Thymogen

What it is

Thymogen (L-Glu-L-Trp) is a synthetic dipeptide originally isolated from the thymus homogenate (PMID 36 / 9637345) and later from Thymalin by reversed-phase HPLC. It activates T-cell differentiation, T-cell recognition of peptide-MHC complexes, induces changes in intracellular cyclic nucleotides, and stimulates cytokine (IL-2, IFN) excretion by blood lymphocytes; it also activates neutrophil chemotaxis and phagocytosis. The dipeptide binds with high affinity to murine peritoneal macrophages (Kd ~2.1 nM) and thymocytes (Kd ~3.1 nM), and binding is inhibited by the related peptide bestim. In vitro, Thymogen inhibits ACE activity in endothelial cells and blocks angiotensin I-induced vasoconstriction. Antitumor activity in mice requires the presence of NK cells, perforin-dependent cytolytic activity, and is partly dependent on IL-12, but independent of IFN-γ. Thymogen modulates proliferative and inflammatory pathways in monocyte/macrophage cell lines, increasing tyrosine phosphorylation of cytoplasmic kinases and inhibiting TNF and IL-6 production stimulated by LPS. Its enantiomer (D-Glu-D-Trp, Thymodepressin) shows opposite, immunosuppressive activity, illustrating chiral reciprocal activity (PMID 38732260; PMID 32058926).

Class: Synthetic thymic dipeptide / immunomodulator

What it's studied for

• Immunomodulation / immunocorrection in various clinical settings Mixed
  • Thymogen activated T-cell differentiation, T-cell recognition of peptide-MHC complexes, induced changes in cyclic nucleotides and cytokine excretion, and activated neutrophil chemotaxis and phagocytosis. Used clinically in persons with chronic pathology and immune dysfunction. PMID 9637345 Morozov VG, Khavinson VK (1997). Natural and synthetic thymic peptides as therapeutics for immune dysfunction. Int J Immunopharmacol.
  • Double-blind, randomized, placebo-controlled trial: intranasal thymogen 100 mg once daily for 7 days before surgery restored structural and functional parameters of cellular immunity and significantly decreased postoperative complications. PMID 21957588 Smirnov VS et al. (2011). Application of thymogen for preoperative preparation of elderly patients with tumor processes in abdominal cavity. Adv Gerontol.
  • Thymogen 0.5–0.8 mg per treatment course in 48 patients with acute pancreatitis produced immune-correcting action and positive clinical dynamics, eliminating T-cell immune deficiency. PMID 11452372 Saĭdakhmedova ZT (2000). Immunomodulating activity of thymogen in acute pancreatitis. Vopr Pitan.
  • Clinical effect in 94.4% and laboratory effect in 83.3% of type-1 diabetes patients with secondary immunodeficiency; thymogen removed signs of secondary immunodeficiency via activation of T-lymphocyte differentiation. PMID 9026934 Zhuk EA, Galenok VA (1996). Thymogen in the treatment of type-1 diabetes mellitus. Ter Arkh.
  • Review summarizing long-term clinical efficacy of thymogen (among other peptide bioregulators) for prevention of diseases and treatment of people of different ages, including as a geroprotector. PMID 24003726 Khavinson VKh et al. (2013). Peptide bioregulators: the new class of geroprotectors. Message 2. Clinical studies results. Adv Gerontol.
• Antitumor / antiangiogenic activity (AIDS-Kaposi's sarcoma, renal cell carcinoma, prostate cancer) Human RCT
  • Phase III RCT (n=202): IM862 (L-glu-L-trp) 5 mg intranasally every other day was not superior to placebo in response rate for AIDS-KS; IM862 was associated with shorter time to progression (16 vs 35 weeks, P=0.012). Minimal toxicity. PMID 15598977 Noy A et al. (2005). Angiogenesis inhibitor IM862 is ineffective against AIDS-Kaposi's sarcoma in a phase III trial. J Clin Oncol.
  • Phase II RCT (n=44): IM862 5 mg intranasally (two schedules) showed major responses in 36% of patients; adverse effects limited to mild transient headache, fatigue, tingling, nausea. PMID 10673512 Tulpule A et al. (2000). Results of a randomized study of IM862 nasal solution in the treatment of AIDS-related Kaposi's sarcoma. J Clin Oncol.
  • Phase II trial (n=25): IM862 20 mg intranasally three times daily in 8-week cycles. No objective responses; 8 patients had stable disease (median 6 months). Significant decrease in plasma VEGF levels after 4 and 8 weeks. No grade 2–3 toxicities. PMID 15354209 Deplanque G et al. (2004). Phase II trial of the antiangiogenic agent IM862 in metastatic renal cell carcinoma. Br J Cancer.
  • Phase II RCT (n=71): Intranasal IM862 daily during androgen ablation treatment-free interval did not demonstrate superiority over placebo in prolonging time to PSA progression; well tolerated. PMID 17879948 Mao S et al. (2007). Employing the treatment-free interval of intermittent androgen ablation to screen candidate prostate cancer therapies. Prostate.
  • Animal study: L-glu-L-trp inhibited tumor growth in mice via NK cell cytolytic activity requiring perforin and partly IL-12; IFN-γ not required. No direct cellular toxicity in human tumor cell lines in vitro. PMID 12845648 Smith DL et al. (2003). Natural killer cell cytolytic activity is necessary for in vivo antitumor activity of L-glu-L-trp. Int J Cancer.
• Pulmonary tuberculosis immunotherapy Human observational
  • Comparative study of 553 patients: thymogen plus interferon provided the best result among immunocorrector regimens; combined therapy yielded early benefit and better outcomes in destructive tuberculosis. PMID 10067345 Khudzik LB et al. (1998). Immunotherapy of pulmonary tuberculosis. Probl Tuberk.
  • Thymogen (1% solution, 1 mL injection, 10 doses over 2 days, given at months 2 and 4 of treatment) stimulated T-cell immunity, increased tolerance for anti-TB drugs, resolved intoxication, healed decomposition cavities, and stopped bacteria discharge. PMID 10605346 Medus AI et al. (1999). Effect of thymogen on the state of immunity in destructive pulmonary tuberculosis. Voen Med Zh.
• Acute respiratory viral infections prophylaxis Human observational
  • Intranasal and subcutaneous thymogen administration in a military training unit led to considerable reduction in morbidity, severity, and duration of acute respiratory infections including influenza. PMID 8498021 Furgal SM et al. (1993). Clinico-epidemiological efficacy of thymogen in acute respiratory viral infections in a military collective. Voen Med Zh.
• Inflammatory diseases of the female genital system Human observational
  • Clinical trial in 46 patients with acute endomyometritis and chronic salpingo-oophoritis: thymogen normalized lymphocyte counts, T and B lymphocyte absolute counts, and T lymphocyte functional activity; no complications noted. PMID 1476231 Tsvelev YuV et al. (1992). Thymogen in the complex treatment of inflammatory diseases of the female genital system. Akush Ginekol.
• Liver protection (hepatoprotective / antioxidant in experimental models) Animal studies only
  • Intragastric CCl4-induced hepatopathy model: thymogen suppressed oxidative peroxidation and stimulated reparative regeneration of hepatocytes; Thymogen analogues with D-Ala produced more pronounced effects. PMID 37861903 Chulanova AA et al. (2023). Reparative and antioxidant effects of new analogues of immunomodulator thymogen in experimental model of liver damage. Bull Exp Biol Med.
  • Thymogen at 10 and 100 µg/kg (IP) inhibited lipid peroxidation and stimulated reparative regeneration in hydrazine hepatopathy rat model; increasing dose to 100 µg/kg did not further increase hepatoprotective activity. PMID 40442470 Chulanova AA et al. (2025). Hepatoprotective effects of thymogen analogues in hydrazine hepatopathy in rats. Bull Exp Biol Med.
• ACE inhibition and vascular effects In vitro only
  • Glutamic acid-tryptophan (EW/Thymogen) inhibited ACE activity in HUVECs and blocked angiotensin I-induced vasoconstriction in rat aorta ex vivo; effects were less potent than isoleucine-tryptophan (IW). PMID 28102435 Khedr S et al. (2018). Effects of tryptophan-containing peptides on ACE activity and vessel tone ex vivo and in vivo. Eur J Nutr.
• Monocyte/macrophage anti-inflammatory and proliferative modulation In vitro only
  • Thymogen dipeptide increased tyrosine phosphorylation of mitogen-activated cytoplasmic kinases in THP-1 cells, inhibited LPS-stimulated TNF and IL-6 expression in differentiated THP-1 cells, and reduced monocyte adhesion to activated endothelial cells. PMID 35408963 Avolio F et al. (2022). Peptides regulating proliferative activity and inflammatory pathways in the monocyte/macrophage THP-1 cell line. Int J Mol Sci.
• Oral bioavailability enhancement (lipid/glycosyl conjugation research) In vitro only
  • L-Glu-L-Trp has low membrane permeability and is not orally available in native form; lipid conjugation improved stability to proteolytic enzymes and increased intestinal permeability in Caco-2 cell assays. PMID 17845857 Bergeon JA, Toth I (2007). Enhancement of oral drug absorption — effect of lipid conjugation on enzymatic stability and intestinal permeability of l-Glu-l-Trp-NH2. Bioorg Med Chem.
  • Library of lipid/glycosyl conjugates showed no hemolytic toxicity at 200 µM; enzymatic resistance and apparent permeability were significantly increased for several conjugates in Caco-2 assays; in vivo rat experiment examined absorption rate and bioavailability. PMID 18428206 Bergeon JA et al. (2008). Oral absorption enhancement of dipeptide L-Glu-L-Trp-OH by lipid and glycosyl conjugation. Biopolymers.
• Chromosome protection / antimutagenic activity In vitro only
  • Low thymogen concentrations (0.001–1.0 µg/mL) significantly decreased frequency of formaldehyde-induced chromosome aberrations in lymphocyte cultures without mutagenic activity; high concentrations (10–1000 µg/mL) decreased proliferative activity. PMID 9026996 Rushkovskiĭ SR et al. (1996). Effect of thymogen on chromosome aberration level in a culture of human peripheral blood lymphocytes. Tsitol Genet.
• Phagocytic cell stimulation (neutrophils and monocytes) In vitro only
  • Thymogen at 10 mM stimulated ingestive activity of neutrophils, enhanced oxygen metabolite formation, increased spontaneous and zymosan-induced chemiluminescence, and increased hydrogen peroxide synthesis in monocytes by ~80% and in neutrophils by a greater magnitude. PMID 12506630 Dambaeva SV et al. (2002). Effect of thymic peptides on the functional activity of phagocytic cells of donor peripheral blood. Zh Mikrobiol Epidemiol Immunobiol.
• Geroprotection / aging Mixed
  • Review of long-term clinical studies; thymogen evaluated as a geroprotector for prevention of age-related diseases. PMID 24003726 Khavinson VKh et al. (2013). Peptide bioregulators: the new class of geroprotectors. Message 2. Adv Gerontol.
  • Review: pineal peptides showed more effective geroprotective effects on thymus involution than thymic peptides (including thymogen) showed on pineal gland involution. PMID 21809618 Lin'kova NS et al. (2011). Characteristics of the pineal gland and thymus relationship in aging. Adv Gerontol.
• Anti-HIV / antiviral (conjugate development) In vitro only
  • Conjugate of d4T with thymogen (tryptophan linkage) showed anti-HIV activity comparable to d4T with no cytotoxicity; an effective synthesis of thymogen was also developed. PMID 10563202 Riakhovskiĭ VV et al. (1999). Conjugates of 2',3'-didehydro-3'-deoxythymidine with thymogen. Synthesis and anti-HIV activity. Bioorg Khim.
• Stress / obsessive-compulsive and psychiatric conditions (adjunct) Human observational
  • In 84 patients with obsessive-compulsive neurosis and generalized tic disease, combined therapy of mexidol, thymogen, and hyperbaric oxygenation was significantly superior to traditional therapy. PMID 20517227 Podsevatkin VG, Kiriukhina SV (2010). Possibilities of the application of antioxidants and antihypoxants in a complex therapy of obsessive conditions. Zh Nevrol Psikhiatr.

Community-reported dosing

Tier key: Research = PMID-cited study · [C] = scraped community source · [S] = model-synthesized from aggregate community reports (softer evidence). How we source.

Safety signals

• Potential acceleration of disease progression in AIDS-Kaposi's sarcoma: Phase III RCT found IM862 (5 mg intranasally every other day) was associated with significantly shorter median time to progression (16 weeks) versus placebo (35 weeks), P=0.012. PMID 15598977
• High thymogen concentrations (10–1000 µg/mL) significantly decreased proliferative activity of lymphocytes in culture — dose-dependent antiproliferative effect at supratherapeutic in vitro concentrations. PMID 9026996
• Mild transient adverse effects (headache, fatigue, tingling, nausea) reported with intranasal IM862 in AIDS-KS Phase II trial; no hematologic adverse effects attributed to treatment. PMID 10673512
• No significant toxicities reported in Phase II prostate cancer trial of intranasal IM862 combined with androgen ablation. PMID 17879948
• No grade 2 or 3 toxicities related to IM862 recorded in Phase II renal cell carcinoma trial (20 mg intranasally three times daily, 8-week cycles). PMID 15354209
• Thymogen described as inducing 'no complications' and having a desensitizing effect in a clinical trial of inflammatory diseases of the female genital system. PMID 1476231

Contraindications

• No explicit contraindications are stated in the reviewed abstracts. The Phase III AIDS-KS trial result (potential acceleration of disease progression) warrants caution in patients with AIDS-related Kaposi's sarcoma. PMID 15598977