Max:
Chimeric means mouse variable region with a human constant region, not CDR grafting (yes, I realize that your response indicates that you know this). There's plenty common between the variable regions of any two mouse antibodies that can be recognized by humans. However, such epitopes have not proven to be strongly immunogenic, if presented to a human in the context of a mouse contsant region, when I last checked (only about, oh, 6 or 7 years ago........ :-). Yes, you're correct..... B1 is not the same antibody that was used by Idec to derive the variable region of C2B8, and anti-id should be no problem.
The thirty patients were *low* grade. The therapy is first-line (therein lies the potential problem for Coulter?). The additional trials in intermediate and high grade patients are exactly that.... additional trials, being conducted by Genentech. No data has been reported (or gathered, probably).
The "story"...... Idec was making a big deal out of this, but they've been quiet for awhile now..... better than 70% of anti-CD20 treated patients who were positive for bcl-2 at initiation of therapy had the marker disappear. Bcl-2 is a potential prognostic marker for NHL. I can't find any references that put the story together, but the abstract below will show you where Idec's rationale was (is?) headed.
Order of approval for low grade..... naked C2B8, Bexxar, and then, if (big if, IMO) C2B8 plus CHOP is better than CHOP alone, first-line C2B8. I don't know the conditions under which Bexxar is being tested as first-line therapy, so take my prediction for what it's worth. Is testing of Bexxar without chemo even ethical?
In any event, it's clear that C2B8 plus CHOP could never finish in time to hurt the launch of Bexxar (relapsed, low-grade). What I'm asking is....... *if* CHOP plus C2B8 led to the occasional cure and *if* patients are sensitized to variable region framework determinants, wouldn't Coulter be in eventual trouble? The same logic would hold for the yttrium conjugate.
Cheers! Rick
Blood 1996 Aug 1;88(3):1046-1051
Prognostic significance of BCL-2 expression and bcl-2 major breakpoint
region rearrangement in diffuse large cell non-Hodgkin's lymphoma: a
British National Lymphoma Investigation Study.
Hill ME, MacLennan KA, Cunningham DC, Vaughan Hudson B, Burke M, Clarke P, Di Stefano F, Anderson L,
Vaughan Hudson G, Mason D, Selby P, Linch DC
Cancer Research Campaign Section of Medicine, Royal Marsden National Health Service Trust, Sutton, UK.
The Bcl-2 protein is capable of preventing apoptosis, and in vitro evidence suggests a role in drug resistance. It is expressed
and the gene is rearranged in a proportion of cases of large-cell non-Hodgkin's lymphoma (NHL), but the clinical significance
of these findings is controversial. The purpose of this study was to determine the influence of both Bcl-2 expression and major
breakpoint region (MBR) bcl-2 rearrangement in a large cohort of prospectively accrued patients with intermediate-grade
B-cell NHL treated in a standardized manner. All patients with Working Formulation F, G, or H NHL treated with
cyclophosphamide, doxorubicin, vincristine, and prednisone (CHOP) chemotherapy in British National Lymphoma investigation
studies between July 1974 and April 1992 were considered for this study if the appropriate paraffin blocks were available.
Paraffin sections from the diagnostic specimen were analyzed for evidence of MBR rearrangement using a polymerase chain
reaction-based method, and for Bcl-2 expression using immunohistochemistry. Failure to achieve complete remission (CR),
relapse, death from NHL, and deaths from all causes were used as end points to measure CR rate, actuarial relapse rate,
actuarial survival from NHL, and actuarial overall survival. One hundred sixty-one suitable patients were identified and tested
for the bcl-2 MBR translocation, with 27 (17%) found to be positive; 153 of these patients were tested with
immunocytochemistry, and 84 (55%) showed evidence of Bcl-2 expression. For patients who achieved CR from the initial
treatment, the relapse rate was significantly higher in those with Bcl-2 expression than in those without. In addition, multivariate
analysis identified Bcl-2 expression as the only factor significantly related to relapse rate in the subjects measured. The
cause-specific survival for NHL in the series as a whole was significantly lower in patients with Bcl-2 expression than in those
without. MBR status had no significant influence on any of the outcome measures, but the number of MBR-positive patients
was relatively small, and larger studies are required. In conclusion, in Working Formulation F, G, and H NHL of B-cell type,
expression of Bcl-2 protein predicted independently for relapse. |
