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Infection and Immunity, December 2009, p. 5659-5667, Vol. 77, No. 12
0019-9567/09/$08.00+0 doi:10.1128/IAI.00167-09
Copyright © 2009, American Society for Microbiology. All Rights Reserved.
Inhibition of Erythrocyte Invasion and Plasmodium falciparum Merozoite Surface Protein 1 Processing by Human Immunoglobulin G1 (IgG1) and IgG3 Antibodies 
Maria Lazarou,1
José A. Guevara Patiño,2,
Richard M. Jennings,2,
Richard S. McIntosh,1
Jianguo Shi,1
Steven Howell,3
Eilish Cullen,4
Tarran Jones,4
Jaime R. Adame-Gallegos,1
Jonathan A. Chappel,4
Jana S. McBride,5
Michael J. Blackman,2
Anthony A. Holder,2* and
Richard J. Pleass1*
Institute of Genetics, School of Biology, Queen's Medical Centre, University of Nottingham, Nottingham NG7 2UH, United Kingdom,1 Divisions of Parasitology,2 Molecular Structure, MRC National Institute for Medical Research, Mill Hill, London NW7 1AA, United Kingdom,3 MRC Technology Mill Hill, London NW7 1AD, United Kingdom,4 Institute of Immunology and Infection Research, School of Biological Sciences, Kings Buildings, University of Edinburgh, Edinburgh EH9 3JT, United Kingdom5
Received 13 February 2009/ Returned for modification 22 April 2009/ Accepted 25 September 2009
Antigen-specific antibodies (Abs) to the 19-kDa carboxy-terminal region of Plasmodium falciparum merozoite surface protein 1 (MSP119) play an important role in protective immunity to malaria. Mouse monoclonal Abs (MAbs) 12.10 and 12.8 recognizing MSP119 can inhibit red cell invasion by interfering with MSP1 processing on the merozoite surface. We show here that this ability is dependent on the intact Ab since Fab and F(ab')2 fragments derived from MAb 12.10, although capable of binding MSP1 with high affinity and competing with the intact antibody for binding to MSP1, were unable to inhibit erythrocyte invasion or MSP1 processing. The DNA sequences of the variable (V) regions of both MAbs 12.8 and 12.10 were obtained, and partial amino acid sequences of the same regions were confirmed by mass spectrometry. Human chimeric Abs constructed by using these sequences, which combine the original mouse V regions with human 
1 and 3 constant regions, retain the ability to bind to both parasites and recombinant MSP119, and both chimeric human immunoglobulin G1s (IgG1s) were at least as good at inhibiting erythrocyte invasion as the parental murine MAbs 12.8 and 12.10. Furthermore, the human chimeric Abs of the IgG1 class (but not the corresponding human IgG3), induced significant NADPH-mediated oxidative bursts and degranulation from human neutrophils. These chimeric human Abs will enable investigators to examine the role of human Fc receptors in immunity to malaria using a transgenic parasite and mouse model and may prove useful in humans for neutralizing parasites as an adjunct to antimalarial drug therapy.
* Corresponding authors. Mailing address for A. A. Holder: Divisions of Parasitology, MRC National Institute for Medical Research, Mill Hill, London NW7 1AA, United Kingdom. Phone: 44 208 81 62175. Fax: 44 208 81 62730. E-mail: aholder{at}nimr.mrc.ac.uk. Mailing address for R. J. Pleass: Institute of Genetics, School of Biology, Queen's Medical Centre, University of Nottingham, Nottingham NG7 2UH, United Kingdom. Phone: 44 115 82 30383. Fax: 44 115 82 30338. E-mail: richard.pleass{at}nottingham.ac.uk
Published ahead of print on 5 October 2009.
Present address: The University of Chicago, AMB G208 (MC 5031), 5841 S. Maryland Avenue, Chicago, IL 60637.
Present address: The Whittington Hospital NHS Trust, Magdala Avenue, London N19 5NF, United Kingdom.
Infection and Immunity, December 2009, p. 5659-5667, Vol. 77, No. 12
0019-9567/09/$08.00+0 doi:10.1128/IAI.00167-09
Copyright © 2009, American Society for Microbiology. All Rights Reserved.
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