An asymmetric tetrabody is a potent and efficacious agonist of the erythropoietin receptor <i>in vitro</i> and <i>in vivo</i>
Bibliographic record
Abstract
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‐Fc 2 ), 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 (Fab) bound to EPOR revealed an epitope distinct from the EPO binding sites, and structural modeling showed that engagement of two of the four binding sites on the Tb could form an asymmetric EPOR dimer nearly identical to the active conformation recruited by EPO. In a knock‐in mouse model, where mouse EPOR was replaced by human EPOR, purified Tb‐Fc 2 stimulated erythropoiesis with greater potency, efficacy, and duration than darbepoetin, a recombinant EPO that is the leading therapeutic erythropoiesis‐stimulating agent (ESA). Collectively, these findings demonstrate that asymmetric tetravalent antibodies such as Tb‐Fc 2 represent promising next‐generation ESAs that provide enhanced potency, efficacy, and durability. Moreover, they may reduce the oncogenic and cardiovascular risks associated with the pleiotropy of EPO.
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How this classification was reachedexpand
Full frame distilled prediction
Teacher imitationNot calibrated prevalence, not ground truth. Human validation pending. Learned from the 10,348 direct Codex labels and 10,348 direct Gemma labels. Candidate is the union of thresholded teacher heads; consensus is their intersection. These outputs are machine_predicted_unvalidated and are not human labels or direct frontier model labels.
Codex and Gemma teacher scores by category
| Category | Codex | Gemma |
|---|---|---|
| Metaresearch | 0.001 | 0.000 |
| Meta-epidemiology (narrow) | 0.000 | 0.000 |
| Meta-epidemiology (broad) | 0.000 | 0.000 |
| Bibliometrics | 0.000 | 0.002 |
| Science and technology studies | 0.000 | 0.001 |
| Scholarly communication | 0.000 | 0.000 |
| Open science | 0.000 | 0.000 |
| Research integrity | 0.000 | 0.000 |
| Insufficient payload (model declined to judge) | 0.000 | 0.000 |
Machine scores (provisional)
The two teacher heads of the student model, read on this work. A score orders the frame for review; it never asserts a category, and the validation status ships verbatim with every row.
Baseline scores from an immature model (maturity gate not passed, 7 training rounds). Scores rank; they never assert a category.
score_only:v0-immature-baseline · verbatim from the scoring run: score_only means the number may rank works, and no category label ships from itClassification
machine, unvalidatedMachine predicted; a candidate call from one teacher head, not a consensus.
How this classification was reached, model by model and score by score, is at the end of the page under "How this classification was reached".