T-cell activation and cytokine production via a bispecific single-chain antibody fragment targeted to blood-stage malaria parasites.
A novel bispecific single-chain antibody fragment (biscFv) has been constructed to address the possibility of a new approach to malaria therapeutic drug development. The biscFv consists of 2 different single-chain antibody fragments linked by a flexible peptide linker (Gly(4)-Ser)(3). Of the 2 scFv fragments, one is directed against a conserved epitope of the 19-kDa C-terminal fragment of the major surface protein of human malignant malaria parasite, Plasmodium falciparum, and the other is directed against the CD3 antigen of human T cells. The biscFv expressed by a recombinant baculovirus retained the antigen-binding properties of the corresponding univalent single-chain antibody fragments and formed a bridge between P falciparum and T cells. In cooperation with T cells, the biscFv specifically induced not only interferon gamma and tumor necrosis factor alpha, but also a significant increase of merozoite phagocytosis and growth inhibition of P falciparum in vitro. Thus, the biscFv possesses highly selective malaria-targeting properties and stimulates T cells to induce cytokines, presumably resulting in activation of macrophages, neutrophils, and natural killer cells, and parasite killing in vivo.
Yoshida
Shigeto
S
Department of Medical Zoology, Jichi Medical School, Tochigi, Japan. shigeto@jichi.ac.jp
Kobayashi
Tominari
T
Matsuoka
Hiroyuki
H
Seki
Chisato
C
Gosnell
William L
WL
Chang
Sandra P
SP
Ishii
Akira
A
D000595:Amino Acid Sequence; D000818:Animals; D018033:Antibodies, Bispecific / Q000737:chemistry / Q000235:genetics / Q000276:immunology*; D000918:Antibody Specificity; D000953:Antigens, Protozoan / Q000276:immunology; D016367:Baculoviridae / Q000235:genetics; D017252:CD3 Complex / Q000276:immunology; D002460:Cell Line; D016207:Cytokines / Q000096:biosynthesis*; D006825:Hybridomas / Q000737:chemistry; D007135:Immunoglobulin Variable Region / Q000737:chemistry / Q000235:genetics / Q000276:immunology; D007371:Interferon-gamma / Q000096:biosynthesis; D007694:Killer Cells, Natural / Q000276:immunology; D008213:Lymphocyte Activation; D008262:Macrophage Activation; D020066:Merozoite Surface Protein 1 / Q000276:immunology; D008969:Molecular Sequence Data; D016853:Muromonab-CD3 / Q000737:chemistry / Q000235:genetics; D018375:Neutrophil Activation; D010587:Phagocytosis; D010963:Plasmodium falciparum / Q000254:growth & development / Q000276:immunology*; D011994:Recombinant Proteins; D057127:Single-Chain Antibodies; D018411:Spodoptera / Q000378:metabolism; D013601:T-Lymphocytes / Q000276:immunology*; D014162:Transfection; D014409:Tumor Necrosis Factor-alpha / Q000096:biosynthesis
C472770:5.2-OKT3 bispecific single-chain antibody fragment; D018033:Antibodies, Bispecific; D000953:Antigens, Protozoan; D017252:CD3 Complex; D016207:Cytokines; D007135:Immunoglobulin Variable Region; D020066:Merozoite Surface Protein 1; D016853:Muromonab-CD3; D011994:Recombinant Proteins; D057127:Single-Chain Antibodies; D014409:Tumor Necrosis Factor-alpha; D007371:Interferon-gamma