Reduced Infection and Mucositis In Chemotherapy-Treated Animals Following Innate Defense Modulation Using a Novel Drug Candidate.
Bibliographic record
Abstract
Abstract Abstract 3781 Innate Defense Regulators (IDRs) are a novel class of synthetic peptides with no antimicrobial activity that enhance microbial infection control while suppressing inflammation. IDRs bind to an intracellular scaffold protein, p62 or sequestosome-1, selectively modulating protein-protein complex formation and signaling downstream of receptors such as Toll-like receptors, IL-1 receptor and TNF receptor. Treatment of mice with IDRs enhanced their survival in bacterial infection models. The anti-infective effect of IDRs was maintained in animals depleted of neutrophils, but abolished in animals depleted of macrophages/monocytes, indicating an important role for macrophages in IDR mediated host protection at the site of infection. IDRs have been shown to transiently increase local chemokine levels (CCL5 and CXCL10), enhance macrophage recruitment to the site of infection and improve the resolution of bacterial infection alone or in conjunction with antibiotics. Recently, the enhanced survival benefit conferred by IDR treatment has been shown in clinically-relevant rat models of neutropenic sepsis after cyclophosphamide treatment. In rats pre-treated with cefamandole, made neutropenic with cyclophosphamide and orally colonized with Pseudomonas aeruginosa, administration of IMX942, the lead clinical candidate in the IDR family, once on day 5 (10mg/kg IV) after the development of fever increased survival from 0% (saline group) to 63%. This increased survival was comparable to the antibiotic treated group (75%) and both the antibiotic and IMX942 treated arms demonstrated marked preservation of the mucosal lining in the ileum. Further investigations in an animal model of mucositis, where pathogenesis is linked to the reaction of the innate defense system, have demonstrated that IDRs have significant efficacy in both oral and gut mucositis. In these studies, C3H/HeN mice are administered 5FU (60mg/kg, intraperitoneal injection) on days -4 and -2, and mucositis is induced on day 0 through the application of a chemical burn on the ventral surface of the tongue. Mucositis is then monitored for 14 days, generally peaking on day 2 or 3. Treatment with IMX942 (25mg/kg, IV) on days -1, 2 and 5 or days 0, 2, and 4 resulted in a statistically significant decrease in the duration and severity of oral mucositis (50% reduction) between days 2 and 14, and in the severity of gut mucositis (63% reduction) as measured by clinical endoscopy on day 4. IMX942 has successfully completed Phase 1 clinical studies, and was very well tolerated at single doses up to 8 mg/kg and at multiple doses (7 daily injections) up to 6.5 mg/kg/day. Phase 2 studies evaluating the efficacy of IMX942 in the amelioration of mucositis and infection in cancer patients undergoing radio- or chemo-therapy are currently being planned. Disclosures: Donini: Inimex Pharmaceuticals Inc.: Employment. Watkins:Inimex Pharmaceuticals Inc.: Consultancy. Palardy:Inimex Pharmaceuticals Inc.: Research Funding. Opal:Inimex Pharmaceuticals Inc.: Research Funding. Sonis:Inimex Pharmaceuticals Inc.: Consultancy; Biomodels, LLC: Equity Ownership; SciClione Pharmaceuticals: Consultancy, Membership on an entity's Board of Directors or advisory committees; Novartis: Consultancy; Biovitrum: Consultancy; Johnson and Johnson: Consultancy; Clinical Assistance Programs: Consultancy; Pfizer: Consultancy; Merck: Consultancy. Abrams:Inimex Pharmaceuticals Inc.: Employment. North:Inimex Pharmaceuticals Inc.: Employment.
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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 | 0.000 | 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 | 0.000 | 0.000 |
| Open science | 0.000 | 0.000 |
| Research integrity | 0.000 | 0.000 |
| 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".