LL-37
Also known as: Cathelicidin LL-37, hCAP18 (precursor), CAMP (gene), FALL-39 (original name), Ropocamptide (development name)
Evidence: Clinical
Overview
The 37-residue human cathelicidin peptide, an innate-immune effector with broad antimicrobial activity; studied topically in human chronic wound-healing trials and as an immune modulator.
LL-37 is the mature 37-residue peptide released from the human cathelicidin precursor hCAP18 in granulocytes (Agerberth et al., 1995; Gudmundsson et al., 1996). It is directly antibacterial in vitro and also acts on host cells, and endogenous hCAP18/LL-37 rises during human skin wound repair while being absent from chronic ulcer epithelium (Heilborn et al., 2003). Clinical development, under the name ropocamptide, has been topical: a 34-patient dose-finding study in venous leg ulcers improved healing at the two lower concentrations (Gronberg et al., 2014), but a 148-patient phase 2b missed its endpoint, with benefit only in a post hoc large-wound subgroup (Mahlapuu et al., 2021). A diabetic foot ulcer trial reported better granulation (Miranda et al., 2023). Elevated endogenous LL-37 drives inflammation in rosacea (Yamasaki et al., 2007). There is no systemic human dosing study.
Benefits
Antimicrobial activity in vitro; faster ulcer healing at low topical concentrations in a 34-patient study but no benefit in the 148-patient phase 2b; better granulation in a diabetic foot ulcer trial
Dosing reference
- Research dose
- 50 to 100 mcg daily (community range, no published systemic human dose; trials applied 0.5 to 3.2 mg/mL topically twice weekly)
- Range
- 50 to 100 mcg, 1x daily
- Reconstitution
- 2 mL bacteriostatic water
- Common vial sizes
- 5 mg
Every published human dose is topical: 0.5, 1.6 or 3.2 mg/mL applied twice weekly for 4 weeks in venous leg ulcers (Gronberg et al., 2014; Mahlapuu et al., 2021) and 0.5 mg/mL cream twice weekly for 4 weeks in diabetic foot ulcers (Miranda et al., 2023). The dose response was inverse in the first study: the lowest concentration performed best and the highest was no better than placebo. An intratumoral study used 250 mcg per tumour weekly (NCT02225366, 4 patients). There is no systemic dosing study and no pharmacokinetic data. Elevated endogenous LL-37 drives rosacea inflammation (Yamasaki et al., 2007) and, complexed with self-DNA, interferon production in psoriasis (Lande et al., 2007).
Mechanism
LL-37 is the only human cathelicidin-derived antimicrobial peptide, cleaved from the hCAP18 precursor in granulocytes (Gudmundsson et al., 1996). It folds into an amphipathic helix that permeabilises microbial membranes. It also acts on host cells: endogenous LL-37 participates in re-epithelialisation of human skin wounds, and blocking it inhibits that repair in organ culture (Heilborn et al., 2003). The same activity drives disease when the peptide is in excess. Increased serine protease activity in rosacea generates cathelicidin fragments that promote skin inflammation (Yamasaki et al., 2007), and LL-37 complexed with self-DNA triggers interferon production by plasmacytoid dendritic cells, the mechanism proposed for psoriasis autoimmunity (Lande et al., 2007). Stability in a non-healing wound environment is limited (PMID 21547341, in sources).
Evidence
Clinical: at least one published human trial or an approved drug
- Predicted from a bone marrow cDNA clone as FALL-39 and shown to be antibacterial; the mature granulocyte peptide is LL-37 (Agerberth et al., 1995; Gudmundsson et al., 1996)
- hCAP18/LL-37 rises in human skin after wounding, is low in chronic ulcers, and antibodies against it block re-epithelialisation in organ-cultured human skin (Heilborn et al., 2003)
- First-in-man trial in 34 patients with hard-to-heal venous leg ulcers: topical LL-37 twice weekly at 0.5 and 1.6 mg/mL raised healing rate constants about six-fold and three-fold versus placebo, while 3.2 mg/mL was no better than placebo (Gronberg et al., 2014)
- Phase 2b (HEAL LL-37, n=148) missed its endpoint: no significant healing difference versus placebo in the full population, with a post hoc benefit only in patients whose wounds were at least 10 cm2 (Mahlapuu et al., 2021)
- A randomised double-blind trial of LL-37 cream in diabetic foot ulcers (NCT04098562) reported a greater granulation index at days 7 to 28 but no reduction in IL-1 alpha, TNF-alpha or bacterial colonisation (Miranda et al., 2023)
- Human-trial status: all controlled human data are topical. Endogenous LL-37 is implicated in rosacea through increased serine protease activity (Yamasaki et al., 2007), and an intratumoral phase 1/2 study in melanoma (NCT02225366) completed with only 4 patients enrolled. No approval anywhere; the development name is ropocamptide
References
- FALL-39, a putative human peptide antibiotic, is cysteine-free and expressed in bone marrow and testis. Agerberth B, Gunne H, Odeberg J, et al., Proceedings of the National Academy of Sciences, 1995
- The human gene FALL39 and processing of the cathelin precursor to the antibacterial peptide LL-37 in granulocytes. Gudmundsson GH, Agerberth B, Odeberg J, et al., European Journal of Biochemistry, 1996
- The cathelicidin anti-microbial peptide LL-37 is involved in re-epithelialization of human skin wounds and is lacking in chronic ulcer epithelium. Heilborn JD, Nilsson MF, Kratz G, et al., Journal of Investigative Dermatology, 2003
- Treatment with LL-37 is safe and effective in enhancing healing of hard-to-heal venous leg ulcers: a randomized, placebo-controlled clinical trial. Gronberg A, Mahlapuu M, Stahle M, Whately-Smith C, Rollman O, Wound Repair and Regeneration, 2014
- Evaluation of LL-37 in healing of hard-to-heal venous leg ulcers: A multicentric prospective randomized placebo-controlled clinical trial. Mahlapuu M, Sidorowicz A, Mikosinski J, et al., Wound Repair and Regeneration, 2021
- Efficacy of LL-37 cream in enhancing healing of diabetic foot ulcer: a randomized double-blind controlled trial. Miranda E, Bramono K, Yunir E, et al., Archives of Dermatological Research, 2023
- Increased serine protease activity and cathelicidin promotes skin inflammation in rosacea. Yamasaki K, Di Nardo A, Bardan A, et al., Nature Medicine, 2007
- Plasmacytoid dendritic cells sense self-DNA coupled with antimicrobial peptide. Lande R, Gregorio J, Facchinetti V, et al., Nature, 2007
Side effects
There is no human dosing basis for systemic use; the only human trial was topical. Injection-site inflammation is expected because the peptide is directly pro-inflammatory. Elevated LL-37 is implicated in rosacea, psoriasis, and lupus, so it should be avoided by anyone with inflammatory skin or autoimmune disease.
Storage
- Storage
- Refrigerate 2-8°C (36-46°F)
- Lyophilized
- 2+ years at room temp, 3+ years refrigerated
- Reconstituted
- 28-30 days refrigerated
Pharmacology
- Half-life
- Not measured in humans. The topical trials applied it twice weekly because the peptide is degraded in a non-healing wound environment (Gronberg et al., 2014; stability study in sources).
- Bioavailability
- Topical application is the only route with human data and acts locally. No systemic bioavailability figure exists; biodistribution has been imaged only in animals by SPECT/CT (PMID 38972467).
- Molecular weight
- 4493.33 Da
- Sequence
- LLGDFFRKSKEKIGKEFKRIVQRIKDFLRNLVPRTES