PMID: 29976677
Title: Targeting the HIV 1 spike and co receptor with bi and trispecific antibodies for single component broad inhibition of entry
Abstract: Protection against acquiring HIV infection may not require a vaccine in the conventional sense, because broadly neutralizing antibodies (bNAbs) alone prevent HIV infection in relevant animal challenge models. Additionally, bNAbs as therapeutics can effectively suppress HIV replication in infected humans and in animal models. Combinations of bNAbs are generally even more effective and bNAb-derived multivalent antibody-like molecules also inhibit HIV replication both in vitro and in vivo. To expand the available array of multi-specific HIV inhibitors, we designed single-component molecules that incorporate two (bispecific) or three (trispecific) bNAbs that recognize HIV Env exclusively, a bispecific CrossMab targeting two epitopes on the major HIV co-receptor, CCR5, and bi- and trispecifics that cross-target both Env and CCR5. These newly designed molecules displayed exceptional breadth, neutralizing 98-100% of a 109-virus panel, as well as additivity and potency compared to the individual parental control IgGs. The bispecific molecules designed as tandem single chain variable fragments (scFvs; 10E8fv-N6fv and m36.4-PRO 140fv) displayed a median IC of 0.0685 and 0.0131 μg/ml, respectively. A trispecific containing 10E8-PGT121-PGDM1400 Env-specific binding sites was equally potent (median IC of 0.0135 μg/ml), while the trispecific molecule targeting Env and CCR5 simultaneously (10E8Fab-PGDM1400fv-PRO 140fv), demonstrated even greater potency with a median IC of 0.007 μg/ml. By design, some of these molecules lacked Fc-mediated effector function; therefore, we also constructed a trispecific prototype possessing reconstituted CH2-CH3 domains to restore Fc receptor binding capacity. The molecules developed here, along with those described previously, possess promise as prophylactic and therapeutic agents against HIV. Broadly neutralizing antibodies (bNAbs) prevent HIV infection in monkey challenge models and suppress HIV replication in infected humans. Combinations of bNAbs are more effective at suppression and antibody-like molecules engineered to have 2 or 3 bNAb combining sites also inhibit HIV replication in monkeys and other animal models. To expand the available array of multi-specific HIV inhibitors, we designed single-component molecules that incorporate two (bispecific) or three (trispecific) bNAb binding sites that recognize the HIV envelope glycoprotein (Env), the HIV co-receptor (CCR5), or that cross-target both Env and CCR5. Several of the bi- and trispecific molecules neutralized most viruses in a diverse cross-clade panel with greater breadth and potency than the individual parental bNAbs. The molecules described here provide additional options to prevent or suppress HIV infection.
Date: 1970-08-22
Year: 2018
Journal: J. Virol.
PMID Author: Khan SN, Sok D, Tran K, Movsesyan A, Dubrovskaya V, Burton D, Wyatt RT
IAVI Topics: HIV Immunogen Design

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