Improving on a good thing
You thought monoclonal antibody (MOAB) Rituxan was the greatest thing since sliced bread? Well, get ready for “bispecific antibodies” that may soon prove to do the job a whole lot better. But before we get to the juicy details, you have to do a bit of reading – promise it won’r hurt even a little bit!
Here is a simple (some may say way over simplified) picture of how conventional monoclonal antibodies look. Rituxan, Campath, Arzerra are all “Y” shaped molecules similar to the picture on the left. The tips of the two arms of the “Y” are the pincers with which the antibody molecule is able to grab on to its target. In Rituxan’s case, the target is the CD20 marker present on all mature B-cells, which includes CLL cells. If you picture Rituxan molecule as a weird kind of lobster, the two pincers of the beast are what allow it to catch its prey. Once the hapless CLL cell is festooned with a bunch of these “lobsters”, it is as if there is a huge “kill me” sign painted on the cancer cell and it is quickly killed by the rest of the immune system. When it comes to killing tagged cells, T-cells are the ones that do most of the heavy lifting.
So, why does Rituxan not work all that well as a single agent in CLL? The reason is that CLL cells do not express a whole lot of CD20 markers on their surface, which means not too many Rituxan molecules can tag the cancer cell, which in turn means the CLL cell does not always attract the attention of killer T-cells. The “kill me” sign is painted on in very small letters, as it were. One of the reasons why it is suggested that ofatumumab (Arzerra) works better than Rituxan is that it is thought to hang on a lot better to the CLL cell without letting go – think of it as better Velcro making the drug molecule stick better to the cancer cell. Even then, there is no guarantee that the tagged CLL cell will automatically attract killer T-cells. This is particularly so in the case of previously treated patients, since they may not have a whole lot of able and willing T-cells patrolling the body any more.
Dating service of the fatal kind
Here is the concept in a nutshell. Won’t it be nice if we can introduce the killer T-cells to the cancerous CLL cells, up close and personal? Mr. T-cell, please meet Ms. CLL cell. Ms. Cancerous CLL cell, please meet your nemesis, the ever so handsome Mr. Killer T-cell. If we can bring the two cells close together, predator and prey, chances are much better that we will get the desired “chemistry”, and the T-cell will kill the CLL cell.
That is pretty much what Micromet’s “BiTE” (Bispecific T-cell Engager) attempted to do – and the latest results suggest they have done a pretty good job of it.
- For starters, Micromet focused on CD19 as the target marker on B-cells. Unlike CD20 (which is expressed to greater or lesser degree depending on the specific nature of the B-cell), all B-cells must express CD19 in copious amounts, no exceptions allowed. Without CD19, a B-cell cannot be a B-cell, it is a classic identifier of all B-cells starting from very young immature B-cells all the way to mature B-cells.
- Next, they looked for a classic marker on T-cells that is involved in activating the T-cell and making it a fearless killer cell. This happens to be the CD3 marker.
- Rather than having a humongously large “Y” shaped molecule such as Rituxan, Campath etc, Micromet managed to get just the tips of the “Y”, the very pincers of the lobster as it were. They attached one pincer that targets CD19 with another pincer that targets CD3 – connected the two pincer tips with a short peptide chain. The picture below may make the concept easier to visualize
Since MT103 combines just the business ends, not the whole big “Y” shaped molecules that are conventional monoclonal antibodies, what we have here is a short rod shaped molecule, very tiny compared in size to a Rituxan molecule. One end of MT103 tags CD3 marker on T-cells, the other end of the rod tags CD19 marker on B-cells. Very simple, very elegant, very compact
As it happens, this compactness is exactly what was needed. It seems the T-cell has to be sufficiently close to the target cell before it can “recognize” it, and then kill it. Since Micromet’s MT103 molecule is a very short rod shaped molecule, it is possible to bring the killer T-cell into close proximity of the victim B-cell.
Voila! Match made in hell. The CD3 hook latches on to a T-cell, and as soon as a B-cell happens by, the other end of the rod with the CD19 hook latches on to that. Or vice-versa. We now have a target b-cell and a killing T-cell locked together in a tight and fatal embrace. No amicable divorce is possible here, this union ends when the B-cell is killed. The T-cell moves on to find its next victim.
If you type “bispecific antibodies” into PubMed search engine, you will get literally thousands of hits. They are a little tough to digest, so I thought I would do you guys a favor and give you a comic strip version of it. You can get a more detailed explanation and glitzy pictures of how the technology works by visiting Micromet’s website.
Below is an abstract I used in reviewing this technology back in 2003 (my, where have all the years in between gone?). I told you I have been following this technology for a long time! This early lab study using cell lines showed that the bispecific antibody approach was far more effective in cell kill. Under identical lab conditions, BiTe technology was 100,000 fold more effective than Rituxan!
Int J Cancer 2002 Aug 20;100(6):690-7
Extremely potent, rapid and costimulation-independent cytotoxic T-cell response against lymphoma cells catalyzed by a single-chain bispecific antibody.
Dreier T, Lorenczewski G, Brandl C, Hoffmann P, Syring U, Hanakam F, Kufer P, Riethmuller G, Bargou R, Baeuerle PA.
Micromet AG, Am Klopferspitz 19, 82152 Martinsried, Germany.
A recent study reported on an anti-CD19/anti-CD3 single-chain bispecific antibody (bscCD19xCD3) exhibiting high activity against human B lymphoma cell lines (Loffler et al., Blood 2000;95:2098-103). In the present study, we have explored in detail the in vitro efficacy, T-cell donor variability, binding characteristics, specificity, kinetics and interleukin-2 (IL-2) dependence of bscCD19xCD3. We found that a majority of human donor T cells tested (n = 86) gave half-maximal B-lymphoma cell lysis (ED(50)) within a range of 10-50 pg/ml bscCD19xCD3, corresponding to sub-picomolar concentrations of the bispecific antibody. Under identical experimental conditions, the anti-CD20 monoclonal antibody rituximab had an at least 100,000-fold lower in vitro efficacy. The extreme potency of bscCD19xCD3 was in sharp contrast to the relatively low affinity of the anti-CD3 and anti-CD19 single-chain Fv portions in K (D) ranges of 10(-7) and 10(-9) M, respectively. Cell lysis by bscCD19xCD3 was predominantly mediated by the population of CD8/CD45RO-positive T cells. Both immortalized CD4- and CD8-positive human T-cell clones were highly active effector cells as well. Cell lysis by bscCD19xCD3 was rapid and specific. The respective parental monoclonal antibodies inhibited cell lysis and CD19-negative cells were not harmed by T cells in the presence of high amounts of bscCD19xCD3. The potent T-cell stimulus IL-2 could not markedly augment the activity of bscCD19xCD3-stimulated T cells. In conclusion, bscCD19xCD3 could redirect unstimulated cytotoxic T cells against CD19-positive cells in an unexpectedly potent, rapid and specific fashion.
Micromet has progressed a long way from lab cell line studies to actual clinical trials in live patients. Their recent press release reporting the results of the clinical trial in ALL (acute lymphoblastic leukemia) caused a flurry of excitement. So much so that the stock was discussed on “Mad Money” program by Jim Cramer ! (I cannot give you financial advice or stock pick tips, any more than I can give you medical advice, please remember that. I personally own zero stocks in Micromet).
“Blinatumomab” is the formal name of Micromet’s MT103 BiTe technology. There is logic behind these outlandish names of drug molecules, but that is not really here nor there. Just don’t let the names intimidate you. I will continue using “BiTE” and MT103 since they are a whole lot simpler to type.
Blinatumomab Achieved 75% Complete Remission In Acute Relapsing Lymphoblastic Leukemia Patients
10 Jun 2011
75% of acute lymphoblastic leukemia patients who had relapsed after standard therapy achieved complete remission with blinatumomab, a medication designed to harness T cells that destroy cancer cells. Blinatumomab makers, Micromet says the drug is “the most advanced of a new class of agents called BiTE® antibodies.”
According to interim results of a Phase II single-arm trial, 9 out of 12 (75%) patients on blinatumomab went into complete remission, or complete remission with partial recovery of blood counts. They achieved a complete molecular response, or had no trace of leukemic cells in their bone marrow. Four patients with genetic abnormalities usually linked to poorer prognoses all achieved complete remission with partial recovery of blood counts.
Chair of the study, Professor Max Topp, Department of Internal Medicine II, University of Wuerzburg, said: “Relapsed/refractory acute lymphoblastic leukemia is a difficult to treat disease that has seen no meaningful improvement in decades. To date blinatumomab has shown an impressive and unprecedented level of efficacy in a patient population with limited therapeutic options.”
The most common negative side effects were peripheral edema, fatigue and fever. Of the twelve patients, two had to have their treatment interrupted because of fully reversible and manageable CNS (central nervous system) events. One developed cytokine release syndrome, which was dealt with by modifying dosage and administering pre-treatment concomitant medication, after which there were no cases of cytokine release syndrome.
Professor Topp said: “These results are particularly striking relative to the fact that the majority of enrolled patients had characteristics typically associated with a dismal outlook.” Standard therapy for those with relapsed/refractory acute lymphoblastic leukemia consists of combination chemotherapy medications, which often fail to achieve remission.
For over three decades no new medication has been approved for relapsing patients. Doctors’ options to improve patients’ long-term outcomes have been very limited. Current therapies achieve remission rates of between 17% and 45%. Standard chemotherapy typically has a mortality rate of up to 23%. On average, only 7% of acute lymphoblastic leukemia patients survive for at least five years after a relapse.
In this study, patients were given blinatumomab as a continuous infusion for 28 days, followed by two weeks with no treatment. Those who achieve complete remission (CR) or CR with partial recovery of blood counts (CRh) within the first two cycles of treatment may receive consolidation with either 3 more cycles of blinatumomab or allogeneic HSCT.
Why is this development of interest to us, CLL patients? for starters, ALL too is a B-cell cancer, just like CLL. The same CD19/CD3 bispecific antibody would likely work in CLL too. Micromet chose to do its early clinical trials with ALL because this acute cancer progresses fast, much more fatal quickly and therefore it is easier for them to showcase what their drug can do. There are some disadvantages to having a “good cancer” like CLL, and in this case the disadvantage is that proving the value of a new drug takes much longer. Drug companies are not known for their patience, they want to make money NOW. But once the concept is proven and well established, there is no doubt in my mind that CLL will be in their cross-hairs. The results they highlight here for ALL are pretty impressive, 75% complete and molecular responses in a very tough to treat bunch of patients who would otherwise be looking at significantly poorer response rates (17% – 45%) with conventional therapies.
Micromet has an open clinical trial using MT103 in NHL – and they include SLL patients in the definition of non-Hodgkin’s lymphoma. Unfortunately, the only centers where this clinical trial is available are in Germany. But if any of our German members have SLL and fit the inclusion criteria, this may be a very good clinical trial to consider. Please refer to the clinicaltrials.gov citation to get the full list of inclusion criteria, contact information etc.
If you are so inclined, here are a couple of much earlier articles I wrote on the subject of new developments such as BiTe technology.
Is this how you spell C-U-R-E ?
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22 comments on "Taking a “BiTE” out of B-cell cancers"
Pretty encouraging technology. Thank you
How does this technology distinguish the CLL B-cells from good B-cells? Or does it?
Fran H:
It does not distinguish between health B-cells and CLL cells. It kills all B-cells, all the way from immature B-cells to fully mature B-cells – including CLL cells. That is the price paid for using CD19 as the target, since all B-cells express it. Fortunately, plasma cells (further downstream product of B-cells) are not targeted, since they do not exhibit CD19. Same goes for stem cells, they are not targeted either.
The hope is that if BiTE technology does a very good job of clearing the CLL, as the body recovers the stem cells will repopulate the B-cell compartment.
One thing that leaves me confused here is hardly any talk of specificity. Does this MT103/BiTe technology wipe out healthy B cells with the same efficiency it wipes out CLL cells? And if the answer is yes, what are the long-term ramifications of living without a major arm of your immune system? What about all those B “long-term memory” cells that spring into action when we are exposed to pathogens we have been exposed to in the past? Are there ramifications of secondary cancers with a greatly diminished “schooled” B cell population? Will patients be required to be on long-term antibiotics, anti-fungal, and anti-viral drugs?
Chaya, Thanks as always. All us cll’ers on hanging in there counting on hopes that enough “time” will be allowed in our disease for there to be a major break through. The downside to the BiTE therapy seems very doable, especailly given the results. Maybe one step closer!
Michael:
You make a very good point. I answered it in part in my earlier response to Fran H.
Loss of mature B-cell compartment happens even with Rituxan, since it too targets CD20 – present on all mature B-cells. The difference here is that MT103 also targets immature B-cells, since they also exhibit the CD19 marker.
If (and it is a big IF), it is possible to get molecular level clearance of CLL cells (as well as all other B-cells, immature or mature), without harming the stem cell compartment, one can hope for repopulation of a fresh batch of healthy B-cells over a period of time. True, memory B-cells will be lost and it may be necessary to re-vaccinate patients. But if T-cells, NK cells, neutrophils, macrophages etc are not harmed, they can provide a significant amount of protection even when healthy B-cells are not present.
While a healthy B-cell compartment is important part of our immune system, it is not quite as critical as T-cell compartment. That is why Campath is so much more immune suppressive than Rituxan, since Campath kills T-cells as well.
The best possible target would be a marker that is expressed copiously by CLL cells only and no other cells. Such a target has not been identified.
Chaya,
Have you ever heard of pairing Rituxan and maitake d fraction for a similar effect of engaging T cells?
My husband terry has been doing well four years out but his day is coming when he will need treatment.I’m still growing my garden for him here in Oklahoma. You were a great help to me after he got diagnosed.
Nancy Moran
Chaya, Would this new technology possibly work for those of us with CLL who are allergic to Rituxan? Thanks for all the great info, Anna
Articles like this are REALLY ENCOURAGING – especially as CLL patients have a lump or two of negative news to live with every day. It’s good to have the good news. BIG THANK YOU, Chaya!
Lawrence
Cornwall, UK
Chaya, if I am understanding this concept correctly, wouldn’t this be less effective in patients who began treatment with depleted T cell populations?
Since CLL patients are rarely tested for those populations of cells, I would imagine to evaluate this new type treatment, testing would have to begin for those as well. Encouraging, at least that new targets are being found, thanks,
Beth, F
Thanks Chaya. This a great article and great news. Best, Jenny
nmoran:
I am no good at answering alternative medicine questions. But if you are asking about the combination of Rituxan with beta glucan (some mushroom extracts contain this subsance), there was a flurry of research on this subject a while back – but nothing more recently. The principle investigator was Dr. Gordon Ross who passed away a few years ago. You can look up our earlier articles on beta glucan by searching for that key phrase in the search box at the top right hand corner of the website.
ellioak:
This bispecific antibody has nothing to do with Rituxan. Allergic reactions to Rituxan would not interfere.
bethcat:
You got it exactly right. Lack of sufficient T-cells (as in patients who had recently been treated with fludarabine or Campath) will compromise response to BiTE technology. There may be ways around it. One option I discussed in my earlier 2003 article (“Is this how you spell CURE?”), I suggested combination of BiTE + patient’s own T-cells grown outside the body into huge armies and infused back. Other possibilities may be using drugs such as Revlimid in combination with BiTE. There have been suggestions that Revlimid increases both number and efficiency of T-cells. But the best time to use this new technology may well be in early stage and chemo naive patients, while the immune system is still intact. If the toxicity is low, I can see how this might be a good frontline early intervention drug to get people into long lasting deep remissions. Dare say a CURE?
Thank you Chaya, for the update. CLL is new to my wife, and a little extra hope is the best news we can get. Thank you for all that you do, which is so meaningful to us. May God guide you always.
Great article. Thank you, Chaya.
Monique
chaya:
as always – thanks for the update. the content is very encouraging and hopeful for now! But, as with other regimens that have come down the road and you have reported on – time will tell!
please keep the updates/news coming! your site is the only resouorceful mechanism for “us” (the cll community) to receive timely updates with credible, realistic and balanced information on what is going on. without cll topics, “we” (the cll community) would be in a void and would be like a mushroom – “in the dark”!
hope all is well?
thanks
alan
alan
After publishing this article I came across a clinical trial that Micromet has for NHL patients – which includes SLL folks in their definition of NHL. I added this information to the bottom of my article. Here is the link to the clinical trials citation:
http://clinicaltrials.gov/ct2/show/NCT00274742
Unfortunately this trial is only available in German centers and only for SLL patients. I hope they will start a new trial for full range CLL folks real soon.
This is encouraging, Chaya. When I need tx., I am hoping to use some med or combo that will not destroy my immune system. That is what seems to be on the near horizon with the CAL-101 and other tyrosine kinase inhibitors and perhaps these bispecific meds will be added to the arsenal. Hope things can move along. Wish the FDA had a faster track for these new drugs that are less toxic. After all, CLL seems to be an orphan disease, if I am understanding things correctly, and it is not easily curable short of a transplant.
Thanks again,
Chris R
Maybe your hopes for a CLL trial may be answered soon? Noticed that Micronet’s Advisory Committee includes: Michael Keating, MD Anderson Cancer Center and that they are a neighbor of yours, headquartered in Rockville, Maryland.
“The company plans to initiate three additional blinatumomab trials in 2011. These include a phase I/II trial in relapsed refractory pediatric ALL patients, phase II trial of blinatumomab in patients with chronic lymphocytic leukemia (CLL) and a phase II trial in patients with MCL.”
Hope your knee is cooperating….
Chaya: is CD 19 expressed on any other cells besides B cells? (side effects)?
john
Ambrose:
CD19 is expressed by B-cells (starting from immature B-cells all the way through mature B-cells), as well as a cell type called follicular dendritic cells. That’s it. That makes it a pretty narrowly defined target.
As Terry Hamblin pointed told me in a personal email, one of the adverse effect that might cause a problem -especially if the dosage is increased – is what is called a “cytokine storm”. There may be “shake and bake” type of response in some patients (fever and chills).
Chaya,
Much of your report seems very positive but I could not help being drawn to the “extreme potency of bscCD19xCD3….” & “cell lysis by CD19xCD3 was rapid & specific.” in the Int. Journal Cancer that you cite. Although the “cytokine storm” events appear to have been managed and avoided for the future, could this approach be too much of a good thing?
From my perspective as a patient who has the misfortune of having the CLL damage the kidneys prior to TX and the rapid and effective response from RF pushing the damage to near death I would pose the following questions:
1) If the response is as potent and rapid for CLLers as other “B” cancer patients does it pose an unacceptable risk to patients with high tumor burdens & or with certain co-morbidities?
2) Should this biotechnology force a change in the strategy of “Wait-n-Watch” given, that as Bethcat pointed out, that this would appear to work better when our immune systems are in better shape with higher numbers of T-Cells?
3) When any given T-Cell finishes off it’s prey does it go on to kill again?
4) Once conjugated, do the B-Cell killers go on to kill too many good guys after CR is achieved or do patients risk entering a created auto-immune like reaction to recovering B-Cell populations?
This would be so much more exciting if it involved an idiotype marker target on the cancer cell.
Looking for the whole enchilada.
Great review in spite of my dubious concerns.
WWW
WWW:
1. There is always chance of unacceptable risk. Only time and well conducted clinical trials will spell out the details. I look at it this way: better to have options to try out, see if they are better than the ones we have now, rather than the same old chemo + more chemo approaches we have right now. We are getting better at tweaking cytokine storm type of responses, better at controlling them if they do occur.
2. Yes, my guess is that if this approach is successful, W&W may indeed become obsolete. That would happen only if the candidate therapy had high value (deep responses) at low cost (adverse effects).
3. T-cells are serial killers. One T-cell can kill may target cells before it is depleted of substances such as perforin and granzyme – you can look up T-cell kill mechanisms by searching for these words.
4. No, I do not see any red flags pointing to autoimmune disease.
5. CLL is a diverse disease. So far we have not found any one standard disease specific marker that is present on all CLL cells of all patients. Idiotype vaccines have to be custom made for each patient, for that very reason – a deal breaker as far as I am concerned.
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