The serum protein transthyretin as a platform for dimerization and tetramerization of antibodies and Fab fragments to enable target clustering.
J Biol Chem
; 295(30): 10446-10455, 2020 07 24.
Article
in En
| MEDLINE
| ID: mdl-32518163
ABSTRACT
Transthyretin (TTR) is an abundant homotetrameric serum protein and was selected here for engineering higher-valency molecules because of its compact size, simple structure, and natural propensity to tetramerize. To demonstrate this utility, we fused TTR to the C terminus of conatumumab, an antibody that targets tumor necrosis factor-related apoptosis-inducing ligand receptor 2, as heavy chains to form antibody dimers and Fab heavy chains to form Fab tetramers. Moreover, we used constant heavy domain 3 heterodimerization substitutions to create TTR-mediated conatumumab tetramers. The conatumumab-TTR fusions displayed substantially enhanced potency in cell-based assays, as well as in murine tumor xenograft models. We conclude that antibody-TTR fusions may provide a powerful platform for multimerizing antibody and Fab fragments to enhance the capabilities of human therapeutics that benefit from target clustering and higher-order antigen-binding valency.
Key words
Full text:
1
Collection:
01-internacional
Database:
MEDLINE
Main subject:
Immunoglobulin Fab Fragments
/
Prealbumin
/
Protein Multimerization
/
Antineoplastic Agents, Immunological
/
Antibodies, Monoclonal
/
Neoplasms, Experimental
Type of study:
Prognostic_studies
Limits:
Animals
/
Humans
Language:
En
Journal:
J Biol Chem
Year:
2020
Document type:
Article
Affiliation country: