441 Reimagining bladder cancer immunotherapy: local non-viral gene delivery of DNA-encoded immune checkpoint inhibitors
Bibliographic record
Abstract
Background enGene has developed Dually Derivatized Oligochitosan® (DDX), a non-viral, non-integrating gene delivery platform designed for local administration to the bladder mucosa via intravesical instillation (IVI). In an ongoing registrational trial ( NCT04752722), the DDX-formulated drug detalimogene voraplasmid is being evaluated for safety and efficacy in Bacillus Calmette-Guérin (BCG)-unresponsive non-muscle-invasive bladder cancer (NMIBC). The preliminary overall complete response (CR) rate is 71% (15/21) with a favorable safety/tolerability profile. To further leverage the potential of the DDX platform, enGene is developing novel formulations for bladder-localized expression of DNA-encoded monoclonal antibodies, specifically, immune checkpoint inhibitors (ICI) which are typically delivered intravenously or subcutaneously. This approach aims to retain antitumor efficacy while avoiding systemic toxicities associated with conventional ICI therapies.Methods Plasmids were designed to co-express the heavy and light chains of two ICI’s, nivolumab and pembrolizumab, using bicistronic single expression cassette or dual-promoter expression cassettes. These constructs were formulated with DDX and screened for in vitro expression and function in relevant cell lines, using paratope-specific and human PD-1/PD-L1 competitive immunoassays. In vivo expression duration, dose response, and systemic exposure were assessed in C57BL/6 mice after IVI. A custom paratope-specific immunoassay on the Meso Scale Discovery platform was used to quantify protein levels. Therapeutic efficacy of ICI-expressing DDX formulation is currently being evaluated in a humanized PD-1 murine orthotopic bladder cancer model.Results The expression constructs for pembrolizumab and nivolumab demonstrated dose-dependent expression in vitro. The PD-1/PD-L1 blocking potency of the expressed ICI was the same as the blocking activity of recombinant ICI from commercial suppliers, confirming their functional integrity. IVI of DDX-packaged nanoparticles containing the ICI-expressing plasmid in C57BL/6 mice led to sustained, dose-dependent expression in the bladder lasting over 28 days. Importantly, systemic exposure remained minimal—approximately 1,000-fold lower than that observed following intravenous administration of recombinant ICI at clinically relevant doses—highlighting the advantage of this localized delivery approach.Conclusions These data demonstrate the potential utility of the DDX platform for localized, sustained expression of DNA-encoded ICI monoclonal antibodies in the bladder with significantly reduced systemic exposure.
Fetched live from OpenAlex and de-inverted. Abstracts are not stored in this database: the inverted indexes are 8.6 GB of the frame’s 9.3 GB of text, and the host has 13 GB free.
How this classification was reachedexpand
Full frame machine prediction
Teacher imitationNot calibrated prevalence, not ground truth. Human validation pending. The Gemma side is a direct model label for every work in the frame, read from the title-only record. The Codex side is a classifier learned from the 10,348 direct Codex labels and calibrated to design-weighted sample rates; fields without enough sample support carry no Codex call. Candidate is the union of the two sides; consensus is their intersection. These outputs are machine_predicted_unvalidated and are not human labels.
Distilled classifier scores by category (both heads)
| Category | Codex | Gemma |
|---|---|---|
| Metaresearch | 0.000 | 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 | 0.001 | 0.000 |
| Open science | 0.000 | 0.000 |
| Research integrity | 0.001 | 0.001 |
| Insufficient payload (model declined to judge) | 0.003 | 0.001 |
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 source (direct Gemma or distilled Codex), 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".