title: Full Length Single Chain Fc Protein (FLSC IgG1) as a Potent Antiviral Therapy Candidate: Implications for In Vivo Studies.
abstract: We have previously shown that FLSC, a chimeric protein containing HIV-1BAL gp120 and the D1 and D2 domains of human CD4, blocks the binding and entry of HIV-1 into target cells by occluding CCR5, the major HIV-1 coreceptor. In an effort to improve the antiviral potential of FLSC, we fused it with the hinge-CH2-CH3 region of human IgG1. The IgG moiety should increase both the affinity and stability in vivo of FLSC, due to the resultant bivalency and an extended serum half-life, thereby increasing its antiviral potency. We previously showed that (FLSC) IgG1 indeed had greater antiviral activity against T cell infections. Here we extend these results to macrophages, for which (FLSC) IgG1 has a more potent antiviral activity than FLSC alone, due in part to its higher binding affinity for CCR5. We also test both compounds in a relevant humanized mouse model and show that, as anticipated, the IgG1 moiety confers a greatly extended half-life. These data, taken together with previous results, suggest potential clinical utility for (FLSC) IgG1 and support further developmental work toward eventual clinical trials.
authors.affiliation: 1 Institute of Human Virology, University of Maryland School of Medicine , Baltimore, Maryland.|2 Department of Microbiology and Immunology, University of Maryland School of Medicine , Baltimore, Maryland.
authors.forename: Olga S
authors.initials: OS
authors.lastname: Latinovic
authors.affiliation: 1 Institute of Human Virology, University of Maryland School of Medicine , Baltimore, Maryland.
authors.forename: Sandra
authors.initials: S
authors.lastname: Medina-Moreno
authors.affiliation: 1 Institute of Human Virology, University of Maryland School of Medicine , Baltimore, Maryland.
authors.forename: Kate
authors.initials: K
authors.lastname: Schneider
authors.affiliation: 1 Institute of Human Virology, University of Maryland School of Medicine , Baltimore, Maryland.|3 Department of Biochemistry and Molecular Biology, University of Maryland School of Medicine , Baltimore, Maryland.
authors.forename: Neelakshi
authors.initials: N
authors.lastname: Gohain
authors.affiliation: 1 Institute of Human Virology, University of Maryland School of Medicine , Baltimore, Maryland.
authors.forename: Juan
authors.initials: J
authors.lastname: Zapata
authors.affiliation: 1 Institute of Human Virology, University of Maryland School of Medicine , Baltimore, Maryland.|3 Department of Biochemistry and Molecular Biology, University of Maryland School of Medicine , Baltimore, Maryland.
authors.forename: Marzena
authors.initials: M
authors.lastname: Pazgier
authors.affiliation: 1 Institute of Human Virology, University of Maryland School of Medicine , Baltimore, Maryland.|4 School of Medicine, University of Maryland School of Medicine , Baltimore, Maryland.
authors.forename: Marvin
authors.initials: M
authors.lastname: Reitz
authors.affiliation: 1 Institute of Human Virology, University of Maryland School of Medicine , Baltimore, Maryland.|5 Department of Pathology, University of Maryland School of Medicine , Baltimore, Maryland.
authors.forename: Joseph
authors.initials: J
authors.lastname: Bryant
authors.affiliation: 1 Institute of Human Virology, University of Maryland School of Medicine , Baltimore, Maryland.|4 School of Medicine, University of Maryland School of Medicine , Baltimore, Maryland.
authors.forename: Robert R
authors.initials: RR
authors.lastname: Redfield
mesh_terms: D000818:Animals; D019380:Anti-HIV Agents / Q000494:pharmacology*; D065100:CCR5 Receptor Antagonists / Q000494:pharmacology*; D015704:CD4 Antigens / Q000494:pharmacology*; D045744:Cell Line, Tumor; D057809:HEK293 Cells; D015699:HIV Envelope Protein gp120 / Q000494:pharmacology*; D015497:HIV-1 / Q000187:drug effects; D006367:HeLa Cells; D006801:Humans; D007141:Immunoglobulin Fc Fragments / Q000494:pharmacology*; D007074:Immunoglobulin G / Q000494:pharmacology*; D008264:Macrophages / Q000187:drug effects* / Q000821:virology; D051379:Mice; D018345:Mice, Knockout; D016513:Mice, SCID; D018613:Microscopy, Confocal; D019713:Receptors, CCR5 / Q000378:metabolism
chemical_list: D019380:Anti-HIV Agents; D065100:CCR5 Receptor Antagonists; D015704:CD4 Antigens; D015699:HIV Envelope Protein gp120; D007141:Immunoglobulin Fc Fragments; D007074:Immunoglobulin G; D019713:Receptors, CCR5