ZW1528, A Bispecific Antibody Targeting IL-4Rα and IL-33, Potently Inhibits Key Mediators of Airway Inflammation
Bibliographic record
Abstract
Abstract Rationale: Chronic obstructive pulmonary disease (COPD) is a difficult-to-treat condition which is characterized by dysregulated type 1/3 (T1/T3) and type 2 (T2) inflammation in the lung. The high prevalence of uncontrolled disease highlights the need to develop therapeutics which can improve outcomes in a larger proportion of patients. IL-33 is a key proinflammatory cytokine associated with airway inflammation and tissue remodelling in COPD. IL-4Rα signalling plays the major role in promoting T2 inflammation and perpetuating disease. ZW1528 bispecific antibody targeting IL-4Rα and IL-33 designed for simultaneous blockade of key mediators of airway inflammation. Methods: ZW1528, an IgG-like bispecific molecule, was constructed using AzymetricTM technology. Binding and blockade of IL-4Rα and IL-33 by ZW1528 was assessed by KinExATM and reporter gene assays. Primary peripheral blood mononuclear cells (PBMC) were used to determine if inhibition of IL-4Rα and IL-33 signalling translated to regulation of immune pathways linked to airway inflammation. PK studies were performed in rodents and non-human primates (NHP). Results: ZW1528 binds to IL-33 and IL-4Rα with sub picomolar or low picomolar affinity, respectively, and effectively blocks IL-4Rα and IL-33 signalling at a comparable level to full-sized monoclonal antibody clinical benchmark controls. The bispecific suppressed IL-4-driven CCL17 production and upregulation of the low affinity IgE receptor CD23 on primary human immune cells in vitro. CD23 blockade was improved compared to bispecific control constructs with Fc-silencing mutations in the IgG1 backbone. In addition, ZW1528 inhibited IFNγ release following IL-33 stimulation of PBMCs. ZW1528 has antibody-like PK in rodent and NHP model; Fc optimization extended half-life of the molecule. Additionally, our bispecific molecule displays promising biophysical stability at 150 mg/mL to support high concentration dosing and subcutaneous administration. Conclusion: ZW1528 potently inhibits key mediators of airway inflammation. ZW1528 demonstrated high affinity binding to both IL-4Rα and IL-33 to drive potent blockade of IL-4, IL-13 and IL-33 induced signalling to decrease T2 and T1 immune responses in immune cells. These data highlighting the ability of ZW1528 to block both T1 and T2 inflammation that may translate to better control of COPD in a larger patient population.
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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 | 0.002 |
| Meta-epidemiology (narrow) | 0.000 | 0.000 |
| Meta-epidemiology (broad) | 0.001 | 0.000 |
| Bibliometrics | 0.000 | 0.000 |
| Science and technology studies | 0.000 | 0.002 |
| 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".