Go to The Journal of Clinical Investigation
  • About
  • Editors
  • Consulting Editors
  • For authors
  • Publication ethics
  • Transfers
  • Advertising
  • Job board
  • Contact
  • Current issue
  • Past issues
  • By specialty
    • COVID-19
    • Cardiology
    • Immunology
    • Metabolism
    • Nephrology
    • Oncology
    • Pulmonology
    • All ...
  • Videos
  • Collections
    • Resource and Technical Advances
    • Clinical Medicine
    • Reviews
    • Editorials
    • Perspectives
    • Top read articles
  • JCI This Month
    • Current issue
    • Past issues

  • Current issue
  • Past issues
  • Specialties
  • In-Press Preview
  • Editorials
  • Viewpoint
  • Top read articles
  • About
  • Editors
  • Consulting Editors
  • For authors
  • Publication ethics
  • Transfers
  • Advertising
  • Job board
  • Contact
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.
View: Text | PDF
Research Article Infectious disease

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

  • Text
  • PDF
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

×

Figure 1

Characterization of CIS43LS.

Options: View larger image (or click on image) Download as PowerPoint
Characterization of CIS43LS.
(A) Binding of CIS43LS to rPfCSP and PfCSP ...
(A) Binding of CIS43LS to rPfCSP and PfCSP peptides by ELISA. CIS43, VRC01 (human anti-HIV-1 IgG1), and 317 (human antibody specific for the NANP-repeat region of PfCSP) were used as control antibodies. (B) Thermodynamic parameters and stoichiometry of binding of CIS43LS to rPfCSP by isothermal calorimetry. The KD, change in Gibbs energy (ΔG) of binding, enthalpy (ΔH), entropy contribution to Gibbs energy (−TΔS), and stoichiometry (N) are shown. Data displayed are representative of 2 independent experiments. (C) Protective effect of CIS43LS on liver burden. Following passive transfer of CIS43LS or CIS43, C57BL/6 mice were challenged i.v. with Pb-PfCSP-LUC SPZ before imaging by IVIS. Differences in liver-stage parasite burden reduction between the VRC01, CIS43, or CIS43LS group compared with the untreated group were determined using the nonparametric Kruskal-Wallis test for multiple comparisons with Dunn’s correction. P values are displayed on the panels. **P = 0.0019 (CIS43) or 0.0099 (CIS43LS). (D) Protective effect on liver burden by CIS43LS at varying concentrations (30–300 μg/mL). Data represent geometric mean with 95% CI (C and D). (E) Sterile protection by CIS43LS following infection by mosquito bites. C57BL/6 mice were challenged with infected mosquitoes following passive transfer of CIS43LS or CIS43 (300 μg per mouse). The presence of parasites was determined through Giemsa staining of blood up to 12 days following challenge. Kaplan-Meier curves, analyzed by the log rank test, show frequencies of mice free of parasites as determined by Giemsa staining of blood. Differences between CIS43LS and CIS43 as compared with untreated mice are shown (P = 0.0001). n = 5 per group (C–E). (F) Apparent affinity of CIS43LS to human and rhesus FcRn at acidic pH 6.0 and physiological pH 7.4. Antibody binding curves are shown in red (raw data) and black (fitted data). The apparent affinity is displayed as KD in nM. A representative of 2 independent experiments is shown. ND, no fit could be determined.

Copyright © 2023 American Society for Clinical Investigation
ISSN 2379-3708

Sign up for email alerts