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Preprint WatchModerateSeptember 12th, 2026

Patient-derived IgG Amplifies Fcγ Receptor-Dependent Colonic Inflammation During Immune Checkpoint Blockade

Voloshyna, I.; Patskovsky, Y.; Sandigursky, S.; Sreenivasaiah, C.; Bayrakta, E. C.; Tardio, E.; Lopez, A. V.; Idga, S.; Ng, C.; Ibrahim, M.; Goldberg, C.; Zhurova, A.; Freih, R.; Mastroianni, J.; Hao, Y.; Mishra, P.; Khodadadi-Jamayran, A.; Mehnert, J.; Silverman, G. J.; Fa'ak, F.; Osman, I.; Krogsgaard, M.

Pretreatment humoral immunity conditions susceptibility to severe immune-related colitis via the IgG-Fc-gamma-receptor axis, with severe-colitis patient IgG amplifying checkpoint-driven colonic inflammation in humanized Fc-gamma-receptor mice.

Moderate contradiction

2 prior failures

Two documented clinical failures match this mechanism, or a single Phase 3 failure is on record.

This preprint reports that baseline serum autoantibody profiles condition susceptibility to severe immune-related colitis during PD-1 and CTLA-4 blockade, and that polyclonal IgG from patients with severe colitis amplified checkpoint-driven colonic inflammation in humanized Fc-gamma-receptor mice but not in wild-type mice. The claim is about a host determinant of toxicity rather than about the efficacy mechanism of PD-1 blockade, so the cross-reference is indirect. Claidex holds two PDCD1 failures that bear on it. In camrelizumab-apatinib-pdcd1-first-line-cervical-cancer-phase2-efficacy-failure the combination was stopped for insufficient efficacy in first-line cervical squamous cell carcinoma, and in pds0101-pembrolizumab-pdcd1-hpv16-head-neck-versatile-003-phase3-strategic-reprioritization a Phase 3 HPV16-positive head and neck program was reprioritized. A related CTLA-4 failure, nivolumab-ipilimumab-ctla4-renal-medullary-carcinoma-phase2-futility-hyperprogression, closed on futility with a hyperprogression signal. If pretreatment humoral immunity predicts who develops severe colitis, it becomes a candidate stratification variable for checkpoint trials whose benefit-risk was marginal, and the finding is worth prospective testing before it is used to select patients.

Abstract excerpt

Immune checkpoint inhibitor (ICI)-associated colitis limits effective cancer immunotherapy, yet host determinants of severe toxicity remain undefined. We investigated whether humoral immunity is associated with subsequent severe immune-related colitis (irC). In melanoma patients, baseline serum autoantibody (AAb) profiling identified a composite antigen signature - a signature-level association rather than validated functional specificities - associated with severe irC, marked by retained reactivity to tumor-associated antigens and relative depletion of antibodies recognizing immune- and mucosal-regulatory proteins. To assess functional relevance, we transferred polyclonal IgG from severe- or non-severe-irC patients into wild-type or humanized Fc{gamma} receptor (hFc{gamma}R) mice treated with anti-PD-1 or anti-CTLA-4. IgG alone did not induce inflammation; however, severe-irC IgG amplified checkpoint-driven colonic inflammation in hFc{gamma}R mice, but not in wild-type mice, with checkpoint-specific remodeling of myeloid, lymphoid, and innate lymphoid compartments. These findings suggest that pretreatment humoral immunity conditions susceptibility to irC via the IgG-Fc{gamma}R axis.

Matching Claidex post-mortems

2 of 2 indexed

This is an automated contradiction flag, not an editorial judgment on the preprint's quality. Flags identify where the preclinical literature and the clinical failure record diverge.