Rational Design and In Vivo Characterization of mRNA-Encoded Broadly Neutralizing Antibody Combinations against HIV-1

• Published in: Antibodies (Basel) Vol. 11; no. 4; p. 67
• Main Authors: Narayanan, Elisabeth, Falcone, Samantha, Elbashir, Sayda M, Attarwala, Husain, Hassett, Kimberly, Seaman, Michael S, Carfi, Andrea, Himansu, Sunny
• Format: Journal Article
• Language: English
• Published: Switzerland MDPI AG 24.10.2022; MDPI
• Subjects: AIDS treatment; antibodies; Antigens; Biotechnology industry; broadly neutralizing antibodies; Care and treatment; Chains; Chromatography; Comparative analysis; Dosage and administration; Drug development; Drug dosages; Env protein; Gene expression; Health aspects; HIV; HIV (Viruses); HIV antibodies; HIV infection; Human immunodeficiency virus; Immunoglobulin G; Lipids; Manufacturing; Messenger RNA; Monoclonal antibodies; mRNA; Neutralization; Neutralizing; Pharmacokinetics; Proteins; Recombinant proteins; RNA polymerase; Severe acute respiratory syndrome; Severe acute respiratory syndrome coronavirus 2; Structure; Vaccines; Viral infections; Viruses; United States; United Kingdom > UK; England; United States > US; antibodies; mRNA; HIV; broadly neutralizing antibodies
• ISSN: 2073-4468; 2073-4468
• DOI: 10.3390/antib11040067

Monoclonal antibodies have been used successfully as recombinant protein therapy; however, for HIV, multiple broadly neutralizing antibodies may be necessary. We used the mRNA-LNP platform for in vivo co-expression of 3 broadly neutralizing antibodies, PGDM1400, PGT121, and N6, directed against the HIV-1 envelope protein. mRNA-encoded HIV-1 antibodies were engineered as single-chain Fc (scFv-Fc) to overcome heavy- and light-chain mismatch. In vitro neutralization breadth and potency of the constructs were compared to their parental IgG form. We assessed the ability of these scFv-Fcs to be expressed individually and in combination in vivo, and neutralization and pharmacokinetics were compared to the corresponding full-length IgGs. Single-chain PGDM1400 and PGT121 exhibited neutralization potency comparable to parental IgG, achieving peak systemic concentrations ≥ 30.81 μg/mL in mice; full-length N6 IgG achieved a peak concentration of 974 μg/mL, but did not tolerate single-chain conversion. The mRNA combination encoding full-length N6 IgG and single-chain PGDM1400 and PGT121 was efficiently expressed in mice, achieving high systemic concentration and desired neutralization potency. Analysis of mice sera demonstrated each antibody contributed towards neutralization of multiple HIV-1 pseudoviruses. Together, these data show that the mRNA-LNP platform provides a promising approach for antibody-based HIV treatment and is well-suited for development of combination therapeutics.