TY - JOUR
T1 - Characterization of the bispecific VHH antibody tarperprumig (ALXN1820) specific for properdin and designed for low-volume administration
AU - Tamburini, Paul
AU - Pedersen, Dennis Vestergaard
AU - Devore, Denise
AU - Cone, Josh
AU - Patel, Rekha
AU - Hunter, Todd
AU - Sun, Fang
AU - Andersen, Gregers Rom
AU - Hunter, Jeffrey
PY - 2024
Y1 - 2024
N2 - 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.
AB - 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.
KW - Animals
KW - Antibodies, Bispecific/immunology
KW - Complement Pathway, Alternative/immunology
KW - Humans
KW - Properdin/immunology
KW - Single-Domain Antibodies/immunology
KW - Bispecific VHH antibody
KW - complement inhibition
KW - preclinical study
KW - antibody structure
KW - antibody engineering
KW - bispecific
KW - properdin
KW - tarperprumig
KW - complement alternative pathway
KW - Antibody analytics
KW - characterization
UR - http://www.scopus.com/inward/record.url?scp=85206274425&partnerID=8YFLogxK
U2 - 10.1080/19420862.2024.2415060
DO - 10.1080/19420862.2024.2415060
M3 - Journal article
C2 - 39397258
SN - 1942-0862
VL - 16
JO - mAbs
JF - mAbs
IS - 1
M1 - 2415060
ER -