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Meds, Mind, Body & Benefits => Research News & Studies => Topic started by: bimazek on September 20, 2007, 07:34:24 pm

Title: PRO 140 great new monoclonal antibody including Animations
Post by: bimazek on September 20, 2007, 07:34:24 pm

imagine a very powerful hiv treatment which you inject only once every two weeks
and it is actually exactly what the human body would produce if the immune system wasnt tricked by hiv
what if a fully human antibody, a fully human monoclonal antibody which has taken 20 years of research just to dev. fully human monoclonal antibodies
was on market to treat hiv

what if this was extremely powerful because it was a molecule that was a human antibody
what if this antibody was working now

what if a perfect Y shaped protein that was human produced, produced inside a human body,
what if your immune system used this monoclonal antibody to identify and neutralize foreign objects, such as bacteria and viruses. what if  this antibody helped direct the appropriate immune response for each different type of foreign object they encounter
http://en.wikipedia.org/wiki/Antibody

that is what PRO 140 great new monoclonal antibody including Animations

here are the great animations

ANIMATIONS

http://www.progenics.com/ani.cfm

remember this is super space age science, that makes creating a molecule of a medicine seem like cave man days, to actually create a protein that is perfectly like what a human body would produce

and produce it in a transgenic mouse

a mouse that has the immune system of a human

i am not sure if that is how the production version of this antibody was produced

but the research version of monoclonal antibodies are produced this way





http://en.wikipedia.org/wiki/Monoclonal_antibodies
Monoclonal antibodies (mAb or moAb) are antibodies that are identical because they were produced by one type of immune cell and are all clones of a single parent cell. Given (almost) any substance, it is possible to create monoclonal antibodies that specifically bind to that substance; they can then serve to detect or purify that substance. This has become an important tool in biochemistry, molecular biology and medicine. When used as medications, the generic name ends in -mab (see "Nomenclature of monoclonal antibodies").



The idea of a "magic bullet" was first proposed by Paul Ehrlich who at the beginning of the 20th century postulated that if a compound could be made that selectively targeted a disease-causing organism, then a toxin for that organism could be delivered along with the agent of selectivity.

In the 1970s the B-cell cancer myeloma was known, and it was understood that these cancerous B-cells all produce a single type of antibody (a paraprotein). This was used to study the structure of antibodies, but it was not yet possible to produce identical antibodies specific to a given antigen.

The process of producing monoclonal antibodies described above was invented by Georges Köhler, César Milstein, and Niels Kaj Jerne in 1975;[1] they shared the Nobel Prize in Physiology or Medicine in 1984 for the discovery. The key idea was to use a line of myeloma cells that had lost their ability to secrete antibodies, come up with a technique to fuse these cells with healthy antibody producing B-cells, and be able to select for the successfully fused cells.

In 1988 Greg Winter and his team pioneered the techniques to humanize monoclonal antibodies,[2] removing the reactions that many monoclonal antibodies caused in some patients.




Title: Re: PRO 140 great new monoclonal antibody including Animations
Post by: Customer on September 22, 2007, 02:52:08 pm
PRO 140 sounds like a great medicine: entry inhibotor (no intra-cellular hassle) with long half-life and potentially very few side effects. Great news Bimazek!


Despite the weaker anti-viral effect, i hope Progenics will continue the development of PRO 542, because it was the only HIV-targeting (instead of T-cell targeting) medicine. It should be understood, that in the clinical latency of HI-infection, HAART does not need to be very efficient in terms of viral load reduction.
 

http://www.projinf.org/bn/bn_091206.html

Progenics Pharmaceuticals has quietly ‘ramped down’ the development of their entry inhibitor PRO-542. The company briefly mentioned this decision in a 2005 press release focusing on their other experimental drug, PRO-140. PRO-542 is a monoclonal antibody entry inhibitor that was designed to block the CD4+ receptor on T cells (this is a mistake: PRO-542 was CD4 decoy, not CD4-blocker).

The company’s brief 2005 press release stated that, “In the HIV therapeutic area, we are concentrating our resources on PRO-140 … and we will ramp down our development efforts on PRO-542, our other HIV product candidate.” The release goes on to say that the company will retain PRO-542 for possible future development.

Since most information resources, including the government’s clinical trials website, still list PRO-542 as being in active development and only a few sites have noted the new trials of PRO-140, Project Inform checked with the manufacturer to get a clearer picture of what their current strategy is and the reasons for it. It appears that the company made the decision to switch to PRO-140 because it appears to be a significantly more potent drug. Laboratory studies show PRO-140 to be 20 times more potent than PRO-542 against wild type HIV.

This excellent half life of PRO-140 suggests it may be possible to dose the drug only once a week or even less frequently. This is particularly significant since, like most monoclonal antibodies, it currently requires intravenous infusion. The company says it is also working on developing an oral form of the drug (PRO 140), although this will be a difficult challenge.


Title: Re: PRO 140 great new monoclonal antibody including Animations
Post by: milker on September 22, 2007, 09:53:39 pm
Because CCR5 receptor is often used by current drugs, and because CCR5 receptor is a major receptor of chemokine for immature dentritic cells it is possible that deregulation of chemokine due to HIV drugs blocking it from T cells may induce skin aging or skin transformation. Aging has been connected with increased chemokine.This product does not deregulate chemokine so the side effects may be less.

The good surprise was that the coating of the cell by the antibody was efficient up to 60 days, which reduces greatly the amount of injections that would be necessary.

More information there:

http://www.poz.com/articles/PRO140_HIV_Entry_761_12672.shtml

Mice used for monoclonal antibody production do not have a human immune system. They have a modified DNA that is bound with a specific human gene, which then helps creates cells that will produce what is expected from that specific gene. Mice are used because they have a "similar" immune system, and do not seem to be particularly affected if the gene induction is unsuccessful (which is another interesting subject).

I don't know if for pro-140 they use mice or recombinant antibodies though.

Milker.
Title: Re: PRO 140 great new monoclonal antibody including Animations
Post by: freewillie99 on October 28, 2008, 01:54:25 pm
Getting there...

http://www.progenics.com/releasedetail.cfm?ReleaseID=343096


Title: Re: PRO 140 great new monoclonal antibody including Animations
Post by: John2038 on October 28, 2008, 04:47:31 pm
Great, fantastic, fabulous, etc

Thanks for this great news. The end of HIV is nearer everyday  8)
Title: Re: PRO 140 great new monoclonal antibody including Animations
Post by: NYCguy on October 28, 2008, 07:10:43 pm
I know it was discussed a long time ago on here, but Sangamo Pharma's Zink Finger technology would supposedly permanently 'turn off' the CCR5 receptor with only one or a few infusions, in theory creating a pool of resistant cells that would also reproduce.

http://www.sangamo.com/human/human_thera_overview.html#HIV

They have been claiming plans to test it forever, which has now been moved to 2008 - which is of course almost over!  Would be exciting if it worked, however.
Title: Re: PRO 140 great new monoclonal antibody including Animations
Post by: leit on October 29, 2008, 09:58:28 am
The end of HIV is nearer everyday

Not even one inch! PRO 140 is just another obstacle to virus replication, like the present ARVs and Selzentry in particular, whilst HIV must be ERADICATED. Then, there will still be the problem of repairing the (immune, but not only) DAMAGES IT CAUSED.

Title: Re: PRO 140 great new monoclonal antibody including Animations
Post by: freewillie99 on October 29, 2008, 04:13:15 pm
leit:

While not necessarily agreeing with John that this moves us closer to "the end of HIV", I do see it as a potentially positive step in the management of the disease.  The less frequent dosing schedule, i.e. weekly or bi weekly, in addition to the low side effect profile, make it a step up from the typical ARV's on the market today.  I look forward to hearing and seeing more positive news about this drug in the future.
Title: Re: PRO 140 great new monoclonal antibody including Animations
Post by: georgep77 on October 29, 2008, 08:13:54 pm
LoL Leit, Pro 140 is at least two inches & great news for everybody  :P

               Agree with u freewillie99
Title: Re: PRO 140 great new monoclonal antibody including Animations
Post by: John2038 on October 30, 2008, 07:06:39 am
It can't be wrong, in the absolute, to says that we are closer everyday to a cure, functional or not.
But the point is not here, I was thinking about the progress we are doing in all domains.

The PRO 140 have to be administered every 2 weeks.
It's definitely a progress compared to twice a day

The adherence problem become smaller, you can easier travel , you have more flexibility on when to take the drug, etc

Exactly what try to achieve the nano particle research, but with the aim that the drug to last even longer.

I consider this as a step toward a functional cure looking only at how long a drug can remain effective without needing another injection
Title: Re: PRO 140 great new monoclonal antibody including Animations
Post by: Jake72 on October 30, 2008, 06:46:11 pm
Maybe I missed something, but would this be a monotherapy?  One dose every other week would be a step up (especially if it has few or no side effects), but if it has to be combined with existing classes then it's a bit of a yawn except for the fact that it would be another option for those who may be running out. 
Title: Re: PRO 140 great new monoclonal antibody including Animations
Post by: leit on October 30, 2008, 11:20:59 pm
would this be a monotherapy?

Not at all!

Quote
it has to be combined with existing classes

Yes.

Quote
it's a bit of a yawn except for the fact that it would be another option for those who may be running out.

Usually, "those who may be running out" of options have been infected infected for a long time and so haven't a CCR5-tropic virus -> PRO 140 (like Selzentry) is useless for them.

These are some of the reasons why I don't understand so much excitement for PRO 140.
Title: Re: PRO 140 great new monoclonal antibody including Animations
Post by: georgep77 on October 30, 2008, 11:43:27 pm
Maybe the excitement is because millions of persons can use PRO 140 in the near future.

                                                         :o

and Jake72 read this report from progenics and you will find that PRO 140 is a monotherapy.


http://www.progenics.com/releasedetail.cfm?ReleaseID=343096
Title: Re: PRO 140 great new monoclonal antibody including Animations
Post by: John2038 on October 31, 2008, 07:02:48 am
R5 = 80-90% naive, 50-60% experimented patients as far as i remember
Falling this classe still preserve the others
If successfull as mono, 1 injection per two weeks, low side effects its great
Title: Re: PRO 140 great new monoclonal antibody including Animations
Post by: leit on November 01, 2008, 02:28:56 am
read this report from progenics and you will find that PRO 140 is a monotherapy.

IF the ONLY aim of a complete suppression of viremia is avoiding resistances, PRO 140 might perhaps be used as a monotherapy (HIV doesn't seem able to mutate escaping it).
OTHERWISE, PRO 140 is not potent enough and will need to be combined with other drugs.

Title: Re: PRO 140 great new monoclonal antibody including Animations
Post by: freewillie99 on November 01, 2008, 01:19:01 pm
leit:

At the risk of sounding completely clueless, if Pro 140 is able to achieve "a complete suppression of viremia" without the risk of mutations, what would you need other meds for?
Title: Re: PRO 140 great new monoclonal antibody including Animations
Post by: a2z on November 01, 2008, 02:09:05 pm
IF the ONLY aim of a complete suppression of viremia is avoiding resistances, PRO 140 might perhaps be used as a monotherapy (HIV doesn't seem able to mutate escaping it).
OTHERWISE, PRO 140 is not potent enough and will need to be combined with other drugs.



Yup and maybe why its exciting is that once you have other drug classes you can take every week or two weeks, then HIV therapy gets much much easier.

Time will tell.
Title: Re: PRO 140 great new monoclonal antibody including Animations
Post by: leit on November 01, 2008, 02:31:58 pm
if Pro 140 is able to achieve "a complete suppression of viremia" without the risk of mutations, what would you need other meds for?

No, "freewillie99", there was probably a misunderstanding.
SINCE PRO 140 alone isn't usually potent enough to completely suppress viremia ° (let alone patients infected with dual/mixed-tropic HIV!!!), there are TWO ALTERNATIVES:
1 - ACCEPT SOME VIREMIA (hoping that CCR5-tropic HIV is TRULY unable to become resistant to PRO 140 AND/OR to shift to CXCR4-tropic!)
2 - ADD OTHER DRUGS to fully suppress viremia.

° "Following treatment with a single [intravenous] 10 mg/kg dose, a greater than 1.0 log10 mean decrease in viral load was maintained for three weeks; at three weeks, the mean reduction was 1.55 log10". 1.55 log10 is roughly 35.5 folds. So, for instance, if one's baseline viremia is 150,000 copies/ml, after three weeks it will be meanly reduced to 4,228 copies/ml.
...But Progenics also writes: "A greater than 1.0 log10 (10-fold) mean reduction in viral load was sustained until three weeks post-treatment at the 10 mg/kg dose level".
So, is it 1.55 log, "greater than" ( ??? ) 1.0 log or... the usual messy press release (http://www.progenics.com/releasedetail.cfm?ReleaseID=343096) ???   ;)
Title: Re: PRO 140 great new monoclonal antibody including Animations
Post by: leit on November 01, 2008, 02:37:57 pm
once you have other drug classes you can take every week or two weeks, then HIV therapy gets much much easier.

IMHO (and Gates Foundation's, too!!!), it's CURE TIME and all the rest is born already old.

Title: Re: PRO 140 great new monoclonal antibody including Animations
Post by: freewillie99 on November 01, 2008, 03:30:26 pm
Thanks, leit.  I have to say that the "log", i.e. "logarithm" part was a bit confusing to me.  Dual tropism aside, at what log reduction does the virus become undetectable? 
Title: Re: PRO 140 great new monoclonal antibody including Animations
Post by: leit on November 01, 2008, 04:32:11 pm
at what log reduction does the virus become undetectable?

It strictly depends on the individual baseline viremia: If one has 500,000 copies/ml (or 5,000) and has to go down to 5 copies/ml (i.e., according to Siliciano, no more ongoing virus replication and only a little HIV released by the reservoirs), a 5 log (respectively, 3 log) reduction is needed!

P.S. Rule of the thumb. Open Windows calculator in scientific mode, type your viremia set-point, divide it by 5, click "=" and finally click "log".

Title: Re: PRO 140 great new monoclonal antibody including Animations
Post by: John2038 on November 02, 2008, 03:45:49 am
leit:

So some as me will enjoy this drug as my last VL is 595, average previous 3000 (3.477)

so if the pro 140 allows me to reduce my vl by 2 log, my vl will become:

3.447 - 2 = 1.447 that is 40 cp/ml

Borderline isn't it ?

And what ? Maybe will I have to add let say Truvada once a day.

Will I still be happy ?

Yes, too much !!

Why ? Because instead of let say Reyataz + Truvada I will use PRO 140 + Truvada (if can be combined of course)

So I will probably save the PIs for later. In more, so far, PRO 140 have very little side effects and is probably much more lipids friendly than a PI.

Now you have to remember the Maraviroc study

Maraviroc + OBR (3 drugs regimens) have allows to make undetectable experimented multi-resitant patients.

Ok, then the PRO 140 is a CCR5 antagonist as well, but it seems with much less side effects.

So leit, why won't this new drug be useful for many of us, why is it not a great news for you ?
Title: Re: PRO 140 great new monoclonal antibody including Animations
Post by: leit on November 02, 2008, 04:42:32 pm
Dear "John2038",

Your calculations, mixing logs and copies/ml and using strange parameters (-2 logs while Progenics wrote -1.55!), don't seem right to me.
Anyway, as far as you are concerned, the final result doesn't change very significatively: assuming that your viremia set-point is 3,477 copies/ml and that PRO 140 is able to decrease it by 1.55 logs (i.e. 35.5 folds), your final viremia will be roughly 97 copies/ml.

But the main point is not this one, because medicine and pharmacology are not arithmetic and other factors (different pharmacokinetic, pharmacodynamics, genetic barriers...) can play VERY important roles. For instance, in the maraviroc trials you recall, there were HOWEVER classic THREE drugs OBRs that helped!
Moreover, if actually PRO 140 doesn't allow HIV to become resistant to it, it would be the FIRST time an anti-HIV drug behaves such a way (even Maraviroc, which could seem the most similar, doesn't).

Bottom line: I think it's absolutely necessary to check the MEDIUM/LONG-TERM virological, immunological and CLINICAL results of PRO 140 through human trials employing it alone AND in combination with present, "classic" drugs. They could reserve big (good or bad) surprises.

Title: Re: PRO 140 great new monoclonal antibody including Animations
Post by: John2038 on November 02, 2008, 10:23:40 pm
Your calculations, mixing logs and copies/ml and using strange parameters (-2 logs while Progenics wrote -1.55!), don't seem right to me.

1) Log basics:

Log base 10 of x: y = log10(x)  ; Log inverse : x = 10^(y) ; Log div: log10 (x/z) = log10 x - log10 z

Example

y = log10 (3000) = 3.477
x = 10^(3.477) = 3000 [cp/ml]
3.477 - 2 = log10 (x) ; x = 10^(1.477) = 30 cp/ml (and not 40) that is 3000/100 = x/z also


2) Progenics results

intravenous:

* At 5 mg/kg (phase 2 study): 1.90 log10 mean maximum decrease in viral load (p = 0.0001)
* At 10 mg/kg (phase 2 study): 2.17 log10 mean maximum decrease in viral load (p = 0.0001)

I just take 2

Anyway, as far as you are concerned, the final result doesn't change very significatively: assuming that your viremia set-point is 3,477 copies/ml and that PRO 140 is able to decrease it by 1.55 logs (i.e. 35.5 folds), your final viremia will be roughly 97 copies/ml.

It is important if the OBR you are taking didn't allows you to reach undetectable.
Taking PRO 140 instead of a 4th drugs sounds beneficial.

But the main point is not this one, because medicine and pharmacology are not arithmetic and other factors (different pharmacokinetic, pharmacodynamics, genetic barriers...) can play VERY important roles.

But your whole point is almost to use arithmetic to contradict the needs of this drugs in medicine.

For instance, in the maraviroc trials you recall, there were HOWEVER classic THREE drugs OBRs that helped!

This is for experimented patients.
For naive, we need to demonstrate if CCR5-antagonist + 2 drugs can be compared to OBR. Maybe yes in which case PRO 140 is a great news for that reason as well.

Example
M184V + T215FIST cause a resistance of 64 folds on FTC and 2 folds on TDF
Let say this patient will be treated with Truvada + Reyataz
Would it be beneficial to use now PRO 140 + Truvada + Reyataz, or PRO 140 + Viread + Reyataz, maybe. But probably a much better solution than Isentress + Truvada + Reyataz, as it will allows to keep Isentress for a later use, and as PRO 140 have a low side effect profile.

Moreover, if actually PRO 140 doesn't allow HIV to become resistant to it, it would be the FIRST time an anti-HIV drug behaves such a way (even Maraviroc, which could seem the most similar, doesn't).

Nobody knows. But we can reasonably expect that the R5 virus will sooner or later mutate to a X4 virus.

Bottom line: I think it's absolutely necessary to check the MEDIUM/LONG-TERM virological, immunological and CLINICAL results of PRO 140 through human trials employing it alone AND in combination with present, "classic" drugs. They could reserve big (good or bad) surprises.

Well leit, in this forum we are discussing news from the actual state of the research.

Regarding PRO 140, I said:

If successful as mono, 1 injection per two weeks, low side effects its great (*)

So far, the intermediate results looks encouraging, and maybe a better formulation can be developed. Lets wait and see.

Now, among the others reasons of happiness:

I'm having a low VL usually (last 595).
Maybe PRO 140 can be beneficial for people like me, as it might allows us to reach undetectable (maybe) without the use of classical drugs. In this case, the use of PRO 140 as a mono therapy is not a problem (as it is usually the case with others drugs from others classes):
PRO 140 won't probably cause the emergence of mutations able to compromise the others classes. Great !

Or maybe PRO 140 + Kaletra will work just fine (if no drugs interactions) as we already knows that Kaletra as mono is not a bad idea (71% virological success at week 144 as far as I remember). Still great !

Sure, lot of studies remains to be done, but this drug allow to open these new perspectives.

Anyway, I also like the idea that a drug can remain potent over a long period of time. I admit that I would have prefer PRO 140 to cause a bigger VL drop, but on the other side, using a CCR5 inhibitor doesn't compromise the use, later, of drugs from others classes, in more that PRO 140 can probably be use as the 4th/5th/etc drug in a salvage regimen, to keep undetectable patients who can't reach this state otherwise (see maraviroc study), or who can, but want preserve some options for later.

Also, if maraviroc have been shown useful in this study, how about PRO 140 replacing the maraviroc then ?

Somewhere, PRO 140 look to me like the Fuzeon, but with less frequent injections (I know, those on fuzeon probably have a x4 virus. But 50-60% don't and still harbor a r5 only), despite I don't know by how many folds the fuzeon is lowering the VL.


NOTE
(*) "If" because PRO 140 have been prescribed as a mono in this trial.
It doesn't means that it has to be use or will be use as mono. But it might.
Title: Re: PRO 140 great new monoclonal antibody including Animations
Post by: freewillie99 on November 03, 2008, 10:06:29 am
I'm looking forward to hearing the results from the upcoming phase 2b/3 trials as they'll be testing an intravenous 20 mg / kilo dose.  The 20 mg dose may confer a full month's reduction in viral load of >2Logs.  Now that would be something.
Title: Re: PRO 140 great new monoclonal antibody including Animations
Post by: leit on November 03, 2008, 11:11:39 am
1) Log basics

:)  My mistake, possibly! Probably, I read your average viremia was 3,477 copies/ml (not 3.477 logs!) and thought you then rounded it off to the thousands (3,000 copies/ml).

Quote
2) Progenics results
intravenous

I think it's not correct to consider the mean MAXIMUM decrease, but the MEAN decrease in viral load that was maintained for three weeks, i.e. 1.55 log10 (or "greater than" ( ??? ) 1.0 log), with 10 mg/kg dose.

Quote
It is important if the OBR you are taking didn't allows you to reach undetectable.

Sure, otherwise it wouldn't have been an OBR, but a fully suppressive HAART!!!

Quote
Taking PRO 140 instead of a 4th drugs sounds beneficial.

PRO 140 would HOWEVER have been a 4th drugs, though possibly better than maraviroc!

Quote
But your whole point is almost to use arithmetic to contradict the needs of this drugs in medicine.

I don't contradict PRO 140 need or, better, its usefulness. I'm only very doubtful about PRO 140 as a breakthrough in HIV treatment.

Quote
For naive, we need to demonstrate if CCR5-antagonist + 2 drugs can be compared to OBR.

That's what I said! We need more and longer human trials employing PRO 140 also in combination with present, "classic" drugs.

Quote
Now, among the others reasons of happiness:
I'm having a low VL usually (last 595).
Maybe PRO 140 can be beneficial for people like me

For sure! But, unfortunately, very few people have such a low viremia...

Quote
Or maybe PRO 140 + Kaletra will work just fine (if no drugs interactions)

May be.

Quote
Sure, lot of studies remains to be done

This is the main point! Let's wait and see.