Psoriasis support - CNTO 1275 today

Author

CNTO 1275 today

JXStern

2006-10-09, 4:28 pm

was: P News

This stuff sounds AMAZING! Get on with Phase III already!!!!!

OK, no word on longer term issues, this shows results at week 16, so
what is the rate of return of p symptoms after that? Does it affect
CD-cell counts like Amevive? Is there a blood test to measure
continuing effectiveness? Is there any increase in bacterial, virus,
or cancerous infections? Any allergic reactions?

But hey, this stuff sounds like a serious second-generation biologic!!

So, what does the -p40 suffix mean after IL12?

http://aiche.confex.com/aiche/2006/...gram/P45957.HTM

"The bioactive form of IL-12 is a 75 kDa heterodimer (IL12p70)
comprised of independently-regulated disulfide-linked 40 kDa (p40) and
35 kDa (p35) subunits. The p40 subunit exists extracellularly as a
monomer (IL12p40) or dimer (IL12(p40)2) and can antagonize the action
of IL12p70."

Oh.

http://www.pubmedcentral.gov/articl...gi?artid=384913
(reports of IL-12 lacking children with bacterial diseases)

Uh-oh.

The problem here being that CNTO 1275 may be too long-acting to be
terribly safe. Have to see. One of the *good* things about Enbrel is
that it clears out quickly when you stop taking it, allowing the
immune system to resume fighting infection.

Maybe they can make a CNTO 1276 that clear out quickly, too. Or, come
up with an anti-CNTO 1275 that you can take to clear it out on demand!

J.

On 9 Oct 2006 09:44:21 -0700, "randall" <ranhub11@aol.com> wrote:

>http://www.docguide.com/news/conten...52572020048EED3
>Human Anti-IL12p40 Shows Promise in Plaque Psoriasis: Presented at EADV
>By Jill Stein
>
>RHODES, GREECE -- October 9, 2006 -- Human anti-IL12p40 (CNTO 1275),
>administered subcutaneously, seems to be an effective psoriasis
>treatment, according to phase 2 results released here at the 15th
>Congress of the European Academy of Dermatology and Venereology (EADV).
>
>The investigational compound is an antagonist to the heterodimeric
>cytokines IL-12 and -23, 2 key cytokines in type 1 immune responses.
>
>Gerald. C. Krueger, MD, professor, dermatology division, university of
>Utah Health Science Center, Salt Lake City, Utah, and colleagues
>randomized 320 patients to subcutaneously injections of human
>anti-IL12p40 or placebo. The active treatment subjects received 1 of 4
>regimens: 1 injection of 50 mg or 100 mg, 4 weekly 50 mg injections, or
>100 mg injections.
>
>The primary study endpoint was the proportion of patients who achieve
>at least 75% improvement in Psoriasis Area and Severity Index (PASI)
>score from baseline at week 12.
>
>Patients assigned to the active treatment received an additional dose
>at week 16 if they did not have an excellent or complete response,
>defined as at least 75% clearing by Physician's Global Assessment
>(PGA). The placebo cohort received 100 mg of human anti-IL12p40 at week
>20.
>
>Participants in the trial had moderate-to-severe plaque psoriasis and
>were candidates for phototherapy or systemic psoriasis treatment. The
>trial excluded patients who were on systemic and topical psoriasis
>medications.
>
>At week 12, the primary endpoint was achieved in 52%, 59%, 67%, and 81%
>of patients treated with each human anti-IL12p40 regimen, respectively,
>compared with 2% of subjects in the placebo arm (P < .001 for each
>versus placebo).
>
>At least a 90% improvement in PASI scores was observed in 23%, 30%,
>44%, and 52% of patients in the respective human anti-IL12p40 groups
>compared with 2% of placebo (P < .001 for each versus placebo).
>
>Eighty-seven patients were re-treated with human anti-IL12p40 at week
>16. Although fewer than half of patients needed to be retreated, the
>overall percentages of patients with > 50%, >75%, and >90% improvement
>in PASI score or who had an excellent response remained relatively
>stable through week 24.
>
>Results also show a correlation between clinical and quality-of-life
>improvements, according to the researchers.
>
>Human anti-IL-12p40 was generally well tolerated.
>
>Many patients reported that psoriasis had no detectabe adverse effect
>on their quality of life after active treatment.
>
>Beyond demonstrating the effectiveness of human anti-IL12p40 in the
>management of psoriasis, the results support the role of the p40 family
>of cytokines in the pathogenesis of this condition, Dr. Kruger said.
>
>The study was sponsored by Centocor.
>
>
>[Presentation title: Results of a Phase II Study of CNTO 1275 in the
>Treatment of Psoriasis. Abstract P035.75]

randall

2006-10-09, 4:28 pm

On Oct 9, 11:02 am, JXStern <JXSternChange...@gte.net> wrote:
> was: P News
>
> This stuff sounds AMAZING! Get on with Phase III already!!!!!
>
> OK, no word on longer term issues, this shows results at week 16, so
> what is the rate of return of p symptoms after that? Does it affect
> CD-cell counts like Amevive? Is there a blood test to measure
> continuing effectiveness? Is there any increase in bacterial, virus,
> or cancerous infections? Any allergic reactions?
>
> But hey, this stuff sounds like a serious second-generation biologic!!
>
> So, what does the -p40 suffix mean after IL12?
>
> http://aiche.confex.com/aiche/2006/...gram/P45957.HTM
>
> "The bioactive form of IL-12 is a 75 kDa heterodimer (IL12p70)
> comprised of independently-regulated disulfide-linked 40 kDa (p40) and
> 35 kDa (p35) subunits. The p40 subunit exists extracellularly as a
> monomer (IL12p40) or dimer (IL12(p40)2) and can antagonize the action
> of IL12p70."
>
> Oh.
>
> http://www.pubmedcentral.gov/articl...gi?artid=384913
> (reports of IL-12 lacking children with bacterial diseases)
>
> Uh-oh.
>
> The problem here being that CNTO 1275 may be too long-acting to be
> terribly safe. Have to see. One of the *good* things about Enbrel is
> that it clears out quickly when you stop taking it, allowing the
> immune system to resume fighting infection.
>
> Maybe they can make a CNTO 1276 that clear out quickly, too. Or, come
> up with an anti-CNTO 1275 that you can take to clear it out on demand!
>

Good work J.

Yet. Aren't we all about low dose around here? With the exception of
those
who obviously require a sledge hammer to budge the stuff.

If I didn't respond so WELL to my monkey business, i'd be on
biologicals right now.

So, say the centocor 1275 (owned by johnson and johnson) product for P
really works with
the exception of it's strength being something one has to watch.

Then we know the subunits of IL-12 are to be dealth with. Figuring out
how
best to design our cocktail with that in mind may be key.

Lets run the group hits for cnto.

http://groups-beta.google.com/group...soriasis&q=cnto

Derk's post from 2004 is encouraging. But his email address
(nospam@nospam.com) doesn't allow me to email him for follow up.

---------------------------------------------------------------

P and IBS have some similarities with IL-12.
http://www.ncbi.nlm.nih.gov/entrez/...l=pubmed_docsum
Cytokine-based therapies in inflammatory bowel disease.

* Kam LY,
* Targan SR.

Cedars-Sinai Medical Center and the UCLA School of Medicine, Los
Angeles, California, USA.

Cytokine-based therapy for inflammatory bowel disease (IBD) has
significantly advanced in the last year. This review highlights some of
the exciting progress that has occurred. The efficacy of anti-tumor
necrosis factor (TNF) monoclonal antibody therapy in Crohn's disease
has promoted further research and the development of other anti-TNF
therapies, such as thalidomide, phosphodiesterase type IV inhibitors,
and new-generation anti-TNF monoclonal antibodies. Current research is
also focused on more proximal events in the inflammatory cascade to
modify T-cell regulation and to decrease the production and activity of
proinflammatory proteins, cytokines, and nuclear regulatory factors.
Concurrently, the emerging role of interleukin (IL)-11, IL-12, and
IL-18 in the perpetuation of chronic inflammation continues to
stimulate much interest. All of these new advancements reveal an
exciting future for IBD therapy.

PMID: 17023962

Crohn's and IL-12
http://www.medicalnewstoday.com/med...hp?newsid=25459

This link looks like the link posted the other day. But is from earlier
this year,
http://www.pslgroup.com/dg/25856e.htm

And rereading the group hits for it, I see this was the trial I could
have gotten in to
back in March-April of this year (06).

Oh well I suppose I could call the derm and see what he thinks. He's
looked at every
single person in the trial and measured their Pasi's before, during and
after. He
may have an interesting take on it.

Yet, we want a low dose deal that is miles from toxic ville.

Back to pubmed.

Ok,
http://www.ncbi.nlm.nih.gov/entrez/...0il-12+subunit*

Look at the second hit. A low dose subunit of IL-12 that is effective
for tumors.
And this hit may be relevant for ____lipid rafts___ and the cell to
cell moa of DC's and NK's.
http://www.ncbi.nlm.nih.gov/entrez/...l=pubmed_docsum

Moving on with the pubmed hits.

HA!

Back to my gut strategy to block the toxicity. LOOK at this abstract.

http://www.ncbi.nlm.nih.gov/entrez/...l=pubmed_docsum
Intranasal immunization with recombinant Lactococcus lactis secreting
murine interleukin-12 enhances antigen-specific Th1 cytokine
production.

* Bermudez-Humaran LG,
* Langella P,
* Cortes-Perez NG,
* Gruss A,
* Tamez-Guerra RS,
* Oliveira SC,
* Saucedo-Cardenas O,
* Montes de Oca-Luna R,
* Le Loir Y.

Unite de Recherches Laitieres et de Genetique Appliquee, INRA, Domaine
de Vilvert, 78352 Jouy en Josas cedex, France.

Interleukin-12 (IL-12), a heterodimeric cytokine, plays an important
role in cellular immunity to several bacterial, viral, and parasitic
infections and has adjuvant activity when it is codelivered with DNA
vaccines. IL-12 has also been used with success in cancer immunotherapy
treatments. However, systemic IL-12 therapy has been limited by
____high levels of toxicity._____ We describe here inducible expression
and secretion of IL-12 in the food-grade lactic acid bacterium
Lactococcus lactis. IL-12 was expressed as two separate polypeptides
(p35-p40) or as a single recombinant polypeptide (scIL-12). The
biological activity of IL-12 produced by the recombinant L. lactis
strain was confirmed in vitro by its ability to induce gamma interferon
(IFN-gamma) production by mouse splenocytes. Local administration of
IL-12-producing strains at the intranasal mucosal surface resulted in
IFN-gamma production in mice. The activity was greater with the single
polypeptide scIL-12. An antigen-specific cellular response (i.e.,
secretion of Th1 cytokines, IL-2, and IFN-gamma) elicited by a
recombinant L. lactis strain displaying a cell wall-anchored human
papillomavirus type 16 E7 antigen was dramatically increased by
coadministration with an L. lactis strain secreting IL-12 protein. Our
data show that IL-12 is produced and secreted in an active form by L.
lactis and that the strategy which we describe can be used to enhance
an antigen-specific immune response and to stimulate local mucosal
immunity.

PMID: 12654805

It would appear that we need to block the subunit that drives the
IL-12. Can we do it with an implantable good bacteria that has been
engineered?
Certainly seems plausible to me, as a gut bug to raise IL-10 has
already been tested. And this will lower our Th1 skew naturally.

randall... low dose from a friendly implantable gut bug! Right on!
Power to the little peoples.

JXStern

2006-10-09, 9:31 pm

On 9 Oct 2006 14:23:48 -0700, "randall" <ranhub11@aol.com> wrote:

>Yet. Aren't we all about low dose around here? With the exception of
>those who obviously require a sledge hammer to budge the stuff.

Yeah. And even a single, low dose of 1275 seems to do the trick for
some. Wonder how that corresponds to initial severity. Hey, wonder
that, a lot.

>If I didn't respond so WELL to my monkey business, i'd be on
>biologicals right now.

I'm jealous.

>So, say the centocor 1275 (owned by johnson and johnson) product for P
>really works with
>the exception of its strength being something one has to watch.

With (a) its MOA, and (b) its persistence, eg halflife.

Still good, maybe excellent, maybe best available, but ...
TANSTAAFL.

>Then we know the subunits of IL-12 are to be dealth with. Figuring out
>how best to design our cocktail with that in mind may be key.

OK, but let's still not think of this as the silver bullet, no matter
how good it is, since we're still fighting the protein and not
preventing its creation, still haven't addressed the trigger.

>randall... low dose from a friendly implantable gut bug! Right on!
>Power to the little peoples.

I'm glad it works for you, and it is upstream and at least suppresses
the IL-12 trigger, but my moves in that direction haven't helped. If
it were that "easy" for most people, I'd think fasting would be even
more effective.

J.