my bias extends way back, back to.........
J Immunol 1998 Apr 15;160(8):3797-804
Potent apoptotic signaling and subsequent unresponsiveness induced by a single CD2 mAb (BTI-322) in activated human peripheral T cells.
Dumont C, Deas O, Mollereau B, Hebib C, Giovino-Barry V, Bernard A, Hirsch F, Charpentier B, Senik A.
Centre National de Recherche Scientifique, UPR 420, Villejuif, France.
Manipulation of CD2 molecules with CD2 mAb pairs has been shown to deliver apoptotic signals to activated mature T cells. We show that BTI-322, a CD2 mAb directed at a peculiar epitope of CD2, can trigger on its own the apoptotic death of IL-2-activated peripheral T cells and of OKT3-stimulated T cells, contrasting in this respect with a series of other mouse or rat CD2 mAb. F(ab')2 fragments were as potent as the whole Ab. BTI-322-induced apoptosis proceeded in a few hours and was independent of the Fas/Fas ligand system. Less than 5 ng/ml of BTI-322, added at the beginning of culture, were able to eliminate within 4 days most CD3+ cells from OKT3- and IL-2-stimulated lymphocytes, the only cells remaining being CD16+CD2- NK cells. T cell proliferative responses induced by a mitogenic CD2 mAb pair or by PHA-P (which mainly binds to CD2) were not inhibited by BTI-322. In this case, the apoptotic effect was successfully counteracted by simultaneous enhancement of T cell divisions. Thus, the killing effect of BTI-322 was most effective when T cells were exclusively stimulated through the CD3/TCR complex. Apoptosis of the responding T cells may explain why T cells recovered from a primary MLC performed in the presence of BTI-322 responded to third party cells but not to the primary stimulatory cells. These data constitute the rational basis for the use of BTI-322 for inducing tolerance in human allotransplantation.
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BTI-322 is the non-humanized version of MEDI's MEDI-507.
These authors showed that, in vitro (the epitope, among primates, is only expressed on human and gorilla, one couldn't do the experiment in chimps and the first in vivo data was derived from MEDI's clinical trials), anti-CD2 treatment induced tolerance that was SPECIFIC to antigen-activated cells.
Convoluted logic from there, but........
1. BGEN and MEDI have published studies that indicate similar or identical mechanisms of action for amevive and MEDI-507 (let me know if you'd like cut and paste abstracts). This is not surprising.
2. MEDI-507 was tested in a very small i.v. phase II trial. Mean PASI reduction was as pronounced at a non-depleting dose as it was at higher doses. IMO, MEDI has made at least one blatant attempt to hide that data.
There's more to the argument, but I've been beating this dead horse for years. My bias/guess..... both companies are depleting T cells that are not involved in disease, and that disease-specific cells would be removed at lower doses.
I would have tested lower doses at a very different frequency of administration (less frequent, prolonged). |
