Do you suggesting that c5aR antagonist may have different therapeutic effects than anti-c5-convertase antibody? By reducing c5b-9 complex level, in addition to c5a level? What is more important and what are difference of this two protein biologic rule?
First, I was suggesting where rkrw could look for better information in c5a other than in alxn data.
Second, I would say yes for the reason you state, c5a and mac assembly are independent, robust inflammatory pathways. But inhibiting c5a, by say c5aR antagonist, will not inhibit mac. The difference between effect of separate pathway inhibition also appears to depend on injury type as well as whether there are circumstances contributing to potentially beneficial pro-inflammatory effects of mac and c5a (unknown).
It is known for example that the mac has positive tissue sparing or repairment recruitment properties, not just lytic properties. It may be a little MAC has repair properties, a lot of MAC lytic. No one knows this for sure.
I believe Alexion has already showed in 1995 that inhibition of C5a in a swine I/R model did not inhibit porcine MAC (C5b-9) and did not ameliorate the presence of inflammatory agents in MI injury to the degree later shown through c5 inh. C5a is important target no doubt and is believed to be active in recruiting white blood cells:
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Inflammation 1996 Feb;20(1):1-9 Related Articles, Links
Comparative effect of C3a and C5a on adhesion molecule expression on neutrophils and endothelial cells.
Foreman KE, Glovsky MM, Warner RL, Horvath SJ, Ward PA.
Department of Pathology, University of Michigan, Ann Arbor, USA.
Complement activation is known to enhance neutrophil binding to human umbilical vein endothelial cells (HUVECs). Recently, we have shown that recombinant human C5a upregulates P-selectin in HUVECs. Unstimulated human neutrophil binding is also increased on C5a stimulated HUVECs. We demonstrate in this report that C5a upregulates CD11b/CD18 in human neutrophils. Also shown is that synthetic C3a57-77 and an analog 15 amino acid C3a peptide (C3a15) neither upregulate CD11b/CD18 nor do the C3a peptides increase P-selectin, ICAM-1 or E-selectin in HUVECs. Thus C5a and not C3a is responsible for early (approximately 30 minutes) neutrophil adhesion to endothelial cells after complement activation.
AND
Immunopharmacology 2000 Mar;46(3):209-22 Related Articles, Links
C3a and C5a enhance granulocyte adhesion to endothelial and epithelial cell monolayers: epithelial and endothelial priming is required for C3a-induced eosinophil adhesion.
Jagels MA, Daffern PJ, Hugli TE.
Department of Immunology, The Scripps Research Institute, La Jolla, CA 92037 USA.
Effects of the anaphylatoxins C3a and C5a on eosinophil and neutrophil adhesion to HUVEC and to primary culture human bronchial epithelial cells (HBEC) were investigated. Activities on both leukocytes and on structural cells were examined. C3a upregulated beta2 integrin expression and caused shedding of L-selectin on eosinophils, but had no effect on neutrophil adhesion molecule expression. C5a upregulated beta2 integrins and caused shedding of L-selectin on both eosinophils and neutrophils. The potency of C5a was equivalent on both cell types; however, the magnitude of the changes in each of these adhesion molecules was significantly greater in neutrophils than eosinophils. Neither C3a nor C5a altered expression of ICAM-1, VCAM-1, E-selectin or P-selectin on either HUVEC or HBEC. C5a induced adhesion of both neutrophils and eosinophils to unstimulated HUVEC or HBEC, and adhesion was further enhanced when HUVEC and HBEC were "primed" with TNF-alpha and IFN-gamma, respectively. C3a failed to enhance adhesion of either eosinophils or neutrophils to unprimed HUVEC or HBEC, and enhanced only eosinophil adhesion to cytokine-primed HUVEC or HBEC. Similar to C3a, C3a(desArg) and a C3a-analog peptide E7 also enhanced eosinophil adhesion only to cytokine-primed HUVEC and HBEC. These results support the traditional view of anaphylatoxins as leukocyte-specific mediators. The specificity of C3a for eosinophils implicates this molecule as a potential participant in allergic inflammation. The pro-adhesive effects of C3a(desArg) suggest that this molecule, previously characterized as a spasmogenically inactive derivative of C3a, may also alter leukocyte dynamics and migration. Finally, activation of endothelium may represent an important control mechanism for C3a-mediated adhesion preventing unchecked eosinophil adhesion to uninflamed systemic vasculature.
AND here is interesting study in renal i/r:
Journal of Clinical Investigation May 2000, Volume 105, Number 10, 1363-1371
Predominant role for C5b-9 in renal ischemia/reperfusion injury
Previous work has indicated that complement is a mediator of ischemia/reperfusion (I/R) injury. To investigate the components of complement responsible for this effect, we examined a model of renal I/R injury in C3-, C4-, C5-, and C6-deficient mice. We occluded the renal arteries and veins (40–58 minutes) and, after reperfusion (0–72 hours), assessed renal structural and functional injury. C3-, C5-, and C6-deficient mice were protected from renal I/R injury, whereas C4-deficient mice were not protected. C6-deficient mice treated with antibody to block C5a generation showed no additional protection from I/R injury.
Reconstitution with C6 alone restored the I/R injury in C6-deficient mice. Tubular epithelial cells were the main structures damaged by complement-mediated attack, and, in contrast, the renal vessels were spared. Neutrophil infiltration and myeloperoxidase activity were reduced in C-deficient mouse kidney, but by a similar extent in C3-deficient and C6-deficient mice. We conclude that the membrane attack complex of complement (in which C5 and C6 participate) may account for the effect of complement on mouse renal I/R injury. Neither C5a-mediated neutrophil infiltration nor the classic pathway, in which C4 participates, appears to contribute to I/R injury in this model. By contrast with other organs, such as the heart, the primary effect of complement in the ischemic area is on the parenchymal cell rather than the vascular endothelial cell. The membrane attack complex of complement is a potential target for prevention of I/R injury in this model.
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I believe most experts believe there is room for a successful c5a inh, but it must be hard to create. In any event, of all I have read, it appears that asthma and sepsis are best targets for anti-c5a and i/r best target for anti-c5. I don't think anti-C5 has been tried in sepsis, so who knows whether any difference?
Much is not known also because it has been difficult to create experimental compounds that inhibit late stage mac assembly that also work in animals, so teasing out exact properties of each is still available for science success.
ALXN result so far does not suggest great rule in reducing PB procedure side effects on pulmunary/CNS function?
They have not pursued PB (pulmonary bypass?) per se. But, of course, CNS is on the radar. ALXN data in cardio i/r shows consistent neurocog improvement, though neuro benefit might just be secondary to cardiovascular benefit via reduction of vascular microemboli. Perhaps there might also be possible neuro benefit in other major surgeries, eg gut. There certainly could be direct benefit to anti-C5 in CNS (though maybe not for pexeli) as there are studies that show activity of terminal complement in cns disease states, MS in particular.
Because of absence of medical training, I freely admit I am on thin ice and could have made very embarrassing remarks. |
