Monoclonal Antibodies

IDEC 152

Date: December 4, 2002

by Chaya Venkat

Homing In On a B-cell Proliferation Marker

Related Articles: Lumiliximab: The Next Drug in CLL?

IDEC-152 is brought to us by the same friendly folks that have brought us Rituxan, Idec Pharmaceuticals. Unlike Rituxan, which is an anti-CD20 monoclonal antibody, IDEC-152 is an anti-CD23 monoclonal antibody. CD23 is called a B-cell differentiation antigen, that is increased as B-lymphocytes pass from a resting stage to an actively proliferating stage. It is sometimes broken off from the B-cell, and can be detected as a soluble fragment in the blood. High concentration of this soluble CD23 is an indication of rapidly progressing disease. It is expressed to a variable degree on follicular mantle B cells but only very occasionally in the splenic marginal zones or in germinal centers. The CD23 clustered antibodies give a characteristic binding pattern with follicular dendritic cells but the antigen is absent on plasma cells and B cell progenitors.

If you recall, a company representative mentioned to one of our members a couple of weeks ago that this new monoclonal will be in clinical trials soon, and that it shows great promise in combination with Rituxan. Here is a link to an excellent review article on monoclonal antibodies in the treatment of blood cancers, from the Moffitt Cancer center, dated April 2002: Moffitt Center Article. I would like to abstract some information from this article, Table 3, to initiate my discussion of IDEC-152, this new Monoclonal antibody is likely to be of interest to us in the future. A good percentage of CLL patients have CD23 positivity, in addition to CD20 positivity.

SCID (Severe Combined Immune Deficient ) mice were injected with human lymphoma cells on Day 0. Half of these mice were set aside as the control group, and every one of them was dead by day 30. The other half of the mice were treated with monoclonal antibodies, either as single agents or in combination. Here are the results:

Survival of SCID Mice with Lymphoma
Mitchell E. Reff, et al., Cancer Control

Antibody	Dose (Micrograms)	% mice alive after day 60
Control Group	0	0 (all dead by day 30)
Rituxan	400	10
IDEC 152	400	40
Rituxan + IDEC 152	200 each	70

Do remember, this is with mice. Hopefully it translates for humans as well.

Meanwhile, here is the announcement of a formal Phase-I clinical trial for use of IDEC-152, for CLL patients:
http://clinicaltrials.gov/show/NCT00046488

Correspondence with Idec Pharmaceuticals

Below is the letter I sent off to a recent contact at IDEC Pharmaceuticals. Surprisingly enough, someone at Idec did get back to us.

Dear Ms. Gillespie:

I enjoyed talking with you this morning.

I would appreciate your help in obtaining any information you can give us about use of IDEC-152 as therapy for Chronic Lymphocytic Leukemia (CLL) patients. 

Please allow me to introduce myself and the group I represent. I am the "owner" and moderator of an internet based CLL patient support and advocacy group. The function of this group is to provide information on cutting edge technologies and therapies that are opening up for our members, especially in the area of biologic therapies such as those based on monoclonal antibodies. By a process of self-selection, our members tend to be younger, in earlier stages of CLL, and most importantly, well informed and pro-active in taking charge of their own health care needs... 

I am quite familiar with references to very successful treatment modalities for CLL, based on various combinations of Rituxan with more conventional chemotherapeutic agents such as Fludarabine, Cyclophosphamide and Pentostatin. While the high percentage response rates in clinical studies of "RFC" combination therapies, especially the unprecedented high rate of complete remissions and respectable number of patients who are now "PCR negative" is very encouraging, many of the members of our group continue to believe that combinations of various monoclonal antibodies, such as Rituxan, Campath and now IDEC-152 are going to be the wave of the future. Since our archives are open only to our members, I have taken the liberty of attaching below one of my recent articles dealing with IDEC- 152 as a Microsoft Word document, for your reference. 

There are several members in our group whose oncologists have treated them with just Rituxan as single agent and front line therapy to control tumor burden, especially in early stage disease. Their experience, while it is "off-label" and anecdotal, has been extremely positive and our group members would like to know more about these types of treatment options. Of obvious interest is the possibility of avoiding potentially mutagenic and highly immune suppressive standard chemotherapy drugs, and instead control  the level of tumor burden and "b-symptoms" with the help of smart drugs such as IDEC-152 and Rituxan. It is our hope that monoclonal antibodies such as these may lend themselves to being used over and over again, potentially as a long-term maintenance drugs. Down the road, when gene therapy and vaccine approaches under investigation become readily available, we believe these modalities would most benefit patients who have  relatively undamaged immune systems. Combining these new approaches with prior monoclonal antibody therapy may well represent the one-two punch needed to fully control the disease.  We would like your help in locating the following information: 

1. Are there currently on-going clinical trials that are designed to use IDEC-152 alone as frontline therapy? If so, we would appreciate contact information. 
2. Does IDEC work with patients and their personal oncologists interested in setting up treatment protocols suited to individual patients, based on using this monoclonal, outside of the clinical trial(s)?
3. We would appreciate references to any published information on use of IDEC-152 as CLL therapy.
4. Is IDEC considering combination therapy using IDEC-152 and Rituxan for CLL patients? 

I thank you for your consideration. My contact information is provided below. 

Yours sincerely, 

Dr. Chaya Venkat
________

Interesting News from IDEC Pharmaceuticals

Just to prove there are still polite and friendly people out there who work for major pharmaceutical companies, I got a phone call back from Dee Wynne of IDEC pharmaceuticals, in response to my email of a few days back. She is in charge of the phase -1 IDEC-152 clinical trial. 

To refresh your memory, IDEC-152 targets CD23, which is expressed on many CLL B-cells. It is a particularly interesting target since it is the so-called activation marker on B-cells, suggesting that cells that display this marker are more likely to proliferate. There have been intriguing leads in murine (mouse) studies that suggest a combination of targeting CD20 (as in Rituxan) and CD23 (as in IDEC 152) has more than additive value, much much more. I have written on this subject before, please look it up in our archives. 

CD23 can also pose some problems in terms of effective dosage, since this marker is easily shed by the B-cells, into the blood serum. There is a chance that much of the anti-CD23 drug will be sopped up by these CD23 fragments floating around in the plasma, and have a hard time getting to the B-cell itself. On the other hand, even the free floating soluble CD23 is worth killing, so to speak, since it can reattach and activate new cells. This is one of the reasons why a high soluble CD23 level ("sCD23" level) is considered to be an indicator of poorer prognosis.  

Ms. Wynne tells me that this phase-1 trial is recruiting only patients who have been through prior therapy. But the prior therapy does not have to be standard chemotherapy, it could be another monoclonal such as Rituxan! So patients who have been through Rituxan therapy might be eligible for IDEC-152. The trial is being conducted at several centers, all the big names are involved: Kanti Rai, Byrd, Susan O'Brien, Ian Flinn, Tom Kipps etc (I might have missed a couple). Those of you who have personal contacts with the big shots, do check around, see what else you can find about this trial, and share with the rest of us. If you have specific questions, let me know and I will try to get you the answers from Ms. Wynne. 

IDEC 152 Press Release

Below is a press release from Dr. Byrd's lab re start of phase-1testing of this monoclonal antibody. As you know , IDEC-152 targets the CD23 marker on B-cells, as opposed to the CD20 marker targeted by Rituxan. CD23 is overexpressed in CLL cells, it is also called the activation marker on B-cells, suggesting that the cells expressing this marker are in the process of proliferating. Targeting this marker makes good sense, the drug is going after the very cells that are resistant to apoptosis (cell suicide) and likely to proliferate. 

However, one of the concerns is that the CD23 marker is easily snapped off of the cell, and a significant concentration of it is swishing around in the blood serum. This is of concern because this "soluble CD23" may grab hold of and sequester the precious drug, preventing it from getting to the cancer cells. Figuring out the right dosages of IDEC-152 that will be therapeutically effective will be a challenging task, and the "right" amount may be different from person to person, adding further complication. 

Nevertheless, this is a development that I am happy to see. Combinations of Rituxan and IDEC-152 yielded truly remarkable results in mouse studies, well beyond simple additive responses. (Please see my previous articles on this subject). Someday, combinations of these very well tolerated and relatively non-toxic monoclonals will replace present day standard chemotherapy drugs.

"MONKEY BUSINESS" AT ROOT OF NEW CANCER THERAPY"

October 29, 2002 COLUMBUS, Ohio — Tiny clumps of cells from the macaque monkey may mean the difference between success and failure for a new cancer therapy designed to help chronic lymphocytic leukemia (CLL) patients beat their disease. This new approach to antibody design - and others - is helping revive interest in the whole field of antibody therapy, a treatment option whose promise had faded somewhat since it was originally conceptualized more than twenty years ago. 

The new drug, temporarily dubbed IDEC-152, is one of a growing number of monoclonal antibodies designed to zero in on cancer cells, but leave healthy cells alone. Scientists think antibodies may be a good way to attack tumors because they are targeted to specific chemical "signatures" — antigens that are exceptionally abundant on the surfaces of many cancer cells. One measure of an effective antibody is its binding ability; a good one will fit snugly like a key in a lock. Once they latch on to the cancer cell, the thinking goes, monoclonal antibodies may be able to disrupt the action of the cancer cell, and even kill it. 

Physicians at the Arthur G. James Cancer Hospital and Richard J. Solove Research Institute are particularly intrigued with IDEC-152 because it's made differently than some they have used in the past and it targets a novel antigen expressed abundantly on CLL cells but not the great majority of normal cells in the body. 

Most of the earliest artificial antibodies used mice components in their development. Patients' immune systems were "reading" the mouse parts as foreign, and, ironically, mounting an immune response (called "HAMA"- human anti-murine antibody) to the very thing that was supposed to help them.  "We're interested in IDEC-152 and some of the newer antibodies in the treatment of leukemia because they are now being engineered differently," says Dr. John Byrd, an expert in leukemia and lymphoma at The James.

IDEC-152 is created by using protein sequences from a monkey that are structurally similar to analogous sequences in humans. Developers hope this so-called "primatized" process will keep patients from rejecting the treatment. 

"Basically, we hope the human body will not read it as foreign, and will accept it," says Byrd. 

Byrd is directing one of the early trials of the drug, and recently treated the first person with cancer in the world to get the compound, a middle-aged man with advanced CLL. It is part of a phase I study, the earliest type of study in a cancer trial, where researchers are simply trying to find out how much of the drug patients can tolerate and if it creates any side effects. 

CLL is the most common leukemia in adults in the United States, with approximately 7,500 new cases a year. It occurs more frequently in men than women, and while often initially responding well to chemotherapy, it often returns with shorter and shorter periods of remission as later treatments are given. 

CLL usually begins in the patient's own immune system, in infection- fighting white blood cells called B cells. Over a period of years, CLL cripples the body's immune system by mass-producing white cells that can't mature to their normal function of producing antibodies. 

IDEC-152 specifically targets the CD23 antigen, which is highly over-expressed in CLL cells. "It makes sense to target CD23 antigens, says Byrd, because they also play a role in regulating cell death. Basically, we hope that mixing IDEC-152 with CLL cells will lead to the death of the malignant cells." 

Trials of the new compound are open in 7 centers across the country. Researchers say results from the early trials should be known within the next 12 months.

The Value of CD23 as a Therapeutic Antibody Target

An anti-CD23 monoclonal drug is of obvious interest to us all, since many CLL patients exhibit this marker to a high degree. This drug is in an early phase clinical trial and at the moment there is not much additional news to report. I understand they are looking only for toxicity and dosage information. Last I heard from one patient who was in the Phase-I trial: at the dosage she received, there was no toxicity but no effect on the CLL either.

A couple more comments on the CD23 marker. The following URL points to a document that lists all of the CD markers, what cells exhibit them, etc. You can click on any particular CD marker you are interested in and it takes you to a page that gives a freat deal of information on that particular marker.  

As far as I could make out from the quickie chart displayed on the website above, CD23 marker is displayed on a variety of cell lines, not just B-cells: Mature B cells, activated macrophages, eosinophils, follicular dendritic cells, and platelets all exhibit this marker. So my guess would be that using this marker as the target would not be as selective as using Rituxan to target CD20, a marker that is present only on mature B-cells. I would worry particularly about the platelets, many of our patients have low platelet counts to begin with, it would not do to have the few they have attacked by the anti- CD23 monoclonal drug. 

On the other hand, not every CLL patient has sufficient expression of CD20 to make him/her a good candidate for Rituxan only therapy. Some other monoclonal would be a good weapon to have in our arsenal. CD23 is also attractive in the sense that it is the B-cell activation marker, it is up-regulated by B-cells when they are proliferating rapidly. Would it not be nice to kill especially those B-cells that are proliferating rapidly and therefore the ones adding to the tumor load? My guess would be that CD23 is too unspecific to take on the full burden for CLL cell kill as a single agent monotherapy, but it might be good as a second line monoclonal, co-administered with Rituxan or Campath, for instance, to get the CLL cells in the crosshairs so to speak.