Serum albumin‐binding V <sub>H</sub> Hs with variable pH sensitivities enable tailored half‐life extension of biologics
Bibliographic record
Abstract
Abstract Prolonged serum half‐life is required for the efficacy of most protein therapeutics. One strategy for half‐life extension is to exploit the long circulating half‐life of serum albumin by incorporating a binding moiety that recognizes albumin. Here, we describe camelid single‐domain antibodies (V H Hs) that bind the serum albumins of multiple species with moderate to high affinity at both neutral and endosomal pH and significantly extend the serum half‐lives of multiple proteins in rats from minutes to days. We serendipitously identified an additional V H H (M75) that is naturally pH‐sensitive: at endosomal pH, binding affinity for human serum albumin (HSA) was dramatically weakened and binding to rat serum albumin (RSA) was undetectable. Domain mapping revealed that M75 bound to HSA domain 1 and 2. Moreover, alanine scanning of HSA His residues suggested a critical role for His247, located in HSA domain 2, in M75 binding and its pH dependence. Isothermal titration calorimetry experiments were suggestive of proton‐linked binding of M75 to HSA, with differing binding enthalpies observed for full‐length HSA and an HSA domain 1‐domain 2 fusion protein in which surface‐exposed His residues were substituted with Ala. M75 conferred moderate half‐life extension in rats, from minutes to hours, likely due to rapid dissociation from RSA during FcRn‐mediated endosomal recycling in tandem with albumin conformational changes induced by M75 binding that prevented interaction with FcRn. Humanized V H Hs maintained in vivo half‐life extension capabilities. These V H Hs represent a new set of tools for extending protein therapeutic half‐life and one (M75) demonstrates a unique pH‐sensitive binding interaction that can be exploited to achieve modest in vivo half‐life.
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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 | 0.000 |
| Science and technology studies | 0.000 | 0.000 |
| Scholarly communication | 0.000 | 0.000 |
| Open science | 0.000 | 0.000 |
| Research integrity | 0.000 | 0.001 |
| 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".