Nader Interview https://biotechintelligence.blogsp
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Posted On: 09/24/2021 10:44:44 PM
Nader Interview https://biotechintelligence.blogspot.com/2020...nader.html
NP not confusing???
Here is the work showing the different IC50s for PA14=PRO140=LL and other CCR5 mABs to block RANTES/CCL5. Obviously LL blocks RANTES, but at higher concentrations than needed for HIV blockage.
Olson Article https://journals.asm.org/doi/10.1128/JVI.73.5.4145-4155.1999
Clearly Maddon was wrong about LL blocking normal CCR5 signaling by CCL5. It does work, and it blocks it very well. I wonder what ever happened to MAB 2D7, a more potent CCR5 immunomodulator than LL.
Quote:
When we held a key opinion meeting Dr. Paul Maddon , inventor, was on the call at my request. I had asked him to come on the call. He said no, no, no, no. There is no GvHD [graft versus host indication] for leronlimab. This was four and a half, five years ago. And he said, No, no, no , everything must stop. Maraviroc stops chemokines from binding. Leronlimab doesn't do that. And that's why we don't have any side effects or toxicity . So stop everything. Everything gets stopped, and the next day or two I told Denis Burger: I want to know why the video that shows mechanism of action of leronlimab by Paul Maddon had indicated that chemokine binding hardly doesn't happen. “Hardly” doesn't mean zero in mathematics. Hardly means something . Need to go check with the company who did the toxicology of leronlimab and find out what amount of PRO 140 [leronlimab] do we need to use to make that happen? And Dennis Burger said, no, no, no, leave it alone, you don't know what the hell you are talking about. Stop it.
Dr. Bruce Montgomery (a board member at that time) says no. Paul said no. I said, Well, I'm going to get it myself.
Quote:
He first found a molecule and it was called (I believe) PRO 540, not 140. In the first year of development of PRO 540, the viral load drop wasn't good enough because it wasn't binding to exactly the right place. Dr. William Olson, (Ph.D. from M.I.T.) worked for Dr. Maddon, said to me that not long after the PRO 540 failure, We went back to the drawing board. I went through thousands and thousands of antibodies, and one morning I came in and I had isolated one antibody and I thought, my God, it binds to one hundred eight point percent of the HIV binding sites . That would mean that HIV would have no way to bind to that site.
NP not confusing???
Here is the work showing the different IC50s for PA14=PRO140=LL and other CCR5 mABs to block RANTES/CCL5. Obviously LL blocks RANTES, but at higher concentrations than needed for HIV blockage.
Olson Article https://journals.asm.org/doi/10.1128/JVI.73.5.4145-4155.1999
Quote:
MAbs PA14 and 2D7, however, blocked calcium mobilization induced by RANTES, although with different potencies (Fig. 3a and b). The 50% inhibitory concentration (IC50) for PA14 calcium influx inhibition was 45 μg/ml, which was approximately eightfold higher than the IC50 for 2D7 (Fig. 3b). RANTES-, MIP-1α-, and MIP-1β-induced calcium fluxes were each inhibited by similar concentrations of PA14 (data not shown).
...
No obvious correlation was observed between the HIV-1 and CC-chemokine inhibitory activities of the MAbs. PA8 to PA12 did not inhibit CC-chemokine induced calcium mobilization in L1.2-CCR5+cells, nor did they mediate signaling through CCR5. Compared with 2D7, PA14 is equipotent at inhibiting HIV-1 fusion and entry but 10-fold less potent at inhibiting RANTES-induced signaling. Whereas 2D7 and RANTES binding maps primarily to ECL2, the PA14 epitope maps to both ECL2 and the Nt domain and may have less potential for steric overlap. These data demonstrate the feasibility of developing chemokine receptor-specific HIV-1 inhibitors that do not block normal receptor activity, an observation with considerable therapeutic implications.
Clearly Maddon was wrong about LL blocking normal CCR5 signaling by CCL5. It does work, and it blocks it very well. I wonder what ever happened to MAB 2D7, a more potent CCR5 immunomodulator than LL.
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