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Msg  12653 of 128371  at  11/10/2016 12:45:21 PM  by

muddyc

The following message was updated on 11/10/2016 12:50:35 PM.

I see ...

   

I’m not going to bother going through the whole presentation (eventually I'll look at the Zika data), I caught the audio of from mid Glenn on, and it seems it largely was a verification of the suspicions that some of us had. LAR was a factor, but the PCA assay was inadequate to the task, or at least that is what it sounded like when they started talking about affinity.

Not to sound like a snob, but the industry folks often leave those more in the academic circles scratching their heads. I love that they make cures and stuff, but some of the details get obscured by stock options, that supposedly the obsessions of academics are not adequately product related.

Since the dawn of mAbs, the use of mAbs to define markers, the development of the whole “cluster of differentiation” naming system (e.g. CD4, CD8 etc), the use of mAbs to characterize cell types, to elicit responses in signal transduction, to elicit lymphokine production, to trigger the complement cascade, to enable immunoprecipitation, purification, demonstrate protein/protein interactions, for immunodetection (western blots, ELISA, FISH) and finally, to provide viral protection,…. Long long ago, way back then, it was known that just because one antibody can compete away the binding of another does not mean they will produce the same result downstream (in this case protection). Such competitive binding is a strong indication that one will get the same downstream result … but it is far from certain, PARTICULARLY as it pertains to, say, protection from viral infection. I’m going to say this was sorted out in the 1980s, but perhaps my memory is a bit off on this.

Glenn and colleagues were surprised that PCA did not 1:1 dictate protection. One thought is they could Go Back to School. I had wondered about and tried to explore on this, but the fact is I can’t look at their lab books, I only get to see what they choose to show. Had they been defending a thesis based on this surety, they’d have gotten a whoopin’, at least where I come from. Seeing that they’ve been kicking the PCA assay around for a few years, it would seem one would have had ample opportunity to do some homework on it. Oooo, yes that is what they say too, they do have ample opportunity, freezers full of archived serum, and it seems they are finally going to do what I have previously argued one would imagine they must have already done … and do some PCA verification versus protection. Crap, they have put hundreds of millions into this, and these trials go on for months and years, one would think that over the course of these years they would have some freeking analysis of these freezers full of serum, and for a couple hundred million maybe even have SPR on every bloody one of the P2 vax arm samples.

Or just be surprised, and then get excited that they have rediscovered the 1980s.

That being said, the maternal franchise appears solid, the biological basis for the differential response of Resolve versus Prepare is very easy to imagine, and perhaps a bigger stick (e.g. adjuvant) will prod along the whole somatic hypermutation/affinity maturation bag of tricks. And of course keeping in mind that in a normal AR year the data likely would have looked much better.

So going forward it seems they believe they are developing/have developed a refinement to the PCA assay that allows them to not only ask whether the serum has antibodies that obscure palivizumab binding, but whether those antibodies have binding characteristics that are predictive of immunity (and I wouldn’t be surprised if it is SPR). If they nail said assay well, it is a stronger surrogate argument, and would enable the development and presentation of more convincing data at every stage. The vision thing would be that one would see PCA+ affinity curves, MN curves, and protection curves (in cases where one has a decent sample size) and get concordant results.
 
 
 


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Replies
Msg # Subject Author Recs Date Posted
12656 Re: I see ... Booooyaaaah 1 11/10/2016 1:06:34 PM
12661 Re: I see ... luckijack 0 11/10/2016 1:31:45 PM
12663 Re: I see ... Takelma02 0 11/10/2016 1:35:24 PM
12668 Re: I see ... Wily.Coyote 0 11/10/2016 2:02:38 PM








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