Inhibition of erythrocyte invasion and Plasmodium falciparum merozoite surface protein 1 processing by human immunoglobulin G1 (IgG1) and IgG3 antibodies.
Antigen-specific antibodies (Abs) to the 19-kDa carboxy-terminal region of Plasmodium falciparum merozoite surface protein 1 (MSP1(19)) play an important role in protective immunity to malaria. Mouse monoclonal Abs (MAbs) 12.10 and 12.8 recognizing MSP1(19) 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 gamma1 and gamma3 constant regions, retain the ability to bind to both parasites and recombinant MSP1(19), 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 Fcgamma 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.
Lazarou
Maria
M
Institute of Genetics, School of Biology, Queen's Medical Centre, University of Nottingham, Nottingham NG7 2UH, United Kingdom.
Guevara Patiño
José A
JA
Jennings
Richard M
RM
McIntosh
Richard S
RS
Shi
Jianguo
J
Howell
Steven
S
Cullen
Eilish
E
Jones
Tarran
T
Adame-Gallegos
Jaime R
JR
Chappel
Jonathan A
JA
McBride
Jana S
JS
Blackman
Michael J
MJ
Holder
Anthony A
AA
Pleass
Richard J
RJ
D000595:Amino Acid Sequence; D000818:Animals; D000911:Antibodies, Monoclonal / Q000276:immunology / Q000378:metabolism; D000913:Antibodies, Protozoan / Q000276:immunology* / Q000378:metabolism; D001483:Base Sequence; D004912:Erythrocytes / Q000469:parasitology*; D006801:Humans; D007140:Immunoglobulin Fab Fragments / Q000378:metabolism; D007074:Immunoglobulin G / Q000276:immunology*; D020066:Merozoite Surface Protein 1 / Q000037:antagonists & inhibitors* / Q000276:immunology / Q000378:metabolism; D051379:Mice; D008969:Molecular Sequence Data; D009504:Neutrophils / Q000276:immunology; D010963:Plasmodium falciparum / Q000276:immunology*; D011485:Protein Binding; D012313:RNA; D016897:Respiratory Burst
D000911:Antibodies, Monoclonal; D000913:Antibodies, Protozoan; D007140:Immunoglobulin Fab Fragments; D007074:Immunoglobulin G; D020066:Merozoite Surface Protein 1; C039919:RNA, recombinant; D012313:RNA