D1.373 - Hypersensitivity to Biologic Therapies: Mechanism of Cross-reactivity

Biologic therapies have significantly advanced the management of type2 (T2) inflammatory diseases. Immediate hypersensitivity reactions (HSRs) to biologic therapies are uncommon but clinically significant. We report two patients with immediate HSRs to multiple IgG-based biologics, with mechanistic confirmation through SDS-PAGE and IgE-Western blot.

We performed: clinical evaluation; allergological study with skin testing and drug provocation test (DPT); and immunochemical analyses, including SDS-PAGE under reducing and non-reducing conditions and IgE-Western blot.

CASE A: A 34-year-old woman with hidradenitis suppurativa. She developed generalized urticaria 1-2 hours after subcutaneous secukinumab, sixth dose. Excipient polysorbate-80 was good tolerated in other medications. Dermatologists asked for treatment with secukinumab or alternatives.

CASE B: A 59-year-old man with severe eosinophilic, non-allergic, corticosteroid-dependent asthma and NSAID hypersensitivity, multiple asthma exacerbations, over 20 hospital admissions since 2015, several stays in the intensive care unit. Discontinued treatment with mepolizumab due to poor asthma control. After first dose of benralizumab and reslizumab he presented anaphylaxis. After first dose of dupilumab he developed an immediate generalized urticaria. Pneumologists asked for evaluation.

Allergological study in Table.

Immunochemical findings (Figure)

CASE-A:

IgE binding to ~50 kDa (IgG1 and IgG2 heavy chain)

IgE binding to ~25 kDa (IgG1 and IgG2 light chain)

CASE-B:

IgE binding to ~50 kDa (IgG1, IgG2 and IgG4 heavy chain)

IgE binding to ~25 kDa (IgG1, IgG2 and IgG4 light chain)

Both patients displayed IgE binding to ~50-kDa and ~25-kDa fragments corresponding to IgG heavy and light chain structures. This reactivity was independent of the biologic’s therapeutic target. The reactivity was found only under reducing conditions.

This indicated IgE recognition of conserved IgG1 ang IgG4 structural domains rather than recognition of antigen-specific regions.

Both cases, with the immediate onset, intradermal reactivity and IgE-Western blot positivity, are consistent with true IgE-mediated endotypes.

We present two cases of structural IgE-mediated cross-reactivity among IgG biologics.

To our knowledge, no previous reports have documented IgE binding to conserved IgG heavy and light chains across different therapeutic antibodies in clinical cases.

These two mechanistic case studies support a previously under-recognized mechanism of IgE-mediated hypersensitivity driven by structural recognition of conserved IgG domains across unrelated biologics.