Acute lymphoblastic leukaemia patients treated with PEGasparaginase develop antibodies to PEG and the succinate linker

Polyethylene glycol (PEG) conjugated asparaginase (PEGasparaginase) is essential for treatment of paediatric acute lymphoblastic leukaemia. We developed an assay identifying antibodies against the PEG-moiety, the linker and the drug itself in patients experiencing hypersensitivity reactions to PEGasparaginase. Eighteen patients treated according to the DCOG ALL-11 protocol, with a neutralizing hypersensitivity reaction to PEGasparaginase to the first PEGasparaginase doses in induction (12 patients) or during intensification after interruption of several months (6 patients) were included. ELISA was used to measure antibodies, coating with the succinimidyl succinate linker conjugated to BSA, PEGfilgrastim and Escherichia coli asparaginase, and using hydrolysed PEGasparaginase and mPEG5,000 for competition. Anti-PEG antibodies were detected in all patients (IgG 100%; IgM 67%) of whom 39% had anti-PEG antibodies exclusively. Pre-existing anti-PEG antibodies were also detected in patients who not previously received a PEGylated therapeutic (58% IgG; 21% IgM). Antibodies against the SS-linker were predominantly detected during induction (50% IgG; 42% IgM). Anti-asparaginase antibodies were detected in only 11% during induction but 94% during intensification. In conclusion, anti-PEG and anti-SS-linker antibodies predominantly play a role in the immunogenic response to PEGasparaginase during induction. Thus, switching to native E. coli asparaginase would be an option for adequate asparaginase treatment

Biochemical response of Norway spruce (<em>Picea abies </em>(L.) Karst.) towards 14-month exposure to ozone and acid mist: Part I - effects on polyphenol and monoterpene metabolism.

Three-year-old clonal Picea abies (L.) Karst. plants, grown either on a sandy (No. 1) or on a calcareous (No. 2) soil, were treated with ozone (100 &mu;g m-3 and peaks of up to 360 &mu;g m-3) and acid mist (pH 3.0) over two vegetation periods. Needles of the current (1987) and previous (1986) year were analysed at the end of the experiment for biosynthetic enzymes and in vivo activity of the phenylpropanoid pathway, for products of polyphenol metabolism (clones 11 and 14), and for mono- and sesquiterpenes (clones 14 and 16). 1. Polyphenol metabolism. The activity of cinnamyl alcohol dehydrogenase, an enzyme of the lignin pathway, was increased by the treatment by up to 83% in the needles of both age classes. Chalcone synthase was measured in mature tree material for the first time. This enzyme, as well as phenylalanine ammonia-lyase activities and the content of catechin, astringin, isorhapontin, picein and p-hydroxyacetophenone, exhibited no significant treatment-dependent differences. However, soil and age-class dependent differences occurred. Pulse-labelling experiments with L[U-14 C]phenylalanine and [2-14 C]acetate were carried out at four different stages of shoot development and showed label incorporation into (+)-catechin and proanthocyanidins. There was no effect of the ozone and acid mist treatment. 2. Monoterpenes. The content of needle terpenes was generally diminished by the ozone and acid mist treatment. Other factors tested, such as clone, needle age and soil, exerted a highly significant influence on the content of most of the needle monoterpenes