11 John O Shea

11 John O Shea


I think we have been fortunate to make some
important discoveries, but obviously you don’t do that in a
vacuum. You do that because there are great people giving you resources to do exciting
things, and equally, I have been blessed by having terrific
people in the lab over the years and the NIH is an amazing
place where people really do come from around the world and then they give their heart and
soul to tough problems.
The other thing I would say is that as much as we’re celebrating NIAMS’ birthday, the
NIH, in general, is a really an amazing place to work.
It’s highly collaborative. So I have been really fortunate over the years
to work with people like Warren Leonard and Bill Paul,
and, more recently, people like Yasmine Belkaid and NIAID; just because they’re NIAID doesn’t
mean we can’t talk to them.
It’s been an amazing opportunity. I have used up almost my first 30 seconds
here so I’ll move on quickly. I’m going to talk a bit about the discovery
of a patient, from Fabio Candotti, who’s now in the Genome
Institute, and how that led us to go back to the lab to understand this gene and back
to the bedside again, so it’s a bedside to bench to bedside
story. In way of disclosure, from the beginning,
this work has also been supported, in part, through a long-
standing collaboration with Pfizer. We here at the NIH have a patent related to this,
so I need to disclose this, and I can tell you I have literally
made hundreds of dollars over this patent over the years, so you
can worry about my ability to be objective. This was the cell phone Steve used to call
me with when NIAMS first started 25 years ago.
But the point is the communication is obviously critical for all aspects of life.
In the immune system, communication is absolutely vital.
That’s what this talk will be about. So, you have all these specialized cells in
the immune system that are critical for host defense, but it is
really critical they talk to each other and tell each other what to do and tailor responses
in — with different types of infection, different types
of micro organisms. But, there is a down side in the way cells
communicate is through cytokines shown here, so that’s what
the arrows represent. Cytokines produce proteins that bind to receptors
that I’ll tell you more about and tell the cells what to
do. There is a down side and that is that cytokines
are critical drivers of autoimmune diseases, the focus of
NIAMS research. We know a lot about cytokines in their role
in autoimmune disease based on animal models or
measurements in patients, but also now with the advances in genomics, we know that these
really have risk alleles for these diseases, but equally
we know from experiments where we have generated novel
drugs targeting cytokines that there are effective treatments for a number of autoimmune diseases,
so these are different types of cytokine receptors
that you have and you can see drugs that have already
been FDA approved. Dan mentioned anakinra, but you know TNF inhibitors, et cetera.
The question we were interested in addressing some time ago was, Can you target intracellular
signaling? So let me tell you how we got involved in that.
So again, these are the major families of cytokine receptors, you have about 200 or
so cytokines, but a large proportion of cytokines bind to these
receptors, the so-called type 1 and 2 cytokines receptor, not
a great name, but it is what it is. But about 60 of our cytokines use this class
of receptors, so everyone knew these were important, but
what was not known is how this class of receptors basically told cells what to do.
It was the intracellular signaling pathway that led from signals outside the cell to
telling the nucleus to change the behavior of this cell that led
us on to the quest to find these molecules. We found one called
Jak 3, shown here. Jak 3 is in a family of a small family of
kinases, Jak1, Jak2, Jak3 and just to make it impossible for non
immunologists to remember this, Tyk2; again, it’s historical, and that’s how these things
get named. But again, time is short and I want to stay on
time. In thinking about Francis’ comments and
Dan’s comments, back when we were doing this, it was actually
really hard to clone a gene. Seems ludicrous, now you sit at home drinking
a cup of coffee, going on the Internet and you could find
out all this stuff, but it took us months and months and months, and the way you do
sequencing at the time they had these big sequencing gels, I
literally read every base pair of Jak3, A, G, base pair by base
pair. Dan, you probably did some of this, as well.
You say is that 1 C or 2 Cs? It was really — you know you’re lucky to
get 200 base pairs at a time. We were fortunate being at the NIH, we had
a super computer. The super computer could give you the blast
search, again, what you could do sitting at home, in a few
seconds, that would take us, astonishingly, it would take us 24 hours.
So, as you were saying in the beginning, it’s just amazing what you can do now with the
human genome. I go on and on and I’m watching the time here.
The key question is having discovered Jak 3 and we thought it was important because
we thought the class of receptors was important, the key
question, the key answer, really, came from a patient shown
here on the next slide. So this is a patient that Fabio Candotti,
who was in my lab at the time, but had done work with Gigi
Notarangelo in Brescha, Italy. This child here, I won’t go into details of clinical
presentation, but she presented with pneumocystis pneumonia and
she had a primary immunodeficiency. And what Gigi and Fabio and we found out,
and later work with Warren Leonard and Rebecca Buckley,
found these patients had Jak 3 mutations. So they present with a disease similar to
what the bubble boy presented with, they have defects in T-
cells, B cells and NK cells, but she’s obviously a little girl. Warren Leonard had discovered
that the bubble boy syndrome is due to mutations in common
gamma chain and with Warren Leonard, we had shown
that’s the way Jak 3 works. Back in this previous slide, the Jak 3 associates with the common
gamma chain.
So that led us to sequence this gene in these patients and we found that they had Jak 3
mutation, patients like this.
We know in these patients you can cure these patients with stem cell transplants and you
really even knew this before we knew the basis of the
disease. That’s the good news for these patients.
It also had an important scientific lesson which pointed to the fact this gene was critical
for the immune system, not critical for other systems, brain,
liver, et cetera, et cetera. That led us to argue that maybe making inhibitors
of Jak3 represent a new class of immunosuppressive drugs, that’s the NIH patent I referred to.
So, again, this summarizes a little bit what I told you. So in these girls, we found mutations
of Jak3. With Warren Leonard, we had shown that Jak3
associates with the common gamma chain, which he had
found was associated with the bubble boy syndrome, X-SCID.
So, in principle, we thought it an ideal target for making an immunosuppressive drug because
we knew from this little girl that you — if you inhibited
this molecule, you wouldn’t have renal metabolic problems, problems you have with other drugs
that are used for immunosuppression. So I went to this meeting in 1993, and I ran
into a colleague who I actually, we were sort of friendly
competitors if you will, when we were working on another project.
But he, Paul Changelian, had moved the Pfizer and I said, “Paul, what are you doing here
at this lymphocyte antibody meeting?” And he said,
“Well, I’m working at Pfizer now. I’m looking for targets of
kinases that we can start working on as new immunosuppressive drugs.”
I said, “Paul, have I got the kinase for you! I have this amazing kinase.”
Terribly important for the reasons I just told you.
So Paul actually bought it and now, 18 years later, in fact, there are not just one Jak
inhibitor that’s out there, there’s multiple.
So I’ll review that for a second. The Pfizer drug is called Tofacitinib, it’s
also referred to as CP 690, 550. The phase 3 studies were reported in the meetings
in London a couple of weeks ago or so. What we know from this is that these drugs
now have efficacy that really is comparable to the biologics.
So the biologics, of course, were revolutionary in the treatment of rheumatoid arthritis,
but these drugs really have a comparable effectiveness and,
more importantly, in many cases, these drugs are used in
patients whose fail biologics. As I’ll get to, the key question, the reason
you do these big studies is safety. I’ll comment on that in a
moment, but the drug is also being studied in psoriasis, phase 3 psoriasis, phase 2 inflammatory
bowel disease. I came back just yesterday from the
transplant meetings. This drug is being studied in transplantation
as well. There are a number of other Jak inhibitors
that have been designed along the way. Ruxolitinib is a Jak1, Jak2 inhibitor. The
idea of using this drug came from the finding that the disease
polycythemia vera is associated with a gain of function Jak2 mutations, so that led to
the idea of purposely targeting Jak1 and Jak2. But, in
fact, this drug is used in rheumatoid arthritis as well, recalling
that Jak 3 and Jak 1 are both important for signaling via this class of cytokines, so,
in one sense, a Jak1 inhibitor could have many of the same effects
as a Jak 3 inhibitor. Its effects in rheumatoid arthritis are
similar to an extent to Tofacitinib. Many other phase 1 and 2 trials on the way
with Jak inhibitors, a variety of diseases not just in
autoimmune diseases, but also cancer, et cetera, et cetera.
There are probably more than 50 ongoing clinical trials with various Jak inhibitors and the
drugs do seem to be efficacious.
That’s very exciting. The key question is, of course, going to be
their safety. They appear to be reasonably so.
You have increased incidence of infection in patients whose get these drugs, but, in
a sense, that’s not terribly surprising with most of the drugs
we use. You have some risk of infection, and that seems to be
the nature of what happens when you immunosuppressed patients.
You don’t have a large increase of opportunistic infections, that’s a big one; there is an
increased incidence of anemia.
And what I didn’t tell you is there are other cytokines like erythropoietin that are
important for production of blood that use Jaks, so that
explains that, but the anemia is not dramatic. The other side effect that’s seen is increased
lipids and again, that was on one level a surprise, one level
not surprise, the drug Tocilizumab, which blocks IL-6, also increases lipids, so the
thought is that this is a reflection of the drug’s ability to block
IL-6, so in one sense, this is an oral Tocilizumab, if you will, that’s
at least part of the mechanism of this drug. That’s the question we’re working on hard,
trying to understand how these drugs are working, are they
predominantly affecting cytokines in the adaptive immune system?
So again, what Dan pointed out, when we first started with this, we didn’t even — the term
innate immune system hadn’t really been coined, but
thanks to Dan’s work and Charlie Janeway and others, we
now know the key role of the innate immune system, so this is a thing we’re thinking
about most recently.
The big surprise with this, this is sort of more from scientific talks where I talk a
lot about exactly what kinases are being targeted with these classes
of drugs, but it really turns out that in the early days, we
thought that absolute specificity for kinases was going to be key.
And that really turns out not to be the case. It has important implications for thinking
about next generation of Jak inhibitors and even next
generation tyrosine kinase inhibitors, in general.
The big questions are here. Exactly how are we going to use these drugs,
what are their efficacies relative to biologics, are they
equivalent, will they supplant the use of some of the biologics in some circumstances?
Will they supplant the use of steroids in some settings, do they have some steroid sparing
effect, or other effects?
Here is my dream. I don’t know if this will actually turn out,
this is not real, just as a proviso. So my hope someday, I’ll go into – I’ll
have poison ivy, be working in my backyard, get a little poison ivy,
go to CVS and be reaching for the steroid cream, but instead of the steroid cream, I’ll
be able to use the Jak inhibitor.
Now it’s not totally fanciful; there are topical Jak inhibitors Ruxolitinib that are
being used in psoriasis. But obviously these are the outstanding questions.
But you can see where the insights from this one patient really gave us an idea of what
targeting this pathway might be.
So I will stop there and thank you very much for your attention.

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