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Dual-Active mAbs Better Than Single-Active Therapy in Stalling SARS-CoV-2
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30th CROI, Conference on Retroviruses and Opportunistic Infections, February 19-22, 2023, Seattle
Mark Mascolini
Combining two monoclonal antibodies (mAbs) to create a dual-active assault against SARS-CoV-2 cleared the coronavirus faster than a single-active mAb and cut chances that resistance to the mAbs would emerge [1]. But have mAbs had their day in the sun as a sleekly tailored therapeutic that can keep people with COVID-19 out of the hospital, out of the ICU, and out of the morgue?
mAbs once led the race to shield people with SARS-CoV-2 infection from rapid progression to life-threatening COVID-19. Donald Trump got a monoclonal antibody cocktail for his COVID-19 [2], and that strategy seemed to get him get out of Walter Reed and back into the White House with striking alacrity for an elderly, overweight man. But mAbs turned out to have an aching Achilles heel: newly evolved SARS-CoV-2 variants easily shifted shape to escape the grasp of current mAbs [3].
At CROI a team from Harvard and Brigham and Women's Hospital rolled out their findings on another mAb cocktail-amubarvimab (BRII-196) and romlusevimab (BRII-198)-recombinant human IgG1 monoclonal antibodies that seek out and snare conserved nonoverlapping regions in the receptor-binding domain of the SARS-CoV-2 spike protein, which the virus uses to latch onto target cells [1].
Both amubarvimab and romlusevimab are active against SARS-CoV-2 variants Alpha, Beta, Gamma, and others, while amubarvimab is expected to be active also against Delta, Epsilon, Lambda, and Mu variants. In the ACTIV-2/A5401 trial, these two mAbs combined to cut the risk of hospital admission and death 79% compared with placebo [4]. The Brigham/Harvard investigators conducted this study to see if viral kinetics and resistance emergence with SARS-CoV-2 differ with single-active mAbs and dual-active mAbs like combined amubarvimab and romlusevimab.
Researchers enrolled 789 participants from January to July 2021 and randomized 389 to amubarvimab plus romlusevimab and 400 to placebo. They measured viral load in participants by collecting deep nasal swabs on study days 0, 3, 7, 14, and 28 and assessing samples with spike gene next-generation sequencing.
Among people randomized to amubarvimab and romlusevimab, the investigators compared viral load changes and resistance emergence in participants who had viral variants sensitive to amubarvimab alone (Delta, Epsilon, Lambda,, and Mu), that is, virus sensitive to single-active mAb therapy, versus participants with virus sensitive to both amubarvimab and romlusevimab (Alpha, Beta, Gamma, others), that is, virus sensitive to dual-active mAb therapy.
This exercise yielded 188 participants with dual-active therapy and 111 with single-active therapy. Median age was similar in the dual and single groups (47 and 48), as was the proportion of women (48% and 47%). A dual-versus-single difference in race/ethnicity (77% and 67% white, 23% and 33% nonwhite) did not reach statistical significance. The dual- and single-active groups were also similar in median days from symptoms to randomization (6 and 5), median baseline total symptom score (11 and 10), and median baseline viral load (4.8 and 4.8 log10 copies/mL).
Comparing the 389 people randomized to amubarvimab and romlusevimab with the 400 randomized to placebo, the researchers recorded significantly greater drops in viral load with the two mAbs at days 3 (P < 0.01) and 7 (P < 0.05). Among mAb-treated people, dual-active treatment induced significantly greater viral load declines than single-active treatment at days 3 (P < 0.0001) and 7 (P < 0.0001). In this analysis, single-active therapy suppressed viremia significantly more than placebo at days 3 (P < 0.001) and 7 (P < 0.001).
As would be expected, emerging resistance mutations proved more frequent in people assigned to the two mAbs than in those assigned to placebo (2.6% vs 0, P < 0.001), because placebo exerts no pressure on the virus to evolve. And people getting a single-active mAb had significantly more resistant virus emerge than those getting dual-active treatment (7.2% vs 1.1%, P < 0.01), because dual-active treatment controlled viral replication better and so limited-but did not stop-viral evolution: People with resistance mutations emerging during treatment had significantly higher SARS-CoV-2 loads at days 0, 3, 7, and 14.
The Boston researchers noted that their analysis is limited by the study group makeup-mainly unvaccinated people infected with pre-omicron variants. With that limitation in mind, they summarized their findings this way:
• Dual-active mAbs cleared SARS-CoV-2 faster than a single-active mAb.
• Resistance to mAbs arose significantly more often in people treated with mAbs than in those getting placebo.
• Emergence of resistant virus was significantly more frequent with a single-active mAb than with dual-active mAbs
The investigators believe their findings support use of combination mAbs for SARS-CoV-2 infection. But the transitory population response to mAbs so far in the pandemic indicates a need for more work to create a durable mAb strategy [3,5].
References
1. Choudhary M, Deo R, Evering TH, et al. Characterization of single versus dual active mAb against SARS-CoV-2. 30th CROI, Conference on Retroviruses and Opportunistic Infections, February 19-22, 2023, Seattle. Abstract 168.
2. Cohen J. Update: Here's what is known about Trump's COVID-19 treatment. Science. October 5, 2020. https://www.science.org/content/article/heres-what-known-about-president-donald-trump-s-covid-19-treatment
3. Huang P. How monoclonal antibodies lost the fight with new COVID variants. npr.org. November 20, 2022.
https://www.npr.org/sections/health-shots/2022/11/20/1137892932/monoclonal-antibodies-covid-treatment
4. Hoy SM. Amubarvimab/romlusevimab: first approval. Drugs. 2022;82:1327-1331. Published online 2022 Aug 23. doi: 10.1007/s40265-022-01759-3
5. Dacon C, Tucker C, Peng L, et al. Broadly neutralizing antibodies target the coronavirus fusion peptide. Science. 2022;377:728-735. DOI: 10.1126/science.abq3773
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