8Q6R

Structure of complement FP in complex with the TPP-3077 VHH

Summary for 8Q6R

• Entry DOI: 10.2210/pdb8q6r/pdb
• Descriptor: The properdin specific VHH TPP-3077, Properdin, beta-D-glucopyranose-(1-3)-alpha-L-fucopyranose, ... (9 entities in total)
• Functional Keywords: complement, antibody, properdin, alternative pathway, immune system
• Biological source: Lama glama; More
• Total number of polymer chains: 6
• Total formula weight: 107272.94

Authors

Andersen, G.R.,Pedersen, D.V. (deposition date: 2023-08-14, release date: 2024-08-28, Last modification date: 2024-11-13)

Primary citation

Tamburini, P.,Pedersen, D.V.,Devore, D.,Cone, J.,Patel, R.,Hunter, T.,Sun, F.,Andersen, G.R.,Hunter, J.
Characterization of the bispecific VHH antibody tarperprumig (ALXN1820) specific for properdin and designed for low-volume administration.
Mabs, 16:2415060-2415060, 2024

PubMed Abstract: 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 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.

PubMed: 39397258
DOI: 10.1080/19420862.2024.2415060

Experimental method

X-RAY DIFFRACTION (1.9 Å)