I repost this abstract (together with some earlier work), indicating that BTI-322 may be the Holy Grail of transplantation biology. Given the mechanism that Bazin has proposed, there is no reason that MEDI should not target all of allograft and autoimmunity. In turn, the AlloMune program would likely partner for $megabucks. The nice thing?..... cash in-hand plus the XenoMune program make this, IMO, a relatively safe investment.
For psoriasis and other autoimmune diseases, the effective (IMO) competition will be CTLA4 from Bristol-Myers Squibb, Zenapax from PDLI/Roche, and anti-CD40L from Idec and/or Biogen.
The rout in second- and third-tier biotechs has created some incredible bargains. If the MEDI-507 data holds for acute rejection or if GvH is not observed in the early AlloMune trials, we'll be on our way, IMO, to 20X. There are many outstanding questions, however.
J Immunol 1998 Apr 15;160(8):3797-3804
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.
J Immunol 1994 May 15;152(10):4861-4872
Mitogenic CD2 monoclonal antibody pairs predispose peripheral T cells to
undergo apoptosis on interaction with a third CD2 monoclonal antibody.
Rouleau M, Mollereau B, Bernard A, Metivier D, Rosenthal-Allieri MA, Charpentier B, Senik A
Cellular Immunology and Transplantation Laboratory, Scientific Cancer Research Institute, Villejuif, France.
When stimulated for a few days with the mitogenic GT2 + T11(1) CD2 mAb pair and IL-2, resting T cells were induced to
proliferate but the introduction into the cultures of a third CD2 mAb resulted in apoptotic cell death of 40 to 60% of the cells.
The death signal was active on T cells entered the cell cycle without causing an apparent cell cycle block and without
discriminating between the G1 and S phases. Apoptosis was not prevented by cycloheximide or actinomycin D, indicating that
the death program was already expressed in preactivated cells awaiting an appropriate signal. A series of Abs, directed at
various cell surface molecules, were unable to trigger apoptosis (except CD3 mAb), whereas most of the CD2 mAb tested
were active, provided the third CD2 mAb was recognizing an epitope different from GT2 and T11(1). Mere aggregation of
CD2 molecules did not seem to be the triggering signal of apoptosis, because cross-linking cell-bound GT2 + T11(1) with an
Ab to mouse IgG had no effect, suggesting that a conformational change was imposed on CD2 molecules by the third CD2
mAb. Stimulation performed in the presence of IL-2 predisposed both CD45R0+ and CD45RA+ T cells to apoptosis,
whereas stimulation in the presence of IL-4 primed only CD45RA+ T cells to undergo this process. Monocytes and potent
co-signals of the CD2 pathway were unable to prevent CD2-induced apoptosis. Thus, successive engagements of the CD2
molecule of mature T cells by two and three CD2 mAbs recognizing distinct epitopes can provide in short term cultures signals
for proliferation and apoptosis, depending on the activation state of the cells. |
