Aβ Immunotherapy: Intracerebral Sequestration of Aβ by an Anti-Aβ Monoclonal Antibody 266 with High Affinity to Soluble Aβ

Abstract

Amyloid ␤ (A␤) immunotherapy is emerging as a promising disease-modifying therapy for Alzheimer's disease, although the precise mechanisms whereby anti-A␤ antibodies act against amyloid deposition and cognitive deficits remain elusive. To test the "peripheral sink" theory, whichpostulatesthattheeffectsofanti-A␤antibodiesinthesystemiccirculationaretopromotetheA␤effluxfrombraintoblood,westudiedthe clearance of 125 I-A␤ 1-40 microinjected into mouse brains after intraperitoneal administration of an anti-A␤ monoclonal antibody 266. 125I-A␤ 1-40 was rapidly eliminated from brains with a half-life of ϳ30 min in control mice, whereas 266 significantly retarded the elimination of A␤, presumably due to formation of A␤-antibody complex in brains. Administration of 266 to APP transgenic mice increased the levels of monomer A␤ species in an antibody-bound form, without affecting that of total A␤. We propose a novel mechanism of A␤ immunotherapy by the class of anti-A␤ antibodies that preferentially bind soluble A␤, i.e., intracerebral, rather than peripheral, sequestration of soluble, monomer form of A␤, thereby preventing the accumulation of multimeric toxic A␤ species in brains.

Low-density lipoprotein receptor overexpression enhances the rate of brain-to-blood Aβ clearance in a mouse model of β-amyloidosis

“…Though it is possible that over longer periods of time (days to weeks), certain anti-Aβ antibodies may alter Aβ metabolism in the brain, this possibility was not assessed in these experiments. A recent study suggested that the anti-Aβ antibody, m266, alters Aβ metabolism in the CNS by entering the brain and sequestering soluble Aβ (49). The small fraction of antibody that entered the brain in our study did not alter Aβ levels in the ISF over a very short timeframe, perhaps a reflection of its lower affinity for Aβ compared with the m266 antibody.…”

Developing Therapeutic Antibodies for Neurodegenerative Disease

“…This hypothesis stipulates that anti-Aβ antibodies cross the BBB and directly block the toxic effects of Aβ while mediating its clearance by promoting microglial engulfment or clearance as a complex via CSF/interstitial fluid (ISF) bulk flow. The latter may explain the peripheral rise in Aβ observed after dosing [28,63]. Consistent with this hypothesis, antibodies that fully engage microglia while binding plaque may cause reduction of amyloid plaque, but also disrupt the BBB causing vasogenic edema [62], a phenomenon renamed amyloid-related imaging abnormalities-edema [64].…”

“…Although there is evidence that peripherally originating or administered antibodies can act centrally [25][26][27][28], the mechanism(s) for such uptake is not entirely clear. Nevertheless, current evidence supports a steady-state equilibrium being established through a passive fluid phase mechanism relying on nonspecific uptake by endocytic vesicles in brain vasculature (Fig.…”

“…Rather, the reduction in brain is related to the amount of anti-BACE1 that crosses the BBB [29]. Finally, preclinical experiments have been conducted to directly test the idea that peripherally administered anti-Aβ antibodies pull Aβ from brain [28]. Results from these studies suggested the opposite: anti-Aβ/Aβ complexes actually are cleared more slowly from the brain and provide additional proof that anti-Aβ antibodies may be exerting their effects centrally in the CNS.…”

Molecular Mechanism Underlying Aβ Immunotherapy: Implications for the Toxic Action of Aβ Oligomers

“…Yamada et al [29] reported that monoclonal m266 with a high affinity for soluble Aβ may sequester soluble monomeric Aβ in the brain thereby preventing the formation of multimeric Aβ and related neurotoxicity. This concept was firstly reported by Solomon et al [22,23] who showed that a monoclonal anti-Aβ antibody prevent samyloid fibril formation.…”