But although he’s been way off base about a lot of things, he may not be that way about everything. I notice (h/t Biotechniques) that he gave a lecture recently at San Jose State, and instead of hearing about the discovery of PCR, the students got an update on Mullis’s company Altermune, whose website website is intertwined with Mullis’s own. The site is worth a look. Mullis has a vigorous writing style, and the rest of the front page is his pitch for his company’s approach to immunotherapy for infectious disease:

We have been slowly developing chemistry- the art of dealing, using instruments we devise, with things that are much too small for us to see. They have plus and minus charges on them that we can’t feel; they have oily places on them much too tiny for us to notice oil and they have water-loving patches too small for us to see oil droplets beading up on the water. Microbes need all of these things, specific types of them, in fact, to survive, and none of them are beyond the scope of our instruments and our synthetic tools. That’s our advantage. Just in this last century we have come to know these things the way we used to know javelins and swords.

How can we help our immune system? Altermune has a shot at it.

Give its antibodies – its workhorse molecules – bionic arms. That’s right, little chemical extensions that allow an old antibody to do new tricks. Altermune, LLC, in collaboration with Biosearch in Novato, CA, this summer, fitted up some antibodies whose job used to be binding to something called galactose-alpha-1,3-galactosyl-beta-1,4-N-acetyl glucosamine, with new bionic arms, synthesized on an Applied Biosystems ABI 3900, arms that can tightly sieze an influenza virion, shake it a little bit for emphasis, and turn it over to a hungry human macrophage for further processing. The change was accomplished with a swallowed drug. No need to send the antibodies back to the factory. Viruses never saw the ABI 3900 coming.

It looks like he’s using DNA aptamers as recognition elements for specific pathogens, which are used to bring on a response from the ubiquitous antibodies that target 1,3-Gal-Gal antigens. Here’s the patent on the technique. And I have to say, that’s not necessarily a crazy idea at all. That epitope has been suggested before as a way to boost immune response, and marrying that to an aptamer could work. (Other aptamer conjugates are under investigation). Of course, the problem (as with all nucleic-acid based things) is, how do you dose it (and how long does it hang around once you do?)

Mullis seems to be talking about oral delivery, which is a real challenge. But that makes me wonder about a report from a company called RXi, which claims to be having some success in delivering their RNAi therapy to macrophages through the gut. They’re packaging things in beta-glucan particles and taking advantage of a transport system (and of the fact that there are macrophages in the gut wall waiting for whatever comes out of the food supply). Perhaps something like this would do the trick for a immunological approach like Altermune’s?

The immune system scares me, to be honest. I think that evolutionarily we’ve always walked a narrow path between “strong enough to fight off threats” and “touchy enough to get you killed”. Versions of the machinery that threw their hosts into anaphylactic shock too easily have been weeded out by strong selection pressure – you probably wouldn’t live long enough to pass that blueprint on. But it’s still a tricky thing to mess with (ask TeGenaro). Using existing antibodies might be the most sensible way to do it. . .

Read the original article at In the Pipeline – Altermune – Real Stuff or Not?

This unnerving thought comes courtesy of two recent studies on VEGF pathway inhibitors which present what calls “intriguing, almost perplexing evidence” of just that. One team studied the effects of an anti-VEGF-receptor antibody or the VEGF kinase inhibitor Sutent (sunitinib) in mouse models of pancreatic cancer or glioblastoma multiformis. These are two very nasty tumors, and they’re just the sort of thing that people would like to be able to treat when a new drug comes along. But treatment with either the antibody or the small molecule significantly increased the number of metastatic cancers in the animal models, and I mean significantly: like 6% highly invasive tumors in the controls versus over 50% in the treated group. Admittedly, those numbers were in immune-compromised animals, but in mice with normal immune function, the numbers of metastatic tumors still rose by two- to four-fold.

The other study looked at injections of either metastatic breast cancer cell lines or melanoma lines in mouse models. The authors reproduced the effects of Sutent on the former – it inhibits growth of locally placed tumors, as it should (on past evidence). But if you inject cells into the bloodstream, the story is different. Pre- or post-injection treatment of the mice with Sutent led to an increase in metastatic tumors and a decrease in survival relative to untreated mice. Similar results were obtained with Nexavar (sorafenib), which also hits the VEGF kinase, among others.

That “among others might be significant. The antibody study does make you think that this is a VEGF-driven effect, but it’s important to remember that both Sutent and Nexavar hit a famously wide variety of kinases. And as a Nature item on these results points out:

It is important to emphasize that both studies clearly recapitulate the clinical data that anti-angiogenic therapies can have significant, albeit transitory, effects on localized tumour growth. However, they raise interesting questions about the timing of anti-angiogenic therapy and whether combining these agents with chemotherapy or other targeted agents can counteract the observed unfavourable effects.

Oh, yes. Among these questions are whether the other VEGF-targeting drugs (like Genentech’s Avastin) have this effect. You’d have to presume that they would. And what about other therapies directed at other anti-angiogenic targets?. They might, if the effect is brought on simply by low oxygen levels in tumor cells, or it might be something specific to VEGF. We also don’t know, in general, which sorts of tumors respond in this way and which don’t. But these findings should have effects on clinical practice, and soon. They didn’t quite come out of the blue – it’s been known since the anti-angiogenic drugs were developed that they didn’t actually seem to cure cancers so much as knock them down for varying lengths of time. And in many cases, patients only survive a few months longer after treatment.

Every time I write something like that, though, I’m tempted to quote Peter Altenberg and say “What’s so only”? But there still seems to be so much more potential in the idea – the same potential that led to a lot of hype and craziness a few years ago – and perhaps we’re beginning to see where things went wrong. Can they be put right, or not?

And you know, perhaps it’s for the best that Judah Folkman himself isn’t still around to see these latest results. I don’t think he would have despaired, but it wouldn’t have been easy news for him to hear. . .

Read the original article at In the Pipeline – Angiogenesis Inhibitors: Helping or Hurting?