Antibody therapeutics with high affinity for FcγRs exacerbate anaphylaxis via FcγR-mediated capture by tumor-associated myeloid cells

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. 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. We identified this difference as being attributed to the ability of tumor-associated monocytic–macrophage lineage cells to capture antibodies via FcγR, altering antibody biodistribution in the spleen, thereby facilitating antigen presentation and activating humoral immunity. Pretreatment with FcγR blocking antibodies attenuated this response, reducing anaphylaxis severity and improving survival. Analysis of clinical therapeutic antibodies also showed that those with a high affinity for FcγRs have a higher risk of inducing anaphylaxis, whereas neutralizing/blocking antibodies with a low or no affinity for FcγRs have a lower risk. Conclusions High affinities for FcγRs were identified as a critical determinant of anaphylaxis and reveal a mechanism linking FcγR-mediated antibody capture by tumor-associated myeloid cells to ADA induction. This contributes to the mechanistic foundation of AllergoOncology, an emerging interdisciplinary field exploring the interplay between cancer pathology and hypersensitivity reactions to therapeutic agents and providing insights for improving the safety and design of antibody therapeutics.