Data from Mechanistic Insights of an Immunological Adverse Event Induced by an Anti-KIT Antibody Drug Conjugate and Mitigation Strategies

• DOI: 10.1158/1078-0432.c.6527409.v1
• Publication Date: 2023-04-01T01:17:34Z
• Authors: Lawrence L'Italien; Olivia Orozco; Tinya Abrams; Lisa Cantagallo; Anu Connor; Jayesh Desai; Hilmar Ebersbach; Hans Gelderblom; Keith Hoffmaster; Emma Lees; Heiko Maacke; Siew Schleyer; Darko Skegro; Si Tuen Lee-Hoeflich
• Keywords: Tryptase

<div>Abstract<p><b>Purpose:</b> Hypersensitivity reactions (HSRs) were observed in three patients dosed a phase I clinical trial treated with LOP628, KIT targeted antibody drug conjugate. Mast cell degranulation was implicated as the root cause for HSR. Underlying mechanism of this reported HSR investigated an aim to identifying potential mitigation strategies.</p><p><b>Experimental Design:</b> Biomarkers mast evaluated patient samples and human peripheral blood cell-derived (PBC-MC) cultures LOP628. Mitigation strategies interrogated include pretreatment cells small molecule inhibitors that target or signaling pathways downstream FcϵR1, FcγR, treatment Fc silencing formats.</p><p><b>Results:</b> Transient elevation serum tryptase 1-hour posttreatment In agreement observation, LOP628 its parental LMJ729 induced PBC-MCs. Unexpectedly, did not abrogate degranulation. By contrast, receptors blunted Furthermore, interference engage by pre-incubation IgG using engineered mutations reduced prevented Characterization Fcγ revealed PBC-MCs expressed both FcγRII low levels FcγRI. Interestingly, increasing level FcγRI upon addition IFNγ, significantly enhanced LOP628-mediated degranulation.</p><p><b>Conclusions:</b> Our data suggest is likely clinic due co-engagement FcγR KIT, resulting activation. <i>Clin Cancer Res; 24(14); 3465–74. ©2018 AACR</i>.</p></div>