As everyone in the field knows, there's a lot of work that has been poured into anti-beta-amyloid antibodies as a potential therapy for Alzheimer's. There are plenty of questions, starting with the amyloid hypothesis itself, but even if you stipulate that, the question that this paper asks is key: do these antibodies engage their target?
And the answer, according to this large team from Melbourne, is, well. . .
. . .All of the antibodies were able to bind Aβ in mouse tissue. How- ever, significant differences were observed in human brain tissue. While bapineuzumab was able to capture a variety of N-terminally truncated Aβ species, the Aβ detected using solanezumab was barely above detection limits while crenezumab did not detect any Aβ. None of the antibodies were able to detect any Aβ species in human blood. Immunoprecipitation experiments using plasma from AD subjects showed that both solanezumab and crenezumab have extensive cross-reactivity with non-Aβ related proteins.
Now that's interesting, isn't it? The paper uses SPR as one analytical technique, which showed that bapineuzumab and crenezumab bound to synthetic chip-immobilized Aβ at nanomolar levels, while solanezumab was probably picomolar. And mass spec showed that the antibodies recogized Aβ from transgenic mouse tissue. But human tissue, that was something else altogether. Bapineuzumab was able to pull out amyloid proteins in some experiments, but the other two were nearly inactive.
It appears that solanezumab and crenezumab are actually quite similar, and are both ineffective. The transgenic mouse studies may, according to this paper, have been a tremendous red herring:
Based on mouse studies, it has been suggested that solanezumab does not work directly on brain Aβ, but instead works as a peripheral sink targeting peripheral Aβ which in turn lowers CNS Aβ by mass action. Indeed when we examined plasma from tg2576 mice, solanezumab was able to detect Aβ1–40 in plasma. However, none of the therapeutic antibodies were able to detect Aβ in either the plasma or the cellular fraction from human AD subjects. . .
The authors suggest that the fact that these antibodies do recognize pure Aβ but still perform so poorly in vivo might be due to cross-reactivity. This is the sort of thing that would surely have been checked by the companies involved, but this paper does report substantial cross-reactivity in human plasma and against some other proteins. One in particular might be worth noting:
One of the proteins pulled down by both solanezumab and crenezumab was the Il12 receptor; this is interesting as a recent publication showed that modulation of the Il12 signaling pathway resulted in cognitive improvements in a transgenic mouse model of AD. It should be noted that a driving force for the selection of solanezumab as a drug candidate for the preventative trials was the post hoc analysis that showed a small, but significant improvement in cognition in the mild AD subjects in Phase 3 trials. . .
So has all this been a waste of time? And is Lilly's continued work on solanezumab, and Genentech's on crenezumab, likely doomed? Thoughts welcomed in the comments. What I'd like to know, even before we get to those big questions, is what these sorts of experiments showed internally, and why these (rather alarming) results haven't been seen by others so far. Or have they?