Optimizing clinical dosing of combination broadly neutralizing antibodies for HIV prevention.
Broadly neutralizing antibodies (bNAbs) are promising agents to prevent HIV infection and achieve HIV remission without antiretroviral therapy (ART). As with ART, bNAb combinations are likely needed to cover HIV's extensive diversity. Not all bNAbs are identical in terms of their breadth, poten...
| Main Authors: | , , , , , , |
|---|---|
| Format: | Article |
| Language: | English |
| Published: |
Public Library of Science (PLoS)
2022-04-01
|
| Series: | PLoS Computational Biology |
| Online Access: | https://doi.org/10.1371/journal.pcbi.1010003 |
| _version_ | 1797829025531428864 |
|---|---|
| author | Bryan T Mayer Allan C deCamp Yunda Huang Joshua T Schiffer Raphael Gottardo Peter B Gilbert Daniel B Reeves |
| author_facet | Bryan T Mayer Allan C deCamp Yunda Huang Joshua T Schiffer Raphael Gottardo Peter B Gilbert Daniel B Reeves |
| author_sort | Bryan T Mayer |
| collection | DOAJ |
| description | Broadly neutralizing antibodies (bNAbs) are promising agents to prevent HIV infection and achieve HIV remission without antiretroviral therapy (ART). As with ART, bNAb combinations are likely needed to cover HIV's extensive diversity. Not all bNAbs are identical in terms of their breadth, potency, and in vivo longevity (half-life). Given these differences, it is important to optimally select the composition, or dose ratio, of combination bNAb therapies for future clinical studies. We developed a model that synthesizes 1) pharmacokinetics, 2) potency against a wide HIV diversity, 3) interaction models for how drugs work together, and 4) correlates that translate in vitro potency to clinical protection. We found optimization requires drug-specific balances between potency, longevity, and interaction type. As an example, tradeoffs between longevity and potency are shown by comparing a combination therapy to a bi-specific antibody (a single protein merging both bNAbs) that takes the better potency but the worse longevity of the two components. Then, we illustrate a realistic dose ratio optimization of a triple combination of VRC07, 3BNC117, and 10-1074 bNAbs. We apply protection estimates derived from both a non-human primate (NHP) challenge study meta-analysis and the human antibody mediated prevention (AMP) trials. In both cases, we find a 2:1:1 dose emphasizing VRC07 is nearly optimal. Our approach can be immediately applied to optimize the next generation of combination antibody prevention and cure studies. |
| first_indexed | 2024-04-09T13:13:46Z |
| format | Article |
| id | doaj.art-b20d108e19284c90906534360439205e |
| institution | Directory Open Access Journal |
| issn | 1553-734X 1553-7358 |
| language | English |
| last_indexed | 2024-04-09T13:13:46Z |
| publishDate | 2022-04-01 |
| publisher | Public Library of Science (PLoS) |
| record_format | Article |
| series | PLoS Computational Biology |
| spelling | doaj.art-b20d108e19284c90906534360439205e2023-05-12T05:30:45ZengPublic Library of Science (PLoS)PLoS Computational Biology1553-734X1553-73582022-04-01184e101000310.1371/journal.pcbi.1010003Optimizing clinical dosing of combination broadly neutralizing antibodies for HIV prevention.Bryan T MayerAllan C deCampYunda HuangJoshua T SchifferRaphael GottardoPeter B GilbertDaniel B ReevesBroadly neutralizing antibodies (bNAbs) are promising agents to prevent HIV infection and achieve HIV remission without antiretroviral therapy (ART). As with ART, bNAb combinations are likely needed to cover HIV's extensive diversity. Not all bNAbs are identical in terms of their breadth, potency, and in vivo longevity (half-life). Given these differences, it is important to optimally select the composition, or dose ratio, of combination bNAb therapies for future clinical studies. We developed a model that synthesizes 1) pharmacokinetics, 2) potency against a wide HIV diversity, 3) interaction models for how drugs work together, and 4) correlates that translate in vitro potency to clinical protection. We found optimization requires drug-specific balances between potency, longevity, and interaction type. As an example, tradeoffs between longevity and potency are shown by comparing a combination therapy to a bi-specific antibody (a single protein merging both bNAbs) that takes the better potency but the worse longevity of the two components. Then, we illustrate a realistic dose ratio optimization of a triple combination of VRC07, 3BNC117, and 10-1074 bNAbs. We apply protection estimates derived from both a non-human primate (NHP) challenge study meta-analysis and the human antibody mediated prevention (AMP) trials. In both cases, we find a 2:1:1 dose emphasizing VRC07 is nearly optimal. Our approach can be immediately applied to optimize the next generation of combination antibody prevention and cure studies.https://doi.org/10.1371/journal.pcbi.1010003 |
| spellingShingle | Bryan T Mayer Allan C deCamp Yunda Huang Joshua T Schiffer Raphael Gottardo Peter B Gilbert Daniel B Reeves Optimizing clinical dosing of combination broadly neutralizing antibodies for HIV prevention. PLoS Computational Biology |
| title | Optimizing clinical dosing of combination broadly neutralizing antibodies for HIV prevention. |
| title_full | Optimizing clinical dosing of combination broadly neutralizing antibodies for HIV prevention. |
| title_fullStr | Optimizing clinical dosing of combination broadly neutralizing antibodies for HIV prevention. |
| title_full_unstemmed | Optimizing clinical dosing of combination broadly neutralizing antibodies for HIV prevention. |
| title_short | Optimizing clinical dosing of combination broadly neutralizing antibodies for HIV prevention. |
| title_sort | optimizing clinical dosing of combination broadly neutralizing antibodies for hiv prevention |
| url | https://doi.org/10.1371/journal.pcbi.1010003 |
| work_keys_str_mv | AT bryantmayer optimizingclinicaldosingofcombinationbroadlyneutralizingantibodiesforhivprevention AT allancdecamp optimizingclinicaldosingofcombinationbroadlyneutralizingantibodiesforhivprevention AT yundahuang optimizingclinicaldosingofcombinationbroadlyneutralizingantibodiesforhivprevention AT joshuatschiffer optimizingclinicaldosingofcombinationbroadlyneutralizingantibodiesforhivprevention AT raphaelgottardo optimizingclinicaldosingofcombinationbroadlyneutralizingantibodiesforhivprevention AT peterbgilbert optimizingclinicaldosingofcombinationbroadlyneutralizingantibodiesforhivprevention AT danielbreeves optimizingclinicaldosingofcombinationbroadlyneutralizingantibodiesforhivprevention |