Yu YJ, Zhang Y, Kenrick M, Hoyte K, Luk W, Lu Y, Atwal J, Elliott JM, Prabhu S, Watts RJ, Dennis MS. Boosting brain uptake of a therapeutic antibody by reducing its affinity for a transcytosis target. Sci Transl Med. 2011 May 25;3(84):84ra44. PubMed.

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  1. Reading the two excellent papers from Genentech, I was quite impressed by their elegant approach to raise anti-BACE1 antibodies that reduce Aβ production in vivo in brain. They further engineered the anti-BACE1 antibody by coupling it with a low-affinity anti-transferrin receptor antibody into a bispecific antibody that efficiently passes the blood-brain barrier. The results are striking, achieving about five to 30 times more penetrance of the antibodies into the brain and about 50 percent Aβ reduction in mouse brains.

    I speculate that the Genentech researchers would already have set out to design humanized TfR/BACE1 antibodies for human clinical trials in the near future. A few additional preclinical results are of interest—for example, chronic effect of anti-TfR/BACE1 on Aβ burden, behavioral effects through reduction in Aβ oligomers or increases in sAPPα levels, and any side effects by saturating TfR-mediated BBB transcytosis, although these are minor issues.

    This approach would readily be applicable to other therapeutic antibodies against AD, especially on passive Aβ immunotherapy. Our colleagues at Tokyo University (Drs. Tomita, Hayashi, and Takatori) have raised a neutralizing antibody against the extracellular domain of nicastrin, a putative substrate receptor of the γ-secretase, initially aiming at reducing Aβ in the brain. The obstacle was the antibody's low penetration into the brain parenchyma, so they first tackled Notch-dependent tumors with the reagents (SfN meeting, 2010). We would love to adopt such an elegant technology in our antibodies.

    With such a powerful therapeutic in our hands, the ultimate questions are when to start Aβ lowering therapy (AD dementia, MCI due to AD, or at the preclinical AD stage?), how long to treat, and what would be the best endpoint(s).

    View all comments by Takeshi Iwatsubo

  2. Here is my quick reaction to these intriguing papers, without the benefit of having had time to fully consider their impact.

    BACE1 is an intracellular target. This raises a level of challenge for antibody action beyond the blood-brain barrier, though it is not impossible to overcome.

    Blocking BACE1 will reduce new amyloid deposition, but accumulating data in the field are increasingly convincing that simply blocking production does not reduce pre-existing deposits, which in humans begin to form many years before symptoms. An argument might be made that BACE1 inhibition may nonetheless reduce oligomers. But this assumes the plaques are not breathing oligomers on their periphery, and that oligomers are the toxic agent in AD, which is still a big assumption.

    The idea of bispecific antibodies is an intriguing one. If this inhibits BACE activity, it might also inhibit transferrin receptor activity. The consequences of that remain to be seen.

    Clearly, inhibiting BACE is a meaningful target for AD. I suspect that an antibody may be as good or better at hitting the target with fewer side effects than a small-molecule drug. Still, a small molecule wins on the basis of cost. This is a creative approach that deserves further evaluation.

    View all comments by Dave Morgan

  3. This pair of papers describes the efficacy of an antibody approach to inhibiting BACE1 activity, as well as an ingenious method for getting higher concentrations of therapeutic antibody into the brain. Passive immunization with a highly specific antibody to BACE1 resulted in a substantial decrease in plasma Aβ40 levels and a lesser decrease in brain Aβ40 levels. By increasing central exposure using a bispecific antibody with a low affinity for the transferrin receptor and a high affinity for BACE1, the investigators were able to demonstrate improved central exposure and greater reductions in brain Aβ levels. The work provides important insights into the biology of BACE1, including the finding that plasma and brain Aβ40 levels were independently modulated by BACE1 inhibition, and significant reductions in plasma Aβ40 had no effect on brain Aβ40 levels. The efficacy of anti-BACE1 treatment was reduced in mouse models carrying the APPswe mutation, supporting the previously proposed hypothesis that this mutation alters the substrate-enzyme interaction. Finally, the work suggests that the BACE1 antibody is internalized into a cell and is capable of altering the activity of the enzyme in a subcellular compartment. This finding suggests that other antibody approaches to intracellular targets may be equally effective.

    However, this approach may have some downsides as a treatment for Alzheimer’s disease. The clearance of the mono-specific BACE1 antibody was dependent on the level of BACE1 expression; BACE1 expression has been reported to increase in Alzheimer’s disease, making it more challenging to predict the therapeutic level that would be needed in a patient to achieve efficacy. Even with the improved central exposure achieved with the bispecific antibody, the modest, but effective, brain antibody concentrations required a high plasma antibody level, which may be difficult to safely maintain. In non-human primates, the changes in CSF Aβ levels were also variable, which could be reflecting an inability to precisely control the degree of Aβ reduction that results from treatment. Theoretically, this approach will reduce both Aβ40 and Aβ42, as well as other Aβ species, although only Aβ40 was measured in this study. If the ratio of Aβ42/Aβ40 is an important aspect of the pathophysiology of AD, any approach that simultaneously lowers both peptides may not be as effective as a targeted approach to lower Aβ42 levels.

    Overall, the combined studies are a significant leap forward in understanding how passive immunization approaches could be harnessed to treat central nervous system disorders, and how efficacious concentrations of antibody can be achieved in brain. It will be exciting to watch the further evolution of this approach toward safe and effective treatments for CNS diseases.

    View all comments by Barbara Tate

  4. Delivery of antibodies into the brain using bispecific antibodies is a very interesting strategy. I would be interested to hear more from the authors about the so-called full-length IgGs generated by cloning VL and VH regions into LPG3 and LPG4 vectors. Have they truly generated full-length IgGs using this technique, or it is only F(ab)2 fragments?

    View all comments by Michael G. Agadjanyan

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