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Monoclonal
Antibodies

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Review of Monoclonal Antibodies in Development

Date: May 18, 2003

by Chaya Venkat

Naming the Agents in Antibody Zoo

Related Articles:
Introduction to Monoclonal Antibodies
Sons of Rituxan and Campath
HuMax-CD20
Lumiliximab
Bexxar

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Have You Heard of This One?

The biotech industry is feverishly designing and testing interesting new monoclonal antibodies for use in a variety of diseases, including CLL. The smart targeting capability of these agents combined with a range of payloads and effector mechanisms offer the hope of effective therapy with little collateral damage. Here is a short catalog of monoclonal antibodies and our comments on what they might mean to CLL patients.

Terminology and Types

Here is a diagram that lays out some of the characteristics of the generations of monoclonal antibodies currently in the proving process. You might already know the rule for naming these agents: a "xi" in the middle (as in rituximab, lumiliximab) indicates a chimeric (part mouse) monoclonal, a "zu" (as in alemtuzumab — Campath-1H) indicates a "humanized" monoclonal and a "mu" (as in ofatumumab — HuMax-CD20) indicates a fully human monoclonal. By the way, the "…mab" ending indicates the agent's scientific (or generic) name, which follows at least some loosely constructed rules and is typically not capitalized. The trade name or product brand name, on the other hand, is selected by the drug company involved for marketing purposes and does not have to follow any particular naming convention, except perhaps marketing appeal. Rituxan and Campath are examples of the latter.

Generations of Monoclonal Antibodies
Mitchell E. Reff, et al., Idec Pharmaceuticals

Epratuzumab (anti-CD22)

There is one clinical study that I am aware of that combines Rituxan, the anti-CD20 monoclonal with epratuzumab, the anti CD-22 monoclonal. This study seems to be limited to NHL patients only, but I think it should be possible to get similar protocols for CLL patients who happen to be both CD20 and CD22 positive.

The results look quite good, for the indolent cases. Also, there is a sense these days that monoclonals take a while for their full effect to be felt, so that partial responses gradually improve to complete responses over time. Any way, here is the press report, it pretty much speaks for itself.

Press Release:

July 24, 2002

IMMUNOTHERAPY 

Immunomedics announces additional interim results of epratuzumab combination in treating non-Hodgkin lymphoma

Immunomedics, Inc., (IMMU) announced at the 38th annual meeting of the American Society of Clinical Oncology in Orlando, Florida, that interim results of the phase II clinical trial testing the cancer therapeutic antibody, epratuzumab, licensed to Amgen (AMGN), in combination with another antibody, rituximab, appear to show a beneficial antilymphoma effect without showing an increase in toxicity.

This combination of CD-22 directed immunotherapy (epratuzumab) and CD- 20 directed immunotherapy (rituximab) is being evaluated at New York- Presbyterian Hospital's Weill Cornell Medical Center for the treatment of relapsed and refractory non-Hodgkin lymphoma (NHL).  A total of 21 patients have been treated in the trial to date, including 16 indolent (low grade) and 5 diffuse large cell (a type of aggressive lymphoma) NHL patients. In the indolent arm of the study, 63% of patients (10 out of 16) had an objective response as measured by standard criteria. This objective response rate is in the range of that observed with single-agent rituximab in other studies targeting a similar patient population. In addition, however, 90% of the responders (9 out of 10) in the indolent patient population achieved a complete response (CR CRu), a rate that is higher, based on historical data, than the one observed with rituximab single agent. Furthermore, all responses are still ongoing with a follow-up up to 16 months. "We are pleased to see a consistent pattern of results as the number of treated patients increases and as the duration of responses seen in follow-up grows," said lead investigator Dr. John Leonard, medical director, oncology services and assistant professor of medicine, division of hematology and medical oncology, department of medicine at Weill Cornell Medical College.

This article was prepared by Immunotherapy Weekly editors from staff and other reports.

Zevalin: An Introduction (Radiolabeled Anti-CD20)

The name "Rituxan" is now a household word for most CLL families. Here is another one that may soon join your vocabulary, "Zevalin". Or, if you are into torturing your little gray cells, you can try to remember "ibritumomab tiuxetan".

You all know Rituxan targets CD20 positive b-cells, and it is a monoclonal antibody, with murine (mouse) ancestry. It was originally approved for NHL, and more recently it is becoming available to CLL patients. I understand it may soon be approved by the FDA for CLL as well. Zevalin follows in Rituxan's footsteps, in that it too is a monoclonal antibody that targets CD20 positive b-cells, with a big added difference: it carries a payload of radioactive Yttrium 90. Think of it as a smart bomb, that not only knows to home in on CD20 positive cells, but then packs the added punch of radioactivity that makes sure the cell it attaches to is killed, as well as several of its neighbors. This is the trade-off: the kill rate is great, but you also need to be careful that not too many innocent by-standers are not killed in the process.

As usual, Zevalin is being studied extensively for NHL, CLL is just getting into the picture. Part of the concern is that bone marrow in CLL patients is much more involved than in NHL patients. Since Zevalin's radioactive payload kills not just the single b-cell it attaches to, but some of the neighboring cells as well, you can understand the concern. A high concentration of CD20 positive CLL cells in the bone marrow may not be a good situation in which to use Zevalin, since it would put at risk killing of adjacent stem cells and progenitor cells necessary for making all the other cells that the body needs to survive.

But there are situations where the use of Zevalin may be warranted, such as in the case of a patient who has been through preparatory chemotherapy regime, such as FRC or some other regime, and has only minimal residual disease (MRD). If a bone marrow biopsy (BMB) also indicates that much of the bone marrow involvement has also been resolved by this front end therapy, Zevalin becomes an option for clearing out the remaining few CLL cells and kick the patient into deep PCR negative status.

Please read my previous article on MRD, and why it may be in your interest to push this into PCR negative territory, to get the logic of this approach. Also, it might be nice to get a refresher into how Rituxan works, there is a folder on this subject in the Files section of CLL topics; also several dozen articles on the subject that you can locate by doing a simple search of the archives. People, the more comfortable you become navigating this website, the more useful you will find the information here.

I have no doubt that Zevalin will also be used in other situations, where the patient is still CD20 positive, but has become refractory to further Rituxan therapy. Remember, one of the major pathways by which Rituxan works is through antibody dependent cell mediated toxicity, and this route may become compromised in some patients. My guess would be that Zevalin has a bigger punch, in the sense of doing the killing by itself, without needing as much  help from the patient's own immune system.

Delivering radiation on a cellular level is heck of a lot more sophisticated than total body irradiation, or even spot radiation. My guess would be that the overall radiation absorbed by the body is a lot less in using a targeted radiotherapy approach such as Zevalin. This is truly a case where less is better, just so it is enough to do the job with fewer "collateral damage". It is interesting to note the similarities between the language of war and cancer therapy. We may soon be hearing about "smart bombs" and "payload" and "collateral damage" on TV, with reference to Iraq. (Editor's Note: Yes, yes, we heard about those. Successful invasion. Bad case of side effects and secondary malignancies.)

Below are two PubMed abstracts that talk about Zevalin, in terms of its use for NHL. This is worth tracking, I am sure the technology will soon trickle down to us folks with CLL, in the near future. (By the way, you may have heard of "Bexxar", which too is a monoclonal antibody with radioactive payload, which also targets CD20 positive cells. Bexxar is significantly behind in getting FDA approvals, and it will be a while before it becomes widely available).

Abstracts:

Ibritumomab tiuxetan radioimmunotherapy for patients with relapsed or refractory non-Hodgkin lymphoma and mild thrombocytopenia: a phase II multicenter trial.

Wiseman GA, Gordon LI, Multani PS, Witzig TE, Spies S, Bartlett NL, Schilder RJ, Murray JL, Saleh M, Allen RS, Grillo-Lopez AJ, White CA.

Division of Nuclear Medicine, Mayo Clinic, Rochester, MN 55905

Mildly thrombocytopenic patients with relapsed or refractory low-grade non-Hodgkin lymphoma (NHL) have an increased risk of chemotherapy-induced myelosuppression following treatment. The safety and efficacy of radioimmunotherapy with a reduced dose of (90)Y ibritumomab tiuxetan (0.3 mCi/kg [11 MBq/kg]; maximum 32 mCi [1.2 GBq]) was evaluated in 30 patients with mild thrombocytopenia (100- 149 x 10(9) platelets/L) who had advanced, relapsed or refractory, low-grade, follicular, or transformed B-cell NHL. The ibritumomab tiuxetan regimen included an infusion of rituximab (250 mg/m(2)) and injection of (111)In ibritumomab tiuxetan (5 mCi [185 MBq]) for dosimetry evaluation, followed 1 week later with rituximab (250 mg/m (2))  and (90)Y ibritumomab tiuxetan (0.3 mCi/kg [11 MBq/kg]). Patients (median age, 61 years; 90% stage III/IV at study entry; 83% follicular lymphoma; and 67% with bone marrow involvement) had a median of 2 prior therapy regimens (range, 1-9). Estimated radiation-absorbed doses were well below the study-defined maximum allowable for all 30 patients. With the use of the International Workshop criteria for NHL response assessment, the overall response rate was 83% (37% complete response, 6.7% complete response unconfirmed, and 40% partial response). Kaplan-Meier estimated median time to progression (TTP) was 9.4 months (range, 1.7-24.6). In responders, Kaplan-Meier estimated median TTP was 12.6 months (range, 4.9-24.6), with 35% of data censored. Toxicity was primarily hematologic, transient, and reversible. The incidence of grade 4 neutropenia, thrombocytopenia, and anemia was 33%, 13%, and 3%, respectively. Reduced-dose ibritumomab tiuxetan is safe and well tolerated and has significant linical activity in this patient population.

Subsequent Chemotherapy Regimens Are Well Tolerated After Radioimmunotherapy With Yttrium-90 Ibritumomab Tiuxetan for Non-Hodgkin's Lymphoma.

Ansell SM, Ristow KM, Habermann TM, Wiseman GA, Witzig TE.

Divisions of Hematology and Nuclear Medicine, Mayo Clinic, Rochester, MN.

PURPOSE: Yttrium-90 ((90)Y) ibritumomab tiuxetan (Zevalin; IDEC Pharmaceutical, San Diego, CA) is an effective therapy for patients with relapsed B-cell non-Hodgkin's lymphoma. The predominant toxicity of (90)Y ibritumomab tiuxetan has been myelosuppression, and concern has been expressed about the tolerability of further treatment after this therapy. The goal of this analysis was to evaluate the therapy given to patients who relapsed after (90)Y ibritumomab tiuxetan.
PATIENTS AND METHODS: A retrospective analysis was performed on 58 patients treated at a single institution on five separate protocols that used (90)Y ibritumomab tiuxetan 0.4 mCi/kg. All patients had experienced disease progression after (90)Y ibritumomab tiuxetan treatment and received subsequent therapy. The toxicity seen in this cohort of patients with subsequent treatment regimens was analyzed and compared with that of control groups who did not receive (90)Y ibritumomab tiuxetan.
RESULTS: The median number of subsequent therapies was two (range, one to seven). Sixteen (28%) of the 58 patients received growth factor support with subsequent chemotherapy, and two patients were treated with reduced doses because of persistent pancytopenia. Eight patients subsequently had an autologous stem-cell transplantation with stem cells collected after (90)Y ibritumomab tiuxetan therapy. Excluding patients hospitalized at the time of transplantation, 13 patients were hospitalized for neutropenic fever, thrombocytopenia, or both. When compared to patients who did not receive (90 Y ibritumomab tiuxetan, there was no significant difference in toxicity.
CONCLUSION: We conclude that chemotherapy or autologous stem-cell transplantation after prior therapy with (90)Y ibritumomab tiuxetan is feasible and reasonably well tolerated. The toxicity with subsequent therapy seems similar to that in patients not treated with (90)Y ibritumomab tiuxetan.

Straight from IDEC

Below are some quotes from IDEC regarding the use of Zevalin, while minimizing damage to stem cells. This is one area of very significant differences between NHL and CLL. Most of us with CLL have higher bone marrow involvement than the typical person with NHL. 

Looking over the numbers, I am not all that excited. The extra level of risk to the bone marrow in case of CLL patients does not seem to be warranted, when the Zevalin results are compared to those obtained using just Rituxan. I guess when one has run out of options, any port in a storm is a good idea, but I do not believe this drug is likely to be our first choice coming out of w&w.

Press Release:

IDEC Pharmaceuticals Corporation (Nasdaq: IDPH) announced it presented updated response duration data of Zevalin(R) (ibritumomab tiuxetan) in its Phase III randomized, controlled study of 143 patients with relapsed or refractory low grade, follicular, or transformed B-cell non-Hodgkins lymphoma (NHL) at the 17th Annual Meeting of the Society for Biological Therapy in San Diego, November 8-10, 2002. 

In the pivotal study, which was previously reported, the treatment arm receiving the Zevalin therapeutic regimen showed an overall response rate (ORR) of 80 percent and a complete response (CR) rate of 34 percent, compared to the Rituxan alone control arm, which showed an overall response rate of 56 percent and a CR rate of 20 percent. The median time to progression (TTP) between the two arms was not statistically different, although there was a trend towards longer TTP in patients with follicular NHL (15.0 months in the Zevalin arm versus 10.2 months in the Rituxan arm) and patients who achieved a CR (24.7 months versus 13.2 months, respectively). A complete response is achieved in a clinical trial when disease is no longer detectable. "Among patients achieving a CR in the Zevalin arm, 32.1 percent are still in remission approximately three to four years (34 to 49 months) later," said Christine A. White, IDEC's Vice President, Medical Affairs. "Rituxan(R) control arm patients had fewer CRs with shorter median duration, however, 36 percent of Rituxan treated patients achieving CR also have remained in remission for approximately three to four years (36 to 51 months)." 

Radioimmunotherapy

During her presentation Dr. White noted: "Zevalin is the only radioimmunotherapy (RIT) that has been compared with Rituxan in a randomized, controlled study in Rituxan-naive patients with relapsed or refractory, low grade, follicular, or transformed B-cell NHL. Both Zevalin and Rituxan can induce long-term durable responses in NHL patients." 

On February 19, 2002, IDEC received marketing approval in the U.S. for Zevalin, which is the first radioimmunotherapy approved by the U.S. Food and Drug Administration (FDA). Zevalin, as part of the Zevalin therapeutic regimen, is indicated for the treatment of relapsed or refractory, low grade, follicular or transformed B-cell non-Hodgkin's lymphoma, including patients with Rituximab-refractory, follicular NHL.

A monoclonal antibody linked to the radioisotope Yttrium-90, Zevalin targets the CD20 antigen on the surface of mature B cells and B-cell tumors, inducing cellular damage in the target and neighboring cells. The Zevalin therapeutic regimen consists of Rituxan preceding Indium-111 Zevalin followed seven to nine days later by a second infusion of Rituxan prior to Yttrium-90 Zevalin.

Safety 

In safety data based upon 349 patients, the most serious adverse reactions of the Zevalin therapeutic regimen included severe infusion reactions and thrombocytopenia (61% of patients with platelet counts less than 50,000 cells/mm3) and neutropenia (57% of patients with absolute neutrophil counts less than 1,000 cells/mm3). Infections requiring hospitalization (7%) and fatal cerebral hemorrhage (less than 1%) have occurred in a minority of patients in clinical studies. Also seen were myeloid malignancies and dyscrasias (myelodysplastic syndrome).

Bexxar and Stem Cell Transplants

There is trial going on at the Clinical Research Division, Fred Hutchinson Cancer Research Center, University of Washington, using high-dose chemo-radio-immunotherapy with autologous stem cell support for relapsed mantle cell lymphoma. The protocol consists of Bexxar followed by Etoposide + cyclophosphamide and the an autologous SCT (Stem Cell Transplant). 

My question is Bexxar does not restrict the amount of bone marrow involvement, and I was wondering why? Zevalin has a restriction requiring no more than 25% bone marrow involvement. Since Bexxar isn't approved, could it be they just don't know yet? Or is the different radioactive isotope used not require this restriction? I haven't been able to find anything out about this, so I was hoping you might be able to help. 

Plus in this trial, the Bexxar is administered first, and then the chemo is administered. That didn't seem logical to me, but... 

You can read the free full text Blood Journal article: High-dose Chemo-radioimmunotherapy. 

Bexxar is an anti-CD20 monoclonal antibody, with a radioactive payload. Think of it as Rituxan with a radioactive kick to it. In this sense both Bexxar and Zevalin are similar. They carry slightly different types of radioactive payloads, with different half-lives (period for which they are active) and distance over which they are active. 

Unlike Rituxan, which only kills the cell to which it gets attached, Bexxar kills neighboring cells as well, because of the radioactive payload. If there are a significant number of CD20 positive cells in the bone marrow, then it follows that the Bexxar will get attached to these cells and kill them, as well as any other bone marrow cells, including stem cells, that happen to be in the vicinity. So, unlike Rituxan, it is possible to have significant killing of bone marrow stem cells with Bexxar, if the load of tumor cells in the bone marrow is high. This is the reason why they put a limit on the bone marrow involvement prior to use of Bexxar. 

But...if the idea here is to kill off the bone marrow completely, prior to an stem cell transplant, then I guess it does not matter if the Bexxar kills of some of the old bone marrow cells. It sounds like the approach in this clinical trial is to do a truly heavy number on the bone marrow, with Bexxar followed by other chemotherapy drugs, prior to the stem cell transplant. In this case, use of Bexxar is not limited by percent of bone marrow infiltration. Who cares, it is all going to get wiped out, anyway, prior to the SCT. 

Editor's Note: for current take on the use of Bexxar in CLL therapy, you may want to read our article dated May 15, 2007 — Bexxar: an Introduction to Radioimmunotherapy.

Bispecific Antibodies — A Fatal Attraction of the Cancer Kind

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.

Here is a simple (way over simple) picture of how Rituxan works: This MOAB has a hook on it that latches on specifically to cells expressing CD20. The whole issue with Rituxan for CLL was that not all the CLL cells expressed CD20, and not in sufficient quantity. It works better for NHL because there are more CD20 units per cell, and almost all of the cells express CD20.

Once the Rituxan is latched on to the CD20 on a B-cell, it lights up the B-cell like a neon sign, and any T-cells that happen to pass by will recognize it for the bad guy it is, and kill it. Of course, there have to be enough T-cells around, to do the job in the first place, and they have to be at the right place at the right time, and not subverted into inactivity by the cancer cells.

Now comes the fatal dating service of bispecific antibodies. Think of these as sort of "Y" shaped entities, one arm of the "Y" has a hook on it for CD3, a cluster designation expressed by vast majority of T-cells. The other arm of the "Y" has a hook for CD19, which is expressed by majority of b-cells. 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 arm of the "Y" 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. No amicable divorce is possible here, this union ends when the B-cell is killed.

This approach is not limited to bispecific antibodies targeting only CD3 and CD19. Basically, it is now possible to have one arm of the "Y" be able to latch on to whatever we decide it should latch on to on the T-cell, and the other arm latch on to specific antigens expressed by the patient's specific tumor. Not  withstanding my frivolity here, these are truly remarkable developments, and our ability to use these technologies is going to be limited only by the speed with which we can test them, get approvals, and convince some big company to go commercial. Money makes the world go round.

The abstract below gives you a flavor of the kind of work that is going on. If you type "bispecific antibodies" into PubMed engine, you 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 instead. Here is one quote from the abstract below that stands out: Comparing the CD3/CD19 bispecific antibody versus Rituxan, the researchers found that "Under identical experimental conditions, the anti-CD20 monoclonal antibody rituximab had an at least 100,000-fold lower in vitro efficacy".

Pretty good, huh? Now we just have to stay alive, till they graduate from cells in petri dishes to mice to men (women).

Abstract:

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.

LMB-2

The background and science behind the immunotoxin LMB-2, as well as the description of a Phase II clinical trial featuring it, has been discussed in a full-length article devoted to this agent: LMB-2.

Ontak

This discussion of Ontak was originally contained in Topics Alert #13.

Ontak is an immunotoxin like LMB-2, which has been reviewed under Clinical Trials on this website. Like LMB-2, Ontak also targets CD25 marker, but instead of the Pseudomonas toxin fragment it carries a fragment of diphtheria toxin. The logic is very similar. Below is an abstract of the results of a Phase II clinical trial that was conducted with mostly very late stage and certainly fludarabine relapsed and refractory patients. In other words, a tough crowd. Out of 18 patients recruited for the study, 12 were available for evaluation (I expect the other patients dropped out of the study before completion, possibly due to poor tolerance of the drug or progressive disease, something that happens frequently when one is dealing with advanced stage patients.)

11 out of the 12 showed reduction in blood CLL counts (remember, peripheral blood CLL cells are the easiest to kill, they are no more than the tip of the iceberg), 6 of these were more than 98% reduction in blood CLL counts. 7 out of 12 patients showed "some" reduction in lymph node size, the two star responders had 60% and 80% reduction respectively. I wish this was a little better, once again it is those dastardly lymph nodes that are the stumbling block. Using pre- and post bone marrow biopsies, 7 out of 11 patients had more than 50% reduction in bone marrow involvement, while 3 of them had more than 98% reduction. Pretty good for this refractory group of patients. Toxicities were not too bad, I am particularly pleased that there was no significant myelosuppression or immunosuppression. This is one area where immunotherapies such as this and LMB-2 have a big advantage over conventional chemotherapy. The progression free survival times may not seem like much, but given the nature of the patient group they are actually quite good. I am sure there will be new clinical trials of Ontak, with slightly different protocols and perhaps with immune boosters such as Cpg-ODN that we discussed in the LMB-2 article, or "Targretin" that appears to have a similar effect (see second abstract below), namely increasing the expression of CD25 marker on the target cancer cells. If you have relapsed or aggressive disease, and not a good candidate for bone marrow transplants because you do not have a well matched sibling donor, it might be worth your while to discuss immunotoxin therapy clinical trials with your doctor. Even people who are looking at a "MUD" (matched unrelated donor) transplant may wish to consider this type of therapy as an intermediate stage, since it does not seem to burn any bridges. Tough decisions to make, but it is better to have a couple more options than have your back against the wall, right?

If you want to read full text articles of either of the abstracts cited below, write to us and we will help you locate the PDFs.

Abstract

Clin Cancer Res. 2003 Sep 1;9(10 Pt 1):3555-61.

A phase II study of DT fusion protein denileukin diftitox in patients with fludarabine-refractory chronic lymphocytic leukemia.

Frankel AE, Fleming DR, Hall PD, Powell BL, Black JH, Leftwich C, Gartenhaus R.

Wake Forest University Baptist Medical Center, Winston-Salem, North Carolina 27157

PURPOSE: Patients with relapsed or refractory chronic lymphocytic leukemia (CLL) have a poor prognosis. We tested the safety and efficacy in these patients of a diphtheria fusion protein DAB(389)IL2 (denileukin diftitox) directed against the interleukin 2 receptor that is expressed by CLL cells.
EXPERIMENTAL DESIGN: DAB(389)IL2 was administered by 60 min i.v. infusions for 5 days every 21 days at 9 or 18 micro g/kg/day for up to eight cycles.
RESULTS: Eighteen patients were treated. The mean age of the patients was 61.8 years. There were 14 males and 4 females. Two had Rai stage I, 6 had Rai stage II, and 10 had Rai stage IV. The mean number of prior treatments was 4.5 (range, 1-11). Responses were evaluated by peripheral CLL counts, computed tomography scans of all nodes and bone marrow biopsies. Twelve patients received greater than or equal to three cycles of DAB(389)IL2 and were evaluable for response. Eleven of 12 patients showed reductions of peripheral CLL cells, with 6 of 11 showing >95% reductions. Seven of 12 patients showed reductions of node diameters on exam and computed tomography scans, and 2 of 12 showed 60 and 80% shrinkage, respectively. Pre and postbone marrow biopsies showed a reduction in CLL marrow index in 11 patients. Seven of 11 patients had >50% reduction, including >98% reduction in 3 patients. DAB(389)IL2 produced 2 of 12 (17%) partial remission and 7 of 12 (58%) minimal responses. Progression-free intervals in the responders were 1, 1, 3+, 4, 9, 10, 10+, 14 and 19+ months. Toxicities were mild to moderate and included asymptomatic, transient transaminasemia, fever, asthenia, hypoalbuminemia, nausea, vomiting, myalgias, rash, anorexia, vascular leak syndrome, and elevated creatinine kinase. Antidiphtheria toxin antibody levels were variable and ranged from 0 to 9 micro g/ml (n = 5).
CONCLUSIONS: DAB(389)IL2 produced a rapid decrease of leukemic cells in the bone marrow and peripheral blood of most chemotherapy refractory CLL patients. Most patients also tolerated DAB(389)IL2 well, without significant myelosuppression and/or immunosuppression. The prolonged progression-free interval and subjectively observed quality-of-life in responders is intriguing. The results suggest DAB(389)IL2 has biological activity in patients with B-cell CLL. Follow-up studies of combinations or altered schedules or doses to improve the response rate are warranted.
PMID: 14506141
____________

(Note: "high-affinity IL-2R" is the same as CD25. Same marker, different way of saying it.)

Blood. 2002 Aug 15;100(4):1399-403.

Immunomodulatory effects of RXR rexinoids: modulation of high-affinity IL-2R expression enhances susceptibility to denileukin diftitox.

Gorgun G, Foss F.

Department of Hematology Oncology and Experimental Therapeutics, Tufts New England Medical Center, Boston, MA

Rexinoids binding to both the retinoic acid receptor (RAR) and retinoid X receptor (RXR) families of rexinoid receptors have demonstrated clinical activity in hematologic malignancies and have been shown to mediate genes associated with both growth and differentiation. RXR rexinoids have demonstrated efficacy in the treatment of cutaneous T-cell lymphomas, but the mechanism of action is unclear. We explored the immunomodulatory effects of RAR and RXR rexinoids in human T- and B-cell leukemia cells and demonstrated that RXR rexinoids are capable of up-regulating high-affinity interleukin-2 receptor (IL-2R) expression. Exposure to 10(-6) to 10(-10) M bexarotene or Panretin for 48 hours was associated with increased expression of both the p55 and p75 subunits of the IL-2R in T-cell leukemias and p75 in B-cell leukemias. Furthermore, rexinoid exposure enhanced susceptibility of the cells to denileukin diftitox fusion toxin-targeting and -intoxicating cells expressing high-affinity IL-2R. These results suggest a rationale for combining rexinoids with IL-2R-targeted therapies in lymphoid malignancies as well as possibly in autoimmune diseases.

PMID: 12149223
____________

Lumiliximab: Another Entry from the Idec Stables

An antibody targeting the CD23 antigen has been covered in our articles titled IDEC 152 and Lumiliximab: The Next Drug in CLL? This drug has the potential to enhance responses in combination therapies featuring other drugs and may even have a role in maintaining remissions — the epitope it targets is the B-cell proliferation marker, CD23.

Improved CD-20 Monoclonals

How can monoclonal antibody therapy be improved for CLL patients? One obvious area is the chosen target. In Rituxan, the chosen target is the CD20 marker. It is actually a pretty good choice. It is now generally accepted that most B-cells display this marker, to varying degrees, but it is not displayed by other important cell lines. That selectivity is important, it is what makes Rituxan therapy non immunosuppressive, non-toxic to the bone marrow, etc. It is understood now that the CD20 marker is not shed into the blood to any great degree, so the drug is not wasted by attaching itself to the junk CD20 floating around in the serum. It is also known that CD20 does not mutate into another form upon being attacked by targeted drugs, and there has been no evidence that cells become refractory to attack by anti-CD20 monoclonals, and repeat administrations of Rituxan are effective. 

So, how can this approach be made more effective? It would be nice if we can get higher rates of CLL cell kill. Right now, the cell kill rates are quite low for CLL, compared to other NHL cancers, when treated with Rituxan. Molecular remissions and PCR negative status is hardly ever reached by just Rituxan therapy alone, for CLL patients. Several mechanisms are suggested for this lower efficiency in killing CLL cells: 

  1. There are fewer CD20 markers per CLL cell, compared to NHL. Therefore fewer Rituxan molecules are attached per CLL cell upon therapy, and this reduces efficiency of cell kill. It would be great if some one were to come up with a way of increasing the expression of CD20 on CLL cells, along the lines of the Ontak/ Targretin pair, where the Targretin is a pre-drug administered to increase the density of expression of CD25, the target for Ontak. It would be nice if we can make every CLL patient light up like a Christmas tree with bright CD20 expression on 100% of the B-cells, prior to Rituxan therapy.
  2. Rituxan is supposed to do very little of the cell kill by itself, it depends upon the body's own immune system (complement and cells like T-cells, NK cells, macrophages, neutrophils etc) to do the killing. I wonder if some one is working on a version of Rituxan like monoclonal, that also carries a pay load of a toxin, along the lines of Ontak. I am not too thrilled with the radioactive payload carrying versions of Rituxan, such as Bexxar and Zevalin. These may work well for NHL patients, but they are too toxic for CLL patients in general, since majority of us have significant bone marrow involvement. The radioactivity of Bexxar and Zevalin cause indiscriminate killing of important stem cells that just happen to be in close proximity to CLL cells, if too much of the drug homes in on cancer cells in the bone marrow. A carefully chosen and selective toxin tipped Rituxan would be interesting, which kills just the cancer cell to which it is attached. This would be especially interesting to late stage and heavily pre-treated patients whose immune system is no longer able to provide the necessary assist in cell kill.
  3. Is there a way of making the Rituxan type monoclonal more effective in the cell kill, without the poison payload? As you know, Rituxan is an "chimeric" monoclonal antibody, i.e., part of it is mouse based and part of it is human based. All antibodies are shaped like a "Y". Each arm of the Y are the pincers that attach selectively and exclusively to the marker of choice, CD20 in the case of Rituxan. This is the part of the molecule that is also based on mouse DNA. The stem of the Y is the human part in Rituxan. This stem of the Y is the part that attracts the T-cells, binds them to it, and gets them to kill the cancer cell. This route of cell kill is called ADCC (Antibody Dependent Cellular Cytotoxicity). It is my impression that several companies, including IDEC, are working on ways of making the stem of the Y more attractive to T-cells, make these immune effector cells home in better on the Rituxan bound cancer cells and thereby increase cell kill. In other words, more effective ADCC. 
  4. Another approach is to increase the stickiness of the arms of the Y. If these pincers hang on more tightly to the CD20 marker on the cancer cells, stay attached for longer periods of time without getting shrugged off so to speak, there is a better chance that the cancer cells will get killed. If the Rituxan molecule falls off of the cancer cell before that cell has been killed, it might get eliminated from the body before it has a chance to do some good. Maintaining high concentrations of the drug within the body, without having it eliminated quickly in the urine or feces is important criteria for efficiency.
  5. Besides ADCC, complement plays an important role in cell kill, and  this has been discussed in some detail in recent article on CLL Topics. Once the CLL cell is targeted by Rituxan, the formation of the antigen-antibody pair (CD20-Rituxan pair), complement fragments quickly coat the cell, "opsonizing" the cell. Presence of complement fragments attracts cells like neutrophils and macrophages and NK cells to the vicinity. These are cells that are capable of destroying and carting away the debris of any cell that has been opsonized by complement.  

The problem is, the body has several layers of fail-safe protections to prevent the body's own cells getting killed by the macrophages etc. Cancer cells use one of these fail-safes to escape attack by macrophages et al, even after they have been tagged by Rituxan, and coated by complement fragments. CLL cells are particularly good at this, which is why the important Complement Dependent Cellular Cytotoxicity (CDCC) does not happen very well in CLL patients. There are markers (CD55, CD59 and others) which are present on CLL cells, that attach to the macrophages and NK cells etc, preventing them from getting activated into a murderous phase. We talked before of immune modulators such as Beta Glucan, that compete with these markers, prevent them from attaching to the macrophages and NK-cell etc, and therefore may facilitate the cell kill via CDCC.  

So my wish list for monoclonal antibodies (MABs) and clinical trials for administering them would include:  

  1. Some way to increase CD20 expression on CLL cells, along the lines of Targretin, which enhances CD25 expression.  
  2. MABs that can do the killing all by them selves, perhaps because they are tipped with a selective and carefully chosen poison, not radioactivity, along the lines of Ontak. 
  3. New versions of Rituxan with stickier arms of the Y, so the drug lasts longer in the body. 
  4. New versions of MABs, with the stem of the Y made to  attract T-cells more effectively.
  5. Potential co-administration of human blood plasma, to increase the amount of complement present at the time of Rituxan administration. Rituxan therapy uses up and depletes complement levels, it makes sense to get these levels back up before administering more MAB.
  6. Co-administration of immune modulators such as IL-2, interferon alpha, GM-CSF (increased production of T-cells and the like to do the killing), and compounds such as Beta glucan to compete with the CD55 and CD59 markers that interfere with and inhibit efficient functioning of the CDCC cell kill mechanism. (See our article, Beta Glucan, Complement and Rituxan, to learn more about beta glucan).
  7. Combination of MABs such as Rituxan that target CD20 marker with other monoclonals that target other markers. An example of this is co-administration of Rituxan with IDEC-152, which targets CD23. This marker is the B-cell activation marker, and abundantly expressed on B- cells, especially when they are multiplying quickly. IDEC-152 is already in clinical trials, and mouse studies with the combo monoclonal approach has shown remarkable synergy. (See previous articles on IDEC-152). My bet, these sorts of combos, using more than one monoclonal at a time, will be in clinical trials before the year is over.
  8. The URLs I gave yesterday to HealthTalk mentions interest in combining Rituxan therapy with Ontak therapy, combining two MABs, one targets CD20 and the other targets CD25. Clinical trials may take off on this front before the end of this year.

HuMax-CD20: Improved CLL Therapy?

I have reported before on Genmab and their HuMax-CD20 monoclonal antibody. Here is some further information, presented at a symposium just yesterday. 

HuMax-CD20 is like Rituxan, in the sense it is a monoclonal antibody that targets the CD20 marker on B-cells. Unlike Rituxan, which is a chimeric antibody (part human, part mouse), HuMax-CD20 is fully human. It is therefore likely to have less toxicity of the type associated with people having allergic reactions to the mouse component. What makes it really interesting, however, is the claim that it is 10 to 100 times more effective than Rituxan. The company Genmab believes the adhesion of the HuMax-CD20 antibody to the B-cell is better than that of Rituxan, and since it sticks to the target cell longer and better, it is able to get around the complement inhibitory proteins (such as CD55 and CD59 we discussed at great length on this site), and thereby initiate effective complement dependent cytotoxicity (CDC) as a mechanism for killing the tagged cells.

If these claims — based on pre-clinical CLL cell studies — are borne out in full fledged mouse studies, followed by human clinical trials, this is good news indeed. CLL is one of the B-cell malignancies that shows the least response to Rituxan, unlike several NHL diseases like follicular lymphoma, for example. Development of a better and more sensitive anti-CD20 monoclonal is just what the doctor would order for CLL. For all the CLL patients with dim expression of CD20, and therefore with expectation of poor response to Rituxan, HuMax-CD20  may prove to be the therapy of choice in future.

My bet is that if these claims are for real, HuMax-CD20 will be in clinical trials no later than 2005. There is a lot of money riding on these drugs and that is always the driver for fast paced race to commercial availability.

Press Release:

Copyright 2003 Drug Week via NewsRx.com and NewsRx.net 

Drug Week 

March 7, 2003 

LEUKEMIA: New HuMax-CD20 and HuMax-EGFr preclinical data presented 

Genmab A/S announced that its HuMax-CD20 human antibody appears to kill tumor cells that are resistant to rituximab, a marketed antibody directed to the same disease target.  In preclinical testing, HuMax-CD20 effectively killed tumor cells from a number of cancer patients who had B-cell chronic lymphocytic leukemia (B-CLL). In side-by-side testing of killing in whole blood, HuMax-CD20 killed up to 50% of the B-CLL tumors compared to no more than 5% for rituximab.   

These data were presented at the Keystone Symposium "Antibody-Based Therapeutics for Cancer" in Banff, Alberta, Canada, by Prof. Jan van de Winkel, chief scientific officer of Genmab.  van de Winkel also presented data showing that recent discoveries about this type of cancer and also about HuMax-CD20 may help explain its ability to kill rituximab resistant cells. These patient tumor cells have very low levels of the CD20 target as well as a high level of cell surface proteins called complement control molecules that  appear to protect cells from a type of immune system killing called  complement dependent cytotoxicity. HuMax-CD20 may be overcoming the resistance because it binds to the CD20 target for a significantly longer period of time than rituximab.  HuMax-CD20 is currently undergoing manufacturing development in preparation for clinical trials.  

"HuMax-CD20 is one of our key focus programs for 2003, and we are very encouraged by this set of biological data" said Lisa N. Drakeman, PhD, Genmab. "The range of diseases we could potentially treat with HuMax-CD20 indicates the large market potential for this antibody." 

"The pre-clinical data for both HuMax-CD20 and HuMax-EGFr shows that by using our cutting-edge technology we can effectively generate antibodies that out-perform earlier cancer therapeutic antibodies", said van de Winkel. "Our antibodies exhibit better binding characteristics, and appear to be far better in engaging immune effector mechanisms that are key for the therapeutic efficacy of anti-cancer antibodies." 

HuMax-CD20 targets the CD20 antigen on B cells and initially Genmab plans to focus on using the antibody for the treatment of non-Hodgkin's Lymphoma (NHL), a cancer involving B cells.

The CD20 antigen is a transmembrane protein on pre-B and mature B lymphocytes. CD20 appears to act as a calcium ion channel, and to regulate early steps in B lymphocyte activation. The molecule is not shed from the cell surface, and is not internalized upon antibody binding. CD20 is found on over 90% of B-cell lymphomas, as well as other lymphoid tumors of B cell origin. 

This article was prepared by Drug Week editors from staff and other reports. 

 

 

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