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10年前，HBs的抗体monoclonal 抗体, 非常高的希望。这一次,希望有更多的成功，
以下Studyforhope给予了非常资料性一课:
stef2011 Mar 06 2012
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC3086357/
The present study reveals that the antiviral effect of anti-HBs against HBV involves not only binding of viral particles in the circulation, but it also involves intracellular antiviral activity by blocking viral particles release from the cells. We have previously demonstrated that anti-HBs is endocytosed into hepatocyte-derived cell lines irrespective of the presence or absence of HBsAg (10). This is likely to occur as a receptor-mediated endocytosis of IgG via the major histocompatibility complex class I-like Fc-receptor, FcRn. We have shown that FcRn is expressed on several liver cell lines and Fc elimination abrogated the IgG biding to the cells, as well as its effect on HBsAg secretion (10). FcRn is the transport receptor for IgG and protects IgG from catabolism after entry into cells (32, 33). This process is likely to operate during chronic HBV infection, as anti-envelope antibodies have been detected in the serum of virtually all patients with chronic hepatitis B when using sensitive assays (34). Intracellular binding and blocking the secretion of HBV particles may have a role for containment of HBV when at low level within cells, for example in subjects with spontaneously resolved HBV infection (35) or in liver transplant recipients having effective long-term HBIg prophylaxis without clinical HBV recurrence (9, 36).
The antiviral activity of HBV neutralizing antibodies may have clinical implications for treatment of chronic hepatitis B. Post-treatment rebound of HBV replication occurs frequently after stopping direct antivirals even after prolonged treatment for many years. Application of anti-HBs, in combination with a potent antiviral agent blocking directly HBV replication, will target different sites of HBV replicative cycle within cells and may reduce the relapse rates, analogous to the approach that was applied successfully after HAART withdrawal in patients with HIV infection (37). Furthermore, after prolonged and effective control of HBV replication in patients treated with potent antivirals, an add-on application of anti-HBs may facilitate HBsAg clearance in appropriately selected patients.
studyforhope
Mar 07, 2012
To: stefano, stephen
This paper is a lale workup - viral dynamics analysis- of the Hepex-B trials that were initiated by XTL, a company based in Israel. Hepex B is a double human monoclonal AB where both antibodies bind to the surface antigen with exceptional high affinity.
Since it is a human monoclonal, no antibodies to the antibody are expected to occur.Thus long term therapy is possible.
The trial used patients with a relatively low HbSAg titer, chronic HBV.
Dramatic, unexpected drops in DNA levels were achieved, also, as expected the surface antigen disappeared temporalily from the patients serum.
The phenomenon of uptake of the antibody into hepatocytes was known from other sources, in this trial it could be shown that this endocytosed AB had an actual effect on virion and likely 22nm particle (HbSAg) secretion.
Dosing was single or multiple, the effect was consistent, but the DNA and surface antigen levels returned to baseline or close to baseline rapidly.
It became clear that despite the dramatic virion level lowering effect, this would have to be a long term treatment, where the blocking of production and reinfection was slowly accompanied by the reduction of cccDNA content in the infected hepatocytes, reducing the reservoir from which the HBV machinery would restart within hours after the blocking AB was eliminated by its inherent turnover.
The situation is similar to a treatment with Myrcludex, where the blockage of reinfection will only slowly tilt the balance between daily destruction of cccDNA and refreshing of cccDNA content by reinfection of new hepatocytes.
It is this balance also that hinders the antivirals to be a cure, since even the best antivirals do not block de novo virion production completely. And the fewer virions produced under antivirals all start to count now, since the liver will absorb und bring all these virions to an infectious event, that leads to a new buildup of a new cccDNA pool in the de novo infected cell.
Before Hepex B there was Ostavir, a humanized monoclonal AB against the surface antigen, that was used in human trials finally in Europe in a combo with Lamuvidine. The trial had to be halted in midstream, because the immune complexes that formed by the association between the Ab and the still substantial amounts of HbSAg accumulated in the patients kkidneys glomerular membranes, causing acute kidney damage. This terminated the Ostavir development.
In the XTL Hepex B trials, this was not seen, possibly because the AB was different and such the nature of the ICs, or the dosing was not long enough or the patients had been better selected for low starting HbSAg or of special interest, the higher intracellular uptake has reduced the serum levels of HbSAg still secreted to such a low level that the ICs became tolerable.
After XTL realized a low feasability of market success with HepexB for chronic HBV, they decided to approach the HBV transplant reinfection market. Another US company by trhe name of Cubists, that produced an antibiotic among other things bought the rights to the US market and started development of Hepex B in the transplant setting with the FDA.
Cubist did not manufacture Hepex B themselves, nor did XTL anymore, but instead a US company -XOMA- spezializing in human hybridoma monoclonal Ab production on the large scale was hired to perform the actual production of the monoclonals to the high standards of the FDA.
A phase II trial with HBV transplant patients was initiated and successfully completed with full protection from reinfection, but, as is the standard now, in combo with an antiviral.
Now cubist wanted to proceed with the phase III registration trial for the transplant setting and XOMA got ready to produce the large quantities of Hepex B needed for this trial for them.
Sadly, the FDA requested such a large number of transplant patients for the phase III that the unavailability and huge cost of this made Cubist to give up on the project and XOMA did not get to produce the Ab for this trial.
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发表于 2015-7-11 09:22
