Characterization of the bispecific VHH antibody tarperprumig (ALXN1820) specific for properdin and designed for low-volume administration
The bispecific antibody tarperprumig (ALXN1820) was developed as a treatment option for diseases involving dysregulated complement alternative pathway (AP) activity that could be administered in small volumes, either subcutaneously or intravenously. Tarperprumig incorporates a C-terminal variable do...
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Taylor & Francis Group
2024-12-01
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| Series: | mAbs |
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| Online Access: | https://www.tandfonline.com/doi/10.1080/19420862.2024.2415060 |
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| author | Paul Tamburini Dennis Vestergaard Pedersen Denise Devore Josh Cone Rekha Patel Todd Hunter Fang Sun Gregers Rom Andersen Jeffrey Hunter |
| author_facet | Paul Tamburini Dennis Vestergaard Pedersen Denise Devore Josh Cone Rekha Patel Todd Hunter Fang Sun Gregers Rom Andersen Jeffrey Hunter |
| author_sort | Paul Tamburini |
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| description | The bispecific antibody tarperprumig (ALXN1820) was developed as a treatment option for diseases involving dysregulated complement alternative pathway (AP) activity that could be administered in small volumes, either subcutaneously or intravenously. Tarperprumig incorporates a C-terminal variable domain of a heavy chain only antibody (VHH) that binds properdin (FP) connected via a flexible linker to an N-terminal VHH that binds human serum albumin (HSA). The purified bispecific VHH antibody exhibits an experimental molecular weight average of 27.4 kDa and can be formulated at > 100 mg/mL. Tarperprumig binds tightly to FP and HSA with sub-nanomolar affinity at pH 7.4 and can associate simultaneously with FP and HSA to form a ternary complex. Tarperprumig potently and dose-dependently inhibits to completion in vitro AP-dependent complement C5b-9 formation, AP-dependent hemolysis, and the AP deposition of C3, FP and C9. X-ray crystallography revealed that the isolated FP-binding VHH recognizes the thrombospondin repeat 5 domain of FP, thereby preventing FP from binding to the AP convertase owing to severe steric hindrance. Tarperprumig cross-reacts with cynomolgus monkey FP and serum albumin. In summary, tarperprumig exhibits properties tailored for subcutaneous administration and is currently in clinical development for the treatment of complement AP-related disorders. |
| format | Article |
| id | doaj-art-753bc6a4e1c84f36a3a965b0c849a86b |
| institution | Kabale University |
| issn | 1942-0862 1942-0870 |
| language | English |
| publishDate | 2024-12-01 |
| publisher | Taylor & Francis Group |
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| series | mAbs |
| spelling | doaj-art-753bc6a4e1c84f36a3a965b0c849a86b2025-01-31T04:19:38ZengTaylor & Francis GroupmAbs1942-08621942-08702024-12-0116110.1080/19420862.2024.2415060Characterization of the bispecific VHH antibody tarperprumig (ALXN1820) specific for properdin and designed for low-volume administrationPaul Tamburini0Dennis Vestergaard Pedersen1Denise Devore2Josh Cone3Rekha Patel4Todd Hunter5Fang Sun6Gregers Rom Andersen7Jeffrey Hunter8Research and Product Development, Alexion, AstraZeneca Rare Disease, New Haven, CT, USADepartment of Molecular Biology and Genetics, Aarhus University, Aarhus, DenmarkResearch and Product Development, Alexion, AstraZeneca Rare Disease, New Haven, CT, USAResearch and Product Development, Alexion, AstraZeneca Rare Disease, New Haven, CT, USAResearch and Product Development, Alexion, AstraZeneca Rare Disease, New Haven, CT, USAResearch and Product Development, Alexion, AstraZeneca Rare Disease, New Haven, CT, USAResearch and Product Development, Alexion, AstraZeneca Rare Disease, New Haven, CT, USADepartment of Molecular Biology and Genetics, Aarhus University, Aarhus, DenmarkResearch and Product Development, Alexion, AstraZeneca Rare Disease, New Haven, CT, USAThe bispecific antibody tarperprumig (ALXN1820) was developed as a treatment option for diseases involving dysregulated complement alternative pathway (AP) activity that could be administered in small volumes, either subcutaneously or intravenously. Tarperprumig incorporates a C-terminal variable domain of a heavy chain only antibody (VHH) that binds properdin (FP) connected via a flexible linker to an N-terminal VHH that binds human serum albumin (HSA). The purified bispecific VHH antibody exhibits an experimental molecular weight average of 27.4 kDa and can be formulated at > 100 mg/mL. Tarperprumig binds tightly to FP and HSA with sub-nanomolar affinity at pH 7.4 and can associate simultaneously with FP and HSA to form a ternary complex. Tarperprumig potently and dose-dependently inhibits to completion in vitro AP-dependent complement C5b-9 formation, AP-dependent hemolysis, and the AP deposition of C3, FP and C9. X-ray crystallography revealed that the isolated FP-binding VHH recognizes the thrombospondin repeat 5 domain of FP, thereby preventing FP from binding to the AP convertase owing to severe steric hindrance. Tarperprumig cross-reacts with cynomolgus monkey FP and serum albumin. In summary, tarperprumig exhibits properties tailored for subcutaneous administration and is currently in clinical development for the treatment of complement AP-related disorders.https://www.tandfonline.com/doi/10.1080/19420862.2024.2415060Bispecific VHH antibodycomplement alternative pathwaycomplement inhibitionpreclinical studyproperdintarperprumig |
| spellingShingle | Paul Tamburini Dennis Vestergaard Pedersen Denise Devore Josh Cone Rekha Patel Todd Hunter Fang Sun Gregers Rom Andersen Jeffrey Hunter Characterization of the bispecific VHH antibody tarperprumig (ALXN1820) specific for properdin and designed for low-volume administration mAbs Bispecific VHH antibody complement alternative pathway complement inhibition preclinical study properdin tarperprumig |
| title | Characterization of the bispecific VHH antibody tarperprumig (ALXN1820) specific for properdin and designed for low-volume administration |
| title_full | Characterization of the bispecific VHH antibody tarperprumig (ALXN1820) specific for properdin and designed for low-volume administration |
| title_fullStr | Characterization of the bispecific VHH antibody tarperprumig (ALXN1820) specific for properdin and designed for low-volume administration |
| title_full_unstemmed | Characterization of the bispecific VHH antibody tarperprumig (ALXN1820) specific for properdin and designed for low-volume administration |
| title_short | Characterization of the bispecific VHH antibody tarperprumig (ALXN1820) specific for properdin and designed for low-volume administration |
| title_sort | characterization of the bispecific vhh antibody tarperprumig alxn1820 specific for properdin and designed for low volume administration |
| topic | Bispecific VHH antibody complement alternative pathway complement inhibition preclinical study properdin tarperprumig |
| url | https://www.tandfonline.com/doi/10.1080/19420862.2024.2415060 |
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