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 IIa 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 EU Clinical Trials Register5)


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 Ib/IIa 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 IIa trial where it will be administered with and without the investigational broadly neutralizing antibodies (bNAbs) 3BNC117 and 10-1074.5

Half-life (T½): In a Phase I 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: Ib/IIa
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; 2018-001165-16 (EudraCT)
Sponsor: Department of infectious Diseases, Aarhus University Hospital
Phase: IIa
Status: This study is ongoing.
Study Purpose: The purpose of this study is to compare the ability of three different treatment strategies – lefitolimod combined with the bNAbs 3BNC117 and 10-1074, lefitolimod alone, and 3BNC117 plus 10-1074 alone – in delaying 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 Ib/IIa 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 February 7, 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 February 7, 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 February 7, 2019.
  4. Mologen AG website. Product pipeline. https://www.mologen.com/en/pipeline. Accessed February 7, 2019.
  5. EU Clinical Trials Register. EudraCT Number: 2018-001165-16; 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 (TITAN). https://www.clinicaltrialsregister.eu/ctr-search/trial/2018-001165-16/DK. Accessed February 7, 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 February 7, 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 February 7, 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 February 7, 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 February 7, 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 February 7, 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 February 7, 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 February 7, 2019.
  13. Zurlo A, Schmidt M, Dax A, et al. Safety, pharmacokinetics and harmacodynamics 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 February 7, 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 February 7, 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 February 7, 2019.

Last Reviewed: February 7, 2019