Leronlimab's partial blockade was lucky happenstan

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Leronlimab's partial blockade was lucky happenstance when it came to other indications.

What chemokines besides RANTES (CCL5) does leronlimab block?

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Have been wondering a lot about differences between maraviroc (and other small molecule inhibitors of CCR5) versus leronlimab in how they bind to CCR5.

Asked these question elsewhere, but haven't gotten good answers. Someone even e-mailed BP, but he punted saying "We can answer the questions. Cytodyn should be able to answer them." Guess I'll try here again:


Obviously both block CCR5, MVC as a small molecule negative allosteric modulator that binds "deep in the pocket," and LL as a humanized IGg4 mAB against CCR5 that binds at the ECL2 and N terminal domain.

Questions I have are:

Why does maraviroc seem to have liver toxicity and LL does not? Is it off target (non-CCR5) effects, toxic metabolites, alteration of CCR5 binding to other ligands, or something else?

Do we know if MVC and LL block other ligands from binding to CCR5 besides CCL5 and HIV gp120 (e.g. CCL3, CCL4, CCL3L1)?

Do we know if MVC or LL block other chemokine GPCRs?

Is there any human data published showing leronlimab blocking RANTES/CCL5 from activating CCR5, or only the original Progenix/Olson work in mice of PA14?

Why did Cytodyn and others for a long time and within the last few months even claim PRO140/leronlimab did not interfere with the normal immune signaling (i.e. RANTES->CCR5)? (Did it have to do with higher doses of PA14 required to block CCL5 binding compared to dose required to inhibit HIV - fusion to T-cells via CCR5?)

Are there other CCR5 antagonists that might be able to block RANTES/CCL5 like LL can? [It was screened as one of the best to block HIV - along with mAB named 2D7, but what about blocking CCL5 binding to CCR5?] I don't think there are any other CCR5 mABs in the clinic now. Other small molecule CCR5 antagonists include vicriviroc, cenicriviroc, and aplaviroc.

Are there advantages to blocking both CCR2 and CCR5 in autoimmune and hyperinflammatory diseases versus CCR5 alone?

Recent questions too. Did anyone understand NP's responses in the interview earlier this week:

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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?

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Was NP trying to say that LL only blocks RANTES binding at high doses, but used the wrong words?