David:
BTRN and fundamentals don't mix. The market for xeno would be MONSTROUS. However, xeno is pure basic research at the moment. BTRN is probably the leader, competitive and then some with ALXN. They lack one acknowledged piece of the puzzle (hyperacute rejection), but they have access to potential solutions through Novartis? They're the best, IMO, at the biology of interaction of stroma and pig stem cells, but nobody is yet good enough.
Therefore, for XenoMune..... I try to assign a value based on access to Sachs, Sykes et al., given that the market would be multi-billion. Sometimes research is shown respect by investors, sometimes it's scoffed at. Recently, we've been in the scoffing phase.
One thing that others won't tell you, but that BTRN doesn't hide..... the issue is not, foremost, dealing with hyperacute rejection (ALXN-related hype addresses only a small part of the picture). One needs to know how to get the pig marrow to engraft and function in humans.
AlloMune..... I was one of the first to conduct graft-versus-leukemia experiments (unfortunately, I liked to do experiments more than publish, and I am therefore now an investor rather than David Sachs' collaborator..... but, for those with access to a medical library who would like to verify..... Fed. Proc. 35:312, 1976). I know this field, and I've long followed the contributions of BTRN's major collaborators. They are top notch, the best and most ethical of scientists. So......
What happens if they successfully report the creation of human bone marrow chimeras such that immunosuppressive drugs are no longer required for the maintenance of a histoincompatible kidney? You need to create the market, as kidney/heart/etc. transplant patients do not currently undergo BMT. That isn't straightforward, and GvH in never a trivial issue. But, early human results from the labs of Dr. Sykes look promising (abstract, graft-versus-lymphoid malignancy, appended below).
What happens? You create an entirely new infrastructure for transplantion, an expensive infrastructure. Companies will scramble to fit into it, but it's not like putting a molecule in a vial and making sure that the pharmacy is stocked.
We know, from gazillions of animal experiments (largely neonatal tolerance), that bone marrow chimerism is the clear solution to maintenance of human populations such that spare parts are readily available. Ethics are an issue....... one wealthy individual that doesn't want to die could come up with the entire BTRN research premium, merely to be a guinea pig. Once conditions for functional engraftment of pig stem cells into primates have been described, then access to appropriate donor pig populations will be the barrier to entry. Use patents can be circumvented.
Which brings us to 507. I was hopeful that there was something magical about 507, such that at least one use patent would not be easy to get around. Publications studying its effects in vitro "teach" that it is magical. The efforts at MEDI, thus far and IMO, teach that it isn't. *Not* results to date, but *efforts*. That is, I'm very disappointed that MEDI is not, apparently, electing to compete more aggressively in autoimmunity.
There are several routes to a pop for BTRN.... (1) for all we know, there could be an AlloMune patient out there now, carrying a histoincomptatible kidney (or heart or ??) who is not currently on immunosuppressive therapy; (2) 507 looks good in psoriasis, or the GvH results to date inspire MEDI to expand clinicals in autoimmunity; (3) conditions for lymphoid engraftment/function are defined, pig to human; (4) Sykes efforts to differentiate graft-versus-malignancy from GvH are increasingly successful, and 460 day remissions become commonplace.
Gotta run my son over to a friend's place.
Cheers! Rick
Lancet 1999 May 22;353(9166):1755-9
Mixed lymphohaemopoietic chimerism and graft-versus-lymphoma effects
after non-myeloablative therapy and HLA-mismatched bone-marrow
transplantation.
Sykes M, Preffer F, McAfee S, Saidman SL, Weymouth D, Andrews DM, Colby C, Sackstein R, Sachs DH,
Spitzer TR
Transplantation Biology Research Center, Surgical Service, Massachusetts General Hospital and Harvard Medical School,
Boston 02129, USA. sykes@helix.mgh.harvard.edu
BACKGROUND: HLA-mismatched donor bone-marrow transplantation after standard myeloablative conditioning therapy for
haematological malignant disorders has been limited by severe graft-versus-host disease (GVHD) and graft failure. We tested a
new approach to find out whether lymphohaemopoietic graft-versus-host reactions could occur without excessive GVHD in
mixed haemopoietic chimeras produced across HLA barriers with non-myeloablative conditioning. METHODS: Five patients
with refractory non-Hodgkin lymphoma underwent bone-marrow transplantation from haploidentical related donors sharing at
least one HLA A, B, or DR allele on the mismatched haplotype. Conditioning included cyclophosphamide and thymic
irradiation before transplantation, and antithymocyte globulin before and after transplantation. The only other GVHD
prophylaxis was cyclosporin. FINDINGS: Four of five patients were evaluable and showed engraftment. Mixed haemopoietic
chimerism was established, with a predominance of donor lymphoid tissue and varying degrees of myeloid chimerism. Two
patients were in GVHD-free states of complete and partial clinical remission at 460 and 103 days after bone-marrow
transplantation. INTERPRETATION: Mixed chimerism can be induced in adult recipients of HLA-mismatched bone-marrow
transplantation by a non-myeloablative conditioning regimen. The antilymphoma responses seen in two patients suggest that
allogeneic bone-marrow transplantation without myeloablative conditioning might have potent immunotherapeutic benefits. |
