Neo-antigens for the serological diagnosis of IgE-mediated drug allergic reactions to antibiotics cephalosporin, carbapenem and monobactam

[EN] New antigens deriving from -lloyl and -llanyl, major and minor determinants, respectively, were produced for beta-lactam antibiotics cefuroxime, cefotaxime, ceftriaxone, meropenem and aztreonam. Twenty beta-lactam antigens were produced using human serum albumin and histone H1 as carrier proteins. Antigens were tested by multiplex in vitro immunoassays and evaluated based on the detection of specific IgG and IgE in the serum samples. Both major and minor determinants were appropriate antigens for detecting specific anti-beta-lactam IgG in immunised rabbit sera. In a cohort of 37 allergic patients, we observed that only the minor determinants (-llanyl antigens) were suitable for determining specific anti-beta-lactam IgE antibodies with high sensitivity (<0.01 IU/mL; 24 ng/L) and specificity (100%). These findings reveal that not only the haptenisation of beta-lactam antibiotics renders improved molecular recognition events when the 4-member beta-lactam ring remains unmodified, but also may contribute to develop promising minor antigens suitable for detecting specific IgE-mediated allergic reactions. This will facilitate the development of sensitive and selective multiplexed in vitro tests for drug-allergy diagnoses to antibiotics cephalosporin, carbapenem and monobactam.This work has been funded by the H2020 programme (Project COBIOPHAD, grant agreement No. 688448), and is an initiative of the Photonics Public Private Partnership (www.photonics21.org); Agencia Estatal de Investigacion (CTQ2016-75749-R, FEDER) and programme UPV-LA FE 2019 (PI05 VALBIOAL). The authors acknowledge the Instituto de Investigacion Sanitaria La Fe, Valencia, Spain, which provided the samples from both allergic patients and controls. 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Boosting the sensitivity of in vitro b-lactam allergy diagnostic tests

[EN] The synthesis of structurally new haptens and the development of suitable antigens are essential for boosting the sensitivity of drug allergy diagnostic testing. Unprecedented structural antigens for benzylpenicillin and amoxicillin are characterised and evaluated in a cohort of 70 subjects with a turnkey solution based on consumer electronics.This work was funded by the H2020 program (project COBIOPHAD, grant agreement No. 688448), an initiative of the Photonics Public Private Partnership; Agencia Estatal de Investigacion (CTQ2016-75749-R, FEDER) and program UPV-La FE 2019 (PI05 VALBIOAL). E. P. M. holds a FPU doctoral fellowship from Ministerio de Educación, Cultura y Deporte.Peña-Mendizábal, E.; Morais, S.; Maquieira Catala, Á. (2020). Boosting the sensitivity of in vitro b-lactam allergy diagnostic tests. Chemical Communications. 56(80):11973-11976. https://doi.org/10.1039/D0CC04903DS11973119765680Van Boeckel, T. P., Gandra, S., Ashok, A., Caudron, Q., Grenfell, B. 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Synthesis of skeletally diverse ß-lactam haptens for the in vitro diagnosis of IgE-mediated drug allergy

[EN] We present the first synthesis of beta-lactam-derived haptens, leveraging the principles of diversity-oriented synthesis to discover compounds for drug allergy in vitro testing. We designed, synthesised, and performed in vitro immunological evaluation on 18 structurally diverse haptens derived from beta-lactam antibiotics. The antigens obtained with the synthesised haptens allow for the detection of specific anti-beta-lactam immunoglobulins G and E. Excellent diagnostic sensitivity (83%) and specificity (100%) were achieved when the panel of antigens was tested against a cohort of 31 human serum samples using a multiplexed compact disc-based in vitro testing tool. We posit that adopting this strategy could aid beta-lactam delabeling initiatives.This work was supported by the H2020 program (project COBIOPHAD, grant agreement No. 688448), Agencia Estatal de Investigacion (PID2019-110713RB-I00, FEDER awarded to S.M.); Generalitat Valenciana (PROMETEO/2020/094 awarded S.M.); and the National Institute of General Medical Sciences (GM- 1R35GM127045 awarded to S.L.S.). E.P.M. was supported by an FPU fellowship from the Ministerio de Educacio¿n, Cultura y Deporte (FPU15/01738 and EST18/00360). B.K.H. was supported by a fellowship from the National Science Foundation (DGE1144152 and DGE1745303).Peña-Mendizábal, E.; Hua, BK.; Ibáñez-Echevarría, E.; Hernández-Fernández De Rojas, D.; Maquieira Catala, A.; Schreiber, SL.; Morais, S. (2022). Synthesis of skeletally diverse ß-lactam haptens for the in vitro diagnosis of IgE-mediated drug allergy. Chemical Communications. 58(40):5964-5967. https://doi.org/10.1039/D2CC01677J59645967584