It will interesting to see if leronlimab holds up to cancer resistance as well as it has with HIV resistance. Leronlimab is also succeeding where other ccr5 antagonists have failed, see some quoted reasons below. The 4 hour counterscreen test for $400 vs the current four week for $2000 is a huge step forward if they are successful, one of my largest concerns because I have read this was possibly a big reason MVC didn’t have the big sale revenue they were predicting back then.


Here is an article about maraviroc and many other ccr5 inhibitors resistance back in 2012. The unique way leronlimab binds compared to the others must be the reason why they have no documented patient resistance, along with reducing side-effects.


https://jvi.asm.org/content/87/2/923

Quote:

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Thus, occluding gp120 engagement of CCR5 was an attractive target for drug development (9). Maraviroc (MVC) became the first, and so far only, FDA-approved small-molecule HIV inhibitor/CCR5 antagonist for use in HIV-infected patients. Other CCR5 antagonists, agonists, and binding antibodies reached various stages of preclinical and clinical development but were eventually abandoned due to off-target complications (10), poor pharmacodynamics and pharmacokinetics (11), and difficulties in screening appropriate patients for treatment due to FDA requirements to counterscreen for CXCR4-using HIV-1 (12, 13).

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Quote:

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Potential pathways of resistance to these inhibitors include coreceptor switching to CXCR4-using viruses (16), increased affinity and binding to CD4 and/or CCR5 (17, 18), use of inhibitor-bound conformations of CCR5 (19, 20), and increased kinetics of membrane fusion (21). Although outgrowth of CXCR4-using virus remains a concern for the therapeutic administration of CCR5 antagonists and is why patients are screened for X4-tropic virus prior to starting a maraviroc regimen, de novo mutations altering coreceptor tropism do not appear to be the preferential pathway for resistance (22, 23). Rather, resistant viruses emerging from in vivo and in vitro mutational pathways have been characterized as utilizing an inhibitor-bound conformation of CCR5 for entry (19, 20, 24).

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