LL-37

What is LL-37?

LL-37 is the mature, biologically active C-terminal fragment of human cationic antimicrobial protein 18 (hCAP18). The human CAMP gene encodes the larger preproprotein; proteolytic processing releases the 37-residue peptide beginning with two leucines. It is found in neutrophils and produced by epithelial cells, macrophages, and other barrier-surface cells. ([UniProt CAMP](https://www.uniprot.org/uniprotkb/P49913/entry))

In water and biological membranes, LL-37 can adopt an amphipathic alpha-helical structure. Its net positive charge and hydrophobic face allow association with negatively charged microbial membranes — helping explain antibacterial, antifungal, antiviral, and antibiofilm findings in laboratory systems. Physiological salt, serum proteins, proteases, and local lipid environment can substantially change that activity.

LL-37 is also a host-defense signaling peptide. Depending on concentration and context, it can recruit immune cells, influence neutrophil survival, activate or dampen Toll-like-receptor signaling, promote endothelial and epithelial responses, and bind extracellular DNA or RNA. The same molecule can appear antimicrobial in one experiment, pro-healing in another, and pro-inflammatory or cytotoxic in a third.

Identity and naming checks

Several related names are not interchangeable. Confirm the vial contains full-length unmodified LL-37 before comparing with any protocol — especially CRAMP, KR-12, and OP-145/P60.4Ac.

An HPLC result labeled “99% pure” does not by itself establish amount, identity, sterility, aggregation state, or usable shelf life. LL-37's amphipathic, cationic character makes formulation unusually important.

Current research and compounding status

LL-37 has no U.S. prescribing label or standardized clinical dosage. FDA's compounding safety page identifies concerns about immunogenicity, peptide-related impurities, active-ingredient characterization, limited human safety information, male reproductive findings in nonclinical research, and context-dependent protumor effects. A Pharmacy Compounding Advisory Committee discussion of LL-37 for possible inclusion on the section 503A bulks list is expected before the end of February 2027. ([FDA safety-risk page](https://www.fda.gov/drugs/human-drug-compounding/certain-bulk-drug-substances-use-compounding-may-present-significant-safety-risks))

A future PCAC recommendation would concern compounding policy — not validate an indication or dose. Human evidence remains route-specific and concentrated in topical wound studies.

Dosage used in human clinical trials

These are experimental doses from supervised clinical programs — not interchangeable treatment instructions. Wound studies used proprietary PVA solution or cream vehicles plus standard wound care. The melanoma trial used direct tumor injection by oncology investigators. Neither route defines an SC dose.

First-in-human venous-leg-ulcer protocol

The 2014 randomized, placebo-controlled study enrolled 34 people with hard-to-heal venous leg ulcers. Everyone completed a three-week open-label placebo run-in, then received LL-37 in 10.5% polyvinyl-alcohol viscous solution or placebo twice weekly for four weeks.

Application amount was 25 µL per cm² of wound area. The 0.5 and 1.6 mg/mL groups had mean ulcer-area reductions of 68% and 50%, respectively — 0.5 mg/mL statistically significant on healing-rate analysis. The 3.2 mg/mL arm showed no healing advantage over placebo — an important non-linear dose-response warning. ([Grönberg et al., 2014](https://pubmed.ncbi.nlm.nih.gov/25041740/))

Phase IIb HEAL LL-37 protocol

The multicenter trial used three-week placebo run-in, randomization to 0.5 mg/mL, 1.6 mg/mL, or placebo, product at 25 µL/cm² twice weekly for 13 weeks with compression therapy, and 16-week follow-up.

Nominal active doses were again 12.5 or 40 mcg/cm² per application. In the full population, neither concentration significantly improved healing versus placebo. In a post-hoc analysis of ulcers ≥10 cm², 28.1% of the 0.5 mg/mL group achieved confirmed complete closure vs 8.1% placebo — hypothesis-generating, not confirmation the trial succeeded overall. ([Mahlapuu et al., 2021](https://pubmed.ncbi.nlm.nih.gov/34687253/))

Diabetic-foot-ulcer cream protocol

The 2023 double-blind trial randomized 25 participants to 0.5 mg/mL LL-37 cream or placebo, applied twice weekly for four weeks with standard DFU care. Granulation index increased at days 7, 14, 21, and 28. IL-1-alpha, TNF-alpha, and aerobic bacterial colonization did not significantly improve. ([Miranda et al., 2023](https://pubmed.ncbi.nlm.nih.gov/37480520/))

This supports further study of this exact cream, population, route, and schedule — not that injected LL-37 treats diabetic foot infection.

Intratumoral melanoma protocol

The completed Phase I study [NCT02225366](https://clinicaltrials.gov/study/NCT02225366) enrolled four participants. Registry describes direct injection into two to four cutaneous tumors once weekly for eight weeks at 250 mcg per tumor injection.

A published participant report described verrucous papules and erythematous plaques with lichenoid clinicopathologic features — confirming local administration can produce clinically important cutaneous immune toxicity. This is not evidence for SC injection near infection, wounds, or suspected tumors. ([Dolkar et al., 2018](https://pubmed.ncbi.nlm.nih.gov/29665030/))

LL-37 research dosage

The table below documents human trial exposures and commonly reported community SC protocols. Repetition documents convention; it does not identify pharmacokinetic rationale or establish safety.

Human evidence supports only narrow, route-specific conclusions. Claims that SC injection targets a nearby wound, gut segment, biofilm, Lyme infection, or tumor are not validated by these studies.

Complete community-anchored 6-week LL-37 research protocol

The most interpretable way to examine the dominant community schedule is a prospective, fixed-exposure observational design — not a published clinical protocol or treatment recommendation. Two fixed groups (100 mcg or 200 mcg SC once daily, five days per week for four weeks) avoid an unvalidated escalation ladder, followed by two weeks without exposure.

Reported LL-37 dosage range

Anecdotal versus clinically studied dosing

The discrepancy is substantial. Community schedules use a different route, more frequent exposure, and usually a different vehicle than every published human program.

LL-37 reconstitution and concentration math

For a U-100 syringe, 100 units equal 1 mL. The tables are arithmetic aids for laboratory planning — they do not prescribe a diluent or create evidence that a multidose injectable preparation remains sterile or chemically stable.

5 mg in 2 mL is a commonly highlighted preset: 2.5 mg/mL = 2,500 mcg/mL = 25 mcg per U-100 unit — so 100 mcg = 4 units and 200 mcg = 8 units.

LL-37 can self-associate, bind to surfaces, undergo proteolysis, and lose recoverable concentration through adsorption. Published wound PVA solution and DFU cream stability do not establish that LL-37 in bacteriostatic water remains suitable for injection for 28 days.

Why LL-37 responses can be non-linear

At sufficient local concentrations, LL-37 can disrupt lipid bilayers — moving from signaling toward host-cell toxicity, hemolysis, or intense inflammation. Serum, salt, and proteins change activity; proteases shorten local persistence; and signaling can reverse with context.

The 2014 wound trial's lowest concentration outperforming the highest is consistent with a concentration-dependent optimum rather than a monotonic dose-response.

Preclinical LL-37 dosage

Mouse CRAMP studies should be listed as related cathelicidin research, not LL-37 dosing. Encapsulated hydrogels, gene-transfected cells, and nanoparticle delivery change local retention and cannot be pooled with free peptide.

How LL-37 may work

1. Direct microbial membrane disruption — cationic amphipathic structure promotes binding to negatively charged microbial surfaces. Affects some biofilms in vitro; does not replace pathogen identification and approved antimicrobial therapy.
2. Chemotaxis and innate immune signaling — pathways involving FPR2/FPRL1, P2X7, EGFR transactivation, and Toll-like receptors. Influences neutrophils, monocytes, T cells, dendritic cells, keratinocytes, and endothelial cells.
3. Wound repair and angiogenesis — promotes keratinocyte migration, epithelial repair, and endothelial responses. Topical development aimed to restore local exposure in chronic wounds with little recoverable endogenous LL-37 at the edge.
4. Nucleic-acid sensing and inflammatory skin disease — can form complexes with self-DNA/RNA and activate plasmacytoid dendritic cells. Excess or altered LL-37 participates in psoriasis and rosacea pathology.
5. Context-dependent cancer biology — anticancer and growth-promoting effects in different models. It is inaccurate to call LL-37 a general anticancer peptide.

What results have actually been shown?

Expected timeline in research

LL-37 dosage evidence ladder

Topical LL-37 dosing is partially characterized — concentration, wound surface dose, frequency, duration, and tolerability have been studied in humans. Efficacy remains uncertain after a negative overall Phase IIb result. Subcutaneous dosing is unestablished.

Safety and adverse effects

Topical venous-ulcer trials reported studied concentrations were generally well tolerated in controlled wound-care settings — limited to those products, routes, eligibility criteria, and monitoring. That reassurance does not establish safety of repeated SC exposure.

Seek urgent evaluation for fever with confusion, rapidly spreading redness, severe wound pain, chest pain, breathing difficulty, facial swelling, or suspected sepsis. LL-37 should never delay antibiotics, surgical source control, vascular assessment, cancer biopsy, or emergency treatment.

Storage and stability

Storage instructions must follow lot-specific analytical data. A 2021 study found 0.5 mg/mL LL-37 cream chemically stable in its specific oil-in-water emulsion — that result cannot be generalized to reconstituted powder, bacteriostatic water, saline, or multidose injection vials.

Avoid automatically assigning a 28-day refrigerated beyond-use period without validated chemical, physical, and microbiological stability evidence.

Anti-doping status

LL-37 is not known for a peptide-specific named entry on the 2026 WADA list. However, WADA's S0 Non-Approved Substances category prohibits pharmacological substances without current approval for human therapeutic use at all times. Competitive athletes should obtain a case-specific determination before exposure. ([2026 WADA Prohibited List](https://www.wada-ama.org/sites/default/files/2025-09/2026list_en_final_clean_september_2025.pdf))

Bottom line

LL-37 has more human dose information than many research peptides, but almost all of it is topical and wound-specific. The most reproducible human exposure is 0.5 mg/mL at 25 µL/cm² twice weekly (12.5 mcg/cm² per application). Even that dose has mixed efficacy evidence.

Daily SC schedules of 100–200 mcg are community conventions without human pharmacokinetic or dose-finding support. A complete research protocol should keep route, concentration, formulation, product quality, monitoring, and stop rules explicit — and should never convert topical, intratumoral, or animal exposures into a general therapeutic dose.

Confirm full-length LL-37 identity (≠ CRAMP, KR-12, OP-145). Topical trial vehicles ≠ bacteriostatic water recon. Higher concentration ≠ reliably better.

Frequently asked questions

References

• Grönberg A, et al.

  Treatment with LL-37 is safe and effective in enhancing healing of hard-to-heal venous leg ulcers

  Wound Repair Regen. 2014.

• Mahlapuu M, et al.

  Evaluation of LL-37 in healing of hard-to-heal venous leg ulcers: Phase IIb RCT

  Wound Repair Regen. 2021.

• Miranda E, et al.

  Efficacy of LL-37 cream in enhancing healing of diabetic foot ulcer

  Arch Dermatol Res. 2023.

• NCT02225366

  Induction of Antitumor Response in Melanoma Patients Using LL37

  ClinicalTrials.gov.

• Dolkar T, et al.

  Dermatologic toxicity from novel therapy using antimicrobial peptide LL-37 in melanoma

  J Cutan Pathol. 2018.

• Heilborn JD, et al.

  LL-37 is involved in re-epithelialization of human skin wounds

  J Invest Dermatol. 2003.

• Ramos R, et al.

  Wound healing activity of the human antimicrobial peptide LL37

  Peptides. 2011.

• Hu Z, et al.

  Antimicrobial cathelicidin peptide LL-37 inhibits pyroptosis and improves survival in septic mice

  Int Immunol. 2016.

• Lande R, et al.

  Plasmacytoid dendritic cells sense self-DNA coupled with antimicrobial peptide

  Nature. 2007.

• FDA

  Certain Bulk Drug Substances for Use in Compounding that May Present Significant Safety Risks

  FDA compounding safety page.

• World Anti-Doping Agency

  2026 Prohibited List

  S0 Non-Approved Substances.