Progress in the Active Immunotherapeutic Approach to Alzheimer’s Disease: Clinical Investigations into AN1792-Associated MeningoencephalitisPride M. · Seubert P. · Grundman M. · Hagen M. · Eldridge J. · Black R.S.
aWyeth Research, Collegeville, Pa. and Pearl River, N.Y., and bElan Pharmaceuticals, San Diego, Calif. and San Francisco, Calif., USA
Background: In a phase 2a clinical trial of AN1792 (Study 201), a potential immunotherapeutic agent for use in Alzheimer’s disease (AD), approximately 6% of the treated AD patients (18/300) developed meningoencephalitis (ME). Objective: To elucidate potential immune mechanisms of treatment-induced ME. Methods: Peripheral blood mononuclear cells obtained from patients who received AN1792 were stimulated in vitro either with β-amyloid (Aβ) or various overlapping peptides of Aβ1–42, followed by quantification of cytokine-secreting cells by enzyme-linked immunosorbent spot assay. Results: A significant difference in the quality of the T-cell responses between patients in Study 201 and those in earlier studies of AN1792 was noted. T-cell responses specific to the carboxy terminus of Aβ elicited from patients’ peripheral blood mononuclear cells in an earlier multiple dose study (Study 102) were Th2 biased, while those from Study 201 were biased toward a proinflammatory Th1 response. Antibody responses in both studies were quantitatively and qualitatively similar (as determined by epitope mapping). The addition of polysorbate 80 to the formulation used in Study 201 is the most likely explanation for the difference in the T-cell response. Conclusion: ME following injection of AN1792 may be related to immune response differences driven by a formulation change. To address this, a novel peptide-carrier protein conjugate using an amino-terminal fragment of Aβ (ACC-001) has been developed to avoid potentially harmful T-cell responses, while maintaining a similar antibody response to that of AN1792. Immunotherapeutic trials using this treatment approach in AD patients are in progress.
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