IgE as a Target to Treat Allergic Asthma

Anti-IgE mAbs provide immunological examples wherein in vitro data have been correlated to in vivo PK and PD, as a measure of in vivo potency. Omalizumab (Xolair®, rhuMAb-E25) is a humanized IgG1 anti-IgE mAb used in the treatment of moderate to severe allergic asthma. This Ab suppresses serumfree IgE levels by selectively binding to IgE, forming small, biologically inert immune complexes (95). By blocking the binding of IgE to high-affinity FceRI, the Ab inhibits cross-linking of IgE bound to FceRI, thereby inhibiting the release of histamine and other proinflammatory mediators of the allergic response (96). Fox et al. related the in vitro formation of immune complexes and the stability of omalizumab to PK and immune complex formation in cynomolgus monkeys (97). More recently, Shulman described a similar strategy using the same Ab for the treatment of allergic respiratory disorders; in vitro data on IgE-mediated inflammatory processes were related to clinical PK and PD, in particular suppression of free IgE (98). A correlation between serum-free IgE levels and clinical outcomes was used to optimize the dosing strategy of omalizumab (95).

High affinity anti-IgE 1 (HAE 1) is a second-generation, high-affinity anti-IgE mAb having the same IgG1 framework as omalizumab but nine amino acid differences in the CDR. Binding affinity measurements using Biacore (based on surface plasmon resonance) indicated that the apparent Kd values of the HAE1-Fab and the omalizumab Fab were 0.66 nM and 15.5 nM, respectively, which reflects an approximately 23-fold higher affinity of the HAE-Fab for IgE (99). Interestingly, this difference was mainly due to a much slower dissociation rate of the HAE1-Fab from the IgE, whereas the association rates of the two molecules with IgE were very similar. An in vitro potency assay demonstrated that the higher affinity of HAE1 for IgE increased its ability to inhibit binding of human IgE to the FceRI receptor by approximately 50-fold (Fig. 2, upper panel).

The increased potency of HAE1 offered two potential benefits relative to current omalizumab therapy: (i) treatment of patients with higher baseline IgE

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