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DBL%20Hendrix%20small.png College chemistry, 1983

Derek Lowe The 2002 Model

Dbl%20new%20portrait%20B%26W.png After 10 years of blogging. . .

Derek Lowe, an Arkansan by birth, got his BA from Hendrix College and his PhD in organic chemistry from Duke before spending time in Germany on a Humboldt Fellowship on his post-doc. He's worked for several major pharmaceutical companies since 1989 on drug discovery projects against schizophrenia, Alzheimer's, diabetes, osteoporosis and other diseases. To contact Derek email him directly: Twitter: Dereklowe

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« Update on TGN1412 | Main | Grad School, Blogged »

March 20, 2006

TNG1412: Was There a Warning?

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Posted by Derek

When everyone first heard about the TeGenaro/TGN1412 Phase I disaster, the immediate question was whether it could have been prevented. As mentioned before, the main problem I had was that the volunteers seem to have been dosed fairly quickly, rather than waiting longer to see how the first patient did. That alone would have contained the tragedy to one person. But even then, we'd all be asking how that one case could have been avoided. I'm not well-versed enough in immunology to say for certain, but according to the Times of London, there's some earlier work that might have given everyone pause if it had been sufficiently appreciated.

They quote Angus Dalgleish, a British professor of immunology, as saying that he was amazed that the TGN1412 trial had been allowed, considering that at the ASCO meeting last year, a team from the National Cancer Institute presented the results of a study of an anti-CLTA4 antibody in cancer patients. They didn't see the catastrophic results of TGN1412, but the trial was rough enough. Nearly half of the patients in the high-dose group saw a harmful immune response - most of them recovered, but one needed surgery. That target is another receptor on the surface of T-cells, and it's involved in the same general activation/deactivation pathway that CD28 (TGN1412's target) is. CLTA4 activation blocks the activating effect of the CD28 pathway - in fact, it's only induced after the CD-28 receptor has been stimulated, and it seems to come on in order to damp it down. Immunology's full of these reverse-reverse things.

So one net result of either approach is to enhance CD28 signaling - TeGenaro's antibody strongly activates CD28 directly, and Medarex's inhibits its inhibitory pathway. Still, the two therapies were aiming at opposite endpoints: TeGenaro was mainly hoping to enhance the activity of regulatory T-cells (which would then decrease autoimmune activity) while the NCI group was hoping to generate a stronger overall immune response against renal tumors. Of course, it looks like the "stronger overall immune response" part of this pathway wins out.

Here's the abstract from the meeting, which tells us that the anti-CLTA4 antibody they're talking about is MDX-010, from Medarex. They've been working on it for years, and have (for example) reported similar results in 2004 in a study against metastatic melanoma. Their first attempts in this area were reported in 2003 in PNAS.

And it's still being studied - in fact, it's one of the more advanced things in Medarex's pipeline. Here's a trial that's in recruitment right now for late-stage melanoma, in combination with a potential melanoma vaccine, MDX-1379, and here's one for prostate cancer, in combination with androgen therapy. They wouldn't have made it to Phase III with this if they'd constantly seen the kinds of effects reported by the NCI group.

So the Times article is semi-right, although it gives the impression that there's this one study from last year that should have definitely raised the warning. But anti-CLTA4 therapy has been around for several years now, and it's well-represented in the literature. And it's still in advanced clinical trials, to boot. This is the sort of thing that both TeGenaro and the review board that approved its study would have been well aware of, and would have taken into account. It now appears that blocking CLTA4 is something that has to be approached with caution, while activating CD28 directly is disastrous, but I'm not sure that was obvious before this trial.

Comments (7) + TrackBacks (0) | Category: Clinical Trials


1. Anonymous on March 20, 2006 11:18 AM writes...

Orencia (abatacept) is a CTLA4-Ig fusion protein recently approved by the FDA for rhuematoid arthritis.

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2. Jim Hu on March 20, 2006 1:54 PM writes...

I think this paper may describe the same study.

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3. Anonymous on March 20, 2006 3:43 PM writes...

Abatacept (FDA approved for rheumatoid arthritis in Dec 2005) works the opposite of TGN1412 (a CD28 super-agonist) in that instead of activating CD28 (TGN1412), it prevents binding of CD28 to CD80/86 thus effectively acting as an antagonist to CD28. Please do not confuse abatacept has potentially having the same potential response since the end effect on CD28 is the opposite.

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4. Anonymous on March 21, 2006 12:06 AM writes...

2 points:

1) Agonizing CD28 pathway outside the immune synapse is a crazy thing, and almost guaranteed to break self tolerance, I think

2) For some antibodies, lower doses can be more dangerous than high doses, because they can often have a u shaped curve. This is sometimes due to critical plasma levels thhe that can cross link the target.

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5. Mark Senak on March 21, 2006 11:02 AM writes...

My fear is that the question of prevention will reverberate here, not in the substantive sense, but in the sense that it will offer a political club for those who would grandstand over those who would offer constructive pathways to improvement.

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6. Scott on March 22, 2006 11:10 AM writes...

The co-stimulation needed to activate T cells is there for a reason. Obviously, as we now know, if any mutation resulted in the same 'super activation' of T lymphocytes, the poor offspring wouldn't live too long.

Nature has had billions of years to perfect this balance, and in our hubris we think we can improve on evolution.

As the man said, it doesn't take a rocket scientist (or an immunologist) to see there may be problems with this scheme.

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7. Anonymous on April 1, 2006 12:07 AM writes...

There's plenty of data out there suggesting that aCD28 alone in the absence of TCR stimulation does not activate T cells. So what happened during this trial is somewhat peculiar. Did the mAb activate T cells that were specific for self-Ags that were otherwise tolerized in the absence of the CD28 signal? Or T cell responses to commensal bacteria, etc?

One thing is though, CD28 stimulation is not analogous to CTLA-4 blockade, since the two costimulatory molecules act at different phases of the T cell response (priming vs. effector).

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