TY - JOUR
T1 - Enhancing durability of CIS43 monoclonal antibody by Fc mutation or AAV delivery for malaria prevention
AU - Kisalu, Neville K.
AU - Pereira, Lais D.
AU - Ernste, Keenan
AU - Flores-Garcia, Yevel
AU - Idris, Azza H.
AU - Asokan, Mangaiarkarasi
AU - Dillon, Marlon
AU - MacDonald, Scott
AU - Shi, Wei
AU - Chen, Xuejun
AU - Pegu, Amarendra
AU - Schön, Arne
AU - Zavala, Fidel
AU - Balazs, Alejandro B.
AU - Francica, Joseph R.
AU - Seder, Robert A.
N1 - Funding Information:
We thank T. Zhou and S. Narpala (VRC, NIAID, NIH) for providing mAb VRC01. We thank Sung-Youl Ko (VRC, NIAID, NIH) for running the 2-compartment analysis for the half-life calculation. We thank John-Paul Todd, Elizabeth McCarthy, the Translational Research Program, and the Vaccine Production Plant (VRC, NIAID, NIH) for technical support. We thank Lawrence Wang (VRC, NIAID, NIH) for his comments on this manuscript. This work was supported by the following grants: award P2DA040254 to ABB from the National Institutes for Drug Abuse (NIDA) Avenir New Innovator; grant INV-001763 to FZ from the Bill and Melinda Gates Foundation; contract HHSN261200800001E to AS from the National Cancer Institute (NCI), NIH. YFG and FZ thank the Bloomberg Philanthropies for continued support.
Publisher Copyright:
© 2021, Kisalu et al. This is an open access article published under the terms of the Creative Commons Attribution 4.0 International License.
PY - 2021/2/8
Y1 - 2021/2/8
N2 - 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.
AB - 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.
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U2 - 10.1172/JCI.INSIGHT.143958
DO - 10.1172/JCI.INSIGHT.143958
M3 - Article
C2 - 33332286
AN - SCOPUS:85102090605
SN - 2379-3708
VL - 6
JO - JCI Insight
JF - JCI Insight
IS - 3
M1 - e143958
ER -