Enhancement of Antibody-Dependent Cellular Cytotoxicity and Phagocytosis in Anti-HIV-1 Human-Bovine Chimeric Broadly Neutralizing Antibodies
| Autor: | Bruce D. Wines, Matthew S. Parsons, Anne B. Kristensen, Christopher A Gonelli, Behnaz Heydarchi, Jack Edwards, Damian F. J. Purcell, Georges Khoury, Natalia Salazar-Quiroz, P. Mark Hogarth |
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| Rok vydání: | 2021 |
| Předmět: |
Sexual transmission
medicine.drug_class Recombinant Fusion Proteins Immunology HIV Infections HIV Antibodies Biology Protein Engineering Monoclonal antibody Microbiology Neutralization Cell Line 03 medical and health sciences 0302 clinical medicine Phagocytosis Virology Vaccines and Antiviral Agents medicine Animals Humans Binding site 030304 developmental biology Antibody-dependent cell-mediated cytotoxicity 0303 health sciences Receptors IgG Antibody-Dependent Cell Cytotoxicity Fragment crystallizable region Killer Cells Natural Immunoglobulin G Insect Science HIV-1 biology.protein Cattle Antibody Cell activation Broadly Neutralizing Antibodies 030215 immunology |
| Zdroj: | J Virol |
| ISSN: | 1098-5514 0022-538X |
| DOI: | 10.1128/jvi.00219-21 |
| Popis: | No prophylactic vaccine has provided robust protection against human immunodeficiency virus type 1 (HIV-1). Vaccine-induced broadly neutralizing antibodies (bNAbs) have not been achieved in humans and most animals; however, cows vaccinated with HIV-1 envelope trimers produce bNAbs with unusually long third heavy complementarity-determining regions (CDRH3s). Alongside neutralization, Fc-mediated effector functions, including antibody-dependent cellular cytotoxicity (ADCC) and phagocytosis (ADP), may be critical for in vivo bNAb antiviral activity. Here, we aimed to augment the Fc-dependent effector functions of a chimeric human-bovine bNAb, NC-Cow1, which binds the CD4 binding site (CD4bs) and exhibits broader and more potent neutralization than most human CD4bs bNAbs by using an exceptionally long 60-amino acid (aa) CDRH3. The bovine variable region of NC-Cow1 was paired with a human IgG1 Fc region mutated to create the following three variants: G236R/L328R (GRLR) that abrogates Fc-gamma receptor (FcγR) binding, and two variants that enhance binding, namely, G236A/S239D/I332E (GASDIE) and G236A/S239D/A330L/I332E (GASDALIE). Both GASDIE and GASDALIE improved binding to human FcγRIIA and FcγRIIIA, enhanced human natural killer (NK) cell activation, and mediated higher levels of ADCC and ADP activity than the wild-type human IgG1 Fc. GASDALIE mediated higher phagocytic activity than GASDIE. As expected, GRLR eliminated binding to FcγRs and did not mediate ADCC or ADP. We demonstrated that mutations in the human Fc region of bovine chimeric antibodies with ultralong CDRH3s could enhance antibody effector functions while maintaining envelope binding and neutralization. This study will have significant implications in the development of multifunctional anti-HIV antibodies, which may be important to prevent HIV‐1 transmission in an antibody‐based topical microbicide. IMPORTANCE Despite successful antiviral chemotherapy, human immunodeficiency virus (HIV) is still a lifelong persistent virus, and no vaccine yet prevents HIV transmission. Topical microbicides offer an important alternative method to prevent sexual transmission of HIV-1. With the production of highly potent anti-HIV-1 broadly neutralizing antibodies (bNAbs) and multifunctional antibodies, monoclonal antibodies are now important prophylactic agents. Recently discovered anti-HIV-1 bovine bNAbs (with higher potency and breadth than most human bNAbs) could be novel candidates as potent topical microbicides. Our study is significant as it demonstrates the compatibility of combining bovine-derived neutralization with human-derived antibody-effector functions. This study is a new approach to antibody engineering that strengthens the feasibility of using high-potency bovine variable region bNAbs with augmented Fc function and promotes them as a strong candidate for antibody-mediated therapies. |
| Databáze: | OpenAIRE |
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