Ll 37: Safety Profile & Research Summary
24 PubMed CitationsExpert ReviewedGMP CertifiedLast Reviewed: February 2026
Preclinical Research Summary
Key Preclinical Studies
| Study | Model | Key Findings | Ref |
|---|---|---|---|
| Zhang et al. (2022) | C57/BL6 mice, Pan02 PDAC — 20 mg/kg/day IP × 14d | 42% reduction in tumor growth (p<0.05); ↓ MDSCs and M2 macrophages (p<0.01); ↑ CD4+/CD8+ T cells (p<0.01); fewer AEs vs gemcitabine | [11] |
| Overhage et al. (2008) | P. aeruginosa biofilm — 0.5 µg/mL | Inhibits biofilm formation via quorum-sensing downregulation (Las/Rhl); promotes twitching motility at sub-MIC | [7] |
| Wu et al. (2010) | Colon cancer cells | LL-37 inhibits proteasome → activates BMP signaling → p21Waf1 → cell cycle arrest | [10] |
| Koczulla et al. (2003) | Dexamethasone-treated mice — topical LL-37 | Increased vascularization and re-epithelialization; key role in wound regeneration via angiogenesis | [9] |
| Beaumont et al. (2014) | Bone marrow stromal cells | Stimulates proliferation and osteogenic differentiation of BMSCs; recruits MSCs to injury sites | [14] |
| Tuberculosis (in vivo) | M. tuberculosis mice — ~1 mg/kg IT 3x/wk × 28d | 3–10 fold reduction in lung bacilli; effective against drug-sensitive and MDR strains | [7] |
Clinical Trials
| Trial | Population | Intervention | Key Results | Ref |
|---|---|---|---|---|
| Phase IIb VLU | n=148 | Topical 0.5 mg/mL, 3x/wk × 13 wk | Total population: NS. Subgroup (ulcers ≥10 cm²): 28.1% vs 8.1% closure (p=0.0458); healing rate 0.0367/day vs 0.0093/day (p=0.0439) | [16] |
| Phase I/II VLU | n=34 | Topical 0.5/1.6/3.2 mg/mL, 2x/wk × 4 wk | 0.5 mg/mL healing rate 6-fold higher than placebo (p=0.003); ulcer area ↓ 68%; bell-shaped dose-response | [5] |
| RCT — DFU | n=25 | LL-37 cream 0.5 mg/g, 2x/wk × 4 wk | Granulation index significantly ↑ days 7–28 (p<0.05); 11/13 vs 3/12 achieved >0.41 increase; no effect on bacterial load | [13] |
| Phase I Melanoma | n=36 planned | Intratumoral 250–2000 µg/tumor, weekly × 8 wk | Acceptable tolerability; variable biological response; dermatologic toxicity noted | [17] |
Safety Summary
| Parameter | Finding |
|---|---|
| Clinical | Safe and well-tolerated in 148-patient Phase IIb; no systemic safety concerns; mild local reactions (redness, edema) |
| Dose-Dependent | 3.2 mg/mL → increased local reactions; bell-shaped dose-response |
| Cytotoxicity | >13–25 µM towards eukaryotic cells; significantly inhibited by serum |
| Cancer Risk | Context-dependent: anti-tumorigenic in colon/gastric/pancreatic; pro-tumorigenic in breast/lung/ovarian/melanoma |
| Drug Interactions | Synergy with antibiotics (azithromycin, colistin, vancomycin); inhibited by glycosaminoglycans; Vitamin D upregulates expression |
| Stability | Susceptible to protease degradation; short plasma half-life; D-LL-37 enantiomer is protease-resistant |
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References
- Johansson J, Gudmundsson GH, Rottenberg ME, et al. Conformation-dependent antibacterial activity of the naturally occurring human peptide LL-37. Journal of Biological Chemistry. 1998;273(6):3718-3724.
- Gudmundsson GH, Agerberth B, Odeberg J, et al. The human gene FALL39 and processing of the cathelin precursor to the antibacterial peptide LL-37 in granulocytes. European Journal of Biochemistry. 1996;238(2):325-332.
- Ridyard KE, Overhage J. The Potential of Human Peptide LL-37 as an Antimicrobial and Anti-Biofilm Agent. Antibiotics. 2021;10(6):650.
- Duplantier AJ, van Hoek ML. The Human Cathelicidin Antimicrobial Peptide LL-37 as a Potential Treatment for Polymicrobial Infected Wounds. Frontiers in Immunology. 2013;4:143.
- Grönberg A, Mahlapuu M, Ståhle M, et al. Treatment with LL-37 is Safe and Effective in Enhancing Healing of Hard-to-Heal Venous Leg Ulcers: A Randomized, Placebo-Controlled Clinical Trial. Wound Repair and Regeneration. 2014;22(5):613-621.
- Yang B, Good D, Mosaiab T, et al. Significance of LL-37 on Immunomodulation and Disease Outcome. BioMed Research International. 2020;2020:8349712.
- Heilborn JD, Nilsson MF, Kratz G, et al. The cathelicidin anti-microbial peptide LL-37 is involved in re-epithelialization of human skin wounds and is lacking in chronic ulcer epithelium. Journal of Investigative Dermatology. 2003;120(3):379-389.
- Scott MG, Davidson DJ, Gold MR, et al. The human antimicrobial peptide LL-37 is a multifunctional modulator of innate immune responses. The Journal of Immunology. 2002;169(7):3883-3891.
- Svensson D, Nilsson BO. Human antimicrobial/host defense peptide LL-37 may prevent the spread of a local infection through multiple mechanisms: an update. Inflammation Research. 2025;74(1):36.
- Piktel E, Niemirowicz K, Wnorowska U, et al. The Role of Cathelicidin LL-37 in Cancer Development. Archivum Immunologiae et Therapiae Experimentalis. 2016;64(1):33-46.
- Zhang Z, Chen WQ, Zhang SQ, et al. The human cathelicidin peptide LL-37 inhibits pancreatic cancer growth by suppressing autophagy and reprogramming of the tumor immune microenvironment. Frontiers in Pharmacology. 2022;13:906625.
- Lu F, Zhu Y, Zhang G, Liu Z. Renovation as innovation: Repurposing human antibacterial peptide LL-37 for cancer therapy. Frontiers in Pharmacology. 2022;13:944147.
- Miranda E, Bramono K, Yunir E, et al. Efficacy of LL-37 cream in enhancing healing of diabetic foot ulcer: a randomized double-blind controlled trial. Archives of Dermatological Research. 2023;315(9):2623-2633.
- Seil M, Nagant C, Dehaye JP, et al. Spotlight on Human LL-37, an Immunomodulatory Peptide with Promising Cell-Penetrating Properties. Pharmaceuticals. 2010;3(11):3435-3460.
- Ergün FC, Kars MD, Kars G. Development and Characterization of LL37 Antimicrobial-Peptide-Loaded Chitosan Nanoparticles. Polymers. 2025;17(13):1884.
- Mahlapuu M, Sidorowicz A, Mikosinski J, et al. Evaluation of LL-37 in healing of hard-to-heal venous leg ulcers: A multicentric prospective randomized placebo-controlled clinical trial. Wound Repair and Regeneration. 2021;29(6):938-950.
- Ohuchi K, Ikawa T, Amagai R, et al. LL-37 Might Promote Local Invasion of Melanoma by Activating Melanoma Cells and Tumor-Associated Macrophages. Cancers. 2023;15(6):1678.
- Miura S, Garcet S, Li X, et al. Cathelicidin Antimicrobial Peptide LL37 Induces Toll-Like Receptor 8 and Amplifies IL-36γ and IL-17C in Human Keratinocytes. Journal of Investigative Dermatology. 2023;143(5):832-841.e4.
- Lin X, Wang R, Mai S. Advances in delivery systems for the therapeutic application of LL37. Journal of Drug Delivery Science and Technology. 2020;60(9):102016.
- Wu WK, Wang G, Coffelt SB, et al. Emerging Roles of the Host Defense Peptide LL-37 in Human Cancer and its Potential Therapeutic Applications. International Journal of Cancer. 2010;127(8):1741-1747.
- Alalwani SM, Sierigk J, Herr C, et al. The antimicrobial peptide LL-37 modulates the inflammatory and host defense response of human neutrophils. European Journal of Immunology. 2010;40(4):1118-1126.
- Lozeau LD, Kole D, Dominko T, et al. Activity and toxicity of a recombinant LL37 antimicrobial peptide. Frontiers in Bioengineering and Biotechnology. 2016.
- Wan W, Zhang L, Lin Y, et al. Mitochondria-derived peptide MOTS-c: effects and mechanisms related to stress, metabolism and aging. Journal of Translational Medicine. 2023;21(1):36.
- M.D. Anderson Cancer Center. Induction of Antitumor Response in Melanoma Patients Using the Antimicrobial Peptide LL37. ClinicalTrials.gov Protocol NCT02225366. 2015.
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