Comes now some rather disturbing news in the antibody field. These things are extremely important, both as therapeutics and as research reagents, and developing them for either purpose is no stroll down the garden walk. There are a number of techniques for raising and producing antibodies (see that first link), but they all have their complications and limitations. The two biggest branches of that tree are to expose humans (or other animals, including mice that have had their immune systems humanize) to some antigen or infectious agent and isolate the relevant B cells, or to go in vitro and express as much IgG diversity as you can via something like phage or yeast display. That’s a grievous oversimplification on my part, as a brief look at just monoclonal antibody production will show you, but that’s a start.
As the paper under discussion today mentions, though, there’s another very different possibility: computing your way to the antibody you need. That is, to put it lightly, nontrivial – we know more than we ever have about antibody structure and function, but knowing enough to design them from scratch is something else. Still, there have been reports. Two in particular stand out, from Ram Sasisekharan and co-workers at MIT. The second of those papers especially talks about “rational engineering” of an anti-Zika antibody via computational epitope selection, and since rational engineering has not exactly been the key step in antibody work historically, it stands out.
Complications have now ensued. The two papers just referenced do not, interestingly enough, provide a sequence for the new antibodies they discuss. The authors of the new critical look at their work, with affiliations at Adimab, Dartmouth, and MIT, point out that this is an odd thing for any journal to permit, since the idea is that others will be able to reproduce reported work, right? At any rate, they’ve cross-referenced patent applications and GenBank sequences to the published papers from the Sasisekharan group and have arrived at what they believe is the sequence of the computationally derived antibodies. And you know what? They’re extremely damned similar to antibodies that had been reported before, in each case:
We present with a high degree of confidence the actual sequence identity of the designed antibodies, and a more plausible genesis narrative. Comparisons of these sequences to those of previously described human B cell-derived antibodies to the same targets show striking similarities. By contrast, those designed sequences appear very dissimilar from the templates said to have been used to start the design process (Figure 2 and S4); we leave it to the reader to judge the likelihood of these highly homologous sequences being re-discovered coincidentally, or simply derived from existing antibodies targeting the same epitopes as those of the computationally designed antibodies.
For example, the supposedly engineered anti-Zika antibody contains an oddly unnatural bit that turns out to have also been in the previously reported antibody. It was, in that older case, an artifact of the expression vector and is not related to epitope recognition at all. What, the new paper asks, are the odds that you would compute your way to that? (While not deliberately introduced as such, this reminds one of the use of trap streets in the mapmaking business). The paper finishes up with what are without doubt fighting words: “We find it difficult to view these authors’ approach in any light other than an intent to mislead as to the level of originality and significance of the published work.”
The lead author of the new paper, Tillman Gerngross, is not mincing words when asked for comment, either. Here he is talking to Stat:
“We looked at exactly two cases, and in both did we find irregularities. To me, if you’re sitting in the kitchen and two fat cockroaches walk across the floor, what’s the chance that there’s only two?”
Yeah, this is glove-across-the-face material, and no mistake. And there are business implications as well. Visterra is a company focused on antibody engineering, and it was founded out of the Sasisekheran lab. Otsuka acquired them recently for $430 million, and this new report can’t make anyone there very happy. There will be more on this story – pretty sure of that – and it doesn’t look like one of those disputes that will be resolved quietly. Not when it starts off like this.