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

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

The study of myocardial perfusion and coronary anatomy imaging roles in CAD (SPARC): design, rationale, and baseline patient characteristics of a prospective, multicenter observational registry comparing PET, SPECT, and CTA for resource utilization and clinical outcomes.

OBJECTIVES: To design a multicenter study comparing the prognostic value and post-test resource utilization of PET, CT Coronary Angiography (CTA), and SPECT in clinical practice. BACKGROUND: Although PET, CTA, and SPECT are widely used, their relative clinical- and cost-effectiveness are undefined. METHODS: The Study of Myocardial Perfusion and Coronary Anatomy Imaging Roles in CAD (SPARC) is a prospective, multicenter, observational registry that has enrolled 3019 patients undergoing clinically referred SPECT, PET, and CTA with the goal of comparing posttest resource utilization and comparative prognostic value. Resource utilization assessment will enroll intermediate-high likelihood patients without prior CAD, while prognostic assessment will include both these patients and patients with prior CAD. Secondary analyses include assessments of diagnostic accuracy, cost, and referral to revascularization. Sites recruited into at least two of the three imaging arms. Except for semi-quantitative interpretation, site protocols will be used for all imaging studies and images forwarded to an image repository. Follow-up for catheterization, revascularization, cardiac death, myocardial infarction, all-cause death and medication use changes will be performed at 90-day, 1, and 2 years. Standard statistical methods will be used to risk-adjust results within and between study arms. SPARC will have >85% power (two-sided test, alpha = 0.01) to detect a 5% catheterization rate difference at 90 days between the three arms and >90% power to detect a 2% difference in cardiac death, or nonfatal MI within 2 years of the index test.