Pre-clinical safety assessment of VB4-845, an EpCAM binding immunoconjugate
Bibliographic record
Abstract
2136 VB4-845 is a recombinant fusion protein, consisting of a tumor-targeting antibody fragment fused to a truncated form of Pseudomonas exotoxin A (ETA252-608) that specifically targets the epithelial cell adhesion molecule (EpCAM). EpCAM is highly expressed in a wide variety of epithelial carcinomas including squamous cell carcinoma of the head and neck (SCCHN). VB4-845 is currently being evaluated for this indication in a phase II/III clinical trial using an intratumoural route of administration. In order to select an appropriate animal model for pre-clinical studies, the EpCAM amino acid sequence and epitope binding site of VB4-845 were compared among various species (mouse, rat, dog, rhesus monkey, chimpanzee) to that of humans. Amino acid identity varied from 81.6% (mouse) to 97.6% (chimpanzee) to that of humans. The EpCAM epitope amino acid identity varied from 66.7% (mouse) to 100% (rhesus monkey and chimpanzee) to that of humans. However, immunohistochemistry studies showed that VB4-845 did not cross-react with any species other than chimpanzee, a species in which end-point toxicology studies are not possible. Initial safety studies were conducted in Sprague-Dawley rats. As VB4-845 is in advanced clinical trials, additional toxicology and safety pharmacology studies were carried out in a second species, Cynomolgus monkey. Animals were dosed over a range of 0.015 to 3.5 mg/kg which corresponds to 0.03 to 70 mg in humans, up to 100 times greater than the highest clinical dose. The maximum tolerated dose was determined to be 1 mg/kg based on skin lesions at the injection site associated with other localized or systemic findings suggestive of inflammation (limited usage of affected limb, elevated body temperature, neutrophilia). Potential toxicity of repeated doses of VB4-845 was assessed in a four week repeated-dose study (0.035, 0.175, 0.350 mg/kg) which corresponds to the human clinical dose (0.7 mg) up to 10 times (7.0 mg) the proposed clinical dose. The once weekly subcutaneous (SC) administration did not result in any changes in ophthalmoscopy, neurological assessments, electrocardiography, hematology, urinalysis, organ weight data, or macroscopic findings. Clinical signs were limited to reduced appetite that was dose related but did not result in body weight changes. Localized skin lesions at the treatment sites were also dose related but resulted in inconsequential microscopic changes (foci of minimal-slight chronic inflammation and/or hemorrhage) with no evidence of systemic inflammation. The NOEL was determined to be 0.350 mg/kg. Pharmacokinetic analysis indicated that the maximum drug exposure occurred just less than four hours after SC administration. Safety studies continue to support the use of VB4-845 for the treatment of SCCHN and preparation for market registration.
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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 | 0.003 | 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 | 0.001 | 0.001 |
| Scholarly communication | 0.000 | 0.000 |
| Open science | 0.001 | 0.000 |
| Research integrity | 0.000 | 0.001 |
| Insufficient payload (model declined to judge) | 0.005 | 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".