title: Overcoming the Constraints of Anti-HIV/CD89 Bispecific Antibodies That Limit Viral Inhibition.
abstract: Innovative strategies are necessary to maximize the clinical application of HIV neutralizing antibodies. To this end, bispecific constructs of human antibody F240, reactive with well-conserved gp41 epitope and antibody 14A8, reactive with the IgA receptor (CD89) on effector cells, were constructed. A F240 × 14A8 bispecific single chain variable region (scFv) molecule was constructed by linking two scFvs using a conventional GGGGS linker. Despite immunoreactivity with HIV gp41 and neutrophils, this bispecific scFv failed to inhibit HIV infection. This is in sharp contrast to viral inhibition using a chemical conjugate of the Fab of these two antibodies. Therefore, we constructed two novel Fab-like bispecific antibody molecules centered on fusion of the IgG1 CH1 domain or CH1-hinge domain to the C-terminus of F240scFv and fusion of the kappa chain CL domain to the C-terminus of 14A8scFv. Both Bi-Fab antibodies showed significant ADCVI activity for multiple clade B and clade C isolates by arming the neutrophils to inhibit HIV infection. The approach presented in this study is unique for HIV immunotherapy in that the impetus of neutralization is to arm and mobilize PMN to destroy HIV and HIV infected cells.
authors.affiliation: Department of Medicine, Beth Israel Deaconess Medical Center, Boston, MA 02215, USA; Harvard Medical School, Boston, MA 02215, USA.
authors.forename: Xiaocong
authors.identifier: 0000-0002-7145-2616
authors.initials: X
authors.lastname: Yu
authors.affiliation: Department of Medicine, Beth Israel Deaconess Medical Center, Boston, MA 02215, USA.
authors.forename: Mark
authors.initials: M
authors.lastname: Duval
authors.affiliation: Department of Medicine, Beth Israel Deaconess Medical Center, Boston, MA 02215, USA.
authors.forename: Melissa
authors.identifier: 0000-0002-7567-4371
authors.initials: M
authors.lastname: Gawron
authors.affiliation: Department of Medicine, Beth Israel Deaconess Medical Center, Boston, MA 02215, USA; Harvard Medical School, Boston, MA 02215, USA.
authors.forename: Marshall R
authors.initials: MR
authors.lastname: Posner
authors.affiliation: Department of Medicine, Beth Israel Deaconess Medical Center, Boston, MA 02215, USA; Harvard Medical School, Boston, MA 02215, USA.
authors.forename: Lisa A
authors.identifier: 0000-0003-1417-8339
authors.initials: LA
authors.lastname: Cavacini
mesh_terms: D018033:Antibodies, Bispecific / Q000737:chemistry / Q000235:genetics / Q000494:pharmacology*; D057134:Antibodies, Neutralizing; D000920:Antibody-Dependent Cell Cytotoxicity; D015703:Antigens, CD; D002460:Cell Line; D015700:HIV Envelope Protein gp41 / Q000037:antagonists & inhibitors / Q000276:immunology; D015658:HIV Infections / Q000188:drug therapy / Q000276:immunology* / Q000821:virology*; D015497:HIV-1 / Q000187:drug effects* / Q000276:immunology*; D006801:Humans; D011485:Protein Binding; D011961:Receptors, Fc / Q000037:antagonists & inhibitors*; D057127:Single-Chain Antibodies / Q000737:chemistry / Q000235:genetics / Q000494:pharmacology*
chemical_list: D018033:Antibodies, Bispecific; D057134:Antibodies, Neutralizing; D015703:Antigens, CD; C036832:Fc(alpha) receptor; D015700:HIV Envelope Protein gp41; D011961:Receptors, Fc; D057127:Single-Chain Antibodies