Waldenstrom's Macroglobulinemia Project Ideas

AMD3100 and Rituxan (or Humax)
AMD3100 mobilizes WM cells into the bloodstream where Rituxan can easily kill it. If a large number of cells can be chased out of hiding, this may be the most powerful weapon for killing WM that we have. For multiple myeloma, circulating cells changed from 1-2/min to 10-15/min, a 10 fold increase! In addition, it makes the cells in the bone marrow much more susceptible to treatment (in this case, it was Velcade). From the tumor bioluminescence studies, there is about a 5X increase in effectiveness when you use AMD3100 in conjunction with your chosen treatment.

Humax WM dosing clinical trial
Many people either get no impact from Rituxan or become refractory. Humax could be a better alternative for these people because it reportedly binds more strongly to cd20 positive cells and it uses CDC killing in addition to ADCC. A dosing study along the lines presented in the paper below makes a lot of sense to me...you dose based on trying to achieve a target concentration in your blood. This requires higher dosing at the start of treatment, and lower dosing immediately after.

All tested anti-CD20 human mAb were able to induce antibody-dependent cellular cytotoxicity (ADCC) with human effector cells derived from peripheral blood. However, two mAb, 2F2 (ofatumumab) and 7D8, were remarkably active in complement-dependent cytotoxicity (CDC), being able to lyse low CD20-expressing chronic lymphocytic leukaemia (CLL) cells in the presence of human plasma or unfractionated peripheral blood.

We conclude from our study that ofatumumab plasma concentrations of 5–10 µg/ml are sufficient for ensuring sustained activity in vivo. This ofatumumab concentration is expected to be sufficient to saturate and induce maximal killing of circulating B cells. However, the monkey study clearly indicates that much higher ofatumumab plasma concentrations may be required to target CD20-expressing cells resident in the tissues in the initial phase of treatment.
From Estimation of dose requirements for sustained in v...[Br J Haematol. 2007]

Rituxan refractory research
Nobody seems to know why people become refractory to Rituxan. This might be hard to find out, but if we can find it, it would be extremely beneficial.

IMMU-106
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 et al. 10 (8) 2868

Adenosine Phosphorylase inhibitors
I wanted to call your attention to another drug approach currently under trial. A faculty member at Einstein, Vern Schramm (Biochemistry) developed a clever family of drugs that inhibits Adenosine Phosphorylase, an essential enzyme in synthesis of purine nucleotides. Inhibit this and cells can't replicate. Most cells in the body have two pathways but curiously T cells and some B cells only use one, so these cells are especially sensitive to this inhibitor. It is under trial through a company called BioCryst for several T-cell cancers and autoimmune disease. As far as I know it has not been tested against WM or plasma cell disorders.

Telintra
I will alert Telik (my former start up) to Steve Kirsch's web site / diagnosis. An ASCO 2007 abstract showed very good results combining thalidomide with rituxan for Waldenstrom's disease. Telik's drug candidate, Telintra, is in Phase II for myelodysplastic syndrome where it works better than thalidomide, so there is a reasonable chance it would be beneficial to Kirsch as well. Telintra is minimally toxic (less than thalidomide, I believe), which fits into his selection criteria.
http://www.asco.org/ASCO/Abstracts+%26+Virtual+Meeting/Abstracts?&vmview=abst_detail_view&confID=47&abstractID=36194

CD19 antibodies
The molecule CD19 is found on the surface of all B lymphocytes (including the Waldenstrom cells), and so killing via this molecule may take care of the problem. In fact, there are several companies developing antibodies to this molecule (among them Medarex, Astra Zeneca, and a small biotech company, Picobella (picobella.com), of which I am a founder. Ron Levy, from Stanford University, will do the clinical trials for the Picobella anti-CD19 antibody when and if it is produced in enough quantities. Ron Levy was the developer of and clinician behind Rituxan.

Matthias Wabl, Ph.D.
Professor of Microbiology and Immunology Department of Microbiology and Immunology University of California San Francisco, CA

Steve Kirsch home page