Discussion
Urticaria, anaphylaxis, toxicity, cancer, rash, urticaria, pruritus
HYPERSENSITIVITY REACTIONS, OVARIAN CANCER, ANAPHYLAXIS, URTICARIA, ADVERSE EVENTS, CANCER, URTICARIA, SECONDARY
In this clinical trial of an IgE antibody for the treatment of cancer, a manageable safety profile, distinct from that of IgG drugs, was observed and preliminary evidence of efficacy demonstrated. Both anti-tumour activity and adverse events occurred at doses very much lower than typically observed for IgG antibodies. This reflects fundamental differences in Fc-receptor affinity and effector cell biologyOur finding of elevated fold increases in serum concentrations of IL-6, IFNγ, MCP-1 and IL-10 in treated patients is consistent with the mechanism of IgE-induced signalling by tumouricidal effector cells, such as monocytes and macrophages, described in animal surrogates (Fig. In this trial we performed a basophil activation test (BAT) ex vivo on whole unfractionated blood from each patient just prior to dosing, with a rationale of addressing concerns that MOv18 IgE bound to endogenous Fcε receptors might be cross-linked by endogenous antibodies or other circulating factors. The BAT results remained negative in all patients with the exception of one who developed anaphylaxis on their first exposure to MOv18 IgE. The episode resolved rapidly and did not recur after withdrawal of drug. This patient demonstrated a positive BAT at baseline, prior to any exposure to MOv18 IgE. We hypothesise that, in this single patient, both anaphylaxis and the positive BAT at baseline reflected the presence of an endogenous circulating factor able to crosslink the MOv18 IgE antibodies bound to receptors on the surface of effector cells. One such candidate may be autoantibodies to the oligosaccharide galactose-α−1,3-galactose (alpha-GAL): subjects with an endogenous IgE response against this post-translational modification on a therapeutic antibody have been reported to develop Type 1 hypersensitivity reactions during treatment with some monoclonal antibodiesFollowing this single case of anaphylaxis, the trial protocol was amended to exclude any further patients found to have a positive baseline BAT, and no further anaphylaxis was observed. In a separate observational study of blood samples drawn from a series of patients with ovarian cancer, we observed a positive BAT using MOv18 IgE in only one of 42 individualsThe most common adverse events associated with MOv18 IgE were cutaneous, with some patients experiencing a diffuse patchy macular erythematous rash, with or without pruritus, but with urticaria the most frequent toxicity. Although the extent of this rash varied greatly between patients, it was tolerable and transient. Urticaria usually recurred with subsequent doses, but in general it was more prominent with first dose administration and became less obvious with subsequent doses. It is possible this could have been a result of the use of secondary prophylaxis with steroid and antihistamine. Urticaria was associated with symptoms or signs of anaphylaxis only in the single patient referred to above with a positive BAT at baseline. No elevation of the serum tryptase concentration, a diagnostic requirement in cases of anaphylaxisFRα was chosen as the target for testing IgE therapy in a clinical trial. This tumour-associated antigen is present at very low levels in normal tissues