An asymmetric tetrabody is a potent and efficacious agonist of the erythropoietin receptor in vitro and in vivo.

ABSTRACT: Erythropoietin (EPO) initiates EPO receptor (EPOR) signaling in hematopoietic cells by binding to an asymmetric EPOR dimer through two different sites. We engineered dimeric diabody-Fc (Db-Fc) fusion proteins that appeared to act as potent agonists of human EPOR in cell proliferation assays. However, detailed analysis of their oligomeric forms revealed that the predominant Db-Fc species bound EPOR with high affinity but failed to induce cell proliferation. Instead, a minor oligomeric form, identified as a putative tetrabody (Tb) fused to two Fc domains (Tb-Fc₂), proved to be the minimal active form. The existence of a tetrameric agonist was further supported by crystallography, which revealed an asymmetric Tb structure. Additionally, the structure of an antigen-binding fragment

SUBMITTER: Adams JJ 

PROVIDER: S-EPMC12442453 | biostudies-literature | 2025 Oct

REPOSITORIES: biostudies-literature