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

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.

Vaccination in a humanized mouse model elicits highly protective PfCSP-targeting anti-malarial antibodies

“…We previously reported the isolation of a highly potent human mAb that preferentially binds a unique tetrapeptide at the junction of the N terminus and repeat region, NPDP, identifying this subdominant ''junctional epitope'' as a site of vulnerability (Kisalu et al, 2018). CIS43, altered to express an LS mutation in its Fc region to increase its half-life (Kisalu et al, 2021), was found to prevent malaria infection in humans 8 months after a single administration (Gaudinski et al, 2021). Given the potential clinical utility of CIS43, it is critical to understand how this antibody lineage developed and how similar or more potent antibodies might be induced or engineered.…”

Anti-TRAP/SSP2 monoclonal antibodies can inhibit sporozoite infection and enhance protection of anti-CSP monoclonal antibodies

“…It is reasonable to expect that simply increasing the dose of the anti-CSP mAb would have also yielded higher levels of protection in this mouse model. Yet experience with RTS,S-which elicits extremely high levels of anti-CSP antibodies-as well as published data using highly potent anti-CSP mAbs 37,49,57 suggest that increasing anti-CSP titers alone provides diminishing returns. Furthermore, sustaining such high levels of antibodies over years may be unachievable by vaccines or mAb prophylaxis.…”

Editorial: The First Monoclonal Antibody Vaccine to Prevent Malaria Heralds a New Era of Malaria Vaccines to the Plasmodium falciparum Circumsporozoite Protein (PfCSP)

“…Following passive transfer experiments, the monoclonal antibody CIS43 conferred protection in two different mouse models of malaria infection and was shown to bind to Asn-Pro-Asn (NPN) [ 21 ]. In February 2021, Kisalu and colleagues reported the modification of CIS43 via the Fc domain with the LS mutations (CIS43LS) to increase the binding affinity of CIS43 in a study in rhesus macaques and humans [ 22 ]. CIS43LS had a 9-fold to 13-fold increase in binding affinity compared with CIS43 and an increased half-life [ 22 ].…”

“…In February 2021, Kisalu and colleagues reported the modification of CIS43 via the Fc domain with the LS mutations (CIS43LS) to increase the binding affinity of CIS43 in a study in rhesus macaques and humans [ 22 ]. CIS43LS had a 9-fold to 13-fold increase in binding affinity compared with CIS43 and an increased half-life [ 22 ]. Antibody levels were prolonged with the use of adeno-associated virus (AAV) expression, with CIS43LS progressing to clinical trials [ 22 ].…”

“…CIS43LS had a 9-fold to 13-fold increase in binding affinity compared with CIS43 and an increased half-life [ 22 ]. Antibody levels were prolonged with the use of adeno-associated virus (AAV) expression, with CIS43LS progressing to clinical trials [ 22 ].…”