Characterization of the bispecific VHH antibody tarperprumig (ALXN1820) specific for properdin and designed for low-volume administration

• Main Authors: Paul Tamburini (Author), Dennis Vestergaard Pedersen (Author), Denise Devore (Author), Josh Cone (Author), Rekha Patel (Author), Todd Hunter (Author), Fang Sun (Author), Gregers Rom Andersen (Author), Jeffrey Hunter (Author)
• Format: Book
• Published: Taylor & Francis Group, 2024-12-01T00:00:00Z.
• Subjects: article
• Online Access: Connect to this object online.
• Notes: 10.1080/19420862.2024.2415060; 1942-0870; 1942-0862
• Keywords: Bispecific VHH antibody; complement alternative pathway; complement inhibition; preclinical study; properdin; tarperprumig; Therapeutics. Pharmacology; RM1-950; Immunologic diseases. Allergy; RC581-607
• Source: mAbs, Vol 16, Iss 1 (2024)

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.