Enhancing durability of CIS43 monoclonal antibody by Fc mutation or AAV delivery for malaria prevention.

Neville K Kisalu,Joseph R Francica,Keenan Ernste,Yevel Flores-Garcia,Arne Schön,Marlon Dillon,Alejandro B Balazs,Xuejun Chen,Amarendra Pegu,Mangaiarkarasi Asokan,Lais D Pereira,Robert A Seder,Fidel Zavala,Wei Shi,Azza H Idris,Scott Macdonald

doi:10.1172/jci.insight.143958

Abstract

CIS43 is a potent neutralizing human mAb that targets a highly conserved “junctional” epitope in the Plasmodium falciparum (Pf) circumsporozoite protein (PfCSP). Enhancing the durability of CIS43 in vivo will be important for clinical translation. Here, 2 approaches were used to improve the durability of CIS43 in vivo while maintaining potent neutralization. First, the Fc domain was modified with the LS mutations (CIS43LS) to increase CIS43 binding affinity for the neonatal Fc receptor (FcRn). CIS43LS and CIS43 showed comparable in vivo protective efficacy. CIS43LS had 9- to 13-fold increased binding affinity for human (6.2 nM versus 54.2 nM) and rhesus (25.1 nM versus 325.8 nM) FcRn at endosomal pH 6.0 compared with CIS43. Importantly, the half-life of CIS43LS in rhesus macaques increased from 22 days to 39 days compared with CIS43. The second approach for sustaining antibody levels of CIS43 in vivo is through adeno-associated virus (AAV) expression. Mice administered once with AAV-expressing CIS43 had sustained antibody levels of approximately 300 μg/mL and mediated protection against sequential malaria challenges up to 36 weeks. Based on these data, CIS43LS has advanced to phase I clinical trials, and AAV delivery provides a potential next-generation approach for malaria prevention.

Highlights

IntroductionSeveral interventions have significantly contributed to the decrease of malaria case incidence and mortality, including vector control, insecticide-treated bednets, and seasonal malaria chemoprevention
Malaria is a mosquito-borne parasitic disease causing high morbidity and mortality primarily in infants and young children in sub-Saharan Africa
We recently reported on the discovery of CIS43, a human mAb isolated from a subject immunized with an attenuated Plasmodium falciparum (Pf) whole SPZ vaccine (Sanaria PfSPZ Vaccine; ref. 15) that was protected against controlled human malaria infection (CHMI) [16]

Summary

Introduction

Several interventions have significantly contributed to the decrease of malaria case incidence and mortality, including vector control, insecticide-treated bednets, and seasonal malaria chemoprevention. The most transformative modality to control malaria would be a vaccine that provides high-level and durable protection. 5–7), there is more limited immunity and protection in malaria-endemic regions against CHMI [8] or in areas of intense natural transmission [9]. Factors that may influence vaccine efficacy include prior malaria exposure [9, 10], parasite diversity [11, 12], and age [13, 14]. An alternative immune approach independent of the potential factors that limit immunity by vaccination — one that would induce high-level protection for defined periods of time — is through passive immunization with a highly potent mAb

Methods

Results

Conclusion