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Enhancing durability of CIS43 monoclonal antibody by Fc mutation or AAV delivery for malaria prevention
Neville K. Kisalu, … , Joseph R. Francica, Robert A. Seder
Neville K. Kisalu, … , Joseph R. Francica, Robert A. Seder
Published December 17, 2020
Citation Information: JCI Insight. 2021;6(3):e143958. https://doi.org/10.1172/jci.insight.143958.
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Research Article Infectious disease

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

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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.

Authors

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

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Figure 3

Protective efficacy and expression of PfCSP-AAV–induced mAbs in C57BL/6 mice.

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Protective efficacy and expression of PfCSP-AAV–induced mAbs in C57BL/6 ...
(A) Sterile protection by mosquito bite 3 weeks following intramuscular administration of 1 × 1011 genome copies (GC) AAV encoding CIS43, 2A10, or VRC01. C57BL/6 mice were challenged by mosquito bites 3 weeks following AAV administration of the indicated mAb. As a control, 300 μg-rCIS43 was administered 2 hours prior to challenge. Kaplan-Meier curves, analyzed using the log-rank test, show the frequencies of mice free of parasites. Differences between CIS43-AAV–administered or 300 μg rCIS43–treated mice and untreated mice are shown (P = 0.0001). wpa, weeks post-AAV administration; 300 μg-rCIS43, mice that passively received the protective dose of 300 μg of CIS43 at the time of challenge. n = 10 per group; 2A10-AAV, n = 8. (B) Protective effect of PfCSP-AAV expressed mAbs on liver burden 8 weeks following AAV administration. AAV-treated C57BL/6 albino mice were challenged i.v. with Pb-PfCSP-LUC SPZ and imaged by IVIS. Data represent the geometric mean with 95% CI. For liver burden (2 dpc), *P = 0.0159 and ***P = 0.0001; for parasitemia (6 dpc), *P = 0.0102 and ***P = 0.0005. Max burden, naive infected mice; 8 wpa, 8 weeks post-AAV administration; dpc, days postchallenge; hIgG; human IgG1. CIS43 and VRC01, n = 10 per group; 2A10, n = 8. (C–F) Serum hIgG (C) and PfCSP-specific mAb (D) levels, and skin hIgG (E) and PfCSP-specific mAb (F) levels from mice shown in B were measured by ELISA 8 wpa. Differences in antibody concentration, parasite liver burden, or parasitemia between each group and the untreated group were determined using the Kruskal-Wallis test for multiple comparisons with Dunn’s correction. P values are shown on panels. Means ± SD are displayed (C–F).

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