Engineered DNA-encoded monoclonal antibodies targeting Plasmodium falciparum circumsporozoite protein confer single dose protection in a murine malaria challenge model

Abstract

Novel approaches for malaria prophylaxis remain important. Synthetic DNA-encoded monoclonal antibodies (DMAbs) are a promising approach to generate rapid, direct in vivo host-generated mAbs with potential benefits in production simplicity and distribution coupled with genetic engineering. Here, we explore this approach in a malaria challenge model. We engineered germline-reverted DMAbs based on human mAb clones CIS43, 317, and L9 which target a junctional epitope, major repeat, and minor repeat of the Plasmodium falciparum circumsporozoite protein (CSP) respectively. DMAb variants were encoded into a plasmid vector backbone and their expression and binding profiles were characterized. We demonstrate long-term serological expression of DMAb constructs resulting in in vivo efficacy of CIS43 GL and 317 GL in a rigorous mosquito bite mouse challenge model. Additionally, we engineered an Fc modified variant of CIS43 and L9-based DMAbs to ablate binding to C1q to test the impact of complement-dependent Fc function on challenge outcomes. Complement knockout variant DMAbs demonstrated similar protection to that of WT Fc DMAbs supporting the notion that direct binding to the parasite is sufficient for the protection observed. Further investigation of DMAbs for malaria prophylaxis appears of importance.

Expanding the Reach of Monoclonal Antibodies: A Review of Synthetic Nucleic Acid Delivery in Immunotherapy

“…Hyaluronidase treatment, which helps DNA move through the extracellular matrix and enhance plasmid uptake, would be administered either before DNA delivery or co-formulated with DNA [ 67 , 68 ]. Modifying the antibody to resemble the human parental germline antibody sequence would also increase overall production in vivo while preserving functionality [ 68 , 69 ]. Mutations such as triple Fc modification M252Y/S254T/T256E were introduced to promote neonatal Fc receptor-mediated recycling of IgG into circulation, thereby extending mAb half-life [ 70 ].…”

Delivery platforms for broadly neutralizing antibodies

“…DMAbs hold promise to accelerate the deployment of new therapeutic interventions and provide preclinical tools for rapid evaluation of biological products. DMAbs have been tested for IgG production targeting prevention and treatment of diverse infectious diseases [15,20,22,23,25,28–36,37 ▪ ,38 ▪▪ ], and cancer [39–45] (Table 1. Current approaches for DNA delivery of antibodies).…”