Other Names: MGN1703, dSLIM-30L1, double-stem-loop immunomodulator 30L1 Drug Class: Latency-Reversing Agents Registry Number: 1548439-51-5 (CAS) Chemical Class: Oligonucleotides Organization: Mologen AG Phase of Development: Lefitolimod is in Phase 2a development as an HIV therapeutic.

(Compound details obtained from ChemIDplus Advanced,1 Clinical Infectious Diseases article,2 NCI Drug Dictionary,3 Mologen AG website,4 and ClinicalTrials.gov5)


Mechanism of Action: Latency-reversing agent, specifically a toll-like receptor 9 (TLR9) agonist.2 Lefitolimod is a synthetic oligonucleotide that belongs to a family of molecules known as double-stem loop immunomodulators (dSLIM). dSLIM molecules have a covalently closed dumbbell-shaped structure and are made of unmodified double-stranded DNA (to form the stem), single-stranded DNA (to form the two flanking loops), and a natural phosphodiester backbone. Three nonmethylated CG motifs are contained within the sequences of each of the two loops. Because of its unique structure, lefitolimod is considered a significantly safer therapeutic than early generation synthetic TLR9 agonists belonging to the CpG-oligodeoxynucleotide (CpG-ODN) family.3,6-8

Lefitolimod works by binding to and activating TLR9, a pattern-recognition receptor (PRR) that is part of the innate host defense mechanism. In resting immune cells, TLR9 is expressed only on plasmacytoid dendritic cells (pDCs) and B cells and is activated by nonmethylated CG DNA sequences found in certain bacterial and viral genomes, as well as mammalian mitochondrial DNA from damaged cells.3,6,7,9,10 Lefitolimod has been shown to trigger numerous inflammatory and immune responses that are associated with antipathogenic and antitumor effects.6,7,9 Responses associated with lefitolimod’s anti-HIV effect include (1) induction of cytokine release, including type I interferon-alfa (IFN-alfa) and CXCL10; (2) activation of pDCs, natural killer (NK) cells, and T cells; and (3) enhancement of NK cell degranulatory potential, intracellular IFN-gamma production, and NK cell-mediated viral inhibition.7,11

Lefitolimod has also been shown to disrupt HIV latency via an indirect mechanism of action.7 As such, it has been investigated in a Phase 1b/2a trial (NCT02443935) for its potential to reactivate HIV expression in latently infected cells and enhance host antiviral immune responses.12 Currently, lefitolimod is being evaluated in a Phase 2a trial where it will be administered with the investigational broadly neutralizing antibodies (bNAbs) 3BNC117 and 10-1074.5

Half-life (T½): In a Phase 1 crossover study of a single subcutaneous (SC) dose of lefitolimod 60 mg and a single SC dose of placebo in healthy participants, the median half-life of lefitolimod was 12.7 hours.13

Select Clinical Trials

Study Identifiers: TEACH study; NCT02443935
Sponsor: University of Aarhus
Phase: 1b/2a
Status: This study has been completed.
Study Purpose: The purpose of this open-label study was to evaluate whether lefitolimod could 1) reactivate HIV expression in latently infected cells, 2) enhance antiviral immune responses, 3) reduce latent HIV reservoir size, and 4) delay the time to viral rebound after analytical treatment interruption (ATI) of ART. The safety of lefitolimod was also assessed throughout the trial.
Study Population:
  • Participants were adults with HIV who had been on ART for at least 12 months.
  • Participants had HIV RNA <50 copies/mL and CD4 counts >350 cells/mm3 at screening.2,12,14
Selected Study Results:
Study Identifiers: TITAN; NCT03837756
Sponsor: University of Aarhus
Phase: 2a
Status: This study is currently recruiting participants.
Study Purpose: The purpose of this study is to evaluate the safety of lefitolimod administered with the bNAbs 3BNC117 and 10-1074 and to evaluate whether this combination therapy can delay the time to viral rebound during an ATI of ART.
Study Population:
  • Participants are adults with HIV who have been on ART for at least 18 months.
  • Participants have had HIV RNA <50 copies/mL for at least 15 months and have CD4 counts >500 cells/mm3 at screening.
  • Participants have HIV that is sensitive to 3BNC117 and 10-1074.5

Adverse Events

In the first part of the Phase 1b/2a TEACH study (NCT02443935), 15 participants enrolled and completed 4 weeks of lefitolimod treatment while on ART plus two follow-up visits. Among a total of 81 reported adverse events (AEs), 57 were related to lefitolimod. Injection site reaction (mainly transient erythema) was the most common drug-related AE. Except for four cases of neutropenia (of which three cases were Grade 2 and one case was Grade 3), all drug-related AEs were Grade 1. All AEs, including the cases of neutropenia, resolved spontaneously.2

Researchers also analyzed participants’ colon tissue samples collected at baseline and after 4 weeks of dosing with lefitolimod and found that lefitolimod did not cause any damaging tissue inflammation in the colon.15

In the second part of the TEACH study, 14 participants were enrolled to receive an additional 24 weeks of lefitolimod treatment plus ART, followed by an ATI of ART. During this time, there were 139 drug-related AEs reported. The drug-related AEs were similar to those that have been previously reported.14

Drug Interactions

Drug-drug interactions associated with lefitolimod are currently unknown.


  1. United States National Library of Medicine. ChemIDplus Advanced: Lefitolimod. https://chem.nlm.nih.gov/chemidplus/rn/1548439-51-5. Accessed November 1, 2019
  2. Vibholm L, Schleimann MH, Højen JF, et al. Short-course Toll-like receptor 9 agonist treatment impacts innate immunity and plasma viremia in individuals with human immunodeficiency virus infection. Clin Infect Dis. 2017;64(12). https://academic.oup.com/cid/article/64/12/1686/3064483. Accessed November 1, 2019
  3. National Cancer Institute (NCI). NCI Drug Dictionary: TLR9 agonist MGN1703. https://www.cancer.gov/publications/dictionaries/cancer-drug/def/tlr9-agonist-mgn1703. Accessed November 1, 2019
  4. Mologen AG website. Product pipeline. https://www.mologen.com/en/pipeline. Accessed November 1, 2019
  5. University of Aarhus. Combining a TLR9 agonist with broadly neutralizing antibodies for reservoir reduction and immunological control of HIV infection: an investigator-initiated randomized, placebo-controlled, Phase IIa trial. In: ClinicalTrials.gov. Bethesda (MD): National Library of Medicine (US). Registered on February 7, 2019. NLM Identifier: NCT03837756. https://clinicaltrials.gov/ct2/show/NCT03837756. Accessed November 1, 2019
  6. Wittig B, Schmidt M, Scheithauer W, Schmoll H-J. MGN1703, an immunomodulator and toll-like receptor 9 (TLR-9) agonist: From bench to bedside. Crit Rev Oncol Hematol. 2015;94(1). https://www.croh-online.com/article/S1040-8428(14)00210-8/fulltext. Accessed November 1, 2019
  7. Offersen R, Nissen SK, Rasmussen TA, et al. A novel toll-like receptor 9 agonist, MGN1703, enhances HIV-1 transcription and NK cell-mediated inhibition of HIV-1-infected autologous CD4+ T cells. Kirchhoff F, ed. J Virol. 2016;90(9). https://www.ncbi.nlm.nih.gov/pmc/articles/PMC4836316/. Accessed November 1, 2019
  8. Schmidt M, Hagner N, Marco A, König-Merediz SA, Schroff M, Wittig B. Design and structural requirements of the potent and safe TLR-9 agonistic immunomodulator MGN1703. Nucleic Acid Ther. 2015;25(3). https://www.ncbi.nlm.nih.gov/pmc/articles/PMC4440985/. Accessed November 1, 2019
  9. Kapp K, Kleuss C, Schroff M, Wittig B. Genuine immunomodulation with dSLIM. Mol Ther Nucleic Acids. 2014;3(6). https://www.ncbi.nlm.nih.gov/pmc/articles/PMC4078763/. Accessed November 1, 2019
  10. Horscroft NJ, Pryde DC, Bright H. Antiviral applications of Toll-like receptor agonists. J Antimicrob Chemother. 2012;67(4). https://academic.oup.com/jac/article/67/4/789/862403. Accessed November 1, 2019
  11. Mologen AG: Press release, dated March 14, 2016. Extension of TEACH study based on supportive first study results. https://otp.tools.investis.com/clients/de/mologen_ag/dgap/dgap_1/dgap-story.aspx?cid=2294&culture=en-US&newsid=9407. Accessed November 1, 2019
  12. University of Aarhus. Toll-like receptor 9 enhancement of antiviral immunity in chronic HIV-1 infection: a Phase 1b/2a trial. In: ClinicalTrials.gov. Bethesda (MD): National Library of Medicine (US). Registered on April 30, 2015. NLM Identifier: NCT02443935. https://clinicaltrials.gov/ct2/show/NCT02443935. Accessed November 1, 2019
  13. Zurlo A, Schmidt M, Dax A, et al. Safety, pharmacokinetics and  pharmacodynamics from a clinical trial with healthy volunteers using the immunotherapeutic TLR-9 agonist MGN1703. Ann Oncol. 2015;26(Suppl 8). http://annonc.oxfordjournals.org/content/26/suppl_8/viii10.3.full.pdf+html. Accessed November 1, 2019
  14. Vibholm LK, Frattari G, Schleimann MH, et al. Effect of 24 weeks TLR9 agonist therapy on CTL responses and viral rebound during ATI. Poster presented at: Conference on Retroviruses and Opportunistic Infections (CROI): March 4-7, 2018; Boston, MA. Poster 357. http://www.croiconference.org/sites/default/files/posters-2018/1430_Vibholm_357.pdf. Accessed November 1, 2019
  15. Krarup AR, Schleimann MH, Vibholm LK, et al. TLR9 agonist triggers potent intestinal antiviral response in HIV+ individuals on ART. Abstract presented at: Conference on Retroviruses and Opportunistic Infections (CROI); February 13-16, 2017; Seattle, WA. Abstract 314. http://www.croiconference.org/sessions/tlr9-agonist-triggers-potent-intestinal-antiviral-response-hiv-individuals-art. Accessed November 1, 2019

Last Reviewed: November 1, 2019