SAR443809: a selective inhibitor of the complement alternative pathway, targeting complement factor Bb Article Swipe
Vaishnavi Rajagopal
,
Nina C. Leksa
,
Ronald D. Gorham
,
Siddharth Jindal
,
Soumya Nair
,
Kevin E. Knockenhauer
,
Joanne Chan
,
Tony Byun
,
Courtney J. Mercadante
,
Stephen J. Moore
,
Sandip Panicker
,
Graham C. Parry
,
Michael Storek
·
YOU?
·
· 2023
· Open Access
·
· DOI: https://doi.org/10.1182/bloodadvances.2022009028
YOU?
·
· 2023
· Open Access
·
· DOI: https://doi.org/10.1182/bloodadvances.2022009028
Dysregulated activation of the complement system is implicated in the onset or progression of several diseases. Most clinical-stage complement inhibitors target the inactive complement proteins present at high concentrations in plasma, which increases target-mediated drug disposition and necessitates high drug levels to sustain therapeutic inhibition. Furthermore, many efforts are aimed at inhibiting only terminal pathway activity, which leaves opsonin-mediated effector functions intact. We describe the discovery of SAR443809, a specific inhibitor of the alternative pathway C3/C5 convertase (C3bBb). SAR443809 selectively binds to the activated form of factor B (factor Bb) and inhibits alternative pathway activity by blocking the cleavage of C3, leaving the initiation of classical and lectin complement pathways unaffected. Ex vivo experiments with patient-derived paroxysmal nocturnal hemoglobinuria erythrocytes show that, although terminal pathway inhibition via C5 blockade can effectively inhibit hemolysis, proximal complement inhibition with SAR443809 inhibits both hemolysis and C3b deposition, abrogating the propensity for extravascular hemolysis. Finally, intravenous and subcutaneous administration of the antibody in nonhuman primates demonstrated sustained inhibition of complement activity for several weeks after injection. Overall, SAR443809 shows strong potential for treatment of alternative pathway-mediated disorders.
Related Topics
Concepts
Alternative complement pathway
Complement system
Hemolysis
Paroxysmal nocturnal hemoglobinuria
Classical complement pathway
Complement factor B
Opsonin
C3-convertase
Pharmacology
Factor H
Complement component 5
Chemistry
Effector
Immunology
Antibody
Biology
Metadata
- Type
- article
- Language
- en
- Landing Page
- https://doi.org/10.1182/bloodadvances.2022009028
- https://ashpublications.org/bloodadvances/article-pdf/7/16/4258/2072787/blooda_adv-2022-009028-main.pdf
- OA Status
- gold
- Cited By
- 5
- References
- 28
- Related Works
- 10
- OpenAlex ID
- https://openalex.org/W4323804654
All OpenAlex metadata
Raw OpenAlex JSON
- OpenAlex ID
-
https://openalex.org/W4323804654Canonical identifier for this work in OpenAlex
- DOI
-
https://doi.org/10.1182/bloodadvances.2022009028Digital Object Identifier
- Title
-
SAR443809: a selective inhibitor of the complement alternative pathway, targeting complement factor BbWork title
- Type
-
articleOpenAlex work type
- Language
-
enPrimary language
- Publication year
-
2023Year of publication
- Publication date
-
2023-03-10Full publication date if available
- Authors
-
Vaishnavi Rajagopal, Nina C. Leksa, Ronald D. Gorham, Siddharth Jindal, Soumya Nair, Kevin E. Knockenhauer, Joanne Chan, Tony Byun, Courtney J. Mercadante, Stephen J. Moore, Sandip Panicker, Graham C. Parry, Michael StorekList of authors in order
- Landing page
-
https://doi.org/10.1182/bloodadvances.2022009028Publisher landing page
- PDF URL
-
https://ashpublications.org/bloodadvances/article-pdf/7/16/4258/2072787/blooda_adv-2022-009028-main.pdfDirect link to full text PDF
- Open access
-
YesWhether a free full text is available
- OA status
-
goldOpen access status per OpenAlex
- OA URL
-
https://ashpublications.org/bloodadvances/article-pdf/7/16/4258/2072787/blooda_adv-2022-009028-main.pdfDirect OA link when available
- Concepts
-
Alternative complement pathway, Complement system, Hemolysis, Paroxysmal nocturnal hemoglobinuria, Classical complement pathway, Complement factor B, Opsonin, C3-convertase, Pharmacology, Factor H, Complement component 5, Chemistry, Effector, Immunology, Antibody, BiologyTop concepts (fields/topics) attached by OpenAlex
- Cited by
-
5Total citation count in OpenAlex
- Citations by year (recent)
-
2025: 2, 2024: 1, 2023: 2Per-year citation counts (last 5 years)
- References (count)
-
28Number of works referenced by this work
- Related works (count)
-
10Other works algorithmically related by OpenAlex
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| abstract_inverted_index.high | 28, 39 |
| abstract_inverted_index.many | 47 |
| abstract_inverted_index.only | 53 |
| abstract_inverted_index.show | 121 |
| abstract_inverted_index.vivo | 113 |
| abstract_inverted_index.with | 115, 137 |
| abstract_inverted_index.C3/C5 | 76 |
| abstract_inverted_index.after | 171 |
| abstract_inverted_index.aimed | 50 |
| abstract_inverted_index.binds | 81 |
| abstract_inverted_index.onset | 11 |
| abstract_inverted_index.shows | 175 |
| abstract_inverted_index.that, | 122 |
| abstract_inverted_index.weeks | 170 |
| abstract_inverted_index.which | 32, 57 |
| abstract_inverted_index.factor | 87 |
| abstract_inverted_index.leaves | 58 |
| abstract_inverted_index.lectin | 108 |
| abstract_inverted_index.levels | 41 |
| abstract_inverted_index.strong | 176 |
| abstract_inverted_index.system | 6 |
| abstract_inverted_index.target | 21 |
| abstract_inverted_index.(factor | 89 |
| abstract_inverted_index.efforts | 48 |
| abstract_inverted_index.inhibit | 132 |
| abstract_inverted_index.intact. | 62 |
| abstract_inverted_index.leaving | 102 |
| abstract_inverted_index.pathway | 55, 75, 94, 125 |
| abstract_inverted_index.plasma, | 31 |
| abstract_inverted_index.present | 26 |
| abstract_inverted_index.several | 15, 169 |
| abstract_inverted_index.sustain | 43 |
| abstract_inverted_index.(C3bBb). | 78 |
| abstract_inverted_index.Abstract | 0 |
| abstract_inverted_index.Finally, | 151 |
| abstract_inverted_index.Overall, | 173 |
| abstract_inverted_index.activity | 95, 167 |
| abstract_inverted_index.although | 123 |
| abstract_inverted_index.antibody | 158 |
| abstract_inverted_index.blockade | 129 |
| abstract_inverted_index.blocking | 97 |
| abstract_inverted_index.cleavage | 99 |
| abstract_inverted_index.describe | 64 |
| abstract_inverted_index.effector | 60 |
| abstract_inverted_index.inactive | 23 |
| abstract_inverted_index.inhibits | 92, 139 |
| abstract_inverted_index.nonhuman | 160 |
| abstract_inverted_index.pathways | 110 |
| abstract_inverted_index.primates | 161 |
| abstract_inverted_index.proteins | 25 |
| abstract_inverted_index.proximal | 134 |
| abstract_inverted_index.specific | 70 |
| abstract_inverted_index.terminal | 54, 124 |
| abstract_inverted_index.SAR443809 | 79, 138, 174 |
| abstract_inverted_index.activated | 84 |
| abstract_inverted_index.activity, | 56 |
| abstract_inverted_index.classical | 106 |
| abstract_inverted_index.discovery | 66 |
| abstract_inverted_index.diseases. | 16 |
| abstract_inverted_index.functions | 61 |
| abstract_inverted_index.hemolysis | 141 |
| abstract_inverted_index.increases | 33 |
| abstract_inverted_index.inhibitor | 71 |
| abstract_inverted_index.nocturnal | 118 |
| abstract_inverted_index.potential | 177 |
| abstract_inverted_index.sustained | 163 |
| abstract_inverted_index.treatment | 179 |
| abstract_inverted_index.SAR443809, | 68 |
| abstract_inverted_index.abrogating | 145 |
| abstract_inverted_index.activation | 2 |
| abstract_inverted_index.complement | 5, 19, 24, 109, 135, 166 |
| abstract_inverted_index.convertase | 77 |
| abstract_inverted_index.disorders. | 183 |
| abstract_inverted_index.hemolysis, | 133 |
| abstract_inverted_index.hemolysis. | 150 |
| abstract_inverted_index.implicated | 8 |
| abstract_inverted_index.inhibiting | 52 |
| abstract_inverted_index.inhibition | 126, 136, 164 |
| abstract_inverted_index.inhibitors | 20 |
| abstract_inverted_index.initiation | 104 |
| abstract_inverted_index.injection. | 172 |
| abstract_inverted_index.paroxysmal | 117 |
| abstract_inverted_index.propensity | 147 |
| abstract_inverted_index.alternative | 74, 93, 181 |
| abstract_inverted_index.deposition, | 144 |
| abstract_inverted_index.disposition | 36 |
| abstract_inverted_index.effectively | 131 |
| abstract_inverted_index.experiments | 114 |
| abstract_inverted_index.inhibition. | 45 |
| abstract_inverted_index.intravenous | 152 |
| abstract_inverted_index.progression | 13 |
| abstract_inverted_index.selectively | 80 |
| abstract_inverted_index.therapeutic | 44 |
| abstract_inverted_index.unaffected. | 111 |
| abstract_inverted_index.Dysregulated | 1 |
| abstract_inverted_index.Furthermore, | 46 |
| abstract_inverted_index.demonstrated | 162 |
| abstract_inverted_index.erythrocytes | 120 |
| abstract_inverted_index.necessitates | 38 |
| abstract_inverted_index.subcutaneous | 154 |
| abstract_inverted_index.extravascular | 149 |
| abstract_inverted_index.administration | 155 |
| abstract_inverted_index.clinical-stage | 18 |
| abstract_inverted_index.concentrations | 29 |
| abstract_inverted_index.hemoglobinuria | 119 |
| abstract_inverted_index.patient-derived | 116 |
| abstract_inverted_index.target-mediated | 34 |
| abstract_inverted_index.opsonin-mediated | 59 |
| abstract_inverted_index.pathway-mediated | 182 |
| cited_by_percentile_year.max | 97 |
| cited_by_percentile_year.min | 90 |
| corresponding_author_ids | https://openalex.org/A5090178709 |
| countries_distinct_count | 1 |
| institutions_distinct_count | 13 |
| corresponding_institution_ids | https://openalex.org/I4210111804 |
| sustainable_development_goals[0].id | https://metadata.un.org/sdg/3 |
| sustainable_development_goals[0].score | 0.5400000214576721 |
| sustainable_development_goals[0].display_name | Good health and well-being |
| citation_normalized_percentile.value | 0.76674845 |
| citation_normalized_percentile.is_in_top_1_percent | False |
| citation_normalized_percentile.is_in_top_10_percent | False |