>> Finally in the Bear Sterns presentation of 9/17/02, it was stated that the company "never considered MLN02 to be a key contributor to MLNM’s top or bottom line growth". <<
Wow. Well, I don't agree. That sounds like post-results bull, to me.
Now, returning to the issue that Erik raised......
Integrins are composed of two subunits, the alpha and beta chains. Both are "polymorphic", meaning that they have closely related variants, alpha1, alpha2, alpha3, alphaN, beta1, beta2, beta3, betaN, etc. All individuals of a species possess the variants; they are not "allelic", (segregating in the population and derived from a single gene). That is, each variant has it's own gene.
Let's call one of the two subunit chains "A" and the other "B". Let's also simplify things and say that all individuals only have three subunit genes (not true, there are many!), A4, B1 and B7.
Let's also say that A4 can associate with either B1 or B7, forming the complex molecules A4B1 and A4B7.
Let's also say that both complex molecules have been shown, in some cases, to be expressed on the same effector cell (not always true), that integrins are known to play a role in effector cell migration to inflamed sites, and that the effector cell is thought to play a role in gut inflammation.
So, given all of those givens.......
You have one effector cell with two complex molecules, both of which can get you in trouble. If you neutralize one with anti-B1 or anti-B7, the other one will get you. However, if you use anti-A4, you can (theoretically) neutralize both molecules. If they block integrin function, a cocktail of anti-B1 and anti-B7 might be as effective as the single anti-A4 MAb.
The Biogen antibody (antegren) reacts with A4 (alpha4), but the MLNM antibody (LDP02) reacts with B7 (beta7). The MLNM antibody therefore leaves the A4B1 molecule free to function, and, if A4B1 replicates the bad boy function of A4B7, LDP02 will be ineffective relative to a blocking alpha4-specific MAb.
The trouble? As Erik has pointed to, anti-beta7 is effective in animal models.
Is that clear?
Yes? Well, it's oversimplified, and assumes that there is no independent function of the alpha4 beta7 integrin which is not sterically inhibited by anti-alpha4. In addition, it assumes that other complex molecules containing beta 7 (i.e., alphaE beta7) are not active in gut inflammation.
No? Well, you're in luck, as we won't know what works until all of the data is in, and this is all just hot air to explain why the Biogen trial might succeed given MLNM results.
Now..... I over simplified things, as there ARE polymorphisms for individual integrin genes which DO segregate in the population, and there ARE cells which express only one of the two complex molecules (or at least favor one over the other.... platelets, for example). To my knowledge, none of the segregating polymorphisms play a role in disease, even though there definitely is a genetic determinant of inflammatory bowel disease that is linked to the beta7 gene.
The simplistic rule of thumb was that beta7 integrins were most important for gut disease and that beta1 integrins were most important for asthma and for effector cell interaction with brain endothelium. Immunologists profit from NEVER believing the rule of thumb.
Sorry..... I put that together too quickly, and it may be (1) unclear, and (2) wrong. Gotta run, the kids are starving. |
