Olga S Latinovic
assistant professor working at the Institute of Human Virology (IHV) led by Robert C. Gallo, M.D. at the University of Maryland, School of Medicine in Baltimore, MD, USA.
Title: Full Length Single Chain Fc Protein (FLSC IgG1) as a Potent Antiviral Therapy Candidate: Implications for In Vivo Studies
Biography
Biography: Olga S Latinovic
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. In addition, we previously reported that treatment with the CCR5 small molecule antagonist Maraviroc (MVC) increased the apparent exposure of the (FLSC) IgG1 binding sites on CCR5, leading us to wonder if the two compounds used in combination might synergize in their anti-viral activity. Here we show that this is indeed the case. We demonstrate that fusion protein (FLSC) IgG1, strongly synergizes with the CCR5 antagonist Maraviroc to successfully inhibit both MVC-sensitive and MVC-resistant R5 HIV-1. These data, taken together with previous results, suggest development of further in vivo studies, potential clinical utility for (FLSC) IgG1 and support further developmental work toward eventual clinical trials.