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CD20 Shaving with Rituxan

Date: August 28, 2006

by Chaya Venkat

Are Standard Dosages Way Too Much?

Rituxan Therapy: Old Enough to “Shave”?

Recently PC and I were fortunate to attend the UK CLL Forum where Dr. Ron Taylor presented his findings on a very interesting aspect of Rituxan therapy. Describing Ron Taylor as a “live wire” would be a big understatement, he packs a huge punch into a small body. The subject of his talk was clearly the most controversial and interesting one at the meeting, in that he made a strong case for using a whole lot less Rituxan in treating patients. Based on his elegant work, it is reasonable to ask if most of the patients treated with this drug as a single agent are receiving way too much of the monoclonal antibody. Not only is it possible all this Rituxan is not doing them or our healthcare costs much good, it could be setting them up for resistance to this crucial drug down the road.

At the end of his presentation Dr. Taylor asked an important question: Who will support and fund such research? The money trail is pretty obvious in high profile clinical trials these days. Someone (read corporation) stands to make a lot of money based on the success of the drug under study. Does Genentech have an incentive in funding a clinical trial that, if successful, will mean they will sell a lot less of their block-buster drug Rituxan? Do you want to buy the Brooklyn Bridge? Will high profile cancer centers that have made a name for themselves pushing ever higher drug dosages (heard the phrase “maximum tolerated dose” recently?) be interested in using micro doses of drugs?

You would have been proud of me. When Dr. Taylor asked what he thought was a rhetorical question, who will support and fund such research, I raised my hand way at the back of the room and said “we will”. Sure enough, after going through the inevitable paperwork with the nice folks at University of Virginia, we have committed to support Dr. Taylor’s research to the tune of $25,000 of your hard earned contributions.

The timing of this article is dictated by the fact that a clinical trial exploring this concept has just kicked off and recruiting patients as we speak. This clinical trial is a small, early phase study, enrolling only a small cohort of CLL patients. But the detailed information obtained from lab work that will be done based on their blood samples in Dr. Taylor’s lab will be priceless — and that is the part we will be funding. Dr. Taylor presented complex and compelling technical arguments to support his theory at the UK CLL Forum and in several well reviewed papers. Below is my much more folksy and patient-oriented picture of the science, backed up as always with abstracts of his professional articles. If you wish to read the full text of the articles cited, all you have to do is ask and we can help you locate them.

CD20 Shaving Reaction

Let us get a few basics redefined. I promise I will keep it simple. If you are in the market for more detailed description of how Rituxan works, here are some links (Single Agent Rituxan; Rituxan Enhancements) to explore.

I would have apologized for the cartoon version of his theory, except for the fact that the best cartoon version of the “Shaving Reaction” comes from Ron Taylor himself. One of the dogs below is the hapless B-cell, the other dog is the macrophage, and the rope between the two of them is the CD20-Rituxan pair. One can only hope the “macrophage” is happy to run off with the rope, shave off the CD20-Rituxan pair, and leave the other dog untagged and uneaten.

Tug of War


J Immunol. 2006 Feb 15;176(4):2600-9. Links

The shaving reaction: rituximab/CD20 complexes are removed from mantle cell lymphoma and chronic lymphocytic leukemia cells by THP-1 monocytes.

Beum PV, Kennedy AD, Williams ME, Lindorfer MA, Taylor RP.

Department of Biochemistry and Molecular Genetics, University of Virginia School of Medicine, Charlottesville, VA

Clinical investigations have revealed that infusion of immunotherapeutic mAbs directed to normal or tumor cells can lead to loss of targeted epitopes, a phenomenon called antigenic modulation. Recently, we reported that rituximab treatment of chronic lymphocytic leukemia patients induced substantial loss of CD20 on B cells found in the circulation after rituximab infusion, when rituximab plasma concentrations were high. Such antigenic modulation can severely compromise therapeutic efficacy, and we postulated that B cells had been stripped (shaved) of the rituximab/CD20 complex by monocytes or macrophages in a reaction mediated by FcgammaR. We developed an in vitro model to replicate this in vivo shaving process, based on reacting rituximab-opsonized CD20(+) cells with acceptor THP-1 monocytes. After 45 min at 37 degrees C, rituximab and CD20 are removed from opsonized cells, and both are demonstrable on acceptor THP-1 cells. The reaction occurs equally well in the presence and absence of normal human serum, and monocytes isolated from peripheral blood also promote shaving of CD20 from rituximab-opsonized cells. Tests with inhibitors and use of F(ab')(2) of rituximab indicate transfer of rituximab/CD20 complexes to THP-1 cells is mediated by FcgammaR. Antigenic modulation described in previous reports may have been mediated by such shaving, and our findings may have profound implications for the use of mAbs in the immunotherapy of cancer.

PMID: 16456022 [PubMed - indexed for MEDLINE]

J Immunol. 2004 Mar 1;172(5):3280-8. Links

Rituximab infusion promotes rapid complement depletion and acute CD20 loss in chronic lymphocytic leukemia.

Kennedy AD, Beum PV, Solga MD, DiLillo DJ, Lindorfer MA, Hess CE, Densmore JJ, Williams ME, Taylor RP.

Department of Biochemistry and Molecular Genetics, University of Virginia School of Medicine, Charlottesville, VA

Complement plays an important role in the immunotherapeutic action of the anti-CD20 mAb rituximab, and therefore we investigated whether complement might be the limiting factor in rituximab therapy. Our in vitro studies indicate that at high cell densities, binding of rituximab to human CD20(+) cells leads to loss of complement activity and consumption of component C2. Infusion of rituximab in chronic lymphocytic leukemia patients also depletes complement; sera of treated patients have reduced capacity to C3b opsonize and kill CD20(+) cells unless supplemented with normal serum or component C2. Initiation of rituximab infusion in chronic lymphocytic leukemia patients leads to rapid clearance of CD20(+) cells. However, substantial numbers of B cells, with significantly reduced levels of CD20, return to the bloodstream immediately after rituximab infusion. In addition, a mAb specific for the Fc region of rituximab does not bind to these recirculating cells, suggesting that the rituximab-opsonized cells were temporarily sequestered by the mononuclear phagocytic system, and then released back into the circulation after the rituximab-CD20 complexes were removed by phagocytic cells. Western blots provide additional evidence for this escape mechanism that appears to occur as a consequence of CD20 loss. Treatment paradigms to prevent this escape, such as use of engineered or alternative anti-CD20 mAbs, may allow for more effective immunotherapy of chronic lymphocytic leukemia.

PMID: 14978136 [PubMed - indexed for MEDLINE]

The Clinical Trial

Here is the link to the clinical trial on the website. It has all the background information, inclusion criteria and contact information. I have also provided a quick cheat sheet of the highlights:

Risks and Rewards

So, what’s in it for us, you ask. I would like to see the day when each and every patient questions therapy decisions on the basis of the risks and rewards involved. Let us examine this clinical trial from that perspective.


One of our members wrote and asked the criteria by which we select the projects CLL Topics chooses to sponsor. Good question, I think it is worth answering in public so that all of you can decide what you think of our logic. So far, we have sponsored three clinical trials:

The ongoing green tea extract (EGCG) clinical trial at the Mayo Clinic, Rochester MN (see Project Alpha Kickoff) was our first project. The interim reports look promising: EGCG seems to be beneficial in a subset of our patient population with little or no adverse effects. I will take each and every “free lunch” we can get!

We have announced a formal clinical trial to try and improve the efficacy of annual flu shots by means of an immune modulator adjuvant (Imiquimod, trade name “Aldara”), under the guidance of Professor Terry Hamblin in the U.K. We are pleased that the British patient group UK CLL Support Association is our partner in that effort. We hope to be announcing the recruitment details of this double arm trial before the flu season for this year (Improving Immunizations).

The support announced here for the clinical trial to explore very low dose subcutaneous Rituxan therapy to judge the validity of the shaving reaction proposed by Dr. Taylor is our third project.

A fourth project that did not require cash outlays from CLL Topics is the recent Quality of Life survey that we championed as partners with Mayo Clinic. If you have not taken this survey yet, please do so right away. Here is the (QOL Survey).

All three of these projects have very common features that we find important.

CLL Topics has extremely low overhead costs. We are all volunteers here - and none of us get paid a dime for this work. In fact, most of us pay out of our pockets for the privilege of doing this labor of love. We take very seriously the responsibility of spending your money wisely. Last count, 426 generous donors from all over the world have sent in over $153,000 tax-deductible dollars as of the end of July. You can look up the details of our financial statements by clicking on the document links in the About Us page. Total transparency is another thing we take seriously.

Fund-raising is not a huge part of our charter. I would like to think patient education is our single biggest driver. If, in the process of doing the digging, we come across a worthwhile project that absolutely needs our support, it is wonderful to be able to say “we will”. Take a bow, ladies and gentlemen. Your hard earned dollars make it possible for us to fund these important projects.


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