Monoclonal Antibodies Against Dengue and Other Viruses With Deletion in Fc Region
Posted Sep 30 2008 5:00pm
Description of Invention: The four dengue virus (DENV) serotypes (DENV-1 to DENV-4) are the most important arthropod-borne flaviviruses in terms of morbidity and geographic distribution. Up to 100 million DENV infections occur every year, mostly in tropical and subtropical areas where vector mosquitoes are abundant. Infection with any of the DENV serotypes may be asymptomatic or may lead to classic dengue fever or more severe dengue hemorrhagic fever (DHF) and dengue shock syndrome (DSS), which are increasingly common in the dengue endemic areas. Immunity to the same virus serotype (homotypic immunity) is life-long, whereas immunity to different serotypes (heterotypic immunity) lasts 2–3 months so that infection with a different serotype virus is possible. DHF/DSS often occurs in patients with second, heterotypic DENV infections or in infants with maternally transferred dengue immunity. Severe dengue is a major cause of hospitalization, and fatality rates vary from <1% to 5% in children.
Antibody-dependent enhancement (ADE) has been proposed as an underlying pathogenic mechanism of DHF/DSS. ADE occurs because preexisting subneutralizing antibodies and the infecting DENV form complexes that bind to Fc receptor-bearing cells, leading to increased virus uptake and replication. ADE has been repeatedly demonstrated in vitro using dengue immune sera or monoclonal antibodies and cells of monocytic and recently, B lymphocytic lineages bearing Fc receptors. ADE of DENV-2 infection has also been demonstrated in monkeys infused with a human dengue immune serum.
We have identified chimpanzee–human chimeric IgG1 mAbs capable of neutralizing or binding to one or more DENV serotypes. Cross-reactive IgG 1A5 neutralizes DENV-1 and DENV-2 more efficiently than DENV-3 and DENV-4, and type-specific IgG 5H2 neutralizes DENV-4 at a high titer. Analysis of antigenic variants has localized the IgG 1A5 binding site to the conserved fusion peptide in E. Thus, IgG 1A5 shares many characteristics with the cross-reactive antibodies detected in flavivirus infections.
This application claims a variant of an antibody comprising a polypeptide in the Fc region, which binds an Fc gamma receptor (FcgammaR) with lower affinity than the parent antibody. The variant polypeptide comprises a deletion of nine amino acids at the N-terminus of the CH2 domain in the Fc region. Introduction of the Fc variant abrogates the antibody-mediated dengue virus replication enhancing activity. This invention has important implications for the antibody-mediated prevention of dengue virus infection.
Applications: Immunization against Dengue and/or flaviviruses.
Development Status: Antibody candidates have been synthesized and preclinical studies have been performed.
AP Goncalvez et al. Monoclonal antibody-mediated enhancement of dengue virus infection in vitro and in vivo and strategies for prevention. Proc Natl Acad Sci USA. 2007 May 29;104(22):9422-9427. [ PubMed abs ]
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