequestering ubiquitinated proteins in inclusions.