Novel, fully human, anti-PfCSP antibodies with potent antimalarial activity using a phage display based strategy

Abstract

Developing an effective vaccine against malaria remains a prime goal of human health. The circumsporozoite protein (CSP) is a major surface protein of the sporozoites, and is the target of two licensed Plasmodium falciparum malaria vaccines, RTS,S/AS01, named Mosquirix and R21/Matrix-M. However, to improve the standards set by these vaccines we require a second-generation or prophylactic vaccine. Recently, monoclonal antibodies have emerged as essential biopharmaceutical prophylactic vaccines. The present study targeted recombinant Plasmodium falciparum CSP (rPfCSP) with a phage display of human single-fold scFv Tomlinson libraries I+J and picked fourteen scFvs that represented two independent clones after sequencing; CL1 and CL3. These phages were analysed for their binding to rPfCSP. The selected scFvs were cloned in a human IgG1 Fc tag vector, to generate scFv-Fc full-length antibody clones. CL1 bound rPfCSP protein with a K_D of 3.8x10^-6M and CL3 bound rPfCSP protein with a K_D of 5.6 x 10^-5 M. These antibodies detected native PfCSP on the sporozoite surface. Molecular docking simulation revealed that rPfCSP residues interacting with CL1 and CL3 were downstream of the repeat region. These antibodies inhibited the sporozoite infectivity into HepG2 cells, similar to a gold standard monoclonal antibody, 2A10. Low-dose passive transfer of the CL1 and CL3 antibodies conferred high-level protection when challenged with PfCSP-Pb transgenic parasites in the mouse infection model. The high in vitro and in vivo efficacies of the CL1 and CL3 antibodies have applications in malaria immunoprophylaxis in protecting travellers and military servicemen or as a therapeutic vaccine in malaria elimination programmes.