Tang R, Aibai A, Tamemoto Y et al. Journal for ImmunoTherapy of Cancer. 2026;14:e013316. https://doi.org/10.1136/jitc-2025-013316Abstract
Background Antibody therapeutics have revolutionized cancer treatment, but their use is increasingly associated with adverse events. Among these, anaphylaxis is particularly concerning due to its severity and unpredictability. Our previous studies demonstrated that repeated administration of anti-programmed death-ligand 1 antibodies to tumor-bearing mice induces antidrug antibodies (ADAs) and anaphylaxis. However, the specific characteristics of antibody therapeutics responsible for this effect and the underlying mechanism of ADA production remain poorly understood. This study aimed to identify the immunological and molecular determinants of ADA-associated anaphylaxis following antibody therapeutics in tumor-bearing hosts.
Methods CT26 and 4T1 tumor-bearing mice were repeatedly administered various therapeutic antibodies with differing affinities for Fcγ receptors (FcγRs). Anaphylaxis symptoms, body temperature, and mortality were evaluated. Serum ADA levels were quantified using ELISA. Antibody affinity for mouse FcγR was determined using surface plasmon resonance. Antibody distribution in the spleen was assessed via immunofluorescence staining, and antibody glycosylation was analyzed by liquid chromatography-mass spectrometry. Immune cell populations were examined using flow cytometry.
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High-affinity FcγR-binding anti-PD-L1 antibody clone, 10F.9G2, but not low-affinity clones nor deglycosylated 10F.9G2 induced anaphylaxis. |
Results Repeated administration of antibodies with high affinities for FcγRs to tumor-bearing mice induced robust ADA production and anaphylaxis, whereas antibodies with low affinities for FcγRs against the same target elicited only minimal ADA responses and did not trigger anaphylaxis.