Do immunoglobulin G and immunoglobulin E anti- l -asparaginase antibodies have distinct implications in children with acute lymphoblastic leukemia? A cross-sectional study

Abstract

Backgroundl-Asparaginase is essential in the treatment of childhood acute lymphoblastic leukemia. If immunoglobulin G anti-l-asparaginase antibodies develop, they can lead to faster plasma clearance and reduced efficiency as well as to hypersensitivity reactions, in which immunoglobulin E can also participate. This study investigated the presence of immunoglobulin G and immunoglobulin E anti-l-asparaginase antibodies and their clinical associations.MethodsUnder 16-year-old patients at diagnosis of B-cell acute lymphoblastic leukemia confirmed by flow cytometry and treated with a uniform l-asparaginase and chemotherapy protocol were studied. Immunoglobulin G anti-l-asparaginase antibodies were measured using an enzyme-linked immunosorbent assay. Intradermal and prick skin testing was performed to establish the presence of specific immunoglobulin E anti-l-asparaginase antibodies in vivo. Statistical analysis was used to investigate associations of these antibodies with relevant clinical events and outcomes.ResultsFifty-one children were studied with 42 (82.35%) having anti-l-asparaginase antibodies. In this group immunoglobulin G antibodies alone were documented in 10 (23.8%) compared to immunoglobulin E alone in 18 (42.8%) patients. Immunoglobulin G together with immunoglobulin E were simultaneously present in 14 patients. Children who produced exclusively immunoglobulin G or no antibodies had a lower event-free survival (p-value = 0.024). Eighteen children (35.3%) relapsed with five of nine of this group who had negative skin tests suffering additional relapses (range: 2–4), compared to none of the nine children who relapsed who had positive skin tests (p-value < 0.001).ConclusionChildren with acute lymphoblastic leukemia and isolated immunoglobulin G anti-l-asparaginase antibodies had a higher relapse rate, whereas no additional relapses developed in children with immunoglobulin E anti-l-asparaginase antibodies after the first relapse.

Hypersensitivity reactions to asparaginase in mice are mediated by anti-asparaginase IgE and IgG and the immunoglobulin receptors FcεRI and FcγRIII

“…Few clinical studies of the immune response to ASNase have investigated the role of anti-ASNase IgE on the development of hypersensitivity reactions. 14–16 Based on our results demonstrating detectable plasma levels of anti-ASNase IgE (Figure 1E and F), we believe that antigen-specific recognition and hypersensitivity reactions may be mediated in part by cell-associated IgE. In support of a role for anti-ASNase IgE in the binding or recognition of free ASNase and not ASNase immune complexes, we found that blocking IgE with EM-95 decreases the binding of ASNase to sensitized basophils (Figure 2).…”

“…Moreover, many patients who have circulating anti-ASNase IgG never develop a hypersensitivity reaction. 2,7 Interestingly, few studies have assessed anti-ASNase IgE levels in patients or have suggested a role of anti-ASNase IgE in the ASNase hypersensitivity reaction, 14–16 likely due to a lack of methods available to detect anti-ASNase IgE in the presence of high anti-ASNase IgG levels.…”

Identification of L-asparaginases from Streptomyces strains with competitive activity and immunogenic profiles: a bioinformatic approach

“…However, searching for ASNases of pharmacological interest has been done only rarely. After the identification of two sets of ASNases, we chose T-cell ED as the immunogenicity indicator, according to Cantor et al (2011), Fernandez et al (2014), andGalindo-Rodríguez et al (2017), who proposed that HLA class II molecules play a critical role in the development of specific anti-ASNase antibodies and in hypersensitivity to the enzyme (Cantor et al, 2011;Fernandez et al, 2014;Galindo-Rodríguez et al, 2017). Additionally, it has been shown that proteins that are highly immunogenic generally contain a greater amount of T-cell epitopes, or clusters thereof (Singh et al, 2012).…”

Peer Review #1 of "Identification of L-asparaginases from Streptomyces strains with competitive activity and immunogenic profiles: a bioinformatic approach (v0.2)"

“…Manuscript to be reviewed (2017), who proposed that HLA class II molecules play a critical role in the development of specific anti-ASNase antibodies and in hypersensitivity to the enzyme (Cantor et al, 2011;Fernandez et al, 2014;Galindo-Rodríguez et al, 2017). Additionally, it has been shown that proteins that are highly immunogenic generally contain a greater amount of T-cell epitopes, or clusters thereof (Singh et al, 2012).…”