TB-500 (thymosin beta-4 fragment)

1. 01Skin

   Studied as an injection under the skin (in horses)

   The only body data for TB-500 come from horses in anti-doping tests. It was injected under the skin, and a very small amount reached the blood. No one has tested it in people.

   For experts

   FDA identified one in-vivo pharmacokinetic study: thoroughbred geldings given a single subcutaneous injection had plasma TB-500 peaking at 0.05-0.08 ng/mL between 60 and 120 minutes, falling below the limit of quantification between 6 and 10 hours. Without intravenous data, absolute bioavailability could not be established. FDA found no human pharmacokinetic or pharmacodynamic studies by any route.[src][src]

2. 02Bloodstream

   Chopped up quickly into smaller pieces

   In the blood and organs, enzymes nibble amino acids off the end of the peptide one by one. Lab tests with human blood serum showed the same thing, so some of what circulates is smaller fragments, not TB-500.

   For experts

   Metabolites arise by sequential C-terminal truncation. Incubation with equine liver in vitro gave Ac-LKKTET, Ac-LKKTE, Ac-LKKT, Ac-LKK and Ac-LK plus stereoisomerised forms. In horses, plasma about 2 hours after a subcutaneous injection contained the parent peptide, a stereoisomer, Ac-LKKTE and Ac-LK; urine also contained Ac-LKKTET and Ac-LKK. Rat urine contained mainly Ac-LKKTE, Ac-LKK and Ac-LK. In vitro, human serum, kidney microsomes and liver fractions produced mainly C-terminally truncated metabolites, with Ac-LKKTE and Ac-LKK prominent in some systems. Ac-LK was the main early metabolite in rats and Ac-LKK persisted up to 72 hours. Human in-vivo metabolism has not been studied.[src][src][src]

3. 03Elsewhere

   Copies the actin-binding stretch of its parent protein

   Cells have a protein called actin that acts like scaffolding. The full thymosin beta-4 protein holds spare actin building blocks. TB-500 copies the short stretch that grips actin, but no one has shown that this small piece does the same job.

   For experts

   Residues LKKTET of thymosin beta-4 form its actin-binding region; the full protein binds G-actin but not F-actin and buffers the monomer pool (the 4PL7 crystal structure shows full-length thymosin beta-4 on an actin monomer). FDA notes it is only hypothesised that LKKTETQ shares this buffering capacity, that it remains undetermined whether actin binding explains its reported pro-angiogenic and wound-healing effects, and that N-acetylation may change binding, so activity of the non-acetylated peptide cannot be extrapolated to TB-500.[src][src][src][src]

4. 04Skin

   Wound healing seen in animals, mostly with related molecules

   In rats and mice, the full protein sped up skin wound healing, and a similar piece without the acetyl cap did too. But in a cell-dish test TB-500 itself did nothing, while one of its breakdown pieces helped a little. So it is unclear whether TB-500 works at all.

   For experts

   Full-length thymosin beta-4, given topically or intraperitoneally, increased re-epithelialisation in rat full-thickness wounds (42% over saline at day 4; up to 61% at day 7). The non-acetylated LKKTETQ heptapeptide matched full-length thymosin beta-4 for dermal repair in 26-month-old mice (Philp 2003). In a fibroblast scratch assay, TB-500 did not differ from vehicle, while Ac-LKKTE gave small but significant closure (Rahaman 2024), suggesting activity might depend on conversion to a metabolite. All of this is animal or cell evidence; FDA identified no nonclinical in-vivo studies of wound healing with TB-500 itself.[src][src][src][src]

5. 05Heart

   The parent protein has been tested on heart injury in mice

   Scientists gave the full thymosin beta-4 protein (not TB-500) to mice after a heart attack. It helped heart cells survive and improved heart function. This is mouse research only and has not been shown for TB-500.

   For experts

   In mice after coronary artery ligation, full-length thymosin beta-4 upregulated integrin-linked kinase and Akt activity, enhanced early myocyte survival and improved cardiac function (Bock-Marquette 2004); follow-up work in mouse embryonic hearts and cultured adult epicardial explants reported that it stimulated outgrowth of epicardial progenitor cells (Smart 2007). These are animal and tissue studies of the full-length protein. The review by Sosne et al. maps cell-survival (anti-apoptotic) activity to the N-terminal 15 amino acids rather than the LKKTETQ stretch, and lists ILK/PINCH/Akt activation among activities not yet localised in the molecule. No equivalent data exist for TB-500.[src][src][src]

6. 06Elsewhere

   Human trials so far tested only the full protein

   A few small human trials used the full thymosin beta-4 protein, as a gel on leg ulcers and as eye drops for dry eye. These were early-stage, and none of the results applies to TB-500.

   For experts

   A double-blind, placebo-controlled phase 2 dose-escalation trial of topical full-length thymosin beta-4 in 73 patients with venous stasis ulcers found safety comparable to placebo; the authors suggested that complete healing could be achieved within 3 months in about 25% of patients. A small phase 2 trial of thymosin beta-4 eye drops (nine patients with severe dry eye) reported 35.1% less ocular discomfort and 59.1% less corneal staining than vehicle at day 56. Both are investigational, unapproved, small studies of a different molecule and route from TB-500.[src][src][src]

7. 07Immune system

   Open safety questions for an injected peptide

   Nobody knows what TB-500 does to the body over time, because it has never been safety-tested in people. FDA experts worry that injected peptides can make the immune system react, especially if they are impure or clump together.

   For experts

   FDA states that potential safety risks in humans are unknown: no acute, repeat-dose, genotoxicity, reproductive or carcinogenicity studies were identified. Its review flags a significant immunogenicity risk for an injectable peptide, potentially amplified by aggregation and synthesis-related impurities, and notes that a representative certificate of analysis did not control assay, impurities, endotoxin or aggregates.[src]

Around the world

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