Dramatically Enhanced Immunopotency and Anti-Tumor Activity of Liposome-Encapsulated CpG Oligonucleotides (ODN) in Mice Is Paralleled by Vigorous and Broad-Based Immune Responses in Cynomolgus Monkeys after Both Intravenous (IV) and Subcutaneous (SC) Administration.
Bibliographic record
Abstract
Abstract Immunostimulatory CpG ODN have shown great promise in preclinical studies as an immunotherapeutic agent for treatment of a variety of malignant diseases. They are currently being evaluated in a number of clinical trials, the most advanced being Phase III trials for ProMune® (CpG7909; Coley Pharmaceuticals Group Inc/Pfizer Inc) in NSCLC. We have previously shown that encapsulation in liposomal nanoparticles dramatically enhances the immune activity of CpG ODN (LN-CpG ODN) in murine models and show here that this increased activity translates to enhanced anti-tumor activity when administered iv with monoclonal antibodies (mAbs) to enhance antibody-dependent cellular cytotoxicity. Co-administration of the anti-CD20 mAb Rituxan® with LN-CpG ODN, results in a synergistic increase in life span in excess of 500% in a xenogeneic murine model of B-cell lymphoma compared to ≤100% for either Rituxan or LN-CpG ODN individually. To validate the potential of LN-CpG ODN as an immunotherapeutic for treatment of human disease, we have compared the immune activity of LN-CpG ODN and CpG7909 administered sc and iv in non-human primates. We demonstrate that LN-CpG ODN exhibits significant immunostimulatory activity in cynomologus monkey (Macaca facicularis) with the activation of immune cell populations including NK cells, T-lymphocytes and antigen presenting cells as judged by rapid upregulation of CD69 or CD86 to levels 2–4 fold above control. Consistent with these observations, LN-CpG ODN also induces significant elevation in plasma levels of a number of cytokines and chemokines including IL-1ra and IL-6 and MCP-1 and MIP-1α respectively. Compared to CpG7909, a CpG ODN that has been optimized for human/primate reactivity, LN-CpG ODN is equal or superior in almost all of the immune parameters monitored in these studies including up to 3 fold higher levels of cell activation and plasma cytokines/chemokines than seen with equivalent doses of CpG7909. Moreover, LN-CpG ODN is extremely well tolerated at the doses tested in these studies, with no signs of toxicity based on clinical observations or blood (hematology, chemistry) parameters. Currently, sc represents the preferred route of administration for CpG ODN in the clinic as little to no immune stimulation has been observed when given iv. We believe that iv administered, encapsulated CpG ODN will induce enhanced immune stimulation by targeting CpG ODN to phagocytic immune effector cells. Potential therapeutic advantages include systemic activation of NK cells to enhance the ADCC mechanism of action for mAb drugs and the activation of immune cells at tumor sites. In conclusion, these data demonstrate that encapsulation within liposomal nanoparticles is an effective and feasible strategy by which to enhance the immune activity of CpG ODN in non-human primates and support the potential application of LN-CpG ODN as an effective immunotherapeutic for treatment of human disease.
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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) | 0.001 | 0.000 |
| Meta-epidemiology (broad) | 0.000 | 0.000 |
| Bibliometrics | 0.001 | 0.000 |
| Science and technology studies | 0.000 | 0.000 |
| Scholarly communication | 0.000 | 0.000 |
| Open science | 0.000 | 0.000 |
| Research integrity | 0.001 | 0.001 |
| Insufficient payload (model declined to judge) | 0.002 | 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".