Anti-HIV-1 broadly neutralizing antibody 1-18
Prof. Florian Klein, University of Cologne; Dr Philipp Schommers, University of Cologne; Dr Henning Grüll, University of Cologne
University of Cologne
Antiretroviral therapies (ART) for HIV-1 infected individuals still require a lifelong daily intake of medications with long-term side effects, stigma, and a high need for patients’ compliance. Especially the long-term side effects hamper the use of ART for prevention strategies that would require long-term exposure of ART to large populations of uninfected individuals. Thus, new anti-HIV-1 compounds are needed for future prevention- and therapy-strategies that are effective, have a longer half-life and less side effects than ART. Broadly neutralizing antibodies (bNAbs) targeting the HIV-1 envelope protein (Env) can prevent infection in animal models and are under investigation for passive immunization in clinical trials. Moreover, bNAbs have been demonstrated to suppress viremia and delay viral rebound after interruption of antiretroviral therapy (ART) in HIV-1-infected individuals. While these results highlight the significant clinical potential of bNAbs, pre-existing or de novo HIV-1 resistance cause treatment failure and can strongly limit bNAb applications in human.
We here describe 1-18, a new anti-HIV-1 antibody that is VH1-46–encoded, binds to the CD4 binding site and has outstanding breadth (97%) and potency (GeoMean IC50=0.048 µg/ml). 1-18 was found to show no autoreactivity against human epithelia cells and has a longer half-life than known CD4-binding site antibodies in mice. While targeting the CD4-binding site, 1-18 is not susceptible to typical CD4bs escape mutations and effectively overcomes HIV-1 resistance to other CD4bs bNAbs. Of most promise for therapeutic use, even 1-18 alone fully suppressed viremia in HIV-1–infected humanized mice without selecting for resistant viral variants. The ability of 1-18 to effectively restrict HIV-1 escape pathways provides a new option to successfully prevent and treat HIV-1 infection.
Broadly neutralizing antibody 1-18 could potentially be used for effective prevention- and new therapeutic-strategies against HIV-1. With its long-half life and few side effects, bNAbs like 1-18 that cover >95% of all globally circulating strains could be used for new therapeutic strategies to combat HIV-1. Further it could be given every 3-6 months per intramuscular injection in order to protect against HIV-1 transmission.
Schommers P, Gruell H, Abernathy ME, Tran MK, Dingens AS, Gristick HB, Barnes CO, Schoofs T, Schlotz M, Vanshylla K, Kreer C, Weiland D, Holtick U, Scheid C, Valter MM, van Gils MJ, Sanders RW, Vehreschild JJ, Cornely OA, Lehmann C, Fätkenheuer G, Seaman MS, Bloom JD, Bjorkman PJ, Klein F. Restriction of HIV-1 Escape by a Highly Broad and Potent Neutralizing Antibody. Cell. 2020 Feb 6;180(3):471-489.e22. doi: 10.1016/j.cell.2020.01.010. Epub 2020 Jan 30. PMID: 32004464; PMCID: PMC7042716.
Kreer C, Zehner M, Weber T, Ercanoglu MS, Gieselmann L, Rohde C, Halwe S, Korenkov M, Schommers P, Vanshylla K, Di Cristanziano V, Janicki H, Brinker R, Ashurov A, Krähling V, Kupke A, Cohen-Dvashi H, Koch M, Eckert JM, Lederer S, Pfeifer N, Wolf T, Vehreschild MJGT, Wendtner C, Diskin R, Gruell H, Becker S, Klein F. Longitudinal Isolation of Potent Near-Germline SARS-CoV-2-Neutralizing Antibodies from COVID-19 Patients. Cell. 2020 Aug 20;182(4):843-854.e12. doi: 10.1016/j.cell.2020.06.044. Epub 2020 Jul 13. Erratum in: Cell. 2020 Sep 17;182(6):1663-1673. PMID: 32673567; PMCID: PMC7355337