Name:	MABT5102A
Therapeutic Applications:	Mild to moderate Alzheimer disease
Therapy Types:	Protein: humanized monoclonal antibody against Aβ.
Mechanisms:	Designed to bind and remove the Aβ peptide that accumulates in the brain.
Development Status:	investigational in U.S.
FDA Phase:	Phase I
Primary Medical Role:	Immunotherapy approaches to the treatment of Alzheimer disease are based on the ability of antibodies raised against Aβ peptides to bind to and clear Aβ from the brain, thus removing the peptide and inhibiting the damage to neurons that Aβ inflicts. Active immunotherapy involves inoculating patients with peptides and inducing an individual immune response to Aβ within the patient. The failed clinical trial of AN1792 was an example of this approach. This trial was suspended due to serious adverse effects in which a subset of patients developed encephalitis, or brain inflammation, an autoimmune disease effect of the inoculation. MABT5102A, in contrast, is a passive immunotherapy approach, in which patients are treated with humanized monoclonal antibodies with specificity to Aβ peptides. The treatment with antibodies should bind and clear Aβ, with the potential additional benefit of a better safety and tolerability profile.
Role in Alzheimer's Disease:	MABT5102A is a humanized monoclonal antibody, which binds to Aβ. Aβ is the main constituent of amyloid plaque in the brains of patients with Alzheimer disease and is proposed to be causative in the development of the disease.
Pharmacological Role:	Anti-Aβ antibodies have been shown to prevent the accumulation of Aβ peptides in the brains of transgenic mouse models of AD (Shenk et al., 1999; Bard et al., 2000; DeMattos et al., 2001). Anti-Aβ immunotherapy has been further shown to reverse cognitive decline in transgenic mice (Morgan et al., 2000). In one clinical trial, patients immunized with Aβ peptide who actively generated anti-Aβ antibodies showed a significantly slower rate of decline in cognitive functions (Hock et al., 2003). However, a recent study which followed AN1792 immunized subjects for six years following the Elan clinical trial showed no evidence of improved survival or of an improvement in the time to severe dementia in the AN1792 group versus the placebo group (Holmes et al., 2008).
Contraindications:	Exclusion Criteria: Female patients with reproductive potential History or presence of any clinically significant CNS disease History of treatment with any protein therapeutic targeting Aβ
Dosage:	Single-dose, dose-escalation stage followed by a multidose, parallel-treatment stage.
Companies:	Genentech, Inc.
Notes:	Genentech, Inc., with partner AC Immune SA, has initiated a Phase 1 study of the Safety, Pharmacokinetics, Pharmacodynamics, and Immunogenicity of Anti-Aβ (MABT5102A) in Patients With Mild to Moderate Alzheimer's Disease. This clinical trial NCT00736775, posted on ClinicalTrials.gov, is currently recruiting participants. This record was entered March 19, 2009.

References

Holmes C, Boche D, Wilkinson D, Yadegarfar G, Hopkins V, Bayer A, Jones RW, Bullock R, Love S, Neal JW, Zotova E, Nicoll JA. Long-term effects of Abeta42 immunisation in Alzheimer's disease: follow-up of a randomised, placebo-controlled phase I trial. Lancet. 2008 Jul 19;372(9634):216-23. Abstract and Comments

Gilman S, Koller M, Black RS, Jenkins L, Griffith SG, Fox NC, Eisner L, Kirby L, Rovira MB, Forette F, Orgogozo JM; AN1792(QS-21)-201 Study Team. Clinical effects of Abeta immunization (AN1792) in patients with AD in an interrupted trial. Neurology. 2005 May 10;64(9):1553-62. Abstract

Hock C, Konietzko U, Streffer JR, Tracy J, Signorell A, Muller-Tillmanns B, Lemke U, Henke K, Moritz E, Garcia E, Wollmer MA, Umbricht D, de Quervain DJ, Hofmann M, Maddalena A, Papassotiropoulos A, Nitsch RM. Antibodies against beta-amyloid slow cognitive decline in Alzheimer's disease. Neuron. 2003 May 22;38(4):547-54 Abstract