Replies to post #9129 on Cytodyn Inc (CYDY)

[jboatswain]

I have no problems about your saying there is a difference between MOA of Miraviroc and that of Pro 140. Philosophically speaking, one can find differences between two objects in SOME description; one can also find similarities between the same two objects in ANOTHER description.


Can you tell where the difference lies in mechanism of action, so that Pro 140 is more effective?

One is mAb, another, small molecule. This answer would not work, unless one shows that being mAb is more effective.

MOA of Miraviroc

Maraviroc is an entry inhibitor. Specifically, maraviroc is a negative allosteric modulator of the CCR5 receptor, which is found on the surface of certain human cells. The chemokine receptor CCR5 is an essential co-receptor for most HIV strains and necessary for the entry process of the virus into the host cell. The drug binds to CCR5, thereby blocking the HIV protein gp120 from associating with the receptor. HIV is then unable to enter human macrophages and T cells.[7] Because HIV can also use other coreceptors, such as CXCR4, an HIV tropism test such as a trofile assay must be performed to determine if the drug will be effective.[8]

MOA of Pro 140:

PRO 140 is a lab-made antibody that functions as an entry inhibitor.[7][8] PRO 140 binds to the CCR5 receptor on the CD4 cells, and interferes with HIV's ability to enter the cell. PRO 140, a humanized form of a PA14 antibody, is a chemokine-receptor CCR5 monoclonal antibody and can inhibit CCR5 tropic HIV-1 at concentrations that do not antagonize the natural activity of CCR5 in vitro. HIV-1 entry is mediated by the HIV-1 envelope glycoproteins gp120 and gp41. The gp120 will bind CD4 and the CCR5co receptor molecule, and this triggers gp41-mediated fusion of the viral and cellular membranes. CCR5 is hence needed for the entry of the virus and this infection of healthy cells. PRO 140, the anti-CCR5 monoclonal antibody, can stop HIV from entering the cell and stop viral replication. It prevents the virus-cell binding at a distinct site in the CCR5 co-receptor without interfering with its natural activity. Unlike other entry inhibitors, PRO 140 is a monoclonal antibody. The mechanism of inhibition is competitive rather than allosteric.[9] As such, it must be injected to be effective. However, once inside the body, PRO 140 binds to CCR5 for >60 days,[10] which may allow for dosing as infrequently as every other week.[11][12] Compared to highly-active antiretroviral therapy which has been shown to have treatment-related toxicities for HIV-infected patients, PRO140 has no multi-drug resistance or toxicities.[9]

One difference: Pro 140 not antagonize the natural activity of CCR5 in vivo. Maybe, this can explain why Pro 140 has less AE. How about effectiveness?

Another diff: The mechanism of inhibition is competitive rather than allosteric. Based on the following link on quora, this difference is just a reformulation (allosteric vs competitive) of the above difference.

https://www.quora.com/What-is-the-difference-between-allosteric-and-non-competitive-inhibition