Monoclonal Antibodies el pt

Veltuzumab: Another Anti-CD20 Monoclonal in Clinical Trials

Date: September 21, 2024

by Chaya Venkat

A new monoclonal antibody in the pipeline

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Lumiliximab
HuMax-CD20
CD-20 Shaving
Sons of Rituxan and Campath
Rituxan Therapy
Introduction to Monoclonal Antibodies

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 2024.  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.

Phase I/II Study of Subcutaneously Administered Veltuzumab in NHL and CLL

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:

• “Veltuzumab” is made by a company called Immunomedics. It used to be called IMMU-160 back when it was still being tested in the lab and had not made it into clinical trials, so don’t get flummoxed if you see that handle rather than veltuzumab in some of the press releases and articles.

• This is an early phase trial and they hope to recruit a total of 72 patients, a mix of treated as well as untreated CLL and NHL patients. The study started in January of 2024, but I know that they are still recruiting.

• The trial is offered at a number of sites and you might find one close to home: Savannah, Georgia; Denville, New Jersey; Morristown, New Jersey; New York City; New Hyde Park, New York (Long Island Jewish Medical Center); Lemoyne, Pennsylvania. I highlighted the LIJ recruitment site because that is home to Dr. Kanti Rai, one of our best known research experts.

• This clinical trial is a dose escalation study, intended to identify the safe and effective dose of this new monoclonal antibody.  Patients will be divided into three cohorts, depending on when they enrolled for the study. The dosage of the drug will be escalated from 40mg to 80mg to 160mg in the three cohorts. Compared to the “standard” dose of 375 mg/m2 of Rituxan used most often, it appears veltuzumab requires smaller amounts of the drug.

• Patients will get veltuzumab as subcutaneous shots on alternate weeks, for a total of 4 injections, on alternate weeks. By way of comparison, Rituxan is usually given as an intravenous infusion. That is, unless you are a devotee of Prof. Taylor’s concept of CD20 Shaving and therefore sweet-talked your oncologist to give you micro doses of Rituxan as subcutaneous injections. Prof. Taylor makes a strong case for using much smaller amounts of Rituxan in order to avoid the shaving reaction. We were sufficiently impressed by the science that we funded his research with your donated dollars.

• Here is the link to the official citation for the new veltuzumab clinical trial where you can find more information:  http://clinicaltrials.gov/ct2/show/NCT00546793 . It has phone numbers and contact information, if you want to get additional information.   

• Much of the logic for using veltuzumab comes from the first study where this drug was given as weekly intravenous infusions to NHL patients. It showed good tolerability and even some level of efficacy at weekly intravenous doses as low as 80-120 mg/m2 over 4 consecutive weeks. These clinical results confirmed lab studies using cells followed by mice studies. Laboratory studies using Veltuzumab administered subcutaneously showed potent activity based on B-cell depletion. The current study's goal is to determine if a subcutaneous (SC) dosing schedule of veltuzumab can be established in patients with NHL or CLL

What makes veltuzumab worth studying?

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.

How does veltuzumab compare to Rituxan?

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 2024 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. 2024 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. rstein@gscancer.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.
PMID: 15102696

Here are the take home points that I got from wading through this detailed article:

• Veltuzumab binds to the same CD20 marker that is bound by Rituxan. The new monoclonal seems to show the same “avidity” (desire to bind) as Rituxan, and once bound, it has the same chance of staying stuck to the CD20 marker.  Some of you may remember, we discussed how HuMax-CD20 stayed stuck a lot better than Rituxan, sort of like a bit of well made Velcro that hangs on without getting unstuck, and this was important in improving efficacy of the drug.  It does not appear that veltuzumab has any advantage over Rituxan on this front.

• Neither Rituxan nor IMMU-106 showed much direct cell kill all by themselves. Both need an assist from the patient’s own immune system to do the actual killing of the cancer cells, once they have been tagged by the monoclonal drugs.

• They measured the level of ADCC (antibody dependent cellular cytotoxicity) and complement mediated cell kill for both Rituxan and veltuzumab, using a series of B-cell cancer lines. Both monoclonals had roughly the same level of ability to kill cancer cells by these mechanisms.

• Moving on to mice studies, researchers noted that when infected with B-cell cancers control mice died of disseminated disease with a median survival time of 16.5 days. Median survival in the group treated with Rituxan was extended to 98 days and 70 days for IMMU-106. Pretty much the same improvement for Rituxan and veltuzumab, no statistically significant difference was noted.

• A significant part of the paper was devoted to combining veltuzumab with another monoclonal drug made by the same company, Immunomedics. “Epratuzumab” targets CD22 marker on mature B-cells. We are just beginning to see more and more of these double monoclonal drug therapy combinations – for example, combination of Rituxan and Campath. It will be a while before we get better understanding of the risks and rewards associated with using two (or more) monoclonal drugs in combination.

• Bottom line, I do not see much by way of difference between Rituxan and veltuzumab when it comes to binding to the target cell or killing it by the usual ADCC and complement mediated mechanisms. The advantage of veltuzumab is likely to be in the smaller amount of drug needed and the potential for quick subcutaneous injections because it is thought to have significantly lower adverse effect profile, due to the humanized form of the monoclonal – compared to the partially mouse protein “chimeric” nature of Rituxan.

• I am willing to bet that the company would like to see extension of the present clinical trial we are reviewing here (single agent veltuzumab) to a combination of veltuzumab and the anti-CD22 monoclonal epratuzumab.  And why not, it may have more oomph in terms of efficacy, and Immunomedics can make twice as much money since they make/own both drugs.  From the patients’ perspective, it is intriguing that epratuzumab also comes in a form where it is bound to a radioactive payload, similar to Bexxar and Zevalin we discussed in several earlier articles on radioimmunotherapy. However, something tells me these new drugs are going to be no cheaper and may run into the same financial issues that have hamstrung  radioimmunotherapy drugs up to now.

• If you are interested to read more about the combination of epratuzumab with Rituxan, you might want to read the article whose link is given below.  It discusses the results of a recent “Multicenter Phase II Trial of Immunotherapy With the Humanized Anti-CD22 Antibody, Epratuzumab, in Combination With Rituximab, in Refractory or Recurrent Non-Hodgkin's Lymphoma”: http://jco.ascopubs.org/cgi/content/full/23/22/5044

Editorial

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.