Abeta-immunotherapy for Alzheimer's disease using mannan-amyloid-Beta peptide immunoconjugates.
In Alzheimer's disease (AD) the accumulation of pathological forms of the beta-amyloid (Abeta) peptide are believed to be causal factors in the neurodegeneration that results in the loss of cognitive function in patients. Anti-Abeta antibodies have been shown to reduce Abeta levels in transgenic mouse models of AD and in AN-1792 clinical trial on AD patients; however, the clinical trial was halted when some patients developed meningoencephalitis. Theories on the cause of the adverse events include proinflammatory "primed patients," a Th1-inducing adjuvant, and Abeta autoreactive T cells. New immunotherapy approaches are being developed to eliminate these putative risk factors. Mannan, which is recognized by pattern recognition receptors of the innate immune system, can be utilized as a molecular adjuvant to promote a Th2-mediated immune response to conjugated B cell epitopes. The N-terminus of Abeta was conjugated to mannan, and used to immunize mice with low concentrations of immunoconjugate, without a conventional adjuvant. Mannan induced a significant and highly polarized toward Th2 phenotype anti-Abeta antibody response not only in BALB/c, but also in B6SJL F1 mice. New preclinical trials in AD mouse models may help to develop novel immunogen-adjuvant configurations with the potential to avoid the adverse immune response that occurred in the first clinical trial.
Ghochikyan
Anahit
A
The Institute for Molecular Medicine, Department of Immunology, Huntington Beach, California, USA.
Petrushina
Irina
I
Lees
Andrew
A
Vasilevko
Vitaly
V
Movsesyan
Nina
N
Karapetyan
Adrine
A
Agadjanyan
Michael G
MG
Cribbs
David H
DH
D000544:Alzheimer Disease / Q000276:immunology / Q000628:therapy*; D016229:Amyloid beta-Peptides / Q000737:chemistry* / Q000494:pharmacology; D000818:Animals; D049109:Cell Proliferation; D004195:Disease Models, Animal; D018985:Epitopes, B-Lymphocyte / Q000737:chemistry; D007167:Immunotherapy / Q000379:methods*; D051379:Mice; D008807:Mice, Inbred BALB C; D008810:Mice, Inbred C57BL; D008822:Mice, Transgenic; D010455:Peptides / Q000737:chemistry; D017434:Protein Structure, Tertiary; D012307:Risk Factors
C437846:AN-1792; D016229:Amyloid beta-Peptides; D018985:Epitopes, B-Lymphocyte; D010455:Peptides