Date: September 21, 2008
by Chaya Venkat
Anti-CD20 monoclonals are all the rage these days. Notwithstanding the recent adverse effects reports, Rituxan is the single most important drug discovery in the last decade for CLL patients. I am keeping my fingers crossed that the next in line contender for the anti-CD20 crown HuMax-CD20 will be approved by the FDA early in 2009. Cripes, it takes so darn long for new drugs to go through the clinical trials and regulatory process before we can hope to see them commercially available! Sometimes I get discouraged by the snails’ pace. All the same, if we don’t stoke the research and drug testing pipeline with new candidates, we will never get new and improved drugs. If not us, those of our children unlucky enough to get this familial cancer will benefit from the research we support now.
Today I would like to bring to you attention a new clinical trial testing another new anti-CD20 monoclonal in CLL and NHL patients. Never heard of veltuzumab? You are not alone. Here is the skinny on this new drug:
Our beloved Rituxan is a chimeric antibody, meaning it has both human and mouse protein in it. It is generally thought that a chimeric antibody is better than a fully mouse antibody, since it is less likely to provoke an acute immune response and infusion related adverse effects. Using the same logic, a fully human or humanized monoclonal antibody (such as HuMax-CD20 and veltuzumab) is likely to be even better than the chimeric versions.
While the chimeric nature of Rituxan has not posed insurmountable problems, it may be an advantage to have more completely human antibodies. This is especially so if repeated injections may be desired in patients. In recent years we have begun to see use of Rituxan in treating autoimmune diseases such as AIHA and ITP, even rheumatoid arthritis and Lupus. These patients are likely to be on maintenance administration of Rituxan over many years, and in those circumstance it is far preferable if the antibody used is fully human, with no smidgen of mouse protein to create over-the-top immune reactions with repeated administration of the drug. The lower drug dose and the potential for reduced infusion related adverse effects are among the possible benefits of veltuzumab. Also, if the veltuzumab can be given as a quick jab in the arm, rather than sitting in one of those uncomfortable reclining chairs in the back room while Rituxan does its slow drip-drip-drip act over several hours, I can see how that would be more cost-effective and efficient.
No question about it, Rituxan is the gold standard and all new anti CD20 monoclonal drugs have to compare themselves to it. Below is a 2004 abstract in the Journal of Clinical Cancer Research that gives us a handle on how veltuzumab stacks up against Rituxan. If you are so inclined, click on the link below and you can read the full text of the article for free. Remember, IMMU-106 is just an earlier name for veltuzumab.
Clin Cancer Res. 2004 Apr 15;10(8):2868-78.
Characterization of a new humanized anti-CD20 monoclonal antibody, IMMU-106, and Its use in combination with the humanized anti-CD22 antibody, epratuzumab, for the therapy of non-Hodgkin's lymphoma.
Stein R, Qu Z, Chen S, Rosario A, Shi V, Hayes M, Horak ID, Hansen HJ, Goldenberg DM.
Garden State Cancer Center, Center for Molecular Medicine and Immunology, Belleville, New Jersey 07109, USA. firstname.lastname@example.org
PURPOSE: A new humanized anti-CD20 monoclonal antibody (MAb), IMMU-106, was evaluated to elucidate its action as an antilymphoma therapeutic, as a single agent, and in combination with the anti-CD22 MAb, epratuzumab. EXPERIMENTAL DESIGN: Antiproliferative effects, apoptotic effects, and the ability of IMMU-106 to mediate complement-mediated cytotoxicity and antibody-dependent cellular cytotoxicity on a panel of non-Hodgkin's lymphoma (NHL) cell lines were compared with the chimeric anti-CD20 MAb, rituximab, and evaluated in light of the various levels of antigen expression by the cell lines. In vivo therapy studies were performed in SCID mice bearing disseminated Raji lymphoma. RESULTS: The mechanisms of cytotoxicity of IMMU-106 were found to be similar to rituximab, and include direct apoptosis, antibody-dependent cellular cytotoxicity, and complement-mediated cytotoxicity. IMMU-106 was also found to be very similar to rituximab in terms of antigen-binding specificity, binding avidity, and dissociation constant. Treatment of Raji-bearing SCID mice with IMMU-106 yielded median survival increases of up to 4.2-fold compared with control mice. Survival in mice treated with IMMU-106 plus epratuzumab was compared with IMMU-106 treatment alone. Although the combined treatment did not improve median survival, an increased proportion of long-term survivors was observed. An enhanced antiproliferative effect was also observed in vitro in SU-DHL-6 cells when IMMU-106 was combined with epratuzumab. These findings are consistent with the up-regulation of CD22 expression observed after pretreatment of NHL cells in vitro with CD20 MAb (IMMU-106). CONCLUSIONS: It is expected that in humans IMMU-106 should be at least as effective as rituximab and, due to its human framework construction, it may exhibit different pharmacokinetic, toxicity, and therapy profiles. In addition, it may be possible to enhance efficacy by combination therapy comprised of anti-CD20 and other B-cell lineage targeting MAbs, such as epratuzumab. The current results emphasize that in vitro as well as in vivo studies with many of the NHL cell lines were generally predictive of the known activity of anti-CD20 MAbs in NHL patients, as well as the enhanced efficacy of epratuzumab combined with rituximab observed in early clinical trials.
Here are the take home points that I got from wading through this detailed article:
The percentage of patients who participate in clinical trials is alarmingly low in this country. We can blame drug companies and regulatory agencies such as the FDA all we want. But even if all drug companies worked with salutary zeal developing wonderful new candidate drugs designed specifically with CLL in mind, and the FDA became a model of efficiency, we will not get any new drugs without patients willing to put their bodies on the line by participating in clinical trials. That is a fact of life.
So, who is likely to benefit from participating in this particular clinical trial? The inclusion criteria are sufficiently broad so that many patients will be eligible. If you are considering single agent Rituxan therapy, this clinical trial may fit you well, since veltuzumab and Rituxan seem to share very similar profiles in how they behave. If you are worried about the infusion related toxicity issues associated with Rituxan, if you are type that is allergic to many different things and worry about the mouse protein in Rituxan, this trial may give you a nice way to get a fully humanized anti-CD20 monoclonal that is less likely to cause problems.
But all said and done, you should make decision to participate in clinical trials with your eyes wide open, and only after you have done your best to educate yourself regarding the possible benefits and risks involved. I am a fervent believer in the concept of truly informed consent. At the very least you should ask for and read the full clinical trial protocol. I hope this review will make it a bit easier for you to understand the issues involved. But win, lose or draw, I think every patient who volunteers for a clinical trial is a real hero worthy of our respect and thanks. Without these generous souls willing to put themselves on the line, none of us can look forward to better days and improved therapy options.
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Topic: Monoclonal Antibodies