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Trispecific bNAb Hits 3 Targets but Has Modest
Antiviral Activity in First Human Studies
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CROI 2024 (Conference on Retroviruses and Opportunistic Infections), March 3-6, 2024, Denver
Mark Mascolini
SAR441236, an anti-HIV trispecific broadly neutralizing monoclonal antibody (bNAb) was safe in its first study in humans with HIV and has the advantage of binding to three highly conserved HIV-1 proteins [1]. But despite favorable pharmacokinetics (PKs) and earlier complete protection of macaques from simian HIV (SHIV) challenge [2], SAR441236 had meager antiviral activity in HIV-positive people with or without detectable virus in blood.
Because HIV deftly evolves to avoid elimination, researchers believe protection or cure depends on bNAbs that recognize multiple viral strains and subtypes. Sanofi’s Ling Xu and colleagues engineered a single bNAb that recognizes three highly conserved proteins-two HIV binding sites (VI/V2 and MPER) and a third site (CD4bs) that recruits killer T cell that can theoretically eliminate HIV-1 [2]. Trispecific bNAbs like SAR441236 have broadly neutralized about 99% of more than 200 HIV-1 strains. A 5 mg/kg intravenous dose of SAR441236 completely protected 8 of 8 macaques from a mixture of simian HIVs [2].
Athe Tsibris (Brigham and Women’s Hospital, Boston) and AIDS Clinical Trial Group (ACTG) colleagues at other centers conducted this phase 1 study (ACTG A5377) to assess the safety, PKs, and antiviral activity of SAR441236 in people with HIV and either a detectable or undetectable viral load. To antiretroviral-treated people with a viral load below 50 copies, the researchers gave escalating intravenous (IV) or subcutaneous (SC) single doses of the bNAb, from 0.3 to 10 mg/kg, or four (IV) 30-mg/kg doses every 12 weeks with 72 weeks of follow-up. The investigators randomized these people in a 2-to-1 ratio to SAR441236 or placebo. To antiretroviral-naive people or people untreated in the last 8 weeks, they assessed single open-label intravenous doses of 1 mg/kg or 30 mg/kg.
People with antiretroviral suppression of HIV had to be 18 to 70 years old and taking antiretroviral therapy (ART) for more than 12 months with a viral load below 50 copies for 1 year (with 1 blip below 200 copies allowed) and a CD4 count above 200. Participants with a detectable viral load had to be 18 to 70 years old and naive to ART or off ART for the past 8 weeks. Their viral load had to lie between 5000 and 200,000 copies and their CD4 count above 350. They could have no active opportunistic infections.
Thirty-two people in the ART-suppressed IV group, 7 in the unsuppressed IV group, and 12 in the ART-suppressed SC group had median ages of 54, 26, and 53 and median baseline CD4 counts of 743, 458, and 849. Respective proportions of men were 88%, 100%, and 92%, blacks 38%, 43%, and 33%, whites 50%, 43%, and 42%, and Hispanics 9%, 0%, and 8%.
No one in any group had a trial-defined qualifying adverse event-a treatment-related grade 3 or worse event.
PKs of SAR441236 resembled those of monospecific HIV-1 LS bNAb (that is, bNAbs engineered to prolong half-life). SAR441236 clearance proved 38% greater in people with versus without a detectable viral load. Overall clearance averaged 137 +/- 86 mL/d, volume of distribution 6.3 +/- 2.4 L, SC bioavailability 35 +/- 7%, and half-life 38 +/- 10 days. For participants getting a single dose of SAR441236, Monte Carlo simulation predicted that 30 mg/kg IV every 12 weeks would yield a median steady-state trough concentration of 74 ug/mL (90% PI 25 of 185).
None of 4 antibodies ART-treated people getting the 1 mg/kg SAR441236 IV dose had treatment-induced antidrug antibodies; 1 of 4 treated people getting 3 mg/kg IV had such antibodies, 1 of 4 people getting 10 mg/kg IV had transient treatment-induced antidrug antibodies, and 2 of 9 getting 30 mg/kg IV had antidrug antibodies. None of 4 ART-treated people getting 0.3 mg/kg SC had treatment-induced antidrug antibodies, whereas 2 of 4 getting 1 mg/kg did. Four of 5 untreated people getting 1 mg/kg IV had treatment-induced antidrug antibodies, as did 1 of 2 getting 30 mg/kg IV. All treatment-induced antidrug antibodies in people with an undetectable viral load were transient, low in titer, and did not affect PKs.
Levels of intact provirus from study participants did not change through 72 weeks of follow-up. Plasma viral load in 5 people getting 1 mg/kg of SAR441236 averaged a drop of -0.10 log10 copies after 7 days, while 2 people getting 30 mg/kg averaged a -0.38 log10 copies decline after 7 days. These results indicate modest antiviral activity of SAR441236.
The ACTG team believes their findings, plus the convenience of treating people with a single biologic, “support the evaluation of novel tri- or multi-specific bnAbs for HIV-1 treatment or prevention.”
References
1. Tsibris A, Zheng YE, Capparelli E, et al. A first-in-human study of the trispecific HIV-1 broadly neutralizing antibody, SAR441236. CROI 2024 (Conference on Retroviruses and Opportunistic Infections), March 3-6, 2024, Denver. Abstract 118.
2. Xu L, Amarendra Pegu A, Rao E, et al. Trispecific broadly neutralizing HIV antibodies mediate potent SHIV protection in macaques. Science. 2017 6;358:85-90. doi: 10.1126/science.aan8630. https://www.science.org/doi/10.1126/science.aan8630?url
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