The reality is we are but 1 of the 3 best CCR5 mAb
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Posted On: 05/31/2020 1:17:43 PM
The reality is we are but 1 of the 3 best CCR5 mAb's, and there are others too. We are way way ahead of them, the other two have no active trials, but lets not get complacent when considering the money they have and how much is required to bury a small player with almost no political power. Could one of these be dusted off and repurposed?
Six mouse anti-human CCR5 monoclonal antibodies (mAbs) that showed potent antiviral activities were identified from over 26,000 mouse hybridomas. The epitopes for these mAbs were determined by using various CCR5 mutants, including CCR5/CCR2B chimeras. One mAb, ROAb13, was found to bind to a linear epitope in the N terminus of CCR5. Strikingly, the other five mAbs bind to epitopes derived from extracellular loop 2 (ECL2).
Three CCR5 mAbs, 2D7 (sigmaaldrich), PRO 140 (CYDY), and mAb004 (GlaxoSmithKline), that showed potent antiviral activities are currently in development as potential inhibitors of HIV entry.
The ECL2-recognizing mAbs can be divided into three classes based on the regions from where their epitopes derive. mAbs in the first class bind exclusively to ECL2A. 2D7 is the first such antibody reported whose epitope has been mapped to K171/E172. The novel mAbs ROAb10 and ROAb51 also fall into this class. A few mAbs can be classified into the second class, which recognize epitopes in ECL2B (mainly from Tyr184 to Phe189) (25). The third class of mAbs recognize epitopes derived primarily from ECL2A but also from ECL2B or other domains. mAb PRO 140 falls into this class, because it requires Arg168 in ECL2A and Asp2 in the Nt (30). The novel mAbs ROAb12, ROAb14, and ROAb18 described here also belong to this class. These three mAbs use epitopes from both ECL2A and ECL2B. The third class of mAbs exhibited the most potent antiviral activities, followed by the first class. These data suggest that ECL2A provides the crucial components of the epitopes for CCR5 mAbs with highly potent antiviral activities.
In summary, by screening over 26,000 hybridomas, we found about 400 clones that showed specific binding to CCR5 as demonstrated by cell-based ELISA. However, out of these 400 clones, only 7 showed anti-HIV activity. Furthermore, only six mAb clones showed antiviral potency equal to or better than that of the control mAb 2D7, sufficient for being clinical drug candidates. Out of these six mAbs, except for one mAb, ROAb13, which recognizes a linear epitope residing in the Nt of CCR5, all other five mAbs recognize epitopes derived from ECL2. Besides, the control mAb 2D7, which is in preclinical development as an HIV entry inhibitor, also recognizes a similar epitope in ECL2. In addition, two out of three key residues (Arg168 and Tyr176) that are required for binding by the highly potent CCR5 mAb PRO 140 are located in ECL2. Therefore, based on these data, we hypothesize that CCR5 ECL2 contains the dominant epitopes for potent anti-HIV mAbs.
https://aac.asm.org/content/51/4/1386
Six mouse anti-human CCR5 monoclonal antibodies (mAbs) that showed potent antiviral activities were identified from over 26,000 mouse hybridomas. The epitopes for these mAbs were determined by using various CCR5 mutants, including CCR5/CCR2B chimeras. One mAb, ROAb13, was found to bind to a linear epitope in the N terminus of CCR5. Strikingly, the other five mAbs bind to epitopes derived from extracellular loop 2 (ECL2).
Three CCR5 mAbs, 2D7 (sigmaaldrich), PRO 140 (CYDY), and mAb004 (GlaxoSmithKline), that showed potent antiviral activities are currently in development as potential inhibitors of HIV entry.
The ECL2-recognizing mAbs can be divided into three classes based on the regions from where their epitopes derive. mAbs in the first class bind exclusively to ECL2A. 2D7 is the first such antibody reported whose epitope has been mapped to K171/E172. The novel mAbs ROAb10 and ROAb51 also fall into this class. A few mAbs can be classified into the second class, which recognize epitopes in ECL2B (mainly from Tyr184 to Phe189) (25). The third class of mAbs recognize epitopes derived primarily from ECL2A but also from ECL2B or other domains. mAb PRO 140 falls into this class, because it requires Arg168 in ECL2A and Asp2 in the Nt (30). The novel mAbs ROAb12, ROAb14, and ROAb18 described here also belong to this class. These three mAbs use epitopes from both ECL2A and ECL2B. The third class of mAbs exhibited the most potent antiviral activities, followed by the first class. These data suggest that ECL2A provides the crucial components of the epitopes for CCR5 mAbs with highly potent antiviral activities.
In summary, by screening over 26,000 hybridomas, we found about 400 clones that showed specific binding to CCR5 as demonstrated by cell-based ELISA. However, out of these 400 clones, only 7 showed anti-HIV activity. Furthermore, only six mAb clones showed antiviral potency equal to or better than that of the control mAb 2D7, sufficient for being clinical drug candidates. Out of these six mAbs, except for one mAb, ROAb13, which recognizes a linear epitope residing in the Nt of CCR5, all other five mAbs recognize epitopes derived from ECL2. Besides, the control mAb 2D7, which is in preclinical development as an HIV entry inhibitor, also recognizes a similar epitope in ECL2. In addition, two out of three key residues (Arg168 and Tyr176) that are required for binding by the highly potent CCR5 mAb PRO 140 are located in ECL2. Therefore, based on these data, we hypothesize that CCR5 ECL2 contains the dominant epitopes for potent anti-HIV mAbs.
https://aac.asm.org/content/51/4/1386
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