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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 2

Pharmacokinetic study in Indian rhesus macaques.

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Pharmacokinetic study in Indian rhesus macaques.
(A) Serum concentration...
(A) Serum concentrations of CIS43LS were measured by ELISA following i.v. injection of 10 mg per kg body weight of CIS43 or CIS43LS in rhesus macaques. ****P = <0.0003. (B) The amount of mAb in skin punch homogenates from each group of CIS43- or CIS43LS-treated macaques displayed in A was quantitated over time and is shown. *P = <0.0148. Data represent the mean ± SD, and differences in mAb concentrations between both groups were determined using 2-way ANOVA (A and B). (C and D) ELISA to assess the NHP serum antibodies elicited against CIS43 or CIS43LS (antidrug antibodies, ADA). Competitive ADA ELISA (C) showing CIS43 or CIS43LS binding to rPfCSP in the presence of NHP sera before (Pre) or at the indicated time points after mAb infusion. mAb groups and animals infused with CIS43LS (12M069 and 14D017) or CIS43 (13D084 and 15C049) are indicated. Varying concentrations of mouse mAb 1-1, a CIS43 mouse anti-idiotype antibody, were used as a positive control for the competitive binding of CIS43LS or CIS43 to rPfCSP. Pre, preimmune serum collected at baseline prior to antibody infusion. OD405nm, optical density at 405 nm. Data collected at different time points from the animals that received CIS43LS (red) or CIS43 (blue) are shown; black, mAb 1-1. Direct ADA ELISA (D). CIS43LS or CIS43 was coated onto ELISA plates, and NHP sera were analyzed. Color codes are as in C. Data represent the mean ± SEM (C and D). For all panels, n = 2 per group.

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