Progress in the active immunotherapeutic approach to Alzheimer's disease: clinical investigations into AN1792-associated meningoencephalitis.
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 beta-amyloid (Abeta) or various overlapping peptides of Abeta(1-42), 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 Abeta 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.


CONCLUSIONS
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 Abeta (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.
Pride
Michael
M
Wyeth Research, Collegeville, PA 19426, USA.
Seubert
Peter
P
Grundman
Michael
M
Hagen
Michael
M
Eldridge
John
J
Black
Ronald S
RS
D000544:Alzheimer Disease / Q000188:drug therapy* / Q000453:epidemiology / Q000276:immunology; D023582:Alzheimer Vaccines / Q000009:adverse effects*; D016229:Amyloid beta-Peptides / Q000009:adverse effects*; D000818:Animals; D017322:Clinical Trials, Phase II as Topic / Q000379:methods; D006801:Humans; D016233:Immunotherapy, Active / Q000009:adverse effects* / Q000379:methods; D008590:Meningoencephalitis / Q000139:chemically induced* / Q000453:epidemiology / Q000276:immunology; D015337:Multicenter Studies as Topic / Q000379:methods; D010865:Pilot Projects
C437846:AN-1792; D023582:Alzheimer Vaccines; D016229:Amyloid beta-Peptides