WO2024064826A1 - Anticorps neutralisants dirigés contre la protéine plasmodium falciparum circumsporozoïte et leur utilisation - Google Patents
Anticorps neutralisants dirigés contre la protéine plasmodium falciparum circumsporozoïte et leur utilisation Download PDFInfo
- Publication number
- WO2024064826A1 WO2024064826A1 PCT/US2023/074791 US2023074791W WO2024064826A1 WO 2024064826 A1 WO2024064826 A1 WO 2024064826A1 US 2023074791 W US2023074791 W US 2023074791W WO 2024064826 A1 WO2024064826 A1 WO 2024064826A1
- Authority
- WO
- WIPO (PCT)
- Prior art keywords
- antibody
- seq
- nos
- antigen binding
- binding fragment
- Prior art date
Links
- 230000003472 neutralizing effect Effects 0.000 title description 6
- 101900205473 Plasmodium falciparum Circumsporozoite protein Proteins 0.000 title description 3
- 238000009739 binding Methods 0.000 claims abstract description 383
- 230000027455 binding Effects 0.000 claims abstract description 382
- 239000000427 antigen Substances 0.000 claims abstract description 367
- 108091007433 antigens Proteins 0.000 claims abstract description 364
- 102000036639 antigens Human genes 0.000 claims abstract description 364
- 239000012634 fragment Substances 0.000 claims abstract description 341
- 241000223960 Plasmodium falciparum Species 0.000 claims abstract description 248
- 150000007523 nucleic acids Chemical class 0.000 claims abstract description 130
- 102000039446 nucleic acids Human genes 0.000 claims abstract description 84
- 108020004707 nucleic acids Proteins 0.000 claims abstract description 84
- 208000015181 infectious disease Diseases 0.000 claims abstract description 61
- 239000013598 vector Substances 0.000 claims abstract description 23
- 101710117490 Circumsporozoite protein Proteins 0.000 claims abstract description 21
- 125000003275 alpha amino acid group Chemical group 0.000 claims description 243
- 238000000034 method Methods 0.000 claims description 76
- 210000003046 sporozoite Anatomy 0.000 claims description 71
- 210000004027 cell Anatomy 0.000 claims description 48
- 239000000203 mixture Substances 0.000 claims description 42
- 239000012636 effector Substances 0.000 claims description 29
- 239000003550 marker Substances 0.000 claims description 22
- 230000004048 modification Effects 0.000 claims description 16
- 238000012986 modification Methods 0.000 claims description 16
- 239000000523 sample Substances 0.000 claims description 16
- 210000004185 liver Anatomy 0.000 claims description 15
- 239000012472 biological sample Substances 0.000 claims description 12
- 210000004369 blood Anatomy 0.000 claims description 11
- 239000008280 blood Substances 0.000 claims description 11
- 230000002401 inhibitory effect Effects 0.000 claims description 11
- 210000003494 hepatocyte Anatomy 0.000 claims description 10
- 239000003937 drug carrier Substances 0.000 claims description 8
- 230000035772 mutation Effects 0.000 claims description 6
- 108010047041 Complementarity Determining Regions Proteins 0.000 claims description 5
- 102100026120 IgG receptor FcRn large subunit p51 Human genes 0.000 claims description 5
- 108010068617 neonatal Fc receptor Proteins 0.000 claims description 2
- 239000008194 pharmaceutical composition Substances 0.000 claims description 2
- 108090000623 proteins and genes Proteins 0.000 description 84
- 238000006467 substitution reaction Methods 0.000 description 76
- 235000001014 amino acid Nutrition 0.000 description 75
- 108090000765 processed proteins & peptides Proteins 0.000 description 64
- 102000004169 proteins and genes Human genes 0.000 description 64
- 235000018102 proteins Nutrition 0.000 description 58
- 150000001413 amino acids Chemical class 0.000 description 41
- 108091028043 Nucleic acid sequence Proteins 0.000 description 40
- 102000004196 processed proteins & peptides Human genes 0.000 description 36
- 102100035360 Cerebellar degeneration-related antigen 1 Human genes 0.000 description 31
- 229920001184 polypeptide Polymers 0.000 description 27
- 201000004792 malaria Diseases 0.000 description 22
- 108020004414 DNA Proteins 0.000 description 21
- 230000009545 invasion Effects 0.000 description 21
- 244000045947 parasite Species 0.000 description 20
- 229940024606 amino acid Drugs 0.000 description 19
- 244000052769 pathogen Species 0.000 description 19
- 230000001717 pathogenic effect Effects 0.000 description 19
- 239000003795 chemical substances by application Substances 0.000 description 18
- 208000037265 diseases, disorders, signs and symptoms Diseases 0.000 description 17
- 108060003951 Immunoglobulin Proteins 0.000 description 16
- 201000010099 disease Diseases 0.000 description 16
- 102000018358 immunoglobulin Human genes 0.000 description 16
- NFGXHKASABOEEW-UHFFFAOYSA-N 1-methylethyl 11-methoxy-3,7,11-trimethyl-2,4-dodecadienoate Chemical compound COC(C)(C)CCCC(C)CC=CC(C)=CC(=O)OC(C)C NFGXHKASABOEEW-UHFFFAOYSA-N 0.000 description 15
- 210000005229 liver cell Anatomy 0.000 description 15
- 108091032973 (ribonucleotides)n+m Proteins 0.000 description 14
- 238000001514 detection method Methods 0.000 description 14
- 230000000694 effects Effects 0.000 description 14
- 239000002773 nucleotide Substances 0.000 description 14
- 125000003729 nucleotide group Chemical group 0.000 description 14
- 101100022187 Caenorhabditis elegans mab-10 gene Proteins 0.000 description 12
- 230000000670 limiting effect Effects 0.000 description 12
- 238000002965 ELISA Methods 0.000 description 11
- 238000003556 assay Methods 0.000 description 11
- 238000003776 cleavage reaction Methods 0.000 description 11
- 108020004999 messenger RNA Proteins 0.000 description 11
- 238000013518 transcription Methods 0.000 description 11
- 230000035897 transcription Effects 0.000 description 11
- 238000001727 in vivo Methods 0.000 description 10
- 239000007924 injection Substances 0.000 description 10
- 238000002347 injection Methods 0.000 description 10
- 238000001990 intravenous administration Methods 0.000 description 10
- 210000002381 plasma Anatomy 0.000 description 10
- 229920000642 polymer Polymers 0.000 description 10
- 239000000126 substance Substances 0.000 description 10
- 210000001519 tissue Anatomy 0.000 description 10
- 229960005486 vaccine Drugs 0.000 description 10
- 102000004190 Enzymes Human genes 0.000 description 9
- 108090000790 Enzymes Proteins 0.000 description 9
- 229940088598 enzyme Drugs 0.000 description 9
- 239000013604 expression vector Substances 0.000 description 9
- 230000006870 function Effects 0.000 description 9
- 230000036541 health Effects 0.000 description 9
- 238000004519 manufacturing process Methods 0.000 description 9
- 230000007017 scission Effects 0.000 description 9
- 230000009261 transgenic effect Effects 0.000 description 9
- 239000013603 viral vector Substances 0.000 description 9
- 241000255925 Diptera Species 0.000 description 8
- 241000282412 Homo Species 0.000 description 8
- 239000002299 complementary DNA Substances 0.000 description 8
- 230000009467 reduction Effects 0.000 description 8
- 238000013519 translation Methods 0.000 description 8
- 238000001262 western blot Methods 0.000 description 8
- KQPKMEYBZUPZGK-UHFFFAOYSA-N 4-[(4-azido-2-nitroanilino)methyl]-5-(hydroxymethyl)-2-methylpyridin-3-ol Chemical group CC1=NC=C(CO)C(CNC=2C(=CC(=CC=2)N=[N+]=[N-])[N+]([O-])=O)=C1O KQPKMEYBZUPZGK-UHFFFAOYSA-N 0.000 description 7
- 230000010056 antibody-dependent cellular cytotoxicity Effects 0.000 description 7
- 239000011324 bead Substances 0.000 description 7
- 238000000684 flow cytometry Methods 0.000 description 7
- 230000001976 improved effect Effects 0.000 description 7
- 230000003993 interaction Effects 0.000 description 7
- 210000004962 mammalian cell Anatomy 0.000 description 7
- 150000002482 oligosaccharides Chemical class 0.000 description 7
- 230000009870 specific binding Effects 0.000 description 7
- 208000024891 symptom Diseases 0.000 description 7
- 238000012384 transportation and delivery Methods 0.000 description 7
- FWMNVWWHGCHHJJ-SKKKGAJSSA-N 4-amino-1-[(2r)-6-amino-2-[[(2r)-2-[[(2r)-2-[[(2r)-2-amino-3-phenylpropanoyl]amino]-3-phenylpropanoyl]amino]-4-methylpentanoyl]amino]hexanoyl]piperidine-4-carboxylic acid Chemical compound C([C@H](C(=O)N[C@H](CC(C)C)C(=O)N[C@H](CCCCN)C(=O)N1CCC(N)(CC1)C(O)=O)NC(=O)[C@H](N)CC=1C=CC=CC=1)C1=CC=CC=C1 FWMNVWWHGCHHJJ-SKKKGAJSSA-N 0.000 description 6
- ODHCTXKNWHHXJC-VKHMYHEASA-N 5-oxo-L-proline Chemical compound OC(=O)[C@@H]1CCC(=O)N1 ODHCTXKNWHHXJC-VKHMYHEASA-N 0.000 description 6
- SHZGCJCMOBCMKK-UHFFFAOYSA-N D-mannomethylose Natural products CC1OC(O)C(O)C(O)C1O SHZGCJCMOBCMKK-UHFFFAOYSA-N 0.000 description 6
- 241000588724 Escherichia coli Species 0.000 description 6
- PNNNRSAQSRJVSB-SLPGGIOYSA-N Fucose Natural products C[C@H](O)[C@@H](O)[C@H](O)[C@H](O)C=O PNNNRSAQSRJVSB-SLPGGIOYSA-N 0.000 description 6
- PEDCQBHIVMGVHV-UHFFFAOYSA-N Glycerine Chemical compound OCC(O)CO PEDCQBHIVMGVHV-UHFFFAOYSA-N 0.000 description 6
- SHZGCJCMOBCMKK-DHVFOXMCSA-N L-fucopyranose Chemical compound C[C@@H]1OC(O)[C@@H](O)[C@H](O)[C@@H]1O SHZGCJCMOBCMKK-DHVFOXMCSA-N 0.000 description 6
- ODHCTXKNWHHXJC-GSVOUGTGSA-N Pyroglutamic acid Natural products OC(=O)[C@H]1CCC(=O)N1 ODHCTXKNWHHXJC-GSVOUGTGSA-N 0.000 description 6
- ODHCTXKNWHHXJC-UHFFFAOYSA-N acide pyroglutamique Natural products OC(=O)C1CCC(=O)N1 ODHCTXKNWHHXJC-UHFFFAOYSA-N 0.000 description 6
- 238000004458 analytical method Methods 0.000 description 6
- 230000007423 decrease Effects 0.000 description 6
- 238000000338 in vitro Methods 0.000 description 6
- 238000002595 magnetic resonance imaging Methods 0.000 description 6
- 229920001542 oligosaccharide Polymers 0.000 description 6
- 238000002360 preparation method Methods 0.000 description 6
- 241000894006 Bacteria Species 0.000 description 5
- LYCAIKOWRPUZTN-UHFFFAOYSA-N Ethylene glycol Chemical compound OCCO LYCAIKOWRPUZTN-UHFFFAOYSA-N 0.000 description 5
- 101001111984 Homo sapiens N-acylneuraminate-9-phosphatase Proteins 0.000 description 5
- 102100023906 N-acylneuraminate-9-phosphatase Human genes 0.000 description 5
- 241000224017 Plasmodium berghei Species 0.000 description 5
- 125000000539 amino acid group Chemical group 0.000 description 5
- 230000000295 complement effect Effects 0.000 description 5
- 150000001875 compounds Chemical class 0.000 description 5
- 238000002591 computed tomography Methods 0.000 description 5
- 238000012217 deletion Methods 0.000 description 5
- 230000037430 deletion Effects 0.000 description 5
- 238000011161 development Methods 0.000 description 5
- 230000018109 developmental process Effects 0.000 description 5
- 239000002552 dosage form Substances 0.000 description 5
- 239000003623 enhancer Substances 0.000 description 5
- 230000002255 enzymatic effect Effects 0.000 description 5
- 210000003743 erythrocyte Anatomy 0.000 description 5
- 238000009472 formulation Methods 0.000 description 5
- 230000002068 genetic effect Effects 0.000 description 5
- 238000003018 immunoassay Methods 0.000 description 5
- 239000000463 material Substances 0.000 description 5
- 230000036961 partial effect Effects 0.000 description 5
- 102000040430 polynucleotide Human genes 0.000 description 5
- 108091033319 polynucleotide Proteins 0.000 description 5
- 239000002157 polynucleotide Substances 0.000 description 5
- 230000010076 replication Effects 0.000 description 5
- 239000000243 solution Substances 0.000 description 5
- 241000894007 species Species 0.000 description 5
- 108091026890 Coding region Proteins 0.000 description 4
- 108010021625 Immunoglobulin Fragments Proteins 0.000 description 4
- 102000008394 Immunoglobulin Fragments Human genes 0.000 description 4
- 241001465754 Metazoa Species 0.000 description 4
- OVRNDRQMDRJTHS-UHFFFAOYSA-N N-acelyl-D-glucosamine Natural products CC(=O)NC1C(O)OC(CO)C(O)C1O OVRNDRQMDRJTHS-UHFFFAOYSA-N 0.000 description 4
- MBLBDJOUHNCFQT-LXGUWJNJSA-N N-acetylglucosamine Natural products CC(=O)N[C@@H](C=O)[C@@H](O)[C@H](O)[C@H](O)CO MBLBDJOUHNCFQT-LXGUWJNJSA-N 0.000 description 4
- 102000057297 Pepsin A Human genes 0.000 description 4
- 108090000284 Pepsin A Proteins 0.000 description 4
- 239000002202 Polyethylene glycol Substances 0.000 description 4
- 108020004511 Recombinant DNA Proteins 0.000 description 4
- FAPWRFPIFSIZLT-UHFFFAOYSA-M Sodium chloride Chemical compound [Na+].[Cl-] FAPWRFPIFSIZLT-UHFFFAOYSA-M 0.000 description 4
- 241000700605 Viruses Species 0.000 description 4
- 230000000890 antigenic effect Effects 0.000 description 4
- 239000003430 antimalarial agent Substances 0.000 description 4
- 230000004071 biological effect Effects 0.000 description 4
- 230000015572 biosynthetic process Effects 0.000 description 4
- 230000000903 blocking effect Effects 0.000 description 4
- 229910052799 carbon Inorganic materials 0.000 description 4
- 238000013270 controlled release Methods 0.000 description 4
- 238000001212 derivatisation Methods 0.000 description 4
- 239000000539 dimer Substances 0.000 description 4
- 238000010494 dissociation reaction Methods 0.000 description 4
- 230000005593 dissociations Effects 0.000 description 4
- 239000012530 fluid Substances 0.000 description 4
- 108020001507 fusion proteins Proteins 0.000 description 4
- 102000037865 fusion proteins Human genes 0.000 description 4
- 239000005090 green fluorescent protein Substances 0.000 description 4
- 230000001965 increasing effect Effects 0.000 description 4
- 239000006166 lysate Substances 0.000 description 4
- 238000012423 maintenance Methods 0.000 description 4
- 230000001404 mediated effect Effects 0.000 description 4
- 210000003936 merozoite Anatomy 0.000 description 4
- 239000004005 microsphere Substances 0.000 description 4
- 229920001223 polyethylene glycol Polymers 0.000 description 4
- 238000003752 polymerase chain reaction Methods 0.000 description 4
- 230000009257 reactivity Effects 0.000 description 4
- 230000004044 response Effects 0.000 description 4
- 238000010561 standard procedure Methods 0.000 description 4
- 238000003786 synthesis reaction Methods 0.000 description 4
- 238000012360 testing method Methods 0.000 description 4
- 238000012546 transfer Methods 0.000 description 4
- 238000011282 treatment Methods 0.000 description 4
- XLYOFNOQVPJJNP-UHFFFAOYSA-N water Substances O XLYOFNOQVPJJNP-UHFFFAOYSA-N 0.000 description 4
- -1 95% Chemical compound 0.000 description 3
- 241000701022 Cytomegalovirus Species 0.000 description 3
- 241000702421 Dependoparvovirus Species 0.000 description 3
- 108010043121 Green Fluorescent Proteins Proteins 0.000 description 3
- 102000004144 Green Fluorescent Proteins Human genes 0.000 description 3
- 101710177940 IgG receptor FcRn large subunit p51 Proteins 0.000 description 3
- 108091092195 Intron Proteins 0.000 description 3
- 108060001084 Luciferase Proteins 0.000 description 3
- 239000005089 Luciferase Substances 0.000 description 3
- 241000699670 Mus sp. Species 0.000 description 3
- OVRNDRQMDRJTHS-RTRLPJTCSA-N N-acetyl-D-glucosamine Chemical compound CC(=O)N[C@H]1C(O)O[C@H](CO)[C@@H](O)[C@@H]1O OVRNDRQMDRJTHS-RTRLPJTCSA-N 0.000 description 3
- 108700026244 Open Reading Frames Proteins 0.000 description 3
- 241000224016 Plasmodium Species 0.000 description 3
- 229920001213 Polysorbate 20 Polymers 0.000 description 3
- DNIAPMSPPWPWGF-UHFFFAOYSA-N Propylene glycol Chemical compound CC(O)CO DNIAPMSPPWPWGF-UHFFFAOYSA-N 0.000 description 3
- 240000004808 Saccharomyces cerevisiae Species 0.000 description 3
- VMHLLURERBWHNL-UHFFFAOYSA-M Sodium acetate Chemical compound [Na+].CC([O-])=O VMHLLURERBWHNL-UHFFFAOYSA-M 0.000 description 3
- 238000007792 addition Methods 0.000 description 3
- 230000004075 alteration Effects 0.000 description 3
- 230000003321 amplification Effects 0.000 description 3
- 230000001580 bacterial effect Effects 0.000 description 3
- 230000008901 benefit Effects 0.000 description 3
- 150000001720 carbohydrates Chemical group 0.000 description 3
- 125000003178 carboxy group Chemical group [H]OC(*)=O 0.000 description 3
- 238000006243 chemical reaction Methods 0.000 description 3
- 239000007795 chemical reaction product Substances 0.000 description 3
- 238000007796 conventional method Methods 0.000 description 3
- 229920001577 copolymer Polymers 0.000 description 3
- 230000001419 dependent effect Effects 0.000 description 3
- 229940079593 drug Drugs 0.000 description 3
- 239000003814 drug Substances 0.000 description 3
- 238000012377 drug delivery Methods 0.000 description 3
- 238000004520 electroporation Methods 0.000 description 3
- 230000008030 elimination Effects 0.000 description 3
- 238000003379 elimination reaction Methods 0.000 description 3
- 210000003527 eukaryotic cell Anatomy 0.000 description 3
- 230000033581 fucosylation Effects 0.000 description 3
- 125000000524 functional group Chemical group 0.000 description 3
- 210000000973 gametocyte Anatomy 0.000 description 3
- ZDXPYRJPNDTMRX-UHFFFAOYSA-N glutamine Natural products OC(=O)C(N)CCC(N)=O ZDXPYRJPNDTMRX-UHFFFAOYSA-N 0.000 description 3
- 230000012010 growth Effects 0.000 description 3
- 230000001900 immune effect Effects 0.000 description 3
- 230000002163 immunogen Effects 0.000 description 3
- 238000003364 immunohistochemistry Methods 0.000 description 3
- 238000001114 immunoprecipitation Methods 0.000 description 3
- 238000011534 incubation Methods 0.000 description 3
- 238000001802 infusion Methods 0.000 description 3
- 230000005764 inhibitory process Effects 0.000 description 3
- 238000003780 insertion Methods 0.000 description 3
- 230000037431 insertion Effects 0.000 description 3
- WTFXARWRTYJXII-UHFFFAOYSA-N iron(2+);iron(3+);oxygen(2-) Chemical compound [O-2].[O-2].[O-2].[O-2].[Fe+2].[Fe+3].[Fe+3] WTFXARWRTYJXII-UHFFFAOYSA-N 0.000 description 3
- 239000003446 ligand Substances 0.000 description 3
- 238000011068 loading method Methods 0.000 description 3
- 210000001806 memory b lymphocyte Anatomy 0.000 description 3
- 239000003094 microcapsule Substances 0.000 description 3
- 239000000178 monomer Substances 0.000 description 3
- 239000002105 nanoparticle Substances 0.000 description 3
- 238000003199 nucleic acid amplification method Methods 0.000 description 3
- 239000002245 particle Substances 0.000 description 3
- 229940111202 pepsin Drugs 0.000 description 3
- 238000002823 phage display Methods 0.000 description 3
- 239000013612 plasmid Substances 0.000 description 3
- 239000000256 polyoxyethylene sorbitan monolaurate Substances 0.000 description 3
- 235000010486 polyoxyethylene sorbitan monolaurate Nutrition 0.000 description 3
- 230000004481 post-translational protein modification Effects 0.000 description 3
- 230000002265 prevention Effects 0.000 description 3
- 125000002924 primary amino group Chemical group [H]N([H])* 0.000 description 3
- 230000008569 process Effects 0.000 description 3
- 238000012545 processing Methods 0.000 description 3
- 239000000047 product Substances 0.000 description 3
- 230000000069 prophylactic effect Effects 0.000 description 3
- 230000005180 public health Effects 0.000 description 3
- 230000002285 radioactive effect Effects 0.000 description 3
- 238000002601 radiography Methods 0.000 description 3
- 210000001563 schizont Anatomy 0.000 description 3
- 210000002966 serum Anatomy 0.000 description 3
- 239000001632 sodium acetate Substances 0.000 description 3
- 235000017281 sodium acetate Nutrition 0.000 description 3
- 239000000758 substrate Substances 0.000 description 3
- 125000003396 thiol group Chemical group [H]S* 0.000 description 3
- 239000003053 toxin Substances 0.000 description 3
- 231100000765 toxin Toxicity 0.000 description 3
- 108700012359 toxins Proteins 0.000 description 3
- 230000009466 transformation Effects 0.000 description 3
- YBJHBAHKTGYVGT-ZKWXMUAHSA-N (+)-Biotin Chemical compound N1C(=O)N[C@@H]2[C@H](CCCCC(=O)O)SC[C@@H]21 YBJHBAHKTGYVGT-ZKWXMUAHSA-N 0.000 description 2
- HZAXFHJVJLSVMW-UHFFFAOYSA-N 2-Aminoethan-1-ol Chemical compound NCCO HZAXFHJVJLSVMW-UHFFFAOYSA-N 0.000 description 2
- FPQQSJJWHUJYPU-UHFFFAOYSA-N 3-(dimethylamino)propyliminomethylidene-ethylazanium;chloride Chemical compound Cl.CCN=C=NCCCN(C)C FPQQSJJWHUJYPU-UHFFFAOYSA-N 0.000 description 2
- 108090001008 Avidin Proteins 0.000 description 2
- 108091033380 Coding strand Proteins 0.000 description 2
- 108020004705 Codon Proteins 0.000 description 2
- WQZGKKKJIJFFOK-QTVWNMPRSA-N D-mannopyranose Chemical compound OC[C@H]1OC(O)[C@@H](O)[C@@H](O)[C@@H]1O WQZGKKKJIJFFOK-QTVWNMPRSA-N 0.000 description 2
- 229920002307 Dextran Polymers 0.000 description 2
- BWGNESOTFCXPMA-UHFFFAOYSA-N Dihydrogen disulfide Chemical compound SS BWGNESOTFCXPMA-UHFFFAOYSA-N 0.000 description 2
- WSFSSNUMVMOOMR-UHFFFAOYSA-N Formaldehyde Chemical compound O=C WSFSSNUMVMOOMR-UHFFFAOYSA-N 0.000 description 2
- 102000004961 Furin Human genes 0.000 description 2
- 108090001126 Furin Proteins 0.000 description 2
- 101000840258 Homo sapiens Immunoglobulin J chain Proteins 0.000 description 2
- 108010001336 Horseradish Peroxidase Proteins 0.000 description 2
- 241000598436 Human T-cell lymphotropic virus Species 0.000 description 2
- MHAJPDPJQMAIIY-UHFFFAOYSA-N Hydrogen peroxide Chemical compound OO MHAJPDPJQMAIIY-UHFFFAOYSA-N 0.000 description 2
- 108700005091 Immunoglobulin Genes Proteins 0.000 description 2
- 102100029571 Immunoglobulin J chain Human genes 0.000 description 2
- DCXYFEDJOCDNAF-REOHCLBHSA-N L-asparagine Chemical compound OC(=O)[C@@H](N)CC(N)=O DCXYFEDJOCDNAF-REOHCLBHSA-N 0.000 description 2
- ROHFNLRQFUQHCH-YFKPBYRVSA-N L-leucine Chemical compound CC(C)C[C@H](N)C(O)=O ROHFNLRQFUQHCH-YFKPBYRVSA-N 0.000 description 2
- FFEARJCKVFRZRR-BYPYZUCNSA-N L-methionine Chemical compound CSCC[C@H](N)C(O)=O FFEARJCKVFRZRR-BYPYZUCNSA-N 0.000 description 2
- ROHFNLRQFUQHCH-UHFFFAOYSA-N Leucine Natural products CC(C)CC(N)C(O)=O ROHFNLRQFUQHCH-UHFFFAOYSA-N 0.000 description 2
- 102100029193 Low affinity immunoglobulin gamma Fc region receptor III-A Human genes 0.000 description 2
- 101710099301 Low affinity immunoglobulin gamma Fc region receptor III-A Proteins 0.000 description 2
- 241000699666 Mus <mouse, genus> Species 0.000 description 2
- 206010028980 Neoplasm Diseases 0.000 description 2
- 108090000526 Papain Proteins 0.000 description 2
- 208000030852 Parasitic disease Diseases 0.000 description 2
- 240000009188 Phyllostachys vivax Species 0.000 description 2
- 241000223801 Plasmodium knowlesi Species 0.000 description 2
- 241000223821 Plasmodium malariae Species 0.000 description 2
- 206010035501 Plasmodium malariae infection Diseases 0.000 description 2
- 241001505293 Plasmodium ovale Species 0.000 description 2
- 206010035502 Plasmodium ovale infection Diseases 0.000 description 2
- 239000004372 Polyvinyl alcohol Substances 0.000 description 2
- WCUXLLCKKVVCTQ-UHFFFAOYSA-M Potassium chloride Chemical compound [Cl-].[K+] WCUXLLCKKVVCTQ-UHFFFAOYSA-M 0.000 description 2
- NBBJYMSMWIIQGU-UHFFFAOYSA-N Propionic aldehyde Chemical compound CCC=O NBBJYMSMWIIQGU-UHFFFAOYSA-N 0.000 description 2
- 102000007056 Recombinant Fusion Proteins Human genes 0.000 description 2
- 108010008281 Recombinant Fusion Proteins Proteins 0.000 description 2
- CDBYLPFSWZWCQE-UHFFFAOYSA-L Sodium Carbonate Chemical compound [Na+].[Na+].[O-]C([O-])=O CDBYLPFSWZWCQE-UHFFFAOYSA-L 0.000 description 2
- 108091081024 Start codon Proteins 0.000 description 2
- 108010090804 Streptavidin Proteins 0.000 description 2
- 238000001042 affinity chromatography Methods 0.000 description 2
- 230000009824 affinity maturation Effects 0.000 description 2
- WQZGKKKJIJFFOK-PHYPRBDBSA-N alpha-D-galactose Chemical compound OC[C@H]1O[C@H](O)[C@H](O)[C@@H](O)[C@H]1O WQZGKKKJIJFFOK-PHYPRBDBSA-N 0.000 description 2
- 239000012491 analyte Substances 0.000 description 2
- 238000010171 animal model Methods 0.000 description 2
- 238000013459 approach Methods 0.000 description 2
- 239000008365 aqueous carrier Substances 0.000 description 2
- 238000002869 basic local alignment search tool Methods 0.000 description 2
- 230000009286 beneficial effect Effects 0.000 description 2
- 230000033228 biological regulation Effects 0.000 description 2
- 210000001124 body fluid Anatomy 0.000 description 2
- 230000037396 body weight Effects 0.000 description 2
- 201000011510 cancer Diseases 0.000 description 2
- 235000014633 carbohydrates Nutrition 0.000 description 2
- 239000000969 carrier Substances 0.000 description 2
- 230000015556 catabolic process Effects 0.000 description 2
- 238000004113 cell culture Methods 0.000 description 2
- 239000003153 chemical reaction reagent Substances 0.000 description 2
- 239000005081 chemiluminescent agent Substances 0.000 description 2
- 210000004978 chinese hamster ovary cell Anatomy 0.000 description 2
- 238000010367 cloning Methods 0.000 description 2
- 238000012411 cloning technique Methods 0.000 description 2
- 238000011961 computed axial tomography Methods 0.000 description 2
- 239000000470 constituent Substances 0.000 description 2
- 239000000599 controlled substance Substances 0.000 description 2
- 230000009260 cross reactivity Effects 0.000 description 2
- 125000000151 cysteine group Chemical group N[C@@H](CS)C(=O)* 0.000 description 2
- 230000034994 death Effects 0.000 description 2
- 230000002950 deficient Effects 0.000 description 2
- 238000006731 degradation reaction Methods 0.000 description 2
- 238000013461 design Methods 0.000 description 2
- 238000002059 diagnostic imaging Methods 0.000 description 2
- 230000029087 digestion Effects 0.000 description 2
- 238000001943 fluorescence-activated cell sorting Methods 0.000 description 2
- 230000004927 fusion Effects 0.000 description 2
- 125000000404 glutamine group Chemical group N[C@@H](CCC(N)=O)C(=O)* 0.000 description 2
- 230000013595 glycosylation Effects 0.000 description 2
- 238000006206 glycosylation reaction Methods 0.000 description 2
- 229910001385 heavy metal Inorganic materials 0.000 description 2
- 229920001519 homopolymer Polymers 0.000 description 2
- 210000004408 hybridoma Anatomy 0.000 description 2
- 230000028993 immune response Effects 0.000 description 2
- 238000003119 immunoblot Methods 0.000 description 2
- 238000010820 immunofluorescence microscopy Methods 0.000 description 2
- 229940072221 immunoglobulins Drugs 0.000 description 2
- 238000010348 incorporation Methods 0.000 description 2
- 230000000977 initiatory effect Effects 0.000 description 2
- 230000002452 interceptive effect Effects 0.000 description 2
- 238000007918 intramuscular administration Methods 0.000 description 2
- 238000007912 intraperitoneal administration Methods 0.000 description 2
- 229910052747 lanthanoid Inorganic materials 0.000 description 2
- 150000002602 lanthanoids Chemical class 0.000 description 2
- 238000007834 ligase chain reaction Methods 0.000 description 2
- 238000001638 lipofection Methods 0.000 description 2
- 239000002502 liposome Substances 0.000 description 2
- HQKMJHAJHXVSDF-UHFFFAOYSA-L magnesium stearate Chemical compound [Mg+2].CCCCCCCCCCCCCCCCCC([O-])=O.CCCCCCCCCCCCCCCCCC([O-])=O HQKMJHAJHXVSDF-UHFFFAOYSA-L 0.000 description 2
- 230000005291 magnetic effect Effects 0.000 description 2
- 238000005259 measurement Methods 0.000 description 2
- 229930182817 methionine Natural products 0.000 description 2
- 244000005700 microbiome Species 0.000 description 2
- 239000011859 microparticle Substances 0.000 description 2
- 238000000386 microscopy Methods 0.000 description 2
- 238000010369 molecular cloning Methods 0.000 description 2
- 239000002088 nanocapsule Substances 0.000 description 2
- 239000002159 nanocrystal Substances 0.000 description 2
- 239000002077 nanosphere Substances 0.000 description 2
- 239000013642 negative control Substances 0.000 description 2
- 231100000252 nontoxic Toxicity 0.000 description 2
- 230000003000 nontoxic effect Effects 0.000 description 2
- 210000003250 oocyst Anatomy 0.000 description 2
- 230000003204 osmotic effect Effects 0.000 description 2
- 230000005298 paramagnetic effect Effects 0.000 description 2
- 238000007911 parenteral administration Methods 0.000 description 2
- 230000004962 physiological condition Effects 0.000 description 2
- 239000006187 pill Substances 0.000 description 2
- 229940068977 polysorbate 20 Drugs 0.000 description 2
- 229920002451 polyvinyl alcohol Polymers 0.000 description 2
- 239000013641 positive control Substances 0.000 description 2
- 239000003755 preservative agent Substances 0.000 description 2
- 230000001681 protective effect Effects 0.000 description 2
- 238000001742 protein purification Methods 0.000 description 2
- 238000000746 purification Methods 0.000 description 2
- 230000002829 reductive effect Effects 0.000 description 2
- 210000003079 salivary gland Anatomy 0.000 description 2
- 238000013207 serial dilution Methods 0.000 description 2
- 230000001568 sexual effect Effects 0.000 description 2
- 239000011780 sodium chloride Substances 0.000 description 2
- 235000002639 sodium chloride Nutrition 0.000 description 2
- 239000007787 solid Substances 0.000 description 2
- 238000002798 spectrophotometry method Methods 0.000 description 2
- 238000007920 subcutaneous administration Methods 0.000 description 2
- 239000013589 supplement Substances 0.000 description 2
- 238000002198 surface plasmon resonance spectroscopy Methods 0.000 description 2
- 230000009885 systemic effect Effects 0.000 description 2
- 230000008685 targeting Effects 0.000 description 2
- 238000000954 titration curve Methods 0.000 description 2
- 238000010361 transduction Methods 0.000 description 2
- 230000026683 transduction Effects 0.000 description 2
- 238000002604 ultrasonography Methods 0.000 description 2
- 229920003169 water-soluble polymer Polymers 0.000 description 2
- 230000003442 weekly effect Effects 0.000 description 2
- 108091005957 yellow fluorescent proteins Proteins 0.000 description 2
- LLXVXPPXELIDGQ-UHFFFAOYSA-N (2,5-dioxopyrrolidin-1-yl) 3-(2,5-dioxopyrrol-1-yl)benzoate Chemical compound C=1C=CC(N2C(C=CC2=O)=O)=CC=1C(=O)ON1C(=O)CCC1=O LLXVXPPXELIDGQ-UHFFFAOYSA-N 0.000 description 1
- WNXJIVFYUVYPPR-UHFFFAOYSA-N 1,3-dioxolane Chemical compound C1COCO1 WNXJIVFYUVYPPR-UHFFFAOYSA-N 0.000 description 1
- 101800003405 15 kDa peptide Proteins 0.000 description 1
- DJQYYYCQOZMCRC-UHFFFAOYSA-N 2-aminopropane-1,3-dithiol Chemical compound SCC(N)CS DJQYYYCQOZMCRC-UHFFFAOYSA-N 0.000 description 1
- CYDQOEWLBCCFJZ-UHFFFAOYSA-N 4-(4-fluorophenyl)oxane-4-carboxylic acid Chemical compound C=1C=C(F)C=CC=1C1(C(=O)O)CCOCC1 CYDQOEWLBCCFJZ-UHFFFAOYSA-N 0.000 description 1
- XZIIFPSPUDAGJM-UHFFFAOYSA-N 6-chloro-2-n,2-n-diethylpyrimidine-2,4-diamine Chemical compound CCN(CC)C1=NC(N)=CC(Cl)=N1 XZIIFPSPUDAGJM-UHFFFAOYSA-N 0.000 description 1
- 206010069754 Acquired gene mutation Diseases 0.000 description 1
- 102000002260 Alkaline Phosphatase Human genes 0.000 description 1
- 108020004774 Alkaline Phosphatase Proteins 0.000 description 1
- 102100021266 Alpha-(1,6)-fucosyltransferase Human genes 0.000 description 1
- GUBGYTABKSRVRQ-XLOQQCSPSA-N Alpha-Lactose Chemical compound O[C@@H]1[C@@H](O)[C@@H](O)[C@@H](CO)O[C@H]1O[C@@H]1[C@@H](CO)O[C@H](O)[C@H](O)[C@H]1O GUBGYTABKSRVRQ-XLOQQCSPSA-N 0.000 description 1
- 241000256186 Anopheles <genus> Species 0.000 description 1
- 239000004475 Arginine Substances 0.000 description 1
- DCXYFEDJOCDNAF-UHFFFAOYSA-N Asparagine Natural products OC(=O)C(N)CC(N)=O DCXYFEDJOCDNAF-UHFFFAOYSA-N 0.000 description 1
- 108091003079 Bovine Serum Albumin Proteins 0.000 description 1
- UXVMQQNJUSDDNG-UHFFFAOYSA-L Calcium chloride Chemical compound [Cl-].[Cl-].[Ca+2] UXVMQQNJUSDDNG-UHFFFAOYSA-L 0.000 description 1
- OKTJSMMVPCPJKN-UHFFFAOYSA-N Carbon Chemical compound [C] OKTJSMMVPCPJKN-UHFFFAOYSA-N 0.000 description 1
- 229920002134 Carboxymethyl cellulose Polymers 0.000 description 1
- 108010001857 Cell Surface Receptors Proteins 0.000 description 1
- 102000000844 Cell Surface Receptors Human genes 0.000 description 1
- 241000282693 Cercopithecidae Species 0.000 description 1
- 206010063094 Cerebral malaria Diseases 0.000 description 1
- 108091062157 Cis-regulatory element Proteins 0.000 description 1
- 208000035473 Communicable disease Diseases 0.000 description 1
- 239000004971 Cross linker Substances 0.000 description 1
- 101710112752 Cytotoxin Proteins 0.000 description 1
- FBPFZTCFMRRESA-KVTDHHQDSA-N D-Mannitol Chemical compound OC[C@@H](O)[C@@H](O)[C@H](O)[C@H](O)CO FBPFZTCFMRRESA-KVTDHHQDSA-N 0.000 description 1
- 102000053602 DNA Human genes 0.000 description 1
- 102000016928 DNA-directed DNA polymerase Human genes 0.000 description 1
- 108010014303 DNA-directed DNA polymerase Proteins 0.000 description 1
- 206010061818 Disease progression Diseases 0.000 description 1
- 206010059866 Drug resistance Diseases 0.000 description 1
- 229910052692 Dysprosium Inorganic materials 0.000 description 1
- 241000196324 Embryophyta Species 0.000 description 1
- 241000206602 Eukaryota Species 0.000 description 1
- 229910052693 Europium Inorganic materials 0.000 description 1
- 108091092566 Extrachromosomal DNA Proteins 0.000 description 1
- 229910052688 Gadolinium Inorganic materials 0.000 description 1
- WQZGKKKJIJFFOK-GASJEMHNSA-N Glucose Natural products OC[C@H]1OC(O)[C@H](O)[C@@H](O)[C@@H]1O WQZGKKKJIJFFOK-GASJEMHNSA-N 0.000 description 1
- 239000004366 Glucose oxidase Substances 0.000 description 1
- 108010015776 Glucose oxidase Proteins 0.000 description 1
- WHUUTDBJXJRKMK-UHFFFAOYSA-N Glutamic acid Natural products OC(=O)C(N)CCC(O)=O WHUUTDBJXJRKMK-UHFFFAOYSA-N 0.000 description 1
- 102000003886 Glycoproteins Human genes 0.000 description 1
- 108090000288 Glycoproteins Proteins 0.000 description 1
- 241000238631 Hexapoda Species 0.000 description 1
- 101000819490 Homo sapiens Alpha-(1,6)-fucosyltransferase Proteins 0.000 description 1
- 241000713772 Human immunodeficiency virus 1 Species 0.000 description 1
- 108010073807 IgG Receptors Proteins 0.000 description 1
- 102000009490 IgG Receptors Human genes 0.000 description 1
- 102000009786 Immunoglobulin Constant Regions Human genes 0.000 description 1
- 108010009817 Immunoglobulin Constant Regions Proteins 0.000 description 1
- 108010054477 Immunoglobulin Fab Fragments Proteins 0.000 description 1
- 102000001706 Immunoglobulin Fab Fragments Human genes 0.000 description 1
- 241000235058 Komagataella pastoris Species 0.000 description 1
- QNAYBMKLOCPYGJ-REOHCLBHSA-N L-alanine Chemical compound C[C@H](N)C(O)=O QNAYBMKLOCPYGJ-REOHCLBHSA-N 0.000 description 1
- CKLJMWTZIZZHCS-REOHCLBHSA-N L-aspartic acid Chemical compound OC(=O)[C@@H](N)CC(O)=O CKLJMWTZIZZHCS-REOHCLBHSA-N 0.000 description 1
- AGPKZVBTJJNPAG-WHFBIAKZSA-N L-isoleucine Chemical compound CC[C@H](C)[C@H](N)C(O)=O AGPKZVBTJJNPAG-WHFBIAKZSA-N 0.000 description 1
- COLNVLDHVKWLRT-QMMMGPOBSA-N L-phenylalanine Chemical compound OC(=O)[C@@H](N)CC1=CC=CC=C1 COLNVLDHVKWLRT-QMMMGPOBSA-N 0.000 description 1
- QIVBCDIJIAJPQS-VIFPVBQESA-N L-tryptophane Chemical compound C1=CC=C2C(C[C@H](N)C(O)=O)=CNC2=C1 QIVBCDIJIAJPQS-VIFPVBQESA-N 0.000 description 1
- OUYCCCASQSFEME-QMMMGPOBSA-N L-tyrosine Chemical compound OC(=O)[C@@H](N)CC1=CC=C(O)C=C1 OUYCCCASQSFEME-QMMMGPOBSA-N 0.000 description 1
- KZSNJWFQEVHDMF-BYPYZUCNSA-N L-valine Chemical compound CC(C)[C@H](N)C(O)=O KZSNJWFQEVHDMF-BYPYZUCNSA-N 0.000 description 1
- GUBGYTABKSRVRQ-QKKXKWKRSA-N Lactose Natural products OC[C@H]1O[C@@H](O[C@H]2[C@H](O)[C@@H](O)C(O)O[C@@H]2CO)[C@H](O)[C@@H](O)[C@H]1O GUBGYTABKSRVRQ-QKKXKWKRSA-N 0.000 description 1
- 241000713666 Lentivirus Species 0.000 description 1
- 239000004472 Lysine Substances 0.000 description 1
- KDXKERNSBIXSRK-UHFFFAOYSA-N Lysine Natural products NCCCCC(N)C(O)=O KDXKERNSBIXSRK-UHFFFAOYSA-N 0.000 description 1
- 241000829100 Macaca mulatta polyomavirus 1 Species 0.000 description 1
- 241000124008 Mammalia Species 0.000 description 1
- PWHULOQIROXLJO-UHFFFAOYSA-N Manganese Chemical compound [Mn] PWHULOQIROXLJO-UHFFFAOYSA-N 0.000 description 1
- 229930195725 Mannitol Natural products 0.000 description 1
- 102000018697 Membrane Proteins Human genes 0.000 description 1
- 108010052285 Membrane Proteins Proteins 0.000 description 1
- 241001529936 Murinae Species 0.000 description 1
- NQTADLQHYWFPDB-UHFFFAOYSA-N N-Hydroxysuccinimide Chemical compound ON1C(=O)CCC1=O NQTADLQHYWFPDB-UHFFFAOYSA-N 0.000 description 1
- OVRNDRQMDRJTHS-FMDGEEDCSA-N N-acetyl-beta-D-glucosamine Chemical compound CC(=O)N[C@H]1[C@H](O)O[C@H](CO)[C@@H](O)[C@@H]1O OVRNDRQMDRJTHS-FMDGEEDCSA-N 0.000 description 1
- 108091005461 Nucleic proteins Proteins 0.000 description 1
- 108091034117 Oligonucleotide Proteins 0.000 description 1
- 241000609499 Palicourea Species 0.000 description 1
- 206010057249 Phagocytosis Diseases 0.000 description 1
- 108010004729 Phycoerythrin Proteins 0.000 description 1
- 206010035226 Plasma cell myeloma Diseases 0.000 description 1
- 206010035500 Plasmodium falciparum infection Diseases 0.000 description 1
- 206010036790 Productive cough Diseases 0.000 description 1
- 239000004365 Protease Substances 0.000 description 1
- 208000004756 Respiratory Insufficiency Diseases 0.000 description 1
- 108091028664 Ribonucleotide Proteins 0.000 description 1
- 108091081021 Sense strand Proteins 0.000 description 1
- 238000012300 Sequence Analysis Methods 0.000 description 1
- MTCFGRXMJLQNBG-UHFFFAOYSA-N Serine Natural products OCC(N)C(O)=O MTCFGRXMJLQNBG-UHFFFAOYSA-N 0.000 description 1
- 229920002472 Starch Polymers 0.000 description 1
- 244000057717 Streptococcus lactis Species 0.000 description 1
- 108091008874 T cell receptors Proteins 0.000 description 1
- 102000016266 T-Cell Antigen Receptors Human genes 0.000 description 1
- 108020005038 Terminator Codon Proteins 0.000 description 1
- 239000004098 Tetracycline Substances 0.000 description 1
- AYFVYJQAPQTCCC-UHFFFAOYSA-N Threonine Natural products CC(O)C(N)C(O)=O AYFVYJQAPQTCCC-UHFFFAOYSA-N 0.000 description 1
- 239000004473 Threonine Substances 0.000 description 1
- 101710120037 Toxin CcdB Proteins 0.000 description 1
- 241000251221 Triakidae Species 0.000 description 1
- QIVBCDIJIAJPQS-UHFFFAOYSA-N Tryptophan Natural products C1=CC=C2C(CC(N)C(O)=O)=CNC2=C1 QIVBCDIJIAJPQS-UHFFFAOYSA-N 0.000 description 1
- 229910052770 Uranium Inorganic materials 0.000 description 1
- KZSNJWFQEVHDMF-UHFFFAOYSA-N Valine Natural products CC(C)C(N)C(O)=O KZSNJWFQEVHDMF-UHFFFAOYSA-N 0.000 description 1
- 241000251539 Vertebrata <Metazoa> Species 0.000 description 1
- SXEHKFHPFVVDIR-UHFFFAOYSA-N [4-(4-hydrazinylphenyl)phenyl]hydrazine Chemical compound C1=CC(NN)=CC=C1C1=CC=C(NN)C=C1 SXEHKFHPFVVDIR-UHFFFAOYSA-N 0.000 description 1
- 230000001133 acceleration Effects 0.000 description 1
- 230000009471 action Effects 0.000 description 1
- 230000004913 activation Effects 0.000 description 1
- 239000013543 active substance Substances 0.000 description 1
- 239000003463 adsorbent Substances 0.000 description 1
- 230000002411 adverse Effects 0.000 description 1
- 235000004279 alanine Nutrition 0.000 description 1
- 101150087698 alpha gene Proteins 0.000 description 1
- 150000001371 alpha-amino acids Chemical class 0.000 description 1
- 235000008206 alpha-amino acids Nutrition 0.000 description 1
- 150000001412 amines Chemical class 0.000 description 1
- 238000012870 ammonium sulfate precipitation Methods 0.000 description 1
- 229960000723 ampicillin Drugs 0.000 description 1
- AVKUERGKIZMTKX-NJBDSQKTSA-N ampicillin Chemical compound C1([C@@H](N)C(=O)N[C@H]2[C@H]3SC([C@@H](N3C2=O)C(O)=O)(C)C)=CC=CC=C1 AVKUERGKIZMTKX-NJBDSQKTSA-N 0.000 description 1
- 230000003042 antagnostic effect Effects 0.000 description 1
- 239000003242 anti bacterial agent Substances 0.000 description 1
- 230000000078 anti-malarial effect Effects 0.000 description 1
- 230000000692 anti-sense effect Effects 0.000 description 1
- 229940088710 antibiotic agent Drugs 0.000 description 1
- 230000009830 antibody antigen interaction Effects 0.000 description 1
- 229940125644 antibody drug Drugs 0.000 description 1
- ODKSFYDXXFIFQN-UHFFFAOYSA-N arginine Natural products OC(=O)C(N)CCCNC(N)=N ODKSFYDXXFIFQN-UHFFFAOYSA-N 0.000 description 1
- 230000011681 asexual reproduction Effects 0.000 description 1
- 238000013465 asexual reproduction Methods 0.000 description 1
- 235000009582 asparagine Nutrition 0.000 description 1
- 229960001230 asparagine Drugs 0.000 description 1
- 125000000613 asparagine group Chemical group N[C@@H](CC(N)=O)C(=O)* 0.000 description 1
- 235000003704 aspartic acid Nutrition 0.000 description 1
- 230000002238 attenuated effect Effects 0.000 description 1
- 238000011888 autopsy Methods 0.000 description 1
- 239000003855 balanced salt solution Substances 0.000 description 1
- WQZGKKKJIJFFOK-VFUOTHLCSA-N beta-D-glucose Chemical compound OC[C@H]1O[C@@H](O)[C@H](O)[C@@H](O)[C@@H]1O WQZGKKKJIJFFOK-VFUOTHLCSA-N 0.000 description 1
- 102000005936 beta-Galactosidase Human genes 0.000 description 1
- 108010005774 beta-Galactosidase Proteins 0.000 description 1
- SQVRNKJHWKZAKO-UHFFFAOYSA-N beta-N-Acetyl-D-neuraminic acid Natural products CC(=O)NC1C(O)CC(O)(C(O)=O)OC1C(O)C(O)CO SQVRNKJHWKZAKO-UHFFFAOYSA-N 0.000 description 1
- OQFSQFPPLPISGP-UHFFFAOYSA-N beta-carboxyaspartic acid Natural products OC(=O)C(N)C(C(O)=O)C(O)=O OQFSQFPPLPISGP-UHFFFAOYSA-N 0.000 description 1
- 230000001588 bifunctional effect Effects 0.000 description 1
- 230000008827 biological function Effects 0.000 description 1
- 230000031018 biological processes and functions Effects 0.000 description 1
- 230000029918 bioluminescence Effects 0.000 description 1
- 238000005415 bioluminescence Methods 0.000 description 1
- 229960000074 biopharmaceutical Drugs 0.000 description 1
- 238000001574 biopsy Methods 0.000 description 1
- 229960002685 biotin Drugs 0.000 description 1
- 235000020958 biotin Nutrition 0.000 description 1
- 239000011616 biotin Substances 0.000 description 1
- 208000000144 blackwater fever Diseases 0.000 description 1
- 210000000601 blood cell Anatomy 0.000 description 1
- 239000010839 body fluid Substances 0.000 description 1
- 229940098773 bovine serum albumin Drugs 0.000 description 1
- 239000007975 buffered saline Substances 0.000 description 1
- 239000006172 buffering agent Substances 0.000 description 1
- ZTQSAGDEMFDKMZ-UHFFFAOYSA-N butyric aldehyde Natural products CCCC=O ZTQSAGDEMFDKMZ-UHFFFAOYSA-N 0.000 description 1
- 239000001110 calcium chloride Substances 0.000 description 1
- 229910001628 calcium chloride Inorganic materials 0.000 description 1
- 235000011148 calcium chloride Nutrition 0.000 description 1
- 239000001506 calcium phosphate Substances 0.000 description 1
- 229910000389 calcium phosphate Inorganic materials 0.000 description 1
- 235000011010 calcium phosphates Nutrition 0.000 description 1
- 238000004364 calculation method Methods 0.000 description 1
- 239000002775 capsule Substances 0.000 description 1
- 239000001768 carboxy methyl cellulose Substances 0.000 description 1
- 235000010948 carboxy methyl cellulose Nutrition 0.000 description 1
- 239000008112 carboxymethyl-cellulose Substances 0.000 description 1
- 230000004663 cell proliferation Effects 0.000 description 1
- 230000003833 cell viability Effects 0.000 description 1
- 230000001413 cellular effect Effects 0.000 description 1
- 210000001175 cerebrospinal fluid Anatomy 0.000 description 1
- 238000012412 chemical coupling Methods 0.000 description 1
- 125000003636 chemical group Chemical group 0.000 description 1
- 239000003638 chemical reducing agent Substances 0.000 description 1
- 230000002759 chromosomal effect Effects 0.000 description 1
- 210000000349 chromosome Anatomy 0.000 description 1
- 238000004440 column chromatography Methods 0.000 description 1
- 238000012875 competitive assay Methods 0.000 description 1
- 230000001268 conjugating effect Effects 0.000 description 1
- 230000021615 conjugation Effects 0.000 description 1
- 239000000356 contaminant Substances 0.000 description 1
- 239000013068 control sample Substances 0.000 description 1
- 238000004132 cross linking Methods 0.000 description 1
- 235000018417 cysteine Nutrition 0.000 description 1
- XUJNEKJLAYXESH-UHFFFAOYSA-N cysteine Natural products SCC(N)C(O)=O XUJNEKJLAYXESH-UHFFFAOYSA-N 0.000 description 1
- 231100000433 cytotoxic Toxicity 0.000 description 1
- 231100000599 cytotoxic agent Toxicity 0.000 description 1
- 230000001472 cytotoxic effect Effects 0.000 description 1
- 239000002619 cytotoxin Substances 0.000 description 1
- 230000003247 decreasing effect Effects 0.000 description 1
- 230000003111 delayed effect Effects 0.000 description 1
- 239000005547 deoxyribonucleotide Substances 0.000 description 1
- 125000002637 deoxyribonucleotide group Chemical group 0.000 description 1
- 239000008121 dextrose Substances 0.000 description 1
- 238000003745 diagnosis Methods 0.000 description 1
- 238000012631 diagnostic technique Methods 0.000 description 1
- 230000003467 diminishing effect Effects 0.000 description 1
- 230000005750 disease progression Effects 0.000 description 1
- ZWIBGKZDAWNIFC-UHFFFAOYSA-N disuccinimidyl suberate Chemical compound O=C1CCC(=O)N1OC(=O)CCCCCCC(=O)ON1C(=O)CCC1=O ZWIBGKZDAWNIFC-UHFFFAOYSA-N 0.000 description 1
- KBQHZAAAGSGFKK-UHFFFAOYSA-N dysprosium atom Chemical compound [Dy] KBQHZAAAGSGFKK-UHFFFAOYSA-N 0.000 description 1
- 238000000295 emission spectrum Methods 0.000 description 1
- 239000003995 emulsifying agent Substances 0.000 description 1
- 239000002158 endotoxin Substances 0.000 description 1
- 238000005516 engineering process Methods 0.000 description 1
- OGPBJKLSAFTDLK-UHFFFAOYSA-N europium atom Chemical compound [Eu] OGPBJKLSAFTDLK-UHFFFAOYSA-N 0.000 description 1
- 230000005284 excitation Effects 0.000 description 1
- 230000007717 exclusion Effects 0.000 description 1
- 238000002474 experimental method Methods 0.000 description 1
- 239000013613 expression plasmid Substances 0.000 description 1
- 230000004720 fertilization Effects 0.000 description 1
- GNBHRKFJIUUOQI-UHFFFAOYSA-N fluorescein Chemical compound O1C(=O)C2=CC=CC=C2C21C1=CC=C(O)C=C1OC1=CC(O)=CC=C21 GNBHRKFJIUUOQI-UHFFFAOYSA-N 0.000 description 1
- MHMNJMPURVTYEJ-UHFFFAOYSA-N fluorescein-5-isothiocyanate Chemical compound O1C(=O)C2=CC(N=C=S)=CC=C2C21C1=CC=C(O)C=C1OC1=CC(O)=CC=C21 MHMNJMPURVTYEJ-UHFFFAOYSA-N 0.000 description 1
- 239000007850 fluorescent dye Substances 0.000 description 1
- 230000004907 flux Effects 0.000 description 1
- 230000005714 functional activity Effects 0.000 description 1
- UIWYJDYFSGRHKR-UHFFFAOYSA-N gadolinium atom Chemical compound [Gd] UIWYJDYFSGRHKR-UHFFFAOYSA-N 0.000 description 1
- 229930182830 galactose Natural products 0.000 description 1
- 101150034785 gamma gene Proteins 0.000 description 1
- 238000010353 genetic engineering Methods 0.000 description 1
- 229940116332 glucose oxidase Drugs 0.000 description 1
- 235000019420 glucose oxidase Nutrition 0.000 description 1
- 235000013922 glutamic acid Nutrition 0.000 description 1
- 239000004220 glutamic acid Substances 0.000 description 1
- 150000004676 glycans Chemical class 0.000 description 1
- PCHJSUWPFVWCPO-UHFFFAOYSA-N gold Chemical compound [Au] PCHJSUWPFVWCPO-UHFFFAOYSA-N 0.000 description 1
- 239000010931 gold Substances 0.000 description 1
- 229910052737 gold Inorganic materials 0.000 description 1
- 210000000087 hemolymph Anatomy 0.000 description 1
- 206010019692 hepatic necrosis Diseases 0.000 description 1
- 230000007866 hepatic necrosis Effects 0.000 description 1
- 238000009396 hybridization Methods 0.000 description 1
- 230000007062 hydrolysis Effects 0.000 description 1
- 238000006460 hydrolysis reaction Methods 0.000 description 1
- WGCNASOHLSPBMP-UHFFFAOYSA-N hydroxyacetaldehyde Natural products OCC=O WGCNASOHLSPBMP-UHFFFAOYSA-N 0.000 description 1
- 229910052588 hydroxylapatite Inorganic materials 0.000 description 1
- 238000005286 illumination Methods 0.000 description 1
- 230000036039 immunity Effects 0.000 description 1
- 230000005847 immunogenicity Effects 0.000 description 1
- 230000016784 immunoglobulin production Effects 0.000 description 1
- 239000003547 immunosorbent Substances 0.000 description 1
- 239000007943 implant Substances 0.000 description 1
- 230000006872 improvement Effects 0.000 description 1
- 238000003017 in situ immunoassay Methods 0.000 description 1
- 238000000099 in vitro assay Methods 0.000 description 1
- 238000005462 in vivo assay Methods 0.000 description 1
- 230000002779 inactivation Effects 0.000 description 1
- 230000001939 inductive effect Effects 0.000 description 1
- 230000002458 infectious effect Effects 0.000 description 1
- 230000010354 integration Effects 0.000 description 1
- 238000001361 intraarterial administration Methods 0.000 description 1
- 230000003834 intracellular effect Effects 0.000 description 1
- 238000007913 intrathecal administration Methods 0.000 description 1
- 150000002500 ions Chemical class 0.000 description 1
- 229960000310 isoleucine Drugs 0.000 description 1
- AGPKZVBTJJNPAG-UHFFFAOYSA-N isoleucine Natural products CCC(C)C(N)C(O)=O AGPKZVBTJJNPAG-UHFFFAOYSA-N 0.000 description 1
- 238000005304 joining Methods 0.000 description 1
- 238000002372 labelling Methods 0.000 description 1
- 239000008101 lactose Substances 0.000 description 1
- 230000002045 lasting effect Effects 0.000 description 1
- 150000002632 lipids Chemical class 0.000 description 1
- 239000007788 liquid Substances 0.000 description 1
- 239000012669 liquid formulation Substances 0.000 description 1
- 231100000053 low toxicity Toxicity 0.000 description 1
- 210000000055 macrogametocyte Anatomy 0.000 description 1
- 229920002521 macromolecule Polymers 0.000 description 1
- 210000002540 macrophage Anatomy 0.000 description 1
- 235000019359 magnesium stearate Nutrition 0.000 description 1
- 229910052748 manganese Inorganic materials 0.000 description 1
- 239000011572 manganese Substances 0.000 description 1
- 239000000594 mannitol Substances 0.000 description 1
- 235000010355 mannitol Nutrition 0.000 description 1
- 239000011159 matrix material Substances 0.000 description 1
- 238000001840 matrix-assisted laser desorption--ionisation time-of-flight mass spectrometry Methods 0.000 description 1
- 229910052751 metal Inorganic materials 0.000 description 1
- 239000002184 metal Substances 0.000 description 1
- 210000000052 microgametocyte Anatomy 0.000 description 1
- 231100000324 minimal toxicity Toxicity 0.000 description 1
- 239000003607 modifier Substances 0.000 description 1
- 238000001823 molecular biology technique Methods 0.000 description 1
- 238000007837 multiplex assay Methods 0.000 description 1
- 210000003205 muscle Anatomy 0.000 description 1
- 238000002703 mutagenesis Methods 0.000 description 1
- 231100000350 mutagenesis Toxicity 0.000 description 1
- 201000000050 myeloid neoplasm Diseases 0.000 description 1
- 230000002107 myocardial effect Effects 0.000 description 1
- 229950006780 n-acetylglucosamine Drugs 0.000 description 1
- 230000037125 natural defense Effects 0.000 description 1
- 230000007935 neutral effect Effects 0.000 description 1
- 238000006386 neutralization reaction Methods 0.000 description 1
- 230000003287 optical effect Effects 0.000 description 1
- 238000005457 optimization Methods 0.000 description 1
- 210000000056 organ Anatomy 0.000 description 1
- 230000008520 organization Effects 0.000 description 1
- 239000003002 pH adjusting agent Substances 0.000 description 1
- 239000006179 pH buffering agent Substances 0.000 description 1
- 229940055729 papain Drugs 0.000 description 1
- 235000019834 papain Nutrition 0.000 description 1
- 239000012188 paraffin wax Substances 0.000 description 1
- 230000008506 pathogenesis Effects 0.000 description 1
- 230000007170 pathology Effects 0.000 description 1
- XYJRXVWERLGGKC-UHFFFAOYSA-D pentacalcium;hydroxide;triphosphate Chemical compound [OH-].[Ca+2].[Ca+2].[Ca+2].[Ca+2].[Ca+2].[O-]P([O-])([O-])=O.[O-]P([O-])([O-])=O.[O-]P([O-])([O-])=O XYJRXVWERLGGKC-UHFFFAOYSA-D 0.000 description 1
- 238000012510 peptide mapping method Methods 0.000 description 1
- 238000010647 peptide synthesis reaction Methods 0.000 description 1
- 230000008782 phagocytosis Effects 0.000 description 1
- 239000012071 phase Substances 0.000 description 1
- COLNVLDHVKWLRT-UHFFFAOYSA-N phenylalanine Natural products OC(=O)C(N)CC1=CC=CC=C1 COLNVLDHVKWLRT-UHFFFAOYSA-N 0.000 description 1
- 239000002504 physiological saline solution Substances 0.000 description 1
- 239000013600 plasmid vector Substances 0.000 description 1
- 210000004180 plasmocyte Anatomy 0.000 description 1
- 229920000191 poly(N-vinyl pyrrolidone) Polymers 0.000 description 1
- 229920001308 poly(aminoacid) Polymers 0.000 description 1
- 229920001583 poly(oxyethylated polyols) Polymers 0.000 description 1
- 230000008488 polyadenylation Effects 0.000 description 1
- 229920002704 polyhistidine Polymers 0.000 description 1
- 238000006116 polymerization reaction Methods 0.000 description 1
- 229920001282 polysaccharide Polymers 0.000 description 1
- 239000005017 polysaccharide Substances 0.000 description 1
- 229920000036 polyvinylpyrrolidone Polymers 0.000 description 1
- 239000001267 polyvinylpyrrolidone Substances 0.000 description 1
- 235000013855 polyvinylpyrrolidone Nutrition 0.000 description 1
- 230000001323 posttranslational effect Effects 0.000 description 1
- 239000001103 potassium chloride Substances 0.000 description 1
- 235000011164 potassium chloride Nutrition 0.000 description 1
- 239000000843 powder Substances 0.000 description 1
- 230000003449 preventive effect Effects 0.000 description 1
- 238000004393 prognosis Methods 0.000 description 1
- 230000000644 propagated effect Effects 0.000 description 1
- 238000000159 protein binding assay Methods 0.000 description 1
- 230000002797 proteolythic effect Effects 0.000 description 1
- 238000010791 quenching Methods 0.000 description 1
- 230000000171 quenching effect Effects 0.000 description 1
- 230000005855 radiation Effects 0.000 description 1
- 239000012857 radioactive material Substances 0.000 description 1
- 230000003439 radiotherapeutic effect Effects 0.000 description 1
- 229920005604 random copolymer Polymers 0.000 description 1
- 230000035484 reaction time Effects 0.000 description 1
- 230000010837 receptor-mediated endocytosis Effects 0.000 description 1
- 102000005962 receptors Human genes 0.000 description 1
- 108020003175 receptors Proteins 0.000 description 1
- 238000003259 recombinant expression Methods 0.000 description 1
- 238000010188 recombinant method Methods 0.000 description 1
- 230000006798 recombination Effects 0.000 description 1
- 238000005215 recombination Methods 0.000 description 1
- 230000001105 regulatory effect Effects 0.000 description 1
- 238000011160 research Methods 0.000 description 1
- 201000004193 respiratory failure Diseases 0.000 description 1
- 230000000452 restraining effect Effects 0.000 description 1
- 230000000717 retained effect Effects 0.000 description 1
- 238000012552 review Methods 0.000 description 1
- PYWVYCXTNDRMGF-UHFFFAOYSA-N rhodamine B Chemical compound [Cl-].C=12C=CC(=[N+](CC)CC)C=C2OC2=CC(N(CC)CC)=CC=C2C=1C1=CC=CC=C1C(O)=O PYWVYCXTNDRMGF-UHFFFAOYSA-N 0.000 description 1
- 239000002336 ribonucleotide Substances 0.000 description 1
- 125000002652 ribonucleotide group Chemical group 0.000 description 1
- 210000003705 ribosome Anatomy 0.000 description 1
- 229960004641 rituximab Drugs 0.000 description 1
- 210000003296 saliva Anatomy 0.000 description 1
- 238000012216 screening Methods 0.000 description 1
- 230000003248 secreting effect Effects 0.000 description 1
- 238000000926 separation method Methods 0.000 description 1
- 238000002864 sequence alignment Methods 0.000 description 1
- 238000012163 sequencing technique Methods 0.000 description 1
- 230000036301 sexual development Effects 0.000 description 1
- SQVRNKJHWKZAKO-OQPLDHBCSA-N sialic acid Chemical compound CC(=O)N[C@@H]1[C@@H](O)C[C@@](O)(C(O)=O)OC1[C@H](O)[C@H](O)CO SQVRNKJHWKZAKO-OQPLDHBCSA-N 0.000 description 1
- 150000003384 small molecules Chemical class 0.000 description 1
- 229910000029 sodium carbonate Inorganic materials 0.000 description 1
- 239000001540 sodium lactate Substances 0.000 description 1
- 235000011088 sodium lactate Nutrition 0.000 description 1
- 229940005581 sodium lactate Drugs 0.000 description 1
- 239000008247 solid mixture Substances 0.000 description 1
- 239000007790 solid phase Substances 0.000 description 1
- 239000002904 solvent Substances 0.000 description 1
- 230000037439 somatic mutation Effects 0.000 description 1
- 229940035044 sorbitan monolaurate Drugs 0.000 description 1
- 125000006850 spacer group Chemical group 0.000 description 1
- 210000003802 sputum Anatomy 0.000 description 1
- 208000024794 sputum Diseases 0.000 description 1
- 230000000087 stabilizing effect Effects 0.000 description 1
- 238000012289 standard assay Methods 0.000 description 1
- 239000008107 starch Substances 0.000 description 1
- 235000019698 starch Nutrition 0.000 description 1
- 239000008174 sterile solution Substances 0.000 description 1
- 239000008223 sterile water Substances 0.000 description 1
- 235000000346 sugar Nutrition 0.000 description 1
- PXQLVRUNWNTZOS-UHFFFAOYSA-N sulfanyl Chemical compound [SH] PXQLVRUNWNTZOS-UHFFFAOYSA-N 0.000 description 1
- 230000003319 supportive effect Effects 0.000 description 1
- 239000004094 surface-active agent Substances 0.000 description 1
- 230000004083 survival effect Effects 0.000 description 1
- 238000007910 systemic administration Methods 0.000 description 1
- 239000003826 tablet Substances 0.000 description 1
- 229960002180 tetracycline Drugs 0.000 description 1
- 229930101283 tetracycline Natural products 0.000 description 1
- 235000019364 tetracycline Nutrition 0.000 description 1
- 150000003522 tetracyclines Chemical class 0.000 description 1
- 230000001225 therapeutic effect Effects 0.000 description 1
- 238000002560 therapeutic procedure Methods 0.000 description 1
- 150000003573 thiols Chemical class 0.000 description 1
- 238000004448 titration Methods 0.000 description 1
- 238000003325 tomography Methods 0.000 description 1
- 230000000699 topical effect Effects 0.000 description 1
- 230000001988 toxicity Effects 0.000 description 1
- 231100000419 toxicity Toxicity 0.000 description 1
- 230000005030 transcription termination Effects 0.000 description 1
- 230000002103 transcriptional effect Effects 0.000 description 1
- 238000001890 transfection Methods 0.000 description 1
- 230000014621 translational initiation Effects 0.000 description 1
- 230000032258 transport Effects 0.000 description 1
- QORWJWZARLRLPR-UHFFFAOYSA-H tricalcium bis(phosphate) Chemical compound [Ca+2].[Ca+2].[Ca+2].[O-]P([O-])([O-])=O.[O-]P([O-])([O-])=O QORWJWZARLRLPR-UHFFFAOYSA-H 0.000 description 1
- 239000013638 trimer Substances 0.000 description 1
- 210000003812 trophozoite Anatomy 0.000 description 1
- OUYCCCASQSFEME-UHFFFAOYSA-N tyrosine Natural products OC(=O)C(N)CC1=CC=C(O)C=C1 OUYCCCASQSFEME-UHFFFAOYSA-N 0.000 description 1
- 231100000402 unacceptable toxicity Toxicity 0.000 description 1
- 241000701161 unidentified adenovirus Species 0.000 description 1
- 241001430294 unidentified retrovirus Species 0.000 description 1
- 238000011144 upstream manufacturing Methods 0.000 description 1
- 210000002700 urine Anatomy 0.000 description 1
- 229940124856 vaccine component Drugs 0.000 description 1
- 239000004474 valine Substances 0.000 description 1
- 239000003981 vehicle Substances 0.000 description 1
- 210000003462 vein Anatomy 0.000 description 1
- 108700026220 vif Genes Proteins 0.000 description 1
- 230000036642 wellbeing Effects 0.000 description 1
- 238000009736 wetting Methods 0.000 description 1
- 239000000080 wetting agent Substances 0.000 description 1
Classifications
-
- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07K—PEPTIDES
- C07K16/00—Immunoglobulins [IGs], e.g. monoclonal or polyclonal antibodies
- C07K16/18—Immunoglobulins [IGs], e.g. monoclonal or polyclonal antibodies against material from animals or humans
- C07K16/20—Immunoglobulins [IGs], e.g. monoclonal or polyclonal antibodies against material from animals or humans from protozoa
- C07K16/205—Plasmodium
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
- A61P33/00—Antiparasitic agents
- A61P33/02—Antiprotozoals, e.g. for leishmaniasis, trichomoniasis, toxoplasmosis
- A61P33/06—Antimalarials
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
- A61K39/00—Medicinal preparations containing antigens or antibodies
- A61K2039/505—Medicinal preparations containing antigens or antibodies comprising antibodies
-
- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07K—PEPTIDES
- C07K2317/00—Immunoglobulins specific features
- C07K2317/20—Immunoglobulins specific features characterized by taxonomic origin
- C07K2317/21—Immunoglobulins specific features characterized by taxonomic origin from primates, e.g. man
-
- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07K—PEPTIDES
- C07K2317/00—Immunoglobulins specific features
- C07K2317/30—Immunoglobulins specific features characterized by aspects of specificity or valency
- C07K2317/33—Crossreactivity, e.g. for species or epitope, or lack of said crossreactivity
-
- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07K—PEPTIDES
- C07K2317/00—Immunoglobulins specific features
- C07K2317/30—Immunoglobulins specific features characterized by aspects of specificity or valency
- C07K2317/34—Identification of a linear epitope shorter than 20 amino acid residues or of a conformational epitope defined by amino acid residues
Definitions
- Plasmodium species that infect humans is transmitted through the bite of an infected female Anopheles mosquito, which introduces Plasmodium sporozoites into the bloodstream of the human host.
- the major protein on the surface of the infecting P. falciparum sporozoites is the circumsporozoite protein (PfCSP) and provides a major target for antibodies and vaccines.
- the sporozoites rapidly reach the liver where they are sequestered by hepatocytes and undergo asexual expansion. One week later, the infected hepatocytes rupture and release mature parasites, the merozoites. These then begin the erythrocytic phase of malaria by attaching to and invading red blood cells, or erythrocytes.
- a monoclonal antibody comprises a heavy chain variable region (V H ) and a light chain variable region (V L ) comprising a heavy chain complementarity determining region (HCDR)1, a HCDR2, and a HCDR3, and a light chain complementarity determining region (LCDR)1, a LCDR2, and a LCDR3 of the VH and VL set forth as SEQ ID NOs: 1 and 2, respectively (MAD21-17), SEQ ID NOs: 3 and 4, respectively (MAD21-46), SEQ ID NOs: 5 and 6, respectively (MAD21-53), SEQ ID NOs: 7 and 8, respectively (MAD21-95), SEQ ID NOs: 9 and 10, respectively (MAD21-101), SEQ ID NOs: 11 and 12, respectively (MAD22-17), SEQ ID NOs: 13 and 14, respectively (MAD22-38), SEQ ID NOs: 15 and 16, respectively (MAD22-39), SEQ ID NOs: 17 and 18, respectively (MAD24-01),
- the monoclonal antibody specifically binds to PfCSP and neutralizes P. falciparum.
- compositions including the antibodies and antigen binding fragments, nucleic acids encoding the antibodies and antigen binding fragments, expression vectors comprising the nucleic acids, and isolated host cells that comprise the nucleic acids.
- the nucleic acid molecule encoding a disclosed antibody or antigen binding fragment can be a cDNA or RNA molecule that encodes the antibody or antigen binding fragment.
- the nucleic acid molecule can be a bicistronic expression construct encoding the VH and VL of the antibody or antigen binding fragment.
- the disclosed antibodies and antigen binding fragments potently neutralize PfCSP expressed on infectious sporozoites in vivo. Accordingly, a method is disclosed for inhibiting (including preventing) P. falciparum infection in a subject.
- the method comprises administering an effective amount (that is, an amount effective to inhibit P. falciparum infection in a subject) of one or more of the disclosed antibodies, antigen binding fragments, nucleic acid molecules, vectors, or compositions, to the subject, such as a subject at risk of or having a P. falciparum infection.
- the antibodies, antigen binding fragments, nucleic acid molecules, vectors, and compositions disclosed herein can be used for a variety of additional purposes, such as for diagnosing P.
- FIG.1 Selected vaccinees show high IgG reactivity to sporozoites after blocking plasma with recombinant PfCSP.
- the data represents polyclonal IgG binding to whole P. falciparum sporozoites after incubation of each plasma sample with recombinant PfCSP.
- FIGs.2A-2B mAbs bind to sporozoites that express Pf CSP. Titration curves of mAb binding to wild-type P.
- FIG.3 Disclosed mAbs recognize an ⁇ 60kDa sporozoite expressed protein. Western blot of P. falciparum sporozoite lysate probed with representative isolated mAbs MAD21-46, MAD22-38 and MAD21-101 as well as known PfCSP mAbs CIS43 and mAb10. The HIV-1 mAb VRC01 was used as a negative control.
- FIGs.4A-4I Disclosed mAbs do not bind canonical PfCSP epitopes.
- FIG.5 PfCSP peptide scanning analysis. ELISA analysis of disclosed mAbs binding to a panel of 15-mer overlapping peptides that span the length of PfCSP.
- FIG.6 Disclosed mAbs do not bind recombinant forms of PfCSP.
- FIG.8A-8B The identified mAbs recognize an epitope within the Pf-CSP junctional region and do not show cross-reactivity to the major repeat (NANP) sequences.
- NANP major repeat
- FIG.8A shows the sequences of the PbPfCSP (partial), Pb-PfCSP JRKO (partial), Pb CSP Pf-NANP 12 (partial) and Pb CSP Pf-NANP 4- 5’ (partial) amino acid sequences.
- SEQ ID NOs: 32, 161, 162 and 163 are shown.
- FIG.8B shows results from enzyme linked immunosorbent (ELISA) assays. The findings suggest that the mAb epitope lies within the junction region and that the disclosed mAbs do not cross react with Pf- NANP repeats.
- FIGS.9A-9B The disclosed mAbs recognize a proteolytically processed form of Pf-CSP.
- Binding of the disclosed mAbs to the antigen conjugated beads was measured by flow cytometry in a multiplexed bead-based assay. All mAbs bound to the peptide bearing an N-terminal glutamine which represents the proposed PfCSP N-terminus post-cleavage, and binding was increased towards the peptide bearing an N-terminal pyroglutamic acid. The results evidence that the mAbs target a novel epitope on PfCSP which is dependent upon sporozoite-mediated cleavage and pyroglutamic acid modification of PfCSP. SEQ ID NOs: 164 and 165 are shown.
- SEQ ID NO: 1 is the amino acid sequence of the MAD21-17 VH.
- SEQ ID NO: 2 is the amino acid sequence of the MAD21-17 V L .
- SEQ ID NO: 3 is the amino acid sequence of the MAD21-46 VH.
- SEQ ID NO: 4 is the amino acid sequence of the MAD21-46 VL.
- SEQ ID NO: 5 is the amino acid sequence of the MAD21-53 V H .
- SEQ ID NO: 6 is the amino acid sequence of the MAD21-53 V L .
- SEQ ID NO: 7 is the amino acid sequence of the MAD21-95 V H .
- SEQ ID NO: 8 is the amino acid sequence of the MAD21-95 VL.
- SEQ ID NO: 9 is the amino acid sequence of the MAD21-101 VH.
- SEQ ID NO: 10 is the amino acid sequence of the MAD21-101 VL.
- SEQ ID NO: 11 is the amino acid sequence of the MAD22-17 V H .
- SEQ ID NO: 12 is the amino acid sequence of the MAD22-17 VL.
- SEQ ID NO: 13 is the amino acid sequence of the MAD22-38 VH.
- SEQ ID NO: 14 is the amino acid sequence of the MAD22-38 V L .
- SEQ ID NO: 15 is the amino acid sequence of the MAD22-39 VH.
- SEQ ID NO: 16 is the amino acid sequence of the MAD22-39 V L .
- SEQ ID NO: 17 is the amino acid sequence of the MAD24-01 VH.
- SEQ ID NO: 18 is the amino acid sequence of the MAD24-01 VL.
- SEQ ID NO: 19 is the amino acid sequence of the MAD24-05 V H .
- SEQ ID NO: 20 is the amino acid sequence of the MAD24-05 VL.
- SEQ ID NO: 21 is the amino acid sequence of the MAD24-52 V H .
- SEQ ID NO: 22 is the amino acid sequence of the MAD24-52 V L .
- DIVMTQTPLSSPVTLGQPASISCRSSQSLVHSDGNTYLSWLQQRPGQPPRLLIYKISNRFSGVPDRFSGSGA GTDFTLKISRVEAEDVGVYYCMQATQFPLTFGGGTKVEIK SEQ ID NOs: 23-31 are CDR sequences.
- SEQ ID NO: 32 is a transgenic Plasmodium berghei sporozoite amino acid sequence.
- SEQ ID NOs: 33-67 are CDR sequences.
- SEQ ID NO: 68 is the amino acid sequence of the CIS43 VH.
- SEQ ID NO: 69 is the amino acid sequence of the CIS43 V L .
- SEQ ID NO: 70 is the amino acid sequence of the L9 V H .
- SEQ ID NO: 71 is the amino acid sequence of the L9 VL.
- SEQ ID NO: 72 is an exemplary amino acid sequence for PfCSP (GenBank Acc. No.
- SEQ ID NO: 73 is an exemplary nucleic acid sequence encoding MAD21
- gacatccagatgacccagtctccatcctccctgtctgcatctgtaggagacagagtcaccatcacttgccgggcaaatca cagcattagcagctatttaaattggtatcagcagaaaccagggaaagcccctaagctcctgatctatgctgcatccagtt tgcaaagtggggtcccatcaaggttcagtggcagtggatctgggacagatttcactctcaccatcagcagtctgcaacct gaagattttgcaacttactactgtcaacagagttactataccccatggactttcggccctgggaccaaagtggatatcaa ac SEQ ID NO: 87 is an exemplary nucleic acid sequence encoding MAD22-39 V H .
- gacatccagatgacccagtctccatcctccctgtctgcatctgtaggagacagagtcaccatcacttgccgggcaagtca gagcattatcagctatttaaattggtatcagcagaaaccagggcaagcccctaagctcctgatctatgctgcatccagtt tgcaaagtgggatcccatcaaggttcagtggcagtggatctgggacagatttcactctcaccatcagcagtctgcaacct gaagattttgcaacttactactgtcaacagagttactataccccgtggacgttcggccaagggaccaaggtggaaatcaac SEQ ID NO: 89 is an exemplary nucleic acid sequence encoding MAD24-01 V H .
- Gatattgtgatgacccagactccactctcctcacctgtcacccttggacagccggcctccatctcctgcaggtctagtca aagcctcgtacacagtgatggaaacacctacttgagttggcttcagcagaggccaggccagcctccaagactcctaattt ataagatttctaaccggttctctggggtcccagacagattcagtggggggcagggacagatttcacactgaaaatc agggtggaagctgaggatgtcggggtttattactgcatgcaagctacacaatttcctctcactttcggcggagggac caaggtggagatcaaac SEQ ID NOs: 95-156 are PfCSP peptide sequences
- SEQ ID NO: 157 is the amino acid sequence for the full length heavy chain of MAD21-101.
- SEQ ID NO: 159 is the amino acid sequence of the 317 VH.
- SEQ ID NO: 160 is the amino acid sequence for 317 V L .
- SEQ ID NOs: 161-163 are transgenic Plasmodium berghei sporozoites amino acid sequences.
- SEQ ID Nos: 164-165 are P. falciparum CSP peptide sequences.
- SEQ ID NO: 166 is the amino acid sequence of the 5D5 V H .
- SEQ ID NO: 167 is the amino acid sequence of the 5D5 V L .
- EDLAVYFCQQDYSSPFTFGSGTKLEIK SEQ ID NO: 168 is the amino acid sequence of the mAb10 VH.
- SEQ ID NO: 169 is the amino acid sequence of the mAb10 VL.
- an antigen includes singular or plural antigens and can be considered equivalent to the phrase “at least one antigen.”
- the term “comprises” means “includes.” It is further to be understood that any and all base sizes or amino acid sizes, and all molecular weight or molecular mass values, given for nucleic acids or polypeptides are approximate, and are provided for descriptive purposes, unless otherwise indicated. Although many methods and materials similar or equivalent to those described herein can be used, particular suitable methods and materials are described herein. In case of conflict, the present specification, including explanations of terms, will control.
- 317 Antibody A monoclonal antibody that specifically binds to an epitope on PfCSP and neutralizes malaria infection.
- the CIS317 antibody and methods for its production are described, for example, in Oyen et al. (“Structural basis for antibody recognition of the NANP repeats in Plasmodium falciparum circumsporozoite protein,” Proc Natl Acad Sci USA, 114, E10438-E10445, 2017).
- the amino acid sequences of the heavy and light variable regions of the CIS317 antibody are provided herein as SEQ ID NOs: 159 and 160.
- Administration The introduction of a composition into a subject by a chosen route. Administration can be local or systemic. For example, if the chosen route is intravenous, the composition is administered by introducing the composition into a vein of the subject. Exemplary routes of administration include, but are not limited to, oral, injection (such as subcutaneous, intramuscular, intradermal, intraperitoneal, and intravenous), sublingual, rectal, transdermal (for example, topical), intranasal, vaginal, and inhalation routes.
- Antibody and Antigen Binding Fragment An immunoglobulin, antigen-binding fragment, or derivative thereof, that specifically binds and recognizes an analyte (antigen) such as PfCSP.
- antibody is used herein in the broadest sense and encompasses various antibody structures, including but not limited to monoclonal antibodies, polyclonal antibodies, multispecific antibodies (e.g., bispecific antibodies), and antigen binding fragments, so long as they exhibit the desired antigen-binding activity.
- Non-limiting examples of antibodies include, for example, intact immunoglobulins and variants and fragments thereof that retain binding affinity for the antigen.
- antigen binding fragments include but are not limited to Fv, Fab, Fab', Fab'-SH, F(ab')2; diabodies; linear antibodies; single-chain antibody molecules (e.g. scFv); and multispecific antibodies formed from antibody fragments.
- Antibody fragments include antigen binding fragments either produced by the modification of whole antibodies or those synthesized de novo using recombinant DNA methodologies (see, e.g., Kontermann and Dübel (Eds.), Antibody Engineering, Vols.1-2, 2 nd ed., Springer-Verlag, 2010).
- Antibodies also include genetically engineered forms such as chimeric antibodies (such as humanized murine antibodies) and heteroconjugate antibodies (such as bispecific antibodies).
- An antibody may have one or more binding sites. If there is more than one binding site, the binding sites may be identical to one another or may be different. For instance, a naturally-occurring immunoglobulin has two identical binding sites, a single-chain antibody or Fab fragment has one binding site, while a bispecific or bifunctional antibody has two different binding sites. Typically, a naturally occurring immunoglobulin has heavy (H) chains and light (L) chains interconnected by disulfide bonds. Immunoglobulin genes include the kappa, lambda, alpha, gamma, delta, epsilon and mu constant region genes, as well as the myriad immunoglobulin variable domain genes. There are two types of light chain, lambda ( ⁇ ) and kappa ( ⁇ ).
- Each heavy and light chain contains a constant region (or constant domain) and a variable region (or variable domain).
- the heavy and the light chain variable regions specifically bind the antigen.
- References to “VH” or “VH” refer to the variable region of an antibody heavy chain, including that of an antigen binding fragment, such as Fv, scFv, dsFv or Fab.
- References to “VL” or “VL” refer to the variable domain of an antibody light chain, including that of an Fv, scFv, dsFv or Fab.
- the V H and V L contain a “framework” region interrupted by three hypervariable regions, also called “complementarity-determining regions” or “CDRs” (see, e.g., Kabat et al., Sequences of Proteins of Immunological Interest, 5 th ed., NIH Publication No.91-3242, Public Health Service, National Institutes of Health, U.S. Department of Health and Human Services, 1991).
- CDRs complementarity-determining regions
- amino acid sequence boundaries of a given CDR can be readily determined using any of a number of well-known schemes, including those described by Kabat et al. (Sequences of Proteins of Immunological Interest, 5 th ed., NIH Publication No.91-3242, Public Health Service, National Institutes of Health, U.S. Department of Health and Human Services, 1991; “Kabat” numbering scheme), Al-Lazikani et al., (“Standard conformations for the canonical structures of immunoglobulins,” J. Mol. Bio., 273(4):927-948, 1997; “Chothia” numbering scheme), and Lefranc et al.
- IMGT unique numbering for immunoglobulin and T cell receptor variable domains and Ig superfamily V-like domains Dev. Comp. Immunol., 27(1):55-77, 2003; “IMGT” numbering scheme).
- the CDRs of each chain are typically referred to as CDR1, CDR2, and CDR3 (from the N-terminus to C-terminus), and are also typically identified by the chain in which the particular CDR is located.
- a V H CDR3 is the CDR3 from the V H of the antibody in which it is found
- a V L CDR1 is the CDR1 from the V L of the antibody in which it is found.
- Light chain CDRs are sometimes referred to as LCDR1, LCDR2, and LCDR3.
- Heavy chain CDRs are sometimes referred to as HCDR1, HCDR2, and HCDR3.
- a disclosed antibody includes a heterologous constant domain.
- the antibody includes a constant domain that is different from a native constant domain, such as a constant domain including one or more modifications (such as the “LS” mutations) to increase half-life.
- a “monoclonal antibody” is an antibody obtained from a population of substantially homogeneous antibodies, that is, the individual antibodies comprising the population are identical and/or bind the same epitope, except for possible variant antibodies, for example, containing naturally occurring mutations or arising during production of a monoclonal antibody preparation, such variants generally being present in minor amounts.
- each monoclonal antibody of a monoclonal antibody preparation is directed against a single determinant on an antigen.
- the modifier “monoclonal” indicates the character of the antibody as being obtained from a substantially homogeneous population of antibodies, and is not to be construed as requiring production of the antibody by any particular method.
- the monoclonal antibodies may be made by a variety of techniques, including but not limited to the hybridoma method, recombinant DNA methods, phage-display methods, and methods utilizing transgenic animals containing all or part of the human immunoglobulin loci, such methods and other exemplary methods for making monoclonal antibodies being described herein.
- monoclonal antibodies are isolated from a subject.
- Monoclonal antibodies can have conservative amino acid substitutions which have substantially no effect on antigen binding or other immunoglobulin functions. (See, for example, Greenfield (Ed.), Antibodies: A Laboratory Manual, 2 nd ed.
- a “humanized” antibody or antigen binding fragment includes a human framework region and one or more CDRs from a non-human (such as a mouse, rat, or synthetic) antibody or antigen binding fragment.
- the non-human antibody or antigen binding fragment providing the CDRs is termed a “donor,” and the human antibody or antigen binding fragment providing the framework is termed an “acceptor.”
- all the CDRs are from the donor immunoglobulin in a humanized immunoglobulin. Constant regions need not be present, but if they are, they can be substantially identical to human immunoglobulin constant regions, such as at least about 85-90%, such as about 95% or more identical.
- a “chimeric antibody” is an antibody which includes sequences derived from two different antibodies, which typically are of different species.
- a chimeric antibody includes one or more CDRs and/or framework regions from one human antibody and CDRs and/or framework regions from another human antibody.
- a “fully human antibody” or “human antibody” is an antibody which includes sequences from (or derived from) the human genome, and does not include sequence from another species.
- a human antibody includes CDRs, framework regions, and (if present) an Fc region from (or derived from) the human genome.
- Human antibodies can be identified and isolated using technologies for creating antibodies based on sequences derived from the human genome, for example by phage display or using transgenic animals (see, e.g., Barbas et al. Phage display: A Laboratory Manuel. 1 st Ed. New York: Cold Spring Harbor Laboratory Press, 2004. Print.; Lonberg, Nat. Biotech., 23: 1117-1125, 2005; Lonenberg, Curr. Opin. Immunol., 20:450-459, 2008).
- Antibody or antigen binding fragment that neutralizes P. falciparum An antibody or antigen binding fragment that specifically binds to a P. falciparum antigen (such as PfCSP) in such a way as to inhibit a biological function associated with P.
- PfCSP PfCSP
- an antibody or antigen binding fragment that neutralizes P. falciparum may interfere with the pathogen by binding it in the skin and limiting entry into the blood or entry into the hepatocytes in the liver by interfering with the interaction of the pathogen and one or more cell surface receptors.
- an antibody may interfere with one or more post-attachment interactions of the pathogen with its receptors, for example, by interfering with pathogen internalization by receptor-mediated endocytosis.
- falciparum inhibits sporozoite invasion of hepatocytes, for example, by at least 50% (such as at least 60%, at least 70%, at least 80%, at least 90%, or more) compared to a control antibody or antigen binding fragment.
- an antibody or antigen binding fragment that specifically binds to PfCSP and neutralizes P. falciparum inhibits infection of a human subject by P. falciparum, for example, by at least 50% compared to a control antibody or antigen binding fragment.
- Biological sample A sample obtained from a subject. Biological samples include all clinical samples useful for detection of disease or infection (for example, P.
- Bispecific antibody A recombinant molecule composed of two different antigen binding domains that consequently binds to two different antigenic epitopes.
- Bispecific antibodies include chemically or genetically linked molecules of two antigen-binding domains. The antigen binding domains can be linked using a linker.
- the antigen binding domains can be monoclonal antibodies, antigen-binding fragments (e.g., Fab, scFv), or combinations thereof.
- a bispecific antibody can include one or more constant domains, but does not necessarily include a constant domain.
- Circumsporozoite protein (CSP) The circumsporozoite protein (CSP) is a major malaria parasite surface protein during the sporogonic cycle. PfCSP covers the surface of P. falciparum sporozoites, which are transmitted from the mosquito salivary gland to host hepatocytes.
- An exemplary PfCSP amino acid sequence is provided as SEQ ID NO: 72.
- CIS43 Antibody A monoclonal antibody that specifically binds to an epitope on PfCSP and neutralizes malaria infection.
- the CIS43 antibody and methods for its production are described, for example, in PCT Pub. No. WO 2018/148660.
- the amino acid sequences of the heavy and light variable regions of the CIS43 antibody are provided herein as SEQ ID NOs: 68 and 69.
- Conditions sufficient to form an immune complex Conditions which allow an antibody or antigen binding fragment to bind to its cognate epitope to a detectably greater degree than, and/or to the substantial exclusion of, binding to substantially all other epitopes. Conditions sufficient to form an immune complex are dependent upon the format of the binding reaction and typically are those utilized in immunoassay protocols or those conditions encountered in vivo.
- the conditions employed in the methods are “physiological conditions” which include reference to conditions (e.g., temperature, osmolarity, pH) that are typical inside a living mammal or a mammalian cell. While it is recognized that some organs are subject to extreme conditions, the intra-organismal and intracellular environment normally lies around pH 7 (e.g., from pH 6.0 to pH 8.0, more typically pH 6.5 to 7.5), contains water as the predominant solvent, and exists at a temperature above 0°C and below 50°C.
- physiological conditions e.g., temperature, osmolarity, pH
- Osmolarity is within the range that is supportive of cell viability and proliferation.
- the formation of an immune complex can be detected through conventional methods, for instance immunohistochemistry (IHC), immunoprecipitation (IP), flow cytometry, immunofluorescence microscopy, ELISA, immunoblotting (for example, Western blot), magnetic resonance imaging (MRI), computed tomography (CT) scans, radiography, and affinity chromatography.
- Conjugate A complex of two molecules linked together, for example, linked together by a covalent bond.
- an antibody is linked to an effector molecule; for example, an antibody that specifically binds to CSP from P. falciparum covalently linked to an effector molecule.
- the linkage can be by chemical or recombinant means.
- the linkage is chemical, wherein a reaction between the antibody moiety and the effector molecule has produced a covalent bond formed between the two molecules to form one molecule.
- a peptide linker (short peptide sequence) can optionally be included between the antibody and the effector molecule. Because conjugates can be prepared from two molecules with separate functionalities, such as an antibody and an effector molecule, they are also sometimes referred to as “chimeric molecules.” Conservative variants: “Conservative” amino acid substitutions are those substitutions that do not substantially affect or decrease a function of a protein, such as the ability of the protein to interact with a target protein.
- a PfCSP-specific antibody can include up to 1, 2, 3, 4, 5, 6, 7, 8, 9, or up to 10 conservative substitutions compared to a reference antibody sequence and retain specific binding activity for PfCSP, and/or P. falciparum neutralization activity.
- the term conservative variation also includes the use of a substituted amino acid in place of an unsubstituted parent amino acid. Individual substitutions, deletions or additions which alter, add or delete a single amino acid or a small percentage of amino acids (for instance less than 5%, in some aspects less than 1%) in an encoded sequence are conservative variations where the alterations result in the substitution of an amino acid with a chemically similar amino acid.
- Non-conservative substitutions are those that reduce an activity or function of the PfCSP specific antibody, such as the ability to specifically bind to PfCSP or neutralize P. falciparum.
- Placement in direct physical association includes both in solid and liquid form, which can take place either in vivo or in vitro.
- Contacting includes contact between one molecule and another molecule, for example the amino acid on the surface of one polypeptide, such as an antigen, that contacts another polypeptide, such as an antibody.
- Contacting can also include contacting a cell for example by placing an antibody in direct physical association with a cell.
- Control A reference standard. In some aspects, the control is a negative control, such as sample obtained from a healthy patient not infected with P. falciparum.
- control is a positive control, such as a tissue sample obtained from a patient diagnosed with P. falciparum infection.
- the control is a historical control or standard reference value or range of values (such as a previously tested control sample, such as a group of P. falciparum patients with known prognosis or outcome, or group of samples that represent baseline or normal values).
- a difference between a test sample and a control can be an increase or conversely a decrease.
- the difference can be a qualitative difference or a quantitative difference, for example a statistically significant difference.
- a difference is an increase or decrease, relative to a control, of at least about 5%, such as at least about 10%, at least about 20%, at least about 30%, at least about 40%, at least about 50%, at least about 60%, at least about 70%, at least about 80%, at least about 90%, at least about 100%, at least about 150%, at least about 200%, at least about 250%, at least about 300%, at least about 350%, at least about 400%, or at least about 500%.
- Detectable marker A detectable molecule (also known as a label) that is conjugated directly or indirectly to a second molecule, such as an antibody, to facilitate detection of the second molecule.
- the detectable marker can be capable of detection by ELISA, spectrophotometry, flow cytometry, microscopy or diagnostic imaging techniques (such as CT scans, MRIs, ultrasound, fiberoptic examination, and laparoscopic examination).
- detectable markers include fluorophores, chemiluminescent agents, enzymatic linkages, radioactive isotopes and heavy metals or compounds (for example super paramagnetic iron oxide nanocrystals for detection by MRI).
- Effective amount A quantity of a specific substance sufficient to achieve a desired effect in a subject to whom the substance is administered. For instance, this can be the amount necessary to inhibit a P. falciparum infection, such as the amount necessary to inhibit or prevent P. falciparum sporozoites from invading the liver in the subject or to measurably alter outward symptoms of the P. falciparum infection.
- administration of an effective amount of a disclosed antibody or antigen binding fragment that binds to PfCSP can reduce or inhibit a P.
- falciparum infection for example, as measured by infection of cells, or by number or percentage of subjects infected by the P. falciparum, or by an increase in the survival time of infected subjects, or reduction in symptoms associated with P. falciparum infection
- a desired amount for example by at least 10%, at least 20%, at least 50%, at least 60%, at least 70%, at least 80%, at least 90%, at least 95%, at least 98%, or even at least 100% (elimination or prevention of detectable P. falciparum infection), as compared to a suitable control.
- an effective amount can be determined by varying the dosage and measuring the resulting response, such as, for example, a reduction in pathogen titer. Effective amounts also can be determined through various in vitro, in vivo or in situ immunoassays. An effective amount encompasses a fractional dose that contributes in combination with previous or subsequent administrations to attaining an effective response. For example, an effective amount of an agent can be administered in a single dose, or in several doses, for example daily, during a course of treatment lasting several days or weeks. However, the effective amount can depend on the subject being treated, the severity and type of the condition being treated, and the manner of administration.
- a unit dosage form of the agent can be packaged in an amount, or in multiples of the effective amount, for example, in a vial (e.g., with a pierceable lid) or syringe having sterile components.
- Effector molecule A molecule intended to have or produce a desired effect; for example, a desired effect on a cell to which the effector molecule is targeted. Effector molecules can include, for example, polypeptides and small molecules. In one non-limiting example, the effector molecule is a toxin. Some effector molecules may have or produce more than one desired effect.
- Epitope An antigenic determinant. These are particular chemical groups or peptide sequences on a molecule that are antigenic, i.e.
- an antibody specifically binds a particular antigenic epitope on a polypeptide. In some examples a disclosed antibody specifically binds to an epitope on CSP from P. falciparum.
- Expression Transcription or translation of a nucleic acid sequence.
- an encoding nucleic acid sequence (such as a gene) can be expressed when its DNA is transcribed into RNA or an RNA fragment, which in some examples is processed to become mRNA.
- An encoding nucleic acid sequence (such as a gene) may also be expressed when its mRNA is translated into an amino acid sequence, such as a protein or a protein fragment.
- a heterologous gene is expressed when it is transcribed into an RNA.
- a heterologous gene is expressed when its RNA is translated into an amino acid sequence.
- Regulation of expression can include controls on transcription, translation, RNA transport and processing, degradation of intermediary molecules such as mRNA, or through activation, inactivation, compartmentalization or degradation of specific protein molecules after they are produced.
- Expression Control Sequences Nucleic acid sequences that regulate the expression of a heterologous nucleic acid sequence to which it is operatively linked. Expression control sequences are operatively linked to a nucleic acid sequence when the expression control sequences control and regulate the transcription and, as appropriate, translation of the nucleic acid sequence.
- expression control sequences can include appropriate promoters, enhancers, transcriptional terminators, a start codon (ATG) in front of a protein-encoding gene, splice signals for introns, maintenance of the correct reading frame of that gene to permit proper translation of mRNA, and stop codons.
- control sequences is intended to include, at a minimum, components whose presence can influence expression, and can also include additional components whose presence is advantageous, for example, leader sequences and fusion partner sequences.
- Expression control sequences can include a promoter.
- Expression vector A vector comprising a recombinant polynucleotide comprising expression control sequences operatively linked to a nucleotide sequence to be expressed.
- An expression vector comprises sufficient cis- acting elements for expression; other elements for expression can be supplied by the host cell or in an in vitro expression system.
- expression vectors include cosmids, plasmids (e.g., naked or contained in liposomes) and viruses (e.g., lentiviruses, retroviruses, adenoviruses, and adeno-associated viruses) that incorporate the recombinant polynucleotide.
- a polynucleotide can be inserted into an expression vector that contains a promoter sequence which facilitates the efficient transcription of the inserted genetic sequence of the host.
- Fc region The constant region of an antibody excluding the first heavy chain constant domain. Fc region generally refers to the last two heavy chain constant domains of IgA, IgD, and IgG, and the last three heavy chain constant domains of IgE and IgM. An Fc region may also include part or all of the flexible hinge N-terminal to these domains. For IgA and IgM, an Fc region may or may not include the tailpiece, and may or may not be bound by the J chain.
- the Fc region is typically understood to include immunoglobulin domains C ⁇ 2 and C ⁇ 3 and optionally the lower part of the hinge between C ⁇ 1 and C ⁇ 2. Although the boundaries of the Fc region may vary, the human IgG heavy chain Fc region is usually defined to include residues following C226 or P230 to the Fc carboxyl-terminus, wherein the numbering is according to Kabat.
- the Fc region includes immunoglobulin domains C ⁇ 2 and C ⁇ 3 and optionally the lower part of the hinge between C ⁇ 1 and C ⁇ 2.
- Host cell Cells in which a vector can be propagated and its DNA expressed. The cell may be prokaryotic or eukaryotic. The term also includes any progeny of the subject host cell.
- IgA A polypeptide belonging to the class of antibodies that are substantially encoded by a recognized immunoglobulin alpha gene. In humans, this class or isotype comprises IgA1 and IgA2. IgA antibodies can exist as monomers, polymers (referred to as pIgA) of predominantly dimeric form, and secretory IgA. The constant chain of wild-type IgA contains an 18-amino-acid extension at its C-terminus called the tail piece (tp).
- IgG A polypeptide belonging to the class or isotype of antibodies that are substantially encoded by a recognized immunoglobulin gamma gene. In humans, this class comprises IgG1, IgG2, IgG3, and IgG4.
- Immune complex The binding of antibody or antigen binding fragment (such as a scFv) to a soluble antigen forms an immune complex.
- an immune complex can be detected through conventional methods, for instance immunohistochemistry, immunoprecipitation, flow cytometry, immunofluorescence microscopy, ELISA, immunoblotting (for example, Western blot), magnetic resonance imaging, CT scans, radiography, and affinity chromatography.
- Inhibiting a disease or condition Reducing the full development of a disease or condition in a subject, for example, reducing the full development of a P. falciparum infection in a subject who is at risk of a P. falciparum infection. This includes neutralizing, antagonizing, prohibiting, preventing, restraining, slowing, disrupting, stopping, or reversing progression or severity of the disease or condition.
- inhibiting a disease or condition refers to a prophylactic intervention administered before the disease or condition has begun to develop (for example a treatment initiated in a subject at risk of P. falciparum infection, but not infected by P. falciparum) that reduces subsequent development of the disease or condition and/or ameliorates a sign or symptom of the disease or condition following development.
- the term “ameliorating,” with reference to inhibiting a disease or condition refers to any observable beneficial effect of the prophylactic intervention intended to inhibit the disease or condition.
- the beneficial effect can be evidenced, for example, by a delayed onset of clinical symptoms of the disease or condition in a susceptible subject, a reduction in severity of some or all clinical symptoms of the disease or condition, a slower progression of the disease or condition, an improvement in the overall health or well- being of the subject, a reduction in infection, or by other parameters that are specific to the particular disease or condition.
- the disclosed PfCSP-specific antibodies and antigen binding fragments inhibit the invasion of Plasmodium falciparum sporozoites into human liver cells (hepatocytes).
- the invasion of liver cells is a key event in the infection of a subject with the malaria parasite. Inhibition of the invasion of human liver cells can be measured by one or more of several standard assays (see, for example, Example 1).
- the disclosed PfCSP-specific antibodies and antigen binding fragments can inhibit the invasion of Plasmodium falciparum sporozoites into human liver cells by at least 25%, such as at least 50%, at least 75%, at least 90%, at least 95%, or 100% compared to a suitable control.
- the disclosed PfCSP-specific antibodies and antigen binding fragments inhibit the growth of Plasmodium falciparum in a subject, for example, the antibodies and antigen binding fragments inhibit the multiplication of Plasmodium falciparum in the subject, resulting in a reduction in pathogen load in the subject compared to a relevant control.
- the disclosed PfCSP-specific antibodies and antigen binding fragments can inhibit the growth of Plasmodium falciparum in a subject by at least 25%, such as at least 50%, at least 75%, at least 90%, at least 95%, or 100% compared to a suitable control.
- Isolated A biological component (such as a nucleic acid, peptide, protein or protein complex, for example an antibody) that has been substantially separated, produced apart from, or purified away from other biological components in the cell of the organism in which the component naturally occurs, that is, other chromosomal and extra-chromosomal DNA and RNA, and proteins.
- isolated nucleic acids, peptides and proteins include nucleic acids and proteins purified by standard purification methods.
- nucleic acids, peptides and proteins prepared by recombinant expression in a host cell, as well as, chemically synthesized nucleic acids.
- An isolated nucleic acid, peptide or protein, for example an antibody, can be at least 50%, at least 60%, at least 70%, at least 80%, at least 90%, at least 95%, at least 96%, at least 97%, at least 98%, or at least 99% pure.
- Kabat position A position of a residue in an amino acid sequence that follows the numbering convention delineated by Kabat et al.
- L9 Antibody A monoclonal antibody that specifically binds to an epitope on PfCSP and neutralizes malaria infection. The L9 antibody and methods for its production are described, for example, in PCT Pub. No. WO 2020/227228.
- the amino acid sequences of the heavy and light variable regions of the L9 antibody are provided herein as SEQ ID NOs: 70 and 71.
- Linker A bi-functional molecule that can be used to link two molecules into one contiguous molecule, for example, to link an effector molecule to an antibody.
- Non-limiting examples of peptide linkers include glycine-serine linkers.
- conjugating,” “joining,” “bonding,” or “linking” can refer to making two molecules into one contiguous molecule; for example, linking two polypeptides into one contiguous polypeptide, or covalently attaching an effector molecule or detectable marker radionuclide or other molecule to a polypeptide, such as an scFv.
- the linkage can be either by chemical or recombinant means.
- “Chemical means” refers to a reaction between the antibody moiety and the effector molecule such that there is a covalent bond formed between the two molecules to form one molecule.
- mAb 5D5 Antibody A control monoclonal antibody that specifically binds to an epitope on PfCSP that is used as a control herein. This antibody detects only the un-cleaved form of PfCSP.
- the mAb 5D5 antibody is described, for example, on the internet rcsb.org/structure/6UUD, as available on September 18, 2023.
- the amino acid sequences of the heavy and light variable regions of the mAb 5D5 are provided as SEQ ID NOs: 166 and 167.
- mAb10 Antibody A control monoclonal antibody that specifically binds to an epitope on PfCSP.
- This antibody detects both the cleaved (lower molecular weight) and un-cleaved (higher molecular weight) forms of PfCSP.
- the mAb10 antibody is described, for example, in Kisalu et al., Nat. Med.24, 408-416. 10.1038/nm.4512, 2018 and PCT Publication No. WO 2018/148660.
- the amino acid sequences of the heavy and light variable regions of the mAb10 are provided as SEQ ID NOs: 168 and 169.
- Malaria Malaria is a parasitic infection of humans by the Plasmodium species P. falciparum, P. vivax, P. ovale, P. malariae, and P. knowlesi.
- Infection begins when malaria sporozoites gain access to or are directly injected into the bloodstream of a host by a mosquito. After injection, they migrate to the liver and multiply in hepatocytes for one week. The sporozoites substantially expand in the liver and differentiate to merozoites which are released from the liver into the blood stream, where they infect erythrocytes.
- a schizont is the stage when nuclear division occurs to form individual merozoites which are released to invade other red cells. Malaria clinical symptoms appear during the blood-stage. After several schizogonic cycles, some parasites, instead of becoming schizonts through asexual reproduction, develop into large uninucleate parasites, known as gametocytes. These gametocytes are the sexual blood cell stage forms of the parasite. Sexual development of the malaria parasites involves the female macrogametocyte and the male microgametocyte.
- a mosquito feeds on the blood of an infected host, it can ingest gametocytes within the blood. Fertilization and sexual recombination of the parasite occurs in the mosquito's gut.
- the fertilized parasite which is known as a zygote, then develops into an ookinete.
- the ookinete penetrates the midgut wall of the mosquito and develops into an oocyst, within which many small sporozoites form. When the oocyst ruptures, the sporozoites migrate to the salivary gland of the mosquito via the hemolymph. Once in the saliva of the mosquito, the parasite can be injected into a host, repeating the life cycle.
- Nucleic acid (molecule or sequence): A deoxyribonucleotide or ribonucleotide polymer or combination thereof including without limitation, cDNA, mRNA, genomic DNA, and synthetic (such as chemically synthesized) DNA or RNA.
- the nucleic acid can be double stranded (ds) or single stranded (ss). Where single stranded, the nucleic acid can be the sense strand or the antisense strand.
- Nucleic acids can include natural nucleotides (such as A, T/U, C, and G), and can include analogs of natural nucleotides, such as labeled nucleotides.
- cDNA refers to a DNA that is complementary or identical to an mRNA, in either single stranded or double stranded form.
- Encoding refers to the inherent property of specific sequences of nucleotides in a polynucleotide, such as a gene, a cDNA, or an mRNA, to serve as templates for synthesis of other polymers and macromolecules in biological processes having either a defined sequence of nucleotides (i.e., rRNA, tRNA and mRNA) or a defined sequence of amino acids and the biological properties resulting therefrom.
- a gene encodes a protein if transcription and translation of mRNA produced by that gene produces the protein in a cell or other biological system.
- coding strand the nucleotide sequence of which is identical to the mRNA sequence and is usually provided in sequence listings
- non-coding strand used as the template for transcription
- a “nucleotide sequence encoding an amino acid sequence” includes all nucleotide sequences that are degenerate versions of each other and that encode the same amino acid sequence. Nucleotide sequences that encode proteins and RNA may include introns.
- a first nucleic acid sequence is operably linked with a second nucleic acid sequence when the first nucleic acid sequence is placed in a functional relationship with the second nucleic acid sequence.
- a promoter such as the CMV promoter
- operably linked DNA sequences are contiguous and, where necessary to join two protein-coding regions, in the same reading frame.
- Pharmaceutically acceptable carriers The pharmaceutically acceptable carriers of use are conventional. Remington: The Science and Practice of Pharmacy, 22 nd ed., London, UK: Pharmaceutical Press, 2013, describes compositions and formulations suitable for pharmaceutical delivery of the disclosed agents.
- parenteral formulations usually include injectable fluids that include pharmaceutically and physiologically acceptable fluids such as water, physiological saline, balanced salt solutions, aqueous dextrose, glycerol or the like as a vehicle.
- injectable fluids such as water, physiological saline, balanced salt solutions, aqueous dextrose, glycerol or the like as a vehicle.
- physiologically acceptable fluids such as water, physiological saline, balanced salt solutions, aqueous dextrose, glycerol or the like as a vehicle.
- solid compositions e.g., powder, pill, tablet, or capsule forms
- conventional non-toxic solid carriers can include, for example, pharmaceutical grades of mannitol, lactose, starch, or magnesium stearate.
- compositions to be administered can contain minor amounts of non-toxic auxiliary substances, such as wetting or emulsifying agents, added preservatives (such as non-natural preservatives), and pH buffering agents and the like, for example sodium acetate or sorbitan monolaurate.
- the pharmaceutically acceptable carrier is sterile and suitable for parenteral administration to a subject for example, by injection.
- the active agent and pharmaceutically acceptable carrier are provided in a unit dosage form such as a pill or in a selected quantity in a vial. Unit dosage forms can include one dosage or multiple dosages (for example, in a vial from which metered dosages of the agents can selectively be dispensed).
- Polypeptide A polymer in which the monomers are amino acid residues that are joined together through amide bonds. When the amino acids are alpha-amino acids, either the L-optical isomer or the D- optical isomer can be used, the L-isomers being preferred.
- the terms “polypeptide” or “protein” as used herein are intended to encompass any amino acid sequence and include modified sequences such as glycoproteins.
- a polypeptide includes both naturally occurring proteins, as well as those that are recombinantly or synthetically produced.
- a polypeptide has an amino terminal (N-terminal) end and a carboxy-terminal end. In some aspects, the polypeptide is a disclosed antibody or a fragment thereof.
- a purified peptide preparation is one in which the peptide or protein (such as an antibody) is more enriched than the peptide or protein is in its natural environment within a cell.
- a preparation is purified such that the protein or peptide represents at least 50% of the total peptide or protein content of the preparation.
- a recombinant nucleic acid is one that has a sequence that is not naturally occurring or has a sequence that is made by an artificial combination of two otherwise separated segments of sequence. This artificial combination can be accomplished by chemical synthesis or, more commonly, by the artificial manipulation of isolated segments of nucleic acids, for example, by genetic engineering techniques.
- a recombinant protein is one that has a sequence that is not naturally occurring or has a sequence that is made by an artificial combination of two otherwise separated segments of sequence.
- a recombinant protein is encoded by a heterologous (for example, recombinant) nucleic acid that has been introduced into a host cell, such as a bacterial or eukaryotic cell.
- the nucleic acid can be introduced, for example, on an expression vector having signals capable of expressing the protein encoded by the introduced nucleic acid or the nucleic acid can be integrated into the host cell chromosome.
- Sequence identity The identity between two or more nucleic acid sequences, or two or more amino acid sequences, is expressed in terms of the identity between the sequences.
- Sequence identity can be measured in terms of percentage identity; the higher the percentage, the more identical the sequences.
- Homologs and variants of a VL or a VH of an antibody that specifically binds a target antigen are typically characterized by possession of at least about 75% sequence identity, for example at least about 80%, 85%, 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98% or 99% sequence identity counted over the full-length alignment with the amino acid sequence of interest. Any suitable method may be used to align sequences for comparison. Non-limiting examples of programs and alignment algorithms are described in: Smith and Waterman, Adv. Appl. Math.2(4):482-489, 1981; Needleman and Wunsch, J. Mol.
- the NCBI Basic Local Alignment Search Tool (BLAST) (Altschul et al., J. Mol. Biol.215(3):403-410, 1990) is available from several sources, including the National Center for Biological Information and on the Internet, for use in connection with the sequence analysis programs blastp, blastn, blastx, tblastn, and tblastx. Blastn is used to compare nucleic acid sequences, while blastp is used to compare amino acid sequences. Additional information can be found at the NCBI web site. Generally, once two sequences are aligned, the number of matches is determined by counting the number of positions where an identical nucleotide or amino acid residue is present in both sequences.
- BLAST Basic Local Alignment Search Tool
- the percent sequence identity between the two sequences is determined by dividing the number of matches either by the length of the sequence set forth in the identified sequence, or by an articulated length (such as 100 consecutive nucleotides or amino acid residues from a sequence set forth in an identified sequence), followed by multiplying the resulting value by 100.
- bind When referring to an antibody or antigen binding fragment, refers to a binding reaction which determines the presence of a target protein in the presence of a heterogeneous population of proteins and other biologics.
- an antibody binds preferentially to a particular target protein, peptide or polysaccharide (such as an antigen present on the surface of a pathogen, for example PfCSP) and does not bind in a significant amount to other proteins present in the sample or subject.
- Specific binding can be determined by standard methods. See Harlow & Lane, Antibodies, A Laboratory Manual, 2 nd ed., Cold Spring Harbor Publications, New York (2013), for a description of immunoassay formats and conditions that can be used to determine specific immunoreactivity.
- K D refers to the dissociation constant for a given interaction, such as a polypeptide ligand interaction or an antibody antigen interaction.
- K D refers to the concentration of the individual components of the bimolecular interaction divided by the concentration of the complex.
- An antibody that specifically binds to an epitope on PfCSP is an antibody that binds substantially to PfCSP, including cells or tissue expressing PfCSP, substrate to which the PfCSP is attached, or PfCSP in a biological specimen. It is, of course, recognized that a certain degree of non-specific interaction may occur between an antibody and a non-target (such as a cell that does not express PfCSP). Typically, specific binding results in a much stronger association between the antibody and protein or cells bearing the antigen than between the antibody and protein or cells lacking the antigen.
- Specific binding typically results in greater than 2-fold, such as greater than 5-fold, greater than 10-fold, or greater than 100-fold increase in amount of bound antibody (per unit time) to a protein including the epitope or cell or tissue expressing the target epitope as compared to a protein or cell or tissue lacking this epitope.
- Specific binding to a protein under such conditions requires an antibody that is selected for its specificity for a particular protein.
- a variety of immunoassay formats are appropriate for selecting antibodies or other ligands specifically immunoreactive with a particular protein.
- solid-phase ELISA immunoassays are routinely used to select monoclonal antibodies specifically immunoreactive with a protein.
- Subject Living multi-cellular vertebrate organisms, a category that includes human and non- human mammals.
- a subject is a human.
- a subject is selected that is in need of inhibiting a P. falciparum infection.
- the subject is uninfected and at risk of P. falciparum infection.
- Transformed A transformed cell is a cell into which a nucleic acid molecule has been introduced by molecular biology techniques.
- the term transformed and the like encompasses all techniques by which a nucleic acid molecule might be introduced into such a cell, including transduction with viral vectors, transformation with plasmid vectors, and introduction of DNA by electroporation, lipofection, and particle gun acceleration.
- Vector An entity containing a nucleic acid molecule (such as a DNA or RNA molecule) bearing a promoter(s) that is operationally linked to the coding sequence of a protein of interest and can express the coding sequence.
- Non-limiting examples include a naked or packaged (lipid and/or protein) DNA, a naked or packaged RNA, a subcomponent of a virus or bacterium or other microorganism that may be replication- incompetent, or a virus or bacterium or other microorganism that may be replication-competent.
- a vector is sometimes referred to as a construct.
- Recombinant DNA vectors are vectors having recombinant DNA.
- a vector can include nucleic acid sequences that permit it to replicate in a host cell, such as an origin of replication.
- a vector can also include one or more selectable marker genes and other genetic elements.
- Viral vectors are recombinant nucleic acid vectors having at least some nucleic acid sequences derived from one or more viruses.
- a viral vector comprises a nucleic acid molecule encoding a disclosed antibody or antigen binding fragment that specifically binds to PfCSP and neutralizes P. falciparum.
- the viral vector can be an adeno-associated virus (AAV) vector.
- Isolated monoclonal antibodies and antigen binding fragments that specifically bind an epitope on PfCSP are provided.
- the antibodies and antigen binding fragments can be fully human.
- the antibodies and antigen binding fragments can neutralize P. falciparum, for example the disclosed antibodies can inhibit P. falciparum sporozoite infection of hepatocytes in vitro and P. falciparum sporozoite invasion of liver in vivo.
- compositions comprising the antibodies and antigen binding fragments and a pharmaceutically acceptable carrier.
- Nucleic acids encoding the antibodies or antigen binding fragments, expression vectors (such as DNA and RNA vectors for expression and delivery, as well as adeno-associated virus (AAV) viral vectors) comprising these nucleic acids are also provided.
- the antibodies, antigen binding fragments, nucleic acid molecules, host cells, and compositions can be used for research, diagnostic and prophylactic purposes.
- the disclosed antibodies and antigen binding fragments can be used to diagnose a subject with a P. falciparum infection, or can be administered prophylactically to inhibit P. falciparum infection in a subject. 1.
- monoclonal antibodies and antigen binding fragments refers to isolated monoclonal antibodies that include heavy and/or light chain variable domains (or antigen binding fragments thereof) comprising a CDR1, CDR2, and/or CDR3 with reference to the IMMGT numbering scheme (unless the context indicates otherwise).
- CDR numbering schemes such as the Kabat, Chothia or IMGT numbering schemes
- the amino acid sequence and the CDR positions (according to the IMGT numbering scheme) of the heavy and light chains of exemplary monoclonal antibodies that bind to PfCSP and neutralize P. falciparum are shown in Table 1. Table 1.
- IMGT CDR sequences of PfCSP specific antibodies MAD21-17 VH C DR LCDR1 27-38 QSLLYSSTNKNY 26 LCDR2 56-58 WAS 27 L CDR3 95-103 YYISPLT 28 MAD22-39 VH V H SEQ ID NO: 15 residues AA Se uence CDR a.
- the antibody or antigen binding fragment is based on or derived from the MAD21- 17 antibody, and specifically binds to PfCSP and neutralizes P. falciparum.
- the antibody or antigen binding fragment comprises a VH and a VL comprising the HCDR1, the HCDR2, and the HCDR3, and the LCDR1, the LCDR2, and the LCDR3, respectively (for example, according to IMGT, Kabat, or Chothia), of the MAD21-17 antibody, and specifically binds to PfCSP and neutralizes P. falciparum.
- the antibody or antigen binding fragment comprises a V H comprising an amino acid sequence at least 90% (such as at least 95%, at least 96%, at least 97%, at least 98%, or at least 99%) identical to the amino acid sequence set forth as SEQ ID NO: 1, and specifically binds to PfCSP and neutralizes P. falciparum.
- the antibody or antigen binding fragment comprises a VL comprising an amino acid sequence at least 90% (such as at least 95%, at least 96%, at least 97%, at least 98%, or at least 99%) identical to the amino acid sequence set forth as SEQ ID NO: 2, and specifically binds to PfCSP and neutralizes P. falciparum.
- the antibody or antigen binding fragment comprises a VH and a VL independently comprising amino acid sequences at least 90% (such as at least 95%, at least 96%, at least 97%, at least 98%, or at least 99%) identical to the amino acid sequences set forth as SEQ ID NOs: 1 and 2, respectively, and specifically binds to PfCSP and neutralizes P. falciparum.
- the antibody or antigen binding fragment comprises a VH comprising a HCDR1, a HCDR2, and a HCDR3 as set forth as SEQ ID NOs: 23, 24, and 25, respectively, and a V L comprising a LCDR1, a LCDR2, and a LCDR3 as set forth as SEQ ID NOs: 26, 27, and 28, respectively, and specifically binds to PfCSP and neutralizes P. falciparum.
- the antibody or antigen binding fragment comprises a VH comprising a HCDR1, a HCDR2, and a HCDR3 as set forth as SEQ ID NOs: 23, 24, and 25, respectively, a VL comprising a LCDR1, a LCDR2, and a LCDR3 as set forth as SEQ ID NOs: 26, 27, and 28, respectively, wherein the V H comprises an amino acid sequence at least 90% identical to SEQ ID NO: 1 (such as 95%, 96%, 97%, 98% or 99% identical to SEQ ID NO: 1), the V L comprises an amino acid sequence at least 90% identical to SEQ ID NO: 2 (such as 95%, 96%, 97%, 98% or 99% identical to SEQ ID NO: 2 and the antibody or antigen binding fragment specifically binds to PfCSP and neutralizes P.
- V H comprises an amino acid sequence at least 90% identical to SEQ ID NO: 1 (such as 95%, 96%, 97%, 98% or 99% identical to SEQ ID NO: 1)
- the V L comprises an amino
- the antibody or antigen binding fragment comprises a VH comprising a HCDR1, a HCDR2, and a HCDR3 as set forth as SEQ ID NOs: 23, 24, and 25, respectively, a VL comprising a LCDR1, a LCDR2, and a LCDR3 as set forth as SEQ ID NOs: 26, 27, and 28, respectively, wherein the framework regions of the V H comprise up to 10 (such as up to 1, up to 2, up to 3, up to 4, up to 5, up to 6, up to 7, up to 8, or up to 9) amino acid substitutions (such as conservative amino acid substitutions) compared to the amino acid sequence set forth as one of SEQ ID NO: 1, and the framework regions of the VL comprise up to 10 (such as up to 1, up to 2, up to 3, up to 4, up to 5, up to 6, up to 7, up to 8, or up to 9) amino acid substitutions (such as conservative amino acid substitutions) compared to the amino acid sequence set forth as one of SEQ ID NO: 2, and the antibody or antigen binding fragment
- the antibody or antigen binding fragment comprises a V H comprising the amino acid sequence set forth as SEQ ID NO: 1, and specifically binds to PfCSP and neutralizes P. falciparum.
- the antibody or antigen binding fragment comprises a VL comprising the amino acid sequence set forth as SEQ ID NO: 2, and specifically binds to PfCSP and neutralizes P. falciparum.
- the antibody or antigen binding fragment comprises a V H and a V L comprising the amino acid sequences set forth as SEQ ID NOs: 1 and 2, respectively, and specifically binds to PfCSP and neutralizes P. falciparum.
- the disclosed antibodies and antigen binding fragments inhibit the invasion of Plasmodium falciparum sporozoites into human liver cells, and/or reduce pathogen load Plasmodium falciparum in a subject, compared to a control.
- the antibody or antigen binding fragment is based on or derived from the MAD21- 46 antibody, and specifically binds to PfCSP and neutralizes P. falciparum.
- the antibody or antigen binding fragment comprises a VH and a VL comprising the HCDR1, the HCDR2, and the HCDR3, and the LCDR1, the LCDR2, and the LCDR3, respectively (for example, according to IMGT, Kabat, or Chothia), of the MAD21-46 antibody, and specifically binds to PfCSP and neutralizes P. falciparum.
- the antibody or antigen binding fragment comprises a V H comprising an amino acid sequence at least 90% (such as at least 95%, at least 96%, at least 97%, at least 98%, or at least 99%) identical to the amino acid sequence set forth as SEQ ID NO: 3, and specifically binds to PfCSP and neutralizes P. falciparum.
- the antibody or antigen binding fragment comprises a VL comprising an amino acid sequence at least 90% (such as at least 95%, at least 96%, at least 97%, at least 98%, or at least 99%) identical to the amino acid sequence set forth as SEQ ID NO: 4, and specifically binds to PfCSP and neutralizes P. falciparum.
- the antibody or antigen binding fragment comprises a V H and a V L independently comprising amino acid sequences at least 90% (such as at least 95%, at least 96%, at least 97%, at least 98%, or at least 99%) identical to the amino acid sequences set forth as SEQ ID NOs: 3 and 4, respectively, and specifically binds to PfCSP and neutralizes P. falciparum.
- the antibody or antigen binding fragment comprises a VH comprising a HCDR1, a HCDR2, and a HCDR3 as set forth as SEQ ID NOs: 29, 24, and 25, respectively, and a VL comprising a LCDR1, a LCDR2, and a LCDR3 as set forth as SEQ ID NOs: 26, 27, and 28, respectively, and specifically binds to PfCSP and neutralizes P. falciparum.
- the antibody or antigen binding fragment comprises a VH comprising a HCDR1, a HCDR2, and a HCDR3 as set forth as SEQ ID NOs: 29, 24, and 25, respectively, a VL comprising a LCDR1, a LCDR2, and a LCDR3 as set forth as SEQ ID NOs: 26, 27, and 28, respectively, wherein the VH comprises an amino acid sequence at least 90% identical to SEQ ID NO: 3 (such as 95%, 96%, 97%, 98% or 99% identical to SEQ ID NO: 3), the V L comprises an amino acid sequence at least 90% identical to SEQ ID NO: 4 (such as 95%, 96%, 97%, 98% or 99% identical to SEQ ID NO: 4 and the antibody or antigen binding fragment specifically binds to PfCSP and neutralizes P.
- the antibody or antigen binding fragment comprises a VH comprising a HCDR1, a HCDR2, and a HCDR3 as set forth as SEQ ID NOs: 29, 24, and 25, respectively, a VL comprising a LCDR1, a LCDR2, and a LCDR3 as set forth as SEQ ID NOs: 26, 27, and 28, respectively, wherein the framework regions of the V H comprise up to 10 (such as up to 1, up to 2, up to 3, up to 4, up to 5, up to 6, up to 7, up to 8, or up to 9) amino acid substitutions (such as conservative amino acid substitutions) compared to the amino acid sequence set forth as one of SEQ ID NO: 3, and the framework regions of the VL comprise up to 10 (such as up to 1, up to 2, up to 3, up to 4, up to 5, up to 6, up to 7, up to 8, or up to 9) amino acid substitutions (such as conservative amino acid substitutions) compared to the amino acid sequence set forth as one of SEQ ID NO: 4, and the antibody or antigen binding fragment
- the antibody or antigen binding fragment comprises a V H comprising the amino acid sequence set forth as SEQ ID NO: 3, and specifically binds to PfCSP and neutralizes P. falciparum.
- the antibody or antigen binding fragment comprises a VL comprising the amino acid sequence set forth as SEQ ID NO: 4, and specifically binds to PfCSP and neutralizes P. falciparum.
- the antibody or antigen binding fragment comprises a VH and a VL comprising the amino acid sequences set forth as SEQ ID NOs: 3 and 4, respectively, and specifically binds to PfCSP and neutralizes P. falciparum.
- the disclosed antibodies and antigen binding fragments inhibit the invasion of Plasmodium falciparum sporozoites into human liver cells, and/or reduce pathogen load Plasmodium falciparum in a subject, compared to a control.
- the antibody or antigen binding fragment is based on or derived from the MAD21- 53 antibody, and specifically binds to PfCSP and neutralizes P. falciparum.
- the antibody or antigen binding fragment comprises a VH and a VL comprising the HCDR1, the HCDR2, and the HCDR3, and the LCDR1, the LCDR2, and the LCDR3, respectively (for example, according to IMGT, Kabat, or Chothia), of the MAD21-53 antibody, and specifically binds to PfCSP and neutralizes P. falciparum.
- the antibody or antigen binding fragment comprises a V H comprising an amino acid sequence at least 90% (such as at least 95%, at least 96%, at least 97%, at least 98%, or at least 99%) identical to the amino acid sequence set forth as SEQ ID NO: 5, and specifically binds to PfCSP and neutralizes P. falciparum.
- the antibody or antigen binding fragment comprises a VL comprising an amino acid sequence at least 90% (such as at least 95%, at least 96%, at least 97%, at least 98%, or at least 99%) identical to the amino acid sequence set forth as SEQ ID NO: 6, and specifically binds to PfCSP and neutralizes P. falciparum.
- the antibody or antigen binding fragment comprises a V H and a V L independently comprising amino acid sequences at least 90% (such as at least 95%, at least 96%, at least 97%, at least 98%, or at least 99%) identical to the amino acid sequences set forth as SEQ ID NOs: 5 and 6, respectively, and specifically binds to PfCSP and neutralizes P. falciparum.
- the antibody or antigen binding fragment comprises a VH comprising a HCDR1, a HCDR2, and a HCDR3 as set forth as SEQ ID NOs: 29, 24, and 30, respectively, and a VL comprising a LCDR1, a LCDR2, and a LCDR3 as set forth as SEQ ID NOs: 26, 27, and 28, respectively, and specifically binds to PfCSP and neutralizes P. falciparum.
- the antibody or antigen binding fragment comprises a V H comprising a HCDR1, a HCDR2, and a HCDR3 as set forth as SEQ ID NOs: 29, 24, and 30, respectively, a VL comprising a LCDR1, a LCDR2, and a LCDR3 as set forth as SEQ ID NOs: 26, 27, and 28, respectively, wherein the VH comprises an amino acid sequence at least 90% identical to SEQ ID NO: 5 (such as 95%, 96%, 97%, 98% or 99% identical to SEQ ID NO: 5), the VL comprises an amino acid sequence at least 90% identical to SEQ ID NO: 6 (such as 95%, 96%, 97%, 98% or 99% identical to SEQ ID NO: 6 and the antibody or antigen binding fragment specifically binds to PfCSP and neutralizes P.
- VH comprises an amino acid sequence at least 90% identical to SEQ ID NO: 5 (such as 95%, 96%, 97%, 98% or 99% identical to SEQ ID NO: 5)
- the VL comprises an
- the antibody or antigen binding fragment comprises a VH comprising a HCDR1, a HCDR2, and a HCDR3 as set forth as SEQ ID NOs: 29, 24, and 30, respectively, a VL comprising a LCDR1, a LCDR2, and a LCDR3 as set forth as SEQ ID NOs: 26, 27, and 28, respectively, wherein the framework regions of the VH comprise up to 10 (such as up to 1, up to 2, up to 3, up to 4, up to 5, up to 6, up to 7, up to 8, or up to 9) amino acid substitutions (such as conservative amino acid substitutions) compared to the amino acid sequence set forth as one of SEQ ID NO: 5, and the framework regions of the V L comprise up to 10 (such as up to 1, up to 2, up to 3, up to 4, up to 5, up to 6, up to 7, up to 8, or up to 9) amino acid substitutions (such as conservative amino acid substitutions) compared to the amino acid sequence set forth as one of SEQ ID NO: 6, and the antibody or antigen binding fragment
- the antibody or antigen binding fragment comprises a V H comprising the amino acid sequence set forth as SEQ ID NO: 5, and specifically binds to PfCSP and neutralizes P. falciparum.
- the antibody or antigen binding fragment comprises a VL comprising the amino acid sequence set forth as SEQ ID NO: 6, and specifically binds to PfCSP and neutralizes P. falciparum.
- the antibody or antigen binding fragment comprises a VH and a VL comprising the amino acid sequences set forth as SEQ ID NOs: 5 and 6, respectively, and specifically binds to PfCSP and neutralizes P. falciparum.
- the disclosed antibodies and antigen binding fragments inhibit the invasion of Plasmodium falciparum sporozoites into human liver cells, and/or reduce pathogen load Plasmodium falciparum in a subject, compared to a control.
- the antibody or antigen binding fragment is based on or derived from the MAD21- 95 antibody, and specifically binds to PfCSP and neutralizes P. falciparum.
- the antibody or antigen binding fragment comprises a V H and a V L comprising the HCDR1, the HCDR2, and the HCDR3, and the LCDR1, the LCDR2, and the LCDR3, respectively (for example, according to IMGT, Kabat, or Chothia), of the MAD21-95 antibody, and specifically binds to PfCSP and neutralizes P. falciparum.
- the antibody or antigen binding fragment comprises a VH comprising an amino acid sequence at least 90% (such as at least 95%, at least 96%, at least 97%, at least 98%, or at least 99%) identical to the amino acid sequence set forth as SEQ ID NO: 7, and specifically binds to PfCSP and neutralizes P. falciparum.
- the antibody or antigen binding fragment comprises a V L comprising an amino acid sequence at least 90% (such as at least 95%, at least 96%, at least 97%, at least 98%, or at least 99%) identical to the amino acid sequence set forth as SEQ ID NO: 8, and specifically binds to PfCSP and neutralizes P. falciparum.
- the antibody or antigen binding fragment comprises a VH and a VL independently comprising amino acid sequences at least 90% (such as at least 95%, at least 96%, at least 97%, at least 98%, or at least 99%) identical to the amino acid sequences set forth as SEQ ID NOs: 7 and 8, respectively, and specifically binds to PfCSP and neutralizes P. falciparum.
- the antibody or antigen binding fragment comprises a VH comprising a HCDR1, a HCDR2, and a HCDR3 as set forth as SEQ ID NOs: 23, 24, and 25, respectively, and a VL comprising a LCDR1, a LCDR2, and a LCDR3 as set forth as SEQ ID NOs: 31, 27, and 38, respectively, and specifically binds to PfCSP and neutralizes P. falciparum.
- the antibody or antigen binding fragment comprises a V H comprising a HCDR1, a HCDR2, and a HCDR3 as set forth as SEQ ID NOs: 23, 24, and 25, respectively, a V L comprising a LCDR1, a LCDR2, and a LCDR3 as set forth as SEQ ID NOs: 31, 27, and 38, respectively, wherein the VH comprises an amino acid sequence at least 90% identical to SEQ ID NO: 7 (such as 95%, 96%, 97%, 98% or 99% identical to SEQ ID NO: 7), the VL comprises an amino acid sequence at least 90% identical to SEQ ID NO: 8 (such as 95%, 96%, 97%, 98% or 99% identical to SEQ ID NO: 8 and the antibody or antigen binding fragment specifically binds to PfCSP and neutralizes P.
- the antibody or antigen binding fragment comprises a V H comprising a HCDR1, a HCDR2, and a HCDR3 as set forth as SEQ ID NOs: 23, 24, and 25, respectively, a VL comprising a LCDR1, a LCDR2, and a LCDR3 as set forth as SEQ ID NOs: 31, 27, and 38, respectively, wherein the framework regions of the VH comprise up to 10 (such as up to 1, up to 2, up to 3, up to 4, up to 5, up to 6, up to 7, up to 8, or up to 9) amino acid substitutions (such as conservative amino acid substitutions) compared to the amino acid sequence set forth as one of SEQ ID NO: 7, and the framework regions of the V L comprise up to 10 (such as up to 1, up to 2, up to 3, up to 4, up to 5, up to 6, up to 7, up to 8, or up to 9) amino acid substitutions (such as conservative amino acid substitutions) compared to the amino acid sequence set forth as one of SEQ ID NO: 8, and the antibody or antigen binding
- the antibody or antigen binding fragment comprises a VH comprising the amino acid sequence set forth as SEQ ID NO: 7, and specifically binds to PfCSP and neutralizes P. falciparum.
- the antibody or antigen binding fragment comprises a V L comprising the amino acid sequence set forth as SEQ ID NO: 8, and specifically binds to PfCSP and neutralizes P. falciparum.
- the antibody or antigen binding fragment comprises a VH and a VL comprising the amino acid sequences set forth as SEQ ID NOs: 7 and 8, respectively, and specifically binds to PfCSP and neutralizes P. falciparum.
- the disclosed antibodies and antigen binding fragments inhibit the invasion of Plasmodium falciparum sporozoites into human liver cells, and/or reduce pathogen load Plasmodium falciparum in a subject, compared to a control.
- the antibody or antigen binding fragment is based on or derived from the MAD21- 101 antibody, and specifically binds to PfCSP and neutralizes P. falciparum.
- the antibody or antigen binding fragment comprises a V H and a V L comprising the HCDR1, the HCDR2, and the HCDR3, and the LCDR1, the LCDR2, and the LCDR3, respectively (for example, according to IMGT, Kabat, or Chothia), of the MAD21-101 antibody, and specifically binds to PfCSP and neutralizes P. falciparum.
- the antibody or antigen binding fragment comprises a VH comprising an amino acid sequence at least 90% (such as at least 95%, at least 96%, at least 97%, at least 98%, or at least 99%) identical to the amino acid sequence set forth as SEQ ID NO: 9, and specifically binds to PfCSP and neutralizes P. falciparum.
- the antibody or antigen binding fragment comprises a V L comprising an amino acid sequence at least 90% (such as at least 95%, at least 96%, at least 97%, at least 98%, or at least 99%) identical to the amino acid sequence set forth as SEQ ID NO: 10, and specifically binds to PfCSP and neutralizes P. falciparum.
- the antibody or antigen binding fragment comprises a VH and a VL independently comprising amino acid sequences at least 90% (such as at least 95%, at least 96%, at least 97%, at least 98%, or at least 99%) identical to the amino acid sequences set forth as SEQ ID NOs: 9 and 10, respectively, and specifically binds to PfCSP and neutralizes P. falciparum.
- the antibody or antigen binding fragment comprises a V H comprising a HCDR1, a HCDR2, and a HCDR3 as set forth as SEQ ID NOs: 29, 24, and 33, respectively, and a VL comprising a LCDR1, a LCDR2, and a LCDR3 as set forth as SEQ ID NOs: 26, 27, and 34, respectively, and specifically binds to PfCSP and neutralizes P. falciparum.
- the antibody or antigen binding fragment comprises a VH comprising a HCDR1, a HCDR2, and a HCDR3 as set forth as SEQ ID NOs: 29, 24, and 33, respectively, a V L comprising a LCDR1, a LCDR2, and a LCDR3 as set forth as SEQ ID NOs: 26, 27, and 34, respectively, wherein the V H comprises an amino acid sequence at least 90% identical to SEQ ID NO: 9 (such as 95%, 96%, 97%, 98% or 99% identical to SEQ ID NO: 9), the VL comprises an amino acid sequence at least 90% identical to SEQ ID NO: 10 (such as 95%, 96%, 97%, 98% or 99% identical to SEQ ID NO: 10 and the antibody or antigen binding fragment specifically binds to PfCSP and neutralizes P.
- V H comprises an amino acid sequence at least 90% identical to SEQ ID NO: 9 (such as 95%, 96%, 97%, 98% or 99% identical to SEQ ID NO: 9)
- the VL
- the antibody or antigen binding fragment comprises a V H comprising a HCDR1, a HCDR2, and a HCDR3 as set forth as SEQ ID NOs: 29, 24, and 33, respectively, a V L comprising a LCDR1, a LCDR2, and a LCDR3 as set forth as SEQ ID NOs: 26, 27, and 34, respectively, wherein the framework regions of the VH comprise up to 10 (such as up to 1, up to 2, up to 3, up to 4, up to 5, up to 6, up to 7, up to 8, or up to 9) amino acid substitutions (such as conservative amino acid substitutions) compared to the amino acid sequence set forth as one of SEQ ID NO: 9, and the framework regions of the VL comprise up to 10 (such as up to 1, up to 2, up to 3, up to 4, up to 5, up to 6, up to 7, up to 8, or up to 9) amino acid substitutions (such as conservative amino acid substitutions) compared to the amino acid sequence set forth as one of SEQ ID NO: 10, and the antibody or antigen
- the antibody or antigen binding fragment comprises a VH comprising the amino acid sequence set forth as SEQ ID NO: 9, and specifically binds to PfCSP and neutralizes P. falciparum.
- the antibody or antigen binding fragment comprises a VL comprising the amino acid sequence set forth as SEQ ID NO: 10, and specifically binds to PfCSP and neutralizes P. falciparum.
- the antibody or antigen binding fragment comprises a V H and a V L comprising the amino acid sequences set forth as SEQ ID NOs: 9 and 10, respectively, and specifically binds to PfCSP and neutralizes P. falciparum.
- the disclosed antibodies and antigen binding fragments inhibit the invasion of Plasmodium falciparum sporozoites into human liver cells, and/or reduce pathogen load Plasmodium falciparum in a subject, compared to a control.
- the antibody or antigen binding fragment is based on or derived from the MAD22- 17 antibody, and specifically binds to PfCSP and neutralizes P. falciparum.
- the antibody or antigen binding fragment comprises a V H and a V L comprising the HCDR1, the HCDR2, and the HCDR3, and the LCDR1, the LCDR2, and the LCDR3, respectively (for example, according to IMGT, Kabat, or Chothia), of the MAD22-17 antibody, and specifically binds to PfCSP and neutralizes P. falciparum.
- the antibody or antigen binding fragment comprises a VH comprising an amino acid sequence at least 90% (such as at least 95%, at least 96%, at least 97%, at least 98%, or at least 99%) identical to the amino acid sequence set forth as SEQ ID NO: 11, and specifically binds to PfCSP and neutralizes P. falciparum.
- the antibody or antigen binding fragment comprises a VL comprising an amino acid sequence at least 90% (such as at least 95%, at least 96%, at least 97%, at least 98%, or at least 99%) identical to the amino acid sequence set forth as SEQ ID NO: 12, and specifically binds to PfCSP and neutralizes P. falciparum.
- the antibody or antigen binding fragment comprises a VH and a VL independently comprising amino acid sequences at least 90% (such as at least 95%, at least 96%, at least 97%, at least 98%, or at least 99%) identical to the amino acid sequences set forth as SEQ ID NOs: 11 and 12, respectively, and specifically binds to PfCSP and neutralizes P. falciparum.
- the antibody or antigen binding fragment comprises a V H comprising a HCDR1, a HCDR2, and a HCDR3 as set forth as SEQ ID NOs: 35, 36, and 37, respectively, and a VL comprising a LCDR1, a LCDR2, and a LCDR3 as set forth as SEQ ID NOs: 38, 27, and 39, respectively, and specifically binds to PfCSP and neutralizes P. falciparum.
- the antibody or antigen binding fragment comprises a V H comprising a HCDR1, a HCDR2, and a HCDR3 as set forth as SEQ ID NOs: 35, 36, and 37, respectively, a V L comprising a LCDR1, a LCDR2, and a LCDR3 as set forth as SEQ ID NOs: 38, 27, and 39, respectively, wherein the V H comprises an amino acid sequence at least 90% identical to SEQ ID NO: 11 (such as 95%, 96%, 97%, 98% or 99% identical to SEQ ID NO: 11), the VL comprises an amino acid sequence at least 90% identical to SEQ ID NO: 12 (such as 95%, 96%, 97%, 98% or 99% identical to SEQ ID NO: 12 and the antibody or antigen binding fragment specifically binds to PfCSP and neutralizes P.
- V H comprises an amino acid sequence at least 90% identical to SEQ ID NO: 11 (such as 95%, 96%, 97%, 98% or 99% identical to SEQ ID NO: 11)
- the antibody or antigen binding fragment comprises a V H comprising a HCDR1, a HCDR2, and a HCDR3 as set forth as SEQ ID NOs: 35, 36, and 37, respectively, a V L comprising a LCDR1, a LCDR2, and a LCDR3 as set forth as SEQ ID NOs: 38, 27, and 39, respectively, wherein the framework regions of the VH comprise up to 10 (such as up to 1, up to 2, up to 3, up to 4, up to 5, up to 6, up to 7, up to 8, or up to 9) amino acid substitutions (such as conservative amino acid substitutions) compared to the amino acid sequence set forth as one of SEQ ID NO: 11, and the framework regions of the VL comprise up to 10 (such as up to 1, up to 2, up to 3, up to 4, up to 5, up to 6, up to 7, up to 8, or up to 9) amino acid substitutions (such as conservative amino acid substitutions) compared to the amino acid sequence set forth as one of SEQ ID NO: 12, and the antibody
- the antibody or antigen binding fragment comprises a VH comprising the amino acid sequence set forth as SEQ ID NO: 11, and specifically binds to PfCSP and neutralizes P. falciparum.
- the antibody or antigen binding fragment comprises a V L comprising the amino acid sequence set forth as SEQ ID NO: 12, and specifically binds to PfCSP and neutralizes P. falciparum.
- the antibody or antigen binding fragment comprises a VH and a VL comprising the amino acid sequences set forth as SEQ ID NOs: 11 and 12, respectively, and specifically binds to PfCSP and neutralizes P. falciparum.
- the disclosed antibodies and antigen binding fragments inhibit the invasion of Plasmodium falciparum sporozoites into human liver cells, and/or reduce pathogen load Plasmodium falciparum in a subject, compared to a control.
- the antibody or antigen binding fragment is based on or derived from the MAD22- 38 antibody, and specifically binds to PfCSP and neutralizes P. falciparum.
- the antibody or antigen binding fragment comprises a V H and a V L comprising the HCDR1, the HCDR2, and the HCDR3, and the LCDR1, the LCDR2, and the LCDR3, respectively (for example, according to IMGT, Kabat, or Chothia), of the MAD22-38 antibody, and specifically binds to PfCSP and neutralizes P. falciparum.
- the antibody or antigen binding fragment comprises a VH comprising an amino acid sequence at least 90% (such as at least 95%, at least 96%, at least 97%, at least 98%, or at least 99%) identical to the amino acid sequence set forth as SEQ ID NO: 13, and specifically binds to PfCSP and neutralizes P. falciparum.
- the antibody or antigen binding fragment comprises a V L comprising an amino acid sequence at least 90% (such as at least 95%, at least 96%, at least 97%, at least 98%, or at least 99%) identical to the amino acid sequence set forth as SEQ ID NO: 14, and specifically binds to PfCSP and neutralizes P. falciparum.
- the antibody or antigen binding fragment comprises a VH and a VL independently comprising amino acid sequences at least 90% (such as at least 95%, at least 96%, at least 97%, at least 98%, or at least 99%) identical to the amino acid sequences set forth as SEQ ID NOs: 13 and 14, respectively, and specifically binds to PfCSP and neutralizes P. falciparum.
- the antibody or antigen binding fragment comprises a VH comprising a HCDR1, a HCDR2, and a HCDR3 as set forth as SEQ ID NOs: 40, 41, and 42, respectively, and a VL comprising a LCDR1, a LCDR2, and a LCDR3 as set forth as SEQ ID NOs: 43, 44, and 45, respectively, and specifically binds to PfCSP and neutralizes P. falciparum.
- the antibody or antigen binding fragment comprises a V H comprising a HCDR1, a HCDR2, and a HCDR3 as set forth as SEQ ID NOs: 40, 41, and 42, respectively, a V L comprising a LCDR1, a LCDR2, and a LCDR3 as set forth as SEQ ID NOs: 43, 44, and 45, respectively, wherein the VH comprises an amino acid sequence at least 90% identical to SEQ ID NO: 13 (such as 95%, 96%, 97%, 98% or 99% identical to SEQ ID NO: 13), the VL comprises an amino acid sequence at least 90% identical to SEQ ID NO: 14 (such as 95%, 96%, 97%, 98% or 99% identical to SEQ ID NO: 14 and the antibody or antigen binding fragment specifically binds to PfCSP and neutralizes P.
- VH comprises an amino acid sequence at least 90% identical to SEQ ID NO: 13 (such as 95%, 96%, 97%, 98% or 99% identical to SEQ ID NO: 13)
- the antibody or antigen binding fragment comprises a V H comprising a HCDR1, a HCDR2, and a HCDR3 as set forth as SEQ ID NOs: 40, 41, and 42, respectively, a VL comprising a LCDR1, a LCDR2, and a LCDR3 as set forth as SEQ ID NOs: 43, 44, and 45, respectively, wherein the framework regions of the VH comprise up to 10 (such as up to 1, up to 2, up to 3, up to 4, up to 5, up to 6, up to 7, up to 8, or up to 9) amino acid substitutions (such as conservative amino acid substitutions) compared to the amino acid sequence set forth as one of SEQ ID NO: 13, and the framework regions of the V L comprise up to 10 (such as up to 1, up to 2, up to 3, up to 4, up to 5, up to 6, up to 7, up to 8, or up to 9) amino acid substitutions (such as conservative amino acid substitutions) compared to the amino acid sequence set forth as one of SEQ ID NO: 14, and the
- the antibody or antigen binding fragment comprises a VH comprising the amino acid sequence set forth as SEQ ID NO: 13, and specifically binds to PfCSP and neutralizes P. falciparum.
- the antibody or antigen binding fragment comprises a V L comprising the amino acid sequence set forth as SEQ ID NO: 14, and specifically binds to PfCSP and neutralizes P. falciparum.
- the antibody or antigen binding fragment comprises a VH and a VL comprising the amino acid sequences set forth as SEQ ID NOs: 13 and 14, respectively, and specifically binds to PfCSP and neutralizes P. falciparum.
- the disclosed antibodies and antigen binding fragments inhibit the invasion of Plasmodium falciparum sporozoites into human liver cells, and/or reduce pathogen load Plasmodium falciparum in a subject, compared to a control.
- the antibody or antigen binding fragment is based on or derived from the MAD22- 39 antibody, and specifically binds to PfCSP and neutralizes P. falciparum.
- the antibody or antigen binding fragment comprises a V H and a V L comprising the HCDR1, the HCDR2, and the HCDR3, and the LCDR1, the LCDR2, and the LCDR3, respectively (for example, according to IMGT, Kabat, or Chothia), of the MAD22-39 antibody, and specifically binds to PfCSP and neutralizes P. falciparum.
- the antibody or antigen binding fragment comprises a VH comprising an amino acid sequence at least 90% (such as at least 95%, at least 96%, at least 97%, at least 98%, or at least 99%) identical to the amino acid sequence set forth as SEQ ID NO: 15, and specifically binds to PfCSP and neutralizes P. falciparum.
- the antibody or antigen binding fragment comprises a V L comprising an amino acid sequence at least 90% (such as at least 95%, at least 96%, at least 97%, at least 98%, or at least 99%) identical to the amino acid sequence set forth as SEQ ID NO: 16, and specifically binds to PfCSP and neutralizes P. falciparum.
- the antibody or antigen binding fragment comprises a VH and a VL independently comprising amino acid sequences at least 90% (such as at least 95%, at least 96%, at least 97%, at least 98%, or at least 99%) identical to the amino acid sequences set forth as SEQ ID NOs: 15 and 16, respectively, and specifically binds to PfCSP and neutralizes P. falciparum.
- the antibody or antigen binding fragment comprises a VH comprising a HCDR1, a HCDR2, and a HCDR3 as set forth as SEQ ID NOs: 46, 47, and 48, respectively, and a VL comprising a LCDR1, a LCDR2, and a LCDR3 as set forth as SEQ ID NOs: 49, 44, and 45, respectively, and specifically binds to PfCSP and neutralizes P. falciparum.
- the antibody or antigen binding fragment comprises a V H comprising a HCDR1, a HCDR2, and a HCDR3 as set forth as SEQ ID NOs: 46, 47, and 48, respectively, a V L comprising a LCDR1, a LCDR2, and a LCDR3 as set forth as SEQ ID NOs: 49, 44, and 45, respectively, wherein the VH comprises an amino acid sequence at least 90% identical to SEQ ID NO: 15 (such as 95%, 96%, 97%, 98% or 99% identical to SEQ ID NO: 15), the VL comprises an amino acid sequence at least 90% identical to SEQ ID NO: 16 (such as 95%, 96%, 97%, 98% or 99% identical to SEQ ID NO: 16 and the antibody or antigen binding fragment specifically binds to PfCSP and neutralizes P.
- VH comprises an amino acid sequence at least 90% identical to SEQ ID NO: 15 (such as 95%, 96%, 97%, 98% or 99% identical to SEQ ID NO: 15)
- the antibody or antigen binding fragment comprises a V H comprising a HCDR1, a HCDR2, and a HCDR3 as set forth as SEQ ID NOs: 46, 47, and 48, respectively, a VL comprising a LCDR1, a LCDR2, and a LCDR3 as set forth as SEQ ID NOs: 49, 44, and 45, respectively, wherein the framework regions of the VH comprise up to 10 (such as up to 1, up to 2, up to 3, up to 4, up to 5, up to 6, up to 7, up to 8, or up to 9) amino acid substitutions (such as conservative amino acid substitutions) compared to the amino acid sequence set forth as one of SEQ ID NO: 15, and the framework regions of the V L comprise up to 10 (such as up to 1, up to 2, up to 3, up to 4, up to 5, up to 6, up to 7, up to 8, or up to 9) amino acid substitutions (such as conservative amino acid substitutions) compared to the amino acid sequence set forth as one of SEQ ID NO: 16, and the
- the antibody or antigen binding fragment comprises a VH comprising the amino acid sequence set forth as SEQ ID NO: 15, and specifically binds to PfCSP and neutralizes P. falciparum.
- the antibody or antigen binding fragment comprises a V L comprising the amino acid sequence set forth as SEQ ID NO: 16, and specifically binds to PfCSP and neutralizes P. falciparum.
- the antibody or antigen binding fragment comprises a VH and a VL comprising the amino acid sequences set forth as SEQ ID NOs: 15 and 16, respectively, and specifically binds to PfCSP and neutralizes P. falciparum.
- the disclosed antibodies and antigen binding fragments inhibit the invasion of Plasmodium falciparum sporozoites into human liver cells, and/or reduce pathogen load Plasmodium falciparum in a subject, compared to a control.
- the antibody or antigen binding fragment is based on or derived from the MAD24- 01 antibody, and specifically binds to PfCSP and neutralizes P. falciparum.
- the antibody or antigen binding fragment comprises a V H and a V L comprising the HCDR1, the HCDR2, and the HCDR3, and the LCDR1, the LCDR2, and the LCDR3, respectively (for example, according to IMGT, Kabat, or Chothia), of the MAD24-01 antibody, and specifically binds to PfCSP and neutralizes P. falciparum.
- the antibody or antigen binding fragment comprises a VH comprising an amino acid sequence at least 90% (such as at least 95%, at least 96%, at least 97%, at least 98%, or at least 99%) identical to the amino acid sequence set forth as SEQ ID NO: 17, and specifically binds to PfCSP and neutralizes P. falciparum.
- the antibody or antigen binding fragment comprises a V L comprising an amino acid sequence at least 90% (such as at least 95%, at least 96%, at least 97%, at least 98%, or at least 99%) identical to the amino acid sequence set forth as SEQ ID NO: 18, and specifically binds to PfCSP and neutralizes P. falciparum.
- the antibody or antigen binding fragment comprises a VH and a VL independently comprising amino acid sequences at least 90% (such as at least 95%, at least 96%, at least 97%, at least 98%, or at least 99%) identical to the amino acid sequences set forth as SEQ ID NOs: 17 and 18, respectively, and specifically binds to PfCSP and neutralizes P. falciparum.
- the antibody or antigen binding fragment comprises a VH comprising a HCDR1, a HCDR2, and a HCDR3 as set forth as SEQ ID NOs: 50, 51, and 52, respectively, and a VL comprising a LCDR1, a LCDR2, and a LCDR3 as set forth as SEQ ID NOs: 53, 54, and 55, respectively, and specifically binds to PfCSP and neutralizes P. falciparum.
- the antibody or antigen binding fragment comprises a V H comprising a HCDR1, a HCDR2, and a HCDR3 as set forth as SEQ ID NOs: 50, 51, and 52, respectively, a VL comprising a LCDR1, a LCDR2, and a LCDR3 as set forth as SEQ ID NOs: 53, 54, and 55, respectively, wherein the VH comprises an amino acid sequence at least 90% identical to SEQ ID NO: 17 (such as 95%, 96%, 97%, 98% or 99% identical to SEQ ID NO: 17), the VL comprises an amino acid sequence at least 90% identical to SEQ ID NO: 18 (such as 95%, 96%, 97%, 98% or 99% identical to SEQ ID NO: 18 and the antibody or antigen binding fragment specifically binds to PfCSP and neutralizes P.
- VH comprises an amino acid sequence at least 90% identical to SEQ ID NO: 17 (such as 95%, 96%, 97%, 98% or 99% identical to SEQ ID NO: 17)
- the antibody or antigen binding fragment comprises a VH comprising a HCDR1, a HCDR2, and a HCDR3 as set forth as SEQ ID NOs: 50, 51, and 52, respectively, a VL comprising a LCDR1, a LCDR2, and a LCDR3 as set forth as SEQ ID NOs: 53, 54, and 55, respectively, wherein the framework regions of the VH comprise up to 10 (such as up to 1, up to 2, up to 3, up to 4, up to 5, up to 6, up to 7, up to 8, or up to 9) amino acid substitutions (such as conservative amino acid substitutions) compared to the amino acid sequence set forth as one of SEQ ID NO: 17, and the framework regions of the V L comprise up to 10 (such as up to 1, up to 2, up to 3, up to 4, up to 5, up to 6, up to 7, up to 8, or up to 9) amino acid substitutions (such as conservative amino acid substitutions) compared to the amino acid sequence set forth as one of SEQ ID NO: 18, and the
- the antibody or antigen binding fragment comprises a V H comprising the amino acid sequence set forth as SEQ ID NO: 17, and specifically binds to PfCSP and neutralizes P. falciparum.
- the antibody or antigen binding fragment comprises a VL comprising the amino acid sequence set forth as SEQ ID NO: 18, and specifically binds to PfCSP and neutralizes P. falciparum.
- the antibody or antigen binding fragment comprises a VH and a VL comprising the amino acid sequences set forth as SEQ ID NOs: 17 and 18, respectively, and specifically binds to PfCSP and neutralizes P. falciparum.
- the disclosed antibodies and antigen binding fragments inhibit the invasion of Plasmodium falciparum sporozoites into human liver cells, and/or reduce pathogen load Plasmodium falciparum in a subject, compared to a control.
- the antibody or antigen binding fragment is based on or derived from the MAD24- 05 antibody, and specifically binds to PfCSP and neutralizes P. falciparum.
- the antibody or antigen binding fragment comprises a V H and a V L comprising the HCDR1, the HCDR2, and the HCDR3, and the LCDR1, the LCDR2, and the LCDR3, respectively (for example, according to IMGT, Kabat, or Chothia), of the MAD24-05 antibody, and specifically binds to PfCSP and neutralizes P. falciparum.
- the antibody or antigen binding fragment comprises a VH comprising an amino acid sequence at least 90% (such as at least 95%, at least 96%, at least 97%, at least 98%, or at least 99%) identical to the amino acid sequence set forth as SEQ ID NO: 17, and specifically binds to PfCSP and neutralizes P. falciparum.
- the antibody or antigen binding fragment comprises a V L comprising an amino acid sequence at least 90% (such as at least 95%, at least 96%, at least 97%, at least 98%, or at least 99%) identical to the amino acid sequence set forth as SEQ ID NO: 18, and specifically binds to PfCSP and neutralizes P. falciparum.
- the antibody or antigen binding fragment comprises a VH and a VL independently comprising amino acid sequences at least 90% (such as at least 95%, at least 96%, at least 97%, at least 98%, or at least 99%) identical to the amino acid sequences set forth as SEQ ID NOs: 17 and 18, respectively, and specifically binds to PfCSP and neutralizes P. falciparum.
- the antibody or antigen binding fragment comprises a VH comprising a HCDR1, a HCDR2, and a HCDR3 as set forth as SEQ ID NOs: 56, 57, and 58, respectively, and a VL comprising a LCDR1, a LCDR2, and a LCDR3 as set forth as SEQ ID NOs: 59, 60, and 61, respectively, and specifically binds to PfCSP and neutralizes P. falciparum.
- the antibody or antigen binding fragment comprises a V H comprising a HCDR1, a HCDR2, and a HCDR3 as set forth as SEQ ID NOs: 56, 57, and 58, respectively, a VL comprising a LCDR1, a LCDR2, and a LCDR3 as set forth as SEQ ID NOs: 59, 60, and 61, respectively, wherein the VH comprises an amino acid sequence at least 90% identical to SEQ ID NO: 17 (such as 95%, 96%, 97%, 98% or 99% identical to SEQ ID NO: 17), the V L comprises an amino acid sequence at least 90% identical to SEQ ID NO: 18 (such as 95%, 96%, 97%, 98% or 99% identical to SEQ ID NO: 18 and the antibody or antigen binding fragment specifically binds to PfCSP and neutralizes P.
- VH comprises an amino acid sequence at least 90% identical to SEQ ID NO: 17 (such as 95%, 96%, 97%, 98% or 99% identical to SEQ ID NO
- the antibody or antigen binding fragment comprises a VH comprising a HCDR1, a HCDR2, and a HCDR3 as set forth as SEQ ID NOs: 56, 57, and 58, respectively, a VL comprising a LCDR1, a LCDR2, and a LCDR3 as set forth as SEQ ID NOs: 59, 60, and 61, respectively, wherein the framework regions of the VH comprise up to 10 (such as up to 1, up to 2, up to 3, up to 4, up to 5, up to 6, up to 7, up to 8, or up to 9) amino acid substitutions (such as conservative amino acid substitutions) compared to the amino acid sequence set forth as one of SEQ ID NO: 17, and the framework regions of the V L comprise up to 10 (such as up to 1, up to 2, up to 3, up to 4, up to 5, up to 6, up to 7, up to 8, or up to 9) amino acid substitutions (such as conservative amino acid substitutions) compared to the amino acid sequence set forth as one of SEQ ID NO:
- the antibody or antigen binding fragment comprises a V H comprising the amino acid sequence set forth as SEQ ID NO: 17, and specifically binds to PfCSP and neutralizes P. falciparum.
- the antibody or antigen binding fragment comprises a V L comprising the amino acid sequence set forth as SEQ ID NO: 18, and specifically binds to PfCSP and neutralizes P. falciparum.
- the antibody or antigen binding fragment comprises a VH and a VL comprising the amino acid sequences set forth as SEQ ID NOs: 17 and 18, respectively, and specifically binds to PfCSP and neutralizes P. falciparum.
- the disclosed antibodies and antigen binding fragments inhibit the invasion of Plasmodium falciparum sporozoites into human liver cells, and/or reduce pathogen load Plasmodium falciparum in a subject, compared to a control.
- MAD24-52 In some aspects, the antibody or antigen binding fragment is based on or derived from the MAD24- 52 antibody, and specifically binds to PfCSP and neutralizes P. falciparum.
- the antibody or antigen binding fragment comprises a V H and a V L comprising the HCDR1, the HCDR2, and the HCDR3, and the LCDR1, the LCDR2, and the LCDR3, respectively (for example, according to IMGT, Kabat, or Chothia), of the MAD24-52 antibody, and specifically binds to PfCSP and neutralizes P. falciparum.
- the antibody or antigen binding fragment comprises a VH comprising an amino acid sequence at least 90% (such as at least 95%, at least 96%, at least 97%, at least 98%, or at least 99%) identical to the amino acid sequence set forth as SEQ ID NO: 19, and specifically binds to PfCSP and neutralizes P. falciparum.
- the antibody or antigen binding fragment comprises a V L comprising an amino acid sequence at least 90% (such as at least 95%, at least 96%, at least 97%, at least 98%, or at least 99%) identical to the amino acid sequence set forth as SEQ ID NO: 20, and specifically binds to PfCSP and neutralizes P. falciparum.
- the antibody or antigen binding fragment comprises a V H and a V L independently comprising amino acid sequences at least 90% (such as at least 95%, at least 96%, at least 97%, at least 98%, or at least 99%) identical to the amino acid sequences set forth as SEQ ID NOs: 19 and 20, respectively, and specifically binds to PfCSP and neutralizes P. falciparum.
- the antibody or antigen binding fragment comprises a VH comprising a HCDR1, a HCDR2, and a HCDR3 as set forth as SEQ ID NOs: 62, 63, and 64, respectively, and a VL comprising a LCDR1, a LCDR2, and a LCDR3 as set forth as SEQ ID NOs: 65, 66, and 67, respectively, and specifically binds to PfCSP and neutralizes P. falciparum.
- the antibody or antigen binding fragment comprises a V H comprising a HCDR1, a HCDR2, and a HCDR3 as set forth as SEQ ID NOs: 62, 63, and 64, respectively, a VL comprising a LCDR1, a LCDR2, and a LCDR3 as set forth as SEQ ID NOs: 65, 66, and 67, respectively, wherein the VH comprises an amino acid sequence at least 90% identical to SEQ ID NO: 19 (such as 95%, 96%, 97%, 98% or 99% identical to SEQ ID NO: 19), the VL comprises an amino acid sequence at least 90% identical to SEQ ID NO: 20 (such as 95%, 96%, 97%, 98% or 99% identical to SEQ ID NO: 20 and the antibody or antigen binding fragment specifically binds to PfCSP and neutralizes P.
- VH comprises an amino acid sequence at least 90% identical to SEQ ID NO: 19 (such as 95%, 96%, 97%, 98% or 99% identical to SEQ ID NO
- the antibody or antigen binding fragment comprises a V H comprising a HCDR1, a HCDR2, and a HCDR3 as set forth as SEQ ID NOs: 62, 63, and 64, respectively, a VL comprising a LCDR1, a LCDR2, and a LCDR3 as set forth as SEQ ID NOs: 65, 66, and 67, respectively, wherein the framework regions of the VH comprise up to 10 (such as up to 1, up to 2, up to 3, up to 4, up to 5, up to 6, up to 7, up to 8, or up to 9) amino acid substitutions (such as conservative amino acid substitutions) compared to the amino acid sequence set forth as one of SEQ ID NO: 19, and the framework regions of the V L comprise up to 10 (such as up to 1, up to 2, up to 3, up to 4, up to 5, up to 6, up to 7, up to 8, or up to 9) amino acid substitutions (such as conservative amino acid substitutions) compared to the amino acid sequence set forth as one of SEQ ID NO:
- the antibody or antigen binding fragment comprises a VH comprising the amino acid sequence set forth as SEQ ID NO: 19, and specifically binds to PfCSP and neutralizes P. falciparum.
- the antibody or antigen binding fragment comprises a V L comprising the amino acid sequence set forth as SEQ ID NO: 20, and specifically binds to PfCSP and neutralizes P. falciparum.
- the antibody or antigen binding fragment comprises a VH and a VL comprising the amino acid sequences set forth as SEQ ID NOs: 19 and 20, respectively, and specifically binds to PfCSP and neutralizes P. falciparum.
- the disclosed antibodies and antigen binding fragments inhibit the invasion of Plasmodium falciparum sporozoites into human liver cells, and/or reduce pathogen load Plasmodium falciparum in a subject, compared to a control.
- the antibody or antigen binding fragment can be a human antibody or fragment thereof. Chimeric antibodies are also provided.
- the antibody or antigen binding fragment can include any suitable framework region, such as (but not limited to) a human framework region.
- a heterologous framework region such as, but not limited to a mouse or monkey framework region, can be included in the heavy or light chain of the antibodies.
- the antibody can be of any isotype.
- the antibody can be, for example, an IgM or an IgG antibody, such as IgG1, IgG2, IgG3, or IgG4.
- the class of an antibody that specifically binds PfCSP can be switched with another.
- a nucleic acid molecule encoding V L or V H is isolated such that it does not include any nucleic acid sequences encoding the constant region of the light or heavy chain, respectively.
- a nucleic acid molecule encoding VL or VH is then operatively linked to a nucleic acid sequence encoding a CL or CH from a different class of immunoglobulin molecule. This can be achieved, for example, using a vector or nucleic acid molecule that comprises a CL or CH chain.
- an antibody that specifically binds PfCSP, that was originally IgG may be class switched to an IgM. Class switching can be used to convert one IgG subclass to another, such as from IgG 1 to IgG 2, IgG 3, or IgG 4 .
- exemplary full-length heavy and light chain sequences containing the MAD21-101 VH and VL are provided as SEQ ID NOs: 157 and 158, respectively.
- the disclosed antibodies are oligomers of antibodies, such as dimers, trimers, tetramers, pentamers, hexamers, septamers, octomers and so on.
- the antibody or antigen binding fragment can be derivatized or linked to another molecule (such as another peptide or protein).
- the antibody or antigen binding fragment is derivatized such that the binding to P. falciparum is not affected adversely by the derivatization or labeling.
- the antibody or antigen binding fragment can be functionally linked (by chemical coupling, genetic fusion, noncovalent association or otherwise) to one or more other molecular entities, such as another antibody (for example, a bi-specific antibody or a diabody), a detectable marker, an effector molecule, or a protein or peptide that can mediate association of the antibody or antibody portion with another molecule (such as a streptavidin core region or a polyhistidine tag).
- the antibody or antigen binding fragment specifically binds PfCSP with an affinity (e.g., measured by KD) of no more than 1.0 x 10 -8 M, no more than 5.0 x 10 -8 M, no more than 1.0 x 10 -9 M, no more than 5.0 x 10 -9 M, no more than 1.0 x 10 -10 M, no more than 5.0 x 10 -10 M, or no more than 1.0 x 10 -11 M.
- K D can be measured, for example, by a radiolabeled antigen binding assay (RIA) performed with the Fab version of an antibody of interest and its antigen.
- RIA radiolabeled antigen binding assay
- solution binding affinity of Fabs for antigen is measured by equilibrating Fab with a minimal concentration of ( 125 I)-labeled antigen in the presence of a titration series of unlabeled antigen, then capturing bound antigen with an anti-Fab antibody-coated plate (see, e.g., Chen et al., J. Mol. Biol.293(4):865-881, 1999).
- MICROTITER® multi-well plates (Thermo Scientific) are coated overnight with 5 ⁇ g/ml of a capturing anti-Fab antibody (Cappel Labs) in 50 mM sodium carbonate (pH 9.6), and subsequently blocked with 2% (w/v) bovine serum albumin in PBS for two to five hours at room temperature (approximately 23° C.).
- a non-adsorbent plate (NuncTM Catalog #269620) 100 ⁇ M or 26 pM [ 125 I]-antigen are mixed with serial dilutions of a Fab of interest (e.g., consistent with assessment of the anti-VEGF antibody, Fab-12, in Presta et al., Cancer Res.57(20):4593-4599, 1997).
- the Fab of interest is then incubated overnight; however, the incubation may continue for a longer period (e.g., about 65 hours) to ensure that equilibrium is reached. Thereafter, the mixtures are transferred to the capture plate for incubation at room temperature (e.g., for one hour).
- K D can be measured using surface plasmon resonance assays using a BIACORE®- 2000 or a BIACORE®-3000 (BIAcore, Inc., Piscataway, N.J.) at 25° C with immobilized antigen CM5 chips at ⁇ 10 response units (RU). Briefly, carboxymethylated dextran biosensor chips (CM5, BIACORE®, Inc.) are activated with N-ethyl-N′-(3-dimethylaminopropyl)-carbodiimide hydrochloride (EDC) and N- hydroxysuccinimide (NHS) according to the supplier's instructions.
- CM5 carboxymethylated dextran biosensor chips
- EDC N-ethyl-N′-(3-dimethylaminopropyl)-carbodiimide hydrochloride
- NHS N- hydroxysuccinimide
- Antigen is diluted with 10 mM sodium acetate, pH 4.8, to 5 ⁇ g/ml ( ⁇ 0.2 ⁇ M) before injection at a flow rate of 5 l/minute to achieve approximately 10 response units (RU) of coupled protein. Following the injection of antigen, 1 M ethanolamine is injected to block unreacted groups. For kinetics measurements, two-fold serial dilutions of Fab (0.78 nM to 500 nM) are injected in PBS with 0.05% polysorbate 20 (TWEEN-20TM) surfactant (PBST) at 25° C at a flow rate of approximately 25 l/min.
- TWEEN-20TM polysorbate 20
- association rates (kon) and dissociation rates (koff) are calculated using a simple one-to-one Langmuir binding model (BIACORE® Evaluation Software version 3.2) by simultaneously fitting the association and dissociation sensorgrams.
- the equilibrium dissociation constant (KD) is calculated as the ratio koff/kon. See, e.g., Chen et al., J. Mol. Biol.293:865-881 (1999).
- a multi-specific antibody such as a bi-specific antibody, is provided that comprises an antibody or antigen binding fragment as provided herein, and specifically binds to PfCSP.
- Any suitable method can be used to design and produce the multi-specific antibody, such as crosslinking two or more antibodies, antigen binding fragments (such as scFvs) of the same type or of different types.
- Exemplary methods of making multispecific antibodies include those described in PCT Pub. No. WO2013/163427.
- Non-limiting examples of suitable crosslinkers include those that are heterobifunctional, having two distinctly reactive groups separated by an appropriate spacer (such as m-maleimidobenzoyl-N- hydroxysuccinimide ester) or homobifunctional (such as disuccinimidyl suberate).
- the multi-specific antibody may have any suitable format that allows for antigen binding by the antibody or antigen binding fragment as provided herein, such as any one of MAD21-17, MAD21-46, MAD21-53, MAD21-95, MAD21-101, MAD22-17, MAD22-38, MAD22-39, MAD24-01, MAD24-05, or MAD24-52, or an antigen binding fragment thereof.
- Bispecific single chain antibodies can be encoded by a single nucleic acid molecule.
- Non-limiting examples of bispecific single chain antibodies, as well as methods of constructing such antibodies are provided in U.S. Pat. Nos.8,076,459, 8,017,748, 8,007,796, 7,919,089, 7,820,166, 7,635,472, 7,575,923, 7,435,549, 7,332,168, 7,323,440, 7,235,641, 7,229,760, 7,112,324, 6,723,538. Additional examples of bispecific single chain antibodies can be found in PCT application No. WO 99/54440; Mack et al., J. Immunol., 158(8):3965-3970, 1997; Mack et al., Proc.
- bispecific Fab-scFv (“bibody”) molecules are described, for example, in Schoonjans et al. (J. Immunol., 165(12):7050-7057, 2000) and Willems et al. (J. Chromatogr. B Analyt. Technol.
- a scFv molecule can be fused to one of the VL-CL (L) or VH- CH1 chains, e.g., to produce a bibody one scFv is fused to the C-term of a Fab chain.
- Fragments Antigen binding fragments are encompassed by the present disclosure, such as Fab, F(ab')2, and Fv which include a heavy chain and VL and specifically bind PfCSP. These antibody fragments retain the ability to selectively bind with the antigen and are “antigen-binding” fragments.
- Non-limiting examples of such fragments include: (1) Fab, the fragment which contains a monovalent antigen-binding fragment of an antibody molecule, can be produced by digestion of whole antibody with the enzyme papain to yield an intact light chain and a portion of one heavy chain; (2) Fab', the fragment of an antibody molecule can be obtained by treating whole antibody with pepsin, followed by reduction, to yield an intact light chain and a portion of the heavy chain; (3) (Fab')2, the fragment of the antibody that can be obtained by treating whole antibody with the enzyme pepsin without subsequent reduction; F(ab') 2 is a dimer of two Fab' fragments held together by two disulfide bonds; (4) Fv, a genetically engineered fragment containing the VL and VL expressed as two chains; and (5) Single chain antibody (such as scFv), defined as a genetically engineered molecule containing the V H and the V L linked by a suitable polypeptide linker as a genetically fused single chain molecule (see, e.g.,
- VH-domain-linker domain-VL-domain VL-domain-linker domain-VH-domain
- scFV2 A dimer of a single chain antibody
- Antigen binding fragments can be prepared by proteolytic hydrolysis of the antibody or by expression in a host cell (such as an E. coli cell) of DNA encoding the fragment.
- Antigen binding fragments can also be obtained by pepsin or papain digestion of whole antibodies by conventional methods. For example, antigen binding fragments can be produced by enzymatic cleavage of antibodies with pepsin to provide a 5S fragment denoted F(ab') 2 .
- This fragment can be further cleaved using a thiol reducing agent, and optionally a blocking group for the sulfhydryl groups resulting from cleavage of disulfide linkages, to produce 3.5S Fab' monovalent fragments.
- Other methods of cleaving antibodies such as separation of heavy chains to form monovalent light- heavy chain fragments, further cleavage of fragments, or other enzymatic, chemical, or genetic techniques may also be used, so long as the fragments bind to the antigen that is recognized by the intact antibody.
- amino acid sequence variants of the antibodies and antigen binding fragments provided herein are provided. For example, it may be desirable to improve the binding affinity and/or other biological properties of the antibody.
- Amino acid sequence variants of an antibody may be prepared by introducing appropriate modifications into the nucleotide sequence encoding the antibody, or by peptide synthesis. Such modifications include, for example, deletions from, and/or insertions into and/or substitutions of residues within the amino acid sequences of the antibody. Any combination of deletion, insertion, and substitution can be made to arrive at the final construct, provided that the final construct possesses the desired characteristics, e.g., antigen-binding. In some aspects, antibody variants having one or more amino acid substitutions are provided. Sites of interest for substitutional mutagenesis include the CDRs and the framework regions.
- Amino acid substitutions may be introduced into an antibody of interest and the products screened for a desired activity, e.g., retained/improved antigen binding, decreased immunogenicity, or improved ADCC or CDC.
- the variants typically retain amino acid residues necessary for correct folding and stabilizing between the VH and the VL regions, and will retain the charge characteristics of the residues in order to preserve the low pI and low toxicity of the molecules.
- Amino acid substitutions can be made in the V H and the V L regions to increase yield.
- the antibody or antigen binding fragment can include up to 10 (such as up to 1, up to 2, up to 3, up to 4, up to 5, up to 6, up to 7, up to 8, or up to 9) amino acid substitutions (such as conservative amino acid substitutions) in the framework regions of the heavy chain of the antibody, or the light chain of the antibody, or the heavy and light chains of the antibody, compared to known framework regions, or compared to the framework regions of an antibody as provided herein, and maintain the specific binding activity for PfCSP.
- substitutions, insertions, or deletions may occur within one or more CDRs so long as such alterations do not substantially reduce the ability of the antibody to bind antigen.
- each CDR either is unaltered, or contains no more than one, two or three amino acid substitutions.
- the V L and V H segments can be randomly mutated, such as within HCDR3 region or the LCDR3 region, in a process analogous to the in vivo somatic mutation process responsible for affinity maturation of antibodies during a natural immune response.
- in vitro affinity maturation can be accomplished by amplifying VH and VL regions using PCR primers complementary to the HCDR3 or LCDR3, respectively.
- the primers have been “spiked” with a random mixture of the four nucleotide bases at certain positions such that the resultant PCR products encode V H and V L segments into which random mutations have been introduced into the V H and/or V L CDR3 regions. These randomly mutated V H and V L segments can be tested to determine the binding affinity for PfCSP.
- an antibody or antigen binding fragment is altered to increase or decrease the extent to which the antibody or antigen binding fragment is glycosylated. Addition or deletion of glycosylation sites may be conveniently accomplished by altering the amino acid sequence such that one or more glycosylation sites is created or removed. Where the antibody comprises an Fc region, the carbohydrate attached thereto may be altered.
- Native antibodies produced by mammalian cells typically comprise a branched, biantennary oligosaccharide that is generally attached by an N-linkage to Asn297 of the CH2 domain of the Fc region. See, e.g., Wright et al. Trends Biotechnol.15(1):26-32, 1997.
- the oligosaccharide may include various carbohydrates, e.g., mannose, N-acetyl glucosamine (GlcNAc), galactose, and sialic acid, as well as a fucose attached to a GlcNAc in the “stem” of the biantennary oligosaccharide structure.
- modifications of the oligosaccharide in an antibody may be made in order to create antibody variants with certain improved properties.
- antibody variants are provided having a carbohydrate structure that lacks fucose attached (directly or indirectly) to an Fc region.
- the amount of fucose in such antibody may be from 1% to 80%, from 1% to 65%, from 5% to 65% or from 20% to 40%.
- the amount of fucose is determined by calculating the average amount of fucose within the sugar chain at Asn297, relative to the sum of all glycostructures attached to Asn 297 (e.g.
- Asn297 refers to the asparagine residue located at about position 297 in the Fc region; however, Asn297 may also be located about ⁇ 3 amino acids upstream or downstream of position 297, i.e., between positions 294 and 300, due to minor sequence variations in antibodies. Such fucosylation variants may have improved ADCC function. See, e.g., US Patent Publication Nos. US 2003/0157108 (Presta, L.); US 2004/0093621 (Kyowa Hakko Kogyo Co., Ltd).
- Examples of publications related to “defucosylated” or “fucose-deficient” antibody variants include: US 2003/0157108; WO 2000/61739; WO 2001/29246; US 2003/0115614; US 2002/0164328; US 2004/0093621; US 2004/0132140; US 2004/0110704; US 2004/0110282; US 2004/0109865; WO 2003/085119; WO 2003/084570; WO 2005/035586; WO 2005/035778; WO2005/053742; WO 2002/031140; Okazaki et al., J. Mol.
- Antibody variants are further provided with bisected oligosaccharides, e.g., in which a biantennary oligosaccharide attached to the Fc region of the antibody is bisected by GlcNAc. Such antibody variants may have reduced fucosylation and/or improved ADCC function. Examples of such antibody variants are described, e.g., in WO 2003/011878 (Jean-Mairet et al.); U.S. Pat. No.6,602,684 (Umana et al.); and US 2005/0123546 (Umana et al.). Antibody variants with at least one galactose residue in the oligosaccharide attached to the Fc region are also provided.
- the constant region of the antibody (such as any one of MAD21-17, MAD21-46, MAD21-53, MAD21-95, MAD21-101, MAD22-17, MAD22-38, MAD22-39, MAD24-01, MAD24-05, or MAD24-52) comprises one or more amino acid substitutions to optimize in vivo half-life of the antibody.
- the serum half-life of IgG Abs is regulated by the neonatal Fc receptor (FcRn).
- the antibody comprises an amino acid substitution that increases binding to the FcRn.
- substitutions include substitutions at IgG constant regions T250Q and M428L (see, e.g., Hinton et al., J Immunol., 176(1):346-356, 2006); M428L and N434S (the “LS” mutation, see, e.g., Zalevsky, et al., Nature Biotechnol., 28(2):157-159, 2010); N434A (see, e.g., Petkova et al., Int.
- the disclosed antibodies (such as any one of MAD21-17, MAD21-46, MAD21-53, MAD21-95, MAD21-101, MAD22-17, MAD22-38, MAD22-39, MAD24-01, MAD24-05, or MAD24-52) and antigen binding fragments can be linked to or comprise an Fc polypeptide including any of the substitutions listed above, for example, the Fc polypeptide can include the M428L and N434S substitutions.
- the constant region of the antibody comprises one or more amino acid substitutions to optimize ADCC. ADCC is mediated primarily through a set of closely related Fc ⁇ receptors.
- the antibody comprises one or more amino acid substitutions that increase binding to Fc ⁇ RIIIa.
- Non-limiting examples of such substitutions include substitutions at IgG constant regions S239D and I332E (see, e.g., Lazar et al., Proc. Natl., Acad. Sci. U.S.A., 103(11):4005-4010, 2006); and S239D, A330L, and I332E (see, e.g., Lazar et al., Proc. Natl., Acad. Sci. U.S.A., 103(11):4005-4010, 2006). Combinations of the above substitutions are also included, to generate an IgG constant region with increased binding to FcRn and Fc ⁇ RIIIa. The combinations increase antibody half-life and ADCC.
- such combinations include antibodies with the following amino acid substitutions in the Fc region: (1) S239D/I332E and T250Q/M428L; (2) S239D/I332E and M428L/N434S; (3) S239D/I332E and N434A; (4) S239D/I332E and T307A/E380A/N434A; (5) S239D/I332E and M252Y/S254T/T256E; (6) S239D/A330L/I332E and 250Q/M428L; (7) S239D/A330L/I332E and M428L/N434S; (8) S239D/A330L/I332E and N434A; (9) S239D/A330L/I332E and T307A/E380A/N434A; or (10) S239D/A330L/I332E and M252Y/S254
- the antibodies, or an antigen binding fragment thereof is modified such that it is directly cytotoxic to infected cells, or uses natural defenses such as complement, ADCC, or phagocytosis by macrophages.
- an antibody provided herein may be further modified to contain additional nonproteinaceous moieties.
- the moieties suitable for derivatization of the antibody include but are not limited to water soluble polymers.
- Non-limiting examples of water soluble polymers include, but are not limited to, polyethylene glycol (PEG), copolymers of ethylene glycol/propylene glycol, carboxymethylcellulose, dextran, polyvinyl alcohol, polyvinyl pyrrolidone, poly-1,3-dioxolane, poly-1,3,6- trioxane, ethylene/maleic anhydride copolymer, polyaminoacids (either homopolymers or random copolymers), and dextran or poly(n-vinyl pyrrolidone)polyethylene glycol, propropylene glycol homopolymers, prolypropylene oxide/ethylene oxide co-polymers, polyoxyethylated polyols (e.g., glycerol), polyvinyl alcohol, and mixtures thereof.
- PEG polyethylene glycol
- copolymers of ethylene glycol/propylene glycol carboxymethylcellulose
- dextran polyvinyl alcohol
- Polyethylene glycol propionaldehyde may have advantages in manufacturing due to its stability in water.
- the polymer may be of any molecular weight, and may be branched or unbranched.
- the number of polymers attached to the antibody may vary, and if more than one polymer are attached, they can be the same or different molecules. In general, the number and/or type of polymers used for derivatization can be determined based on considerations including, but not limited to, the particular properties or functions of the antibody to be improved, whether the antibody derivative will be used in an application under defined conditions, etc. B.
- the antibodies and antigen binding fragments that specifically bind to PfCSP can be conjugated to an agent, such as an effector molecule or detectable marker. Both covalent and noncovalent attachment means may be used.
- an effector molecule and detectable markers can be used, including (but not limited to) toxins and radioactive agents such as 125 I, 32 P, 14 C, 3 H and 35 S and other labels, target moieties and ligands, etc.
- the choice of a particular effector molecule or detectable marker depends on the particular target molecule or cell, and the desired biological effect.
- the procedure for attaching an effector molecule or detectable marker to an antibody or antigen binding fragment varies according to the chemical structure of the effector.
- Polypeptides typically contain a variety of functional groups, such as carboxyl (-COOH), free amine (-NH 2 ) or sulfhydryl (-SH) groups, which are available for reaction with a suitable functional group on a polypeptide to result in the binding of the effector molecule or detectable marker.
- the antibody or antigen binding fragment is derivatized to expose or attach additional reactive functional groups. The derivatization may involve attachment of any suitable linker molecule.
- the linker is capable of forming covalent bonds to both the antibody or antigen binding fragment and to the effector molecule or detectable marker.
- Suitable linkers include, but are not limited to, straight or branched-chain carbon linkers, heterocyclic carbon linkers, or peptide linkers.
- the linkers may be joined to the constituent amino acids through their side chains (such as through a disulfide linkage to cysteine) or the alpha carbon, or through the amino, and/or carboxyl groups of the terminal amino acids.
- a suitable method for attaching a given agent to an antibody or antigen binding fragment or other polypeptide can be determined.
- the antibody or antigen binding fragment can be conjugated with a detectable marker; for example, a detectable marker capable of detection by ELISA, spectrophotometry, flow cytometry, microscopy or diagnostic imaging techniques (such as CT, computed axial tomography (CAT), MRI, magnetic resonance tomography (MTR), ultrasound, fiberoptic examination, and laparoscopic examination).
- detectable markers include fluorophores, chemiluminescent agents, enzymatic linkages, radioactive isotopes and heavy metals or compounds (for example super paramagnetic iron oxide nanocrystals for detection by MRI).
- useful detectable markers include fluorescent compounds, including fluorescein, fluorescein isothiocyanate, rhodamine, 5-dimethylamine-1-napthalenesulfonyl chloride, phycoerythrin, lanthanide phosphors and the like.
- Bioluminescent markers are also of use, such as luciferase, green fluorescent protein (GFP), and yellow fluorescent protein (YFP).
- An antibody or antigen binding fragment can also be conjugated with enzymes that are useful for detection, such as horseradish peroxidase, ⁇ - galactosidase, luciferase, alkaline phosphatase, glucose oxidase and the like.
- enzymes that are useful for detection
- an antibody or antigen binding fragment is conjugated with a detectable enzyme, it can be detected by adding additional reagents that the enzyme uses to produce a reaction product that can be discerned.
- the agent horseradish peroxidase is present, the addition of hydrogen peroxide and diaminobenzidine leads to a colored reaction product, which is visually detectable.
- An antibody or antigen binding fragment may also be conjugated with biotin, and detected through indirect measurement of avidin or streptavidin binding.
- the avidin itself can be conjugated with an enzyme or a fluorescent label.
- the antibody or antigen binding fragment can be conjugated with a paramagnetic agent, such as gadolinium. Paramagnetic agents such as superparamagnetic iron oxide are also of use as labels.
- Antibodies can also be conjugated with lanthanides (such as europium and dysprosium), and manganese.
- An antibody or antigen binding fragment may also be labeled with a predetermined polypeptide epitope recognized by a secondary reporter (such as leucine zipper pair sequences, binding sites for secondary antibodies, metal binding domains, epitope tags).
- the antibody or antigen binding fragment can also be conjugated with a radiolabeled amino acid, for example, for diagnostic purposes.
- the radiolabel may be used to detect PfCSP expressing cells by radiography, emission spectra, or other diagnostic techniques.
- labels for polypeptides include, but are not limited to, the following radioisotopes: 3 H, 14 C, 35 S, 90 Y, 99m Tc, 111 In, 125 I, 131 I.
- the radiolabels may be detected, for example, using photographic film or scintillation counters, fluorescent markers may be detected using a photodetector to detect emitted illumination.
- Enzymatic labels are typically detected by providing the enzyme with a substrate and detecting the reaction product produced by the action of the enzyme on the substrate, and colorimetric labels are detected by simply visualizing the colored label.
- the average number of effector molecule or detectable marker moieties per antibody or antigen binding fragment in a conjugate can range, for example, from 1 to 20 moieties per antibody or antigen binding fragment. In some aspects, the average number of effector molecules or detectable marker moieties per antibody or antigen binding fragment in a conjugate range from about 1 to about 2, from about 1 to about 3, about 1 to about 8; from about 2 to about 6; from about 3 to about 5; or from about 3 to about 4.
- the loading (for example, effector molecule per antibody ratio) of a conjugate may be controlled in different ways, for example, by: (i) limiting the molar excess of effector molecule-linker intermediate or linker reagent relative to antibody, (ii) limiting the conjugation reaction time or temperature, (iii) partial or limiting reducing conditions for cysteine thiol modification, (iv) engineering by recombinant techniques the amino acid sequence of the antibody such that the number and position of cysteine residues is modified for control of the number or position of linker-effector molecule attachments.
- Nucleic acid molecules for example, cDNA or RNA molecules encoding the amino acid sequences of antibodies, antigen binding fragments, and conjugates that specifically bind to PfCSP (such as any one of MAD21-17, MAD21-46, MAD21-53, MAD21-95, MAD21-101, MAD22-17, MAD22-38, MAD22-39, MAD24-01, MAD24-05, or MAD24-52) are provided. Nucleic acids encoding these molecules can readily be produced using the amino acid sequences provided herein (such as the CDR sequences and VH and VL sequences), sequences available in the art (such as framework or constant region sequences), and the genetic code.
- a nucleic acid molecules can encode the V H , the V L , or both the V H and V L (for example in a bicistronic expression vector) of a disclosed antibody or antigen binding fragment.
- the nucleic acid molecules can be expressed in a host cell (such as a mammalian cell) to produce a disclosed antibody or antigen binding fragment.
- Exemplary nucleic acid sequences encoding the heavy and light chain variable regions of the disclosed antibodies are provided as SEQ ID NOs: 73-94.
- the genetic code can be used to construct a variety of functionally equivalent nucleic acid sequences, such as nucleic acids which differ in sequence but which encode the same antibody sequence, or encode a conjugate or fusion protein including the VL and/or VH nucleic acid sequence.
- Nucleic acid molecules encoding the antibodies, antigen binding fragments, and conjugates that specifically bind to PfCSP can be prepared by any suitable method including, for example, cloning of appropriate sequences or by direct chemical synthesis by standard methods. Chemical synthesis produces a single stranded oligonucleotide. This can be converted into double stranded DNA by hybridization with a complementary sequence or by polymerization with a DNA polymerase using the single strand as a template.
- Exemplary nucleic acids can be prepared by cloning techniques. Examples of appropriate cloning and sequencing techniques can be found, for example, in Green and Sambrook (Molecular Cloning: A Laboratory Manual, 4 th ed., New York: Cold Spring Harbor Laboratory Press, 2012) and Ausubel et al. (Eds.) (Current Protocols in Molecular Biology, New York: John Wiley and Sons, including supplements). Nucleic acids can also be prepared by amplification methods. Amplification methods include the polymerase chain reaction (PCR), the ligase chain reaction (LCR), the transcription-based amplification system (TAS), and the self-sustained sequence replication system (3SR).
- PCR polymerase chain reaction
- LCR ligase chain reaction
- TAS transcription-based amplification system
- 3SR self-sustained sequence replication system
- the nucleic acid molecules can be expressed in a recombinantly engineered cell such as bacteria, plant, yeast, insect and mammalian cells.
- the antibodies, antigen binding fragments, and conjugates can be expressed as individual proteins including the V H and/or V L (linked to an effector molecule or detectable marker as needed), or can be expressed as a fusion protein. Any suitable method of expressing and purifying antibodies and antigen binding fragments may be used; non-limiting examples are provided in Al- Rubeai (Ed.), Antibody Expression and Production, Dordrecht; New York: Springer, 2011).
- An immunoadhesin can also be expressed.
- nucleic acids encoding a VH and VL, and immunoadhesin are provided.
- the nucleic acid sequences can optionally encode a leader sequence.
- the V H - and V L -encoding DNA fragments can be operatively linked to another fragment encoding a flexible linker, e.g., encoding the amino acid sequence (Gly 4 -Ser) 3 , such that the V H and VL sequences can be expressed as a contiguous single-chain protein, with the VL and VH domains joined by the flexible linker (see, e.g., Bird et al., Science, 242(4877):423-426, 1988; Huston et al., Proc. Natl. Acad. Sci.
- cleavage site can be included in a linker, such as a furin cleavage site.
- the single chain antibody may be monovalent, if only a single VH and VL are used, bivalent, if two VH and VL are used, or polyvalent, if more than two VH and VL are used. Bispecific or polyvalent antibodies may be generated that bind specifically to PfCSP and another antigen.
- the encoded VH and VL optionally can include a furin cleavage site between the VH and VL domains.
- One or more DNA sequences encoding the antibodies, antigen binding fragments, or conjugates can be expressed in vitro by DNA transfer into a suitable host cell.
- the cell may be prokaryotic or eukaryotic. Numerous expression systems available for expression of proteins including E.
- coli other bacterial hosts, yeast, and various higher eukaryotic cells such as the COS, CHO, HeLa and myeloma cell lines, can be used to express the disclosed antibodies and antigen binding fragments. Methods of stable transfer, meaning that the foreign DNA is continuously maintained in the host may be used. Hybridomas expressing the antibodies of interest are also encompassed by this disclosure.
- the expression of nucleic acids encoding the antibodies and antigen binding fragments described herein can be achieved by operably linking the DNA or cDNA to a promoter (which is either constitutive or inducible), followed by incorporation into an expression cassette.
- the promoter can be any promoter of interest, including a cytomegalovirus promoter.
- an enhancer such as a cytomegalovirus enhancer
- the cassettes can be suitable for replication and integration in either prokaryotes or eukaryotes.
- Typical expression cassettes contain specific sequences useful for regulation of the expression of the DNA encoding the protein.
- the expression cassettes can include appropriate promoters, enhancers, transcription and translation terminators, initiation sequences, a start codon (i.e., ATG) in front of a protein-encoding gene, splicing signals for introns, sequences for the maintenance of the correct reading frame of that gene to permit proper translation of mRNA, and stop codons.
- the vector can encode a selectable marker, such as a marker encoding drug resistance (for example, ampicillin or tetracycline resistance).
- a selectable marker such as a marker encoding drug resistance (for example, ampicillin or tetracycline resistance).
- drug resistance for example, ampicillin or tetracycline resistance
- expression cassettes which contain, for example, a strong promoter to direct transcription, a ribosome binding site for translational initiation (e.g., internal ribosomal binding sequences), and a transcription/translation terminator.
- a promoter such as the T7, trp, lac, or lambda promoters, a ribosome binding site, and preferably a transcription termination signal.
- control sequences can include a promoter and/or an enhancer derived from, for example, an immunoglobulin gene, HTLV, SV40 or cytomegalovirus, and a polyadenylation sequence, and can further include splice donor and/or acceptor sequences (for example, CMV and/or HTLV splice acceptor and donor sequences).
- the cassettes can be transferred into the chosen host cell by any suitable method such as transformation or electroporation for E. coli and calcium phosphate treatment, electroporation or lipofection for mammalian cells.
- Cells transformed by the cassettes can be selected by resistance to antibiotics conferred by genes contained in the cassettes, such as the amp, gpt, neo and hyg genes.
- Modifications can be made to a nucleic acid encoding a polypeptide described herein without diminishing its biological activity. Some modifications can be made to facilitate the cloning, expression, or incorporation of the targeting molecule into a fusion protein. Such modifications include, for example, termination codons, sequences to create conveniently located restriction sites, and sequences to add a methionine at the amino terminus to provide an initiation site, or additional amino acids (such as poly His) to aid in purification steps.
- the antibodies, antigen binding fragments, and conjugates can be purified according to standard procedures in the art, including ammonium sulfate precipitation, affinity columns, column chromatography, and the like (see, generally, Simpson et al. (Eds.), Basic methods in Protein Purification and Analysis: A Laboratory Manual, New York: Cold Spring Harbor Laboratory Press, 2009).
- the antibodies, antigen binding fragment, and conjugates need not be 100% pure.
- the polypeptides should be substantially free of endotoxin.
- a disclosed antibody such as any one of MAD21-17, MAD21-46, MAD21-53, MAD21-95, MAD21-101, MAD22-17, MAD22-38, MAD22-39, MAD24-01, MAD24-05, or MAD24-52
- the methods can be used pre-exposure or post-exposure.
- P. falciparum infection does not need to be completely eliminated or inhibited for the method to be effective. For example, the method can decrease P.
- falciparum infection by a desired amount, for example by at least 10%, at least 20%, at least 50%, at least 60%, at least 70%, at least 80%, at least 90%, at least 95%, at least 98%, or even at least 100% (elimination or prevention of detectable P. falciparum infection) as compared to P. falciparum infection in the absence of the treatment.
- the subject can also be treated with an effective amount of an additional agent, such as anti-malaria agent.
- administration of an effective amount of a disclosed antibody, antigen binding fragment, conjugate, or nucleic acid molecule inhibits the establishment of P. falciparum infection and/or subsequent P. falciparum disease progression in a subject, which can encompass any statistically significant reduction in P.
- Antibodies and antigen binding fragments thereof are typically administered by intravenous infusion. Doses of the antibody or antigen binding fragment vary, but generally range between about 0.5 mg/kg to about 50 mg/kg, such as a dose of about 1 mg/kg, about 5 mg/kg, about 10 mg/kg, about 20 mg/kg, about 30 mg/kg, about 40 mg/kg, or about 50 mg/kg. In some aspects, the dose of the antibody or antigen binding fragment can be from about 0.5 mg/kg to about 5 mg/kg, such as a dose of about 1 mg/kg, about 2 mg/kg, about 3 mg/kg, about 4 mg/kg or about 5 mg/kg.
- the antibody or antigen binding fragment is administered according to a dosing schedule determined by a medical practitioner. In some examples, the antibody or antigen binding fragment is administered weekly, every two weeks, every three weeks or every four weeks. In some aspects, the method of inhibiting P. falciparum infection in a subject further comprises administration of one or more additional agents to the subject. Additional agents of interest include, but are not limited to, anti-malaria agents. In some aspects, the method of inhibiting P.
- falciparum infection in a subject comprises administration of a first antibody that specifically binds to PfCSP as disclosed herein (such as any one MAD21-17, MAD21-46, MAD21-53, MAD21-95, MAD21-101, MAD22-17, MAD22-38, MAD22-39, MAD24-01, MAD24-05, or MAD24-52) and a second antibody that that specifically binds to PfCSP (such as L9 or CIS43).
- a subject is administered DNA or RNA encoding a disclosed antibody to provide in vivo antibody production, for example using the cellular machinery of the subject. Any suitable method of nucleic acid administration may be used; non-limiting examples are provided in U.S.
- U.S. Patent No.5,880,103 describes several methods of delivery of nucleic acids encoding proteins to an organism.
- One approach to administration of nucleic acids is direct administration with plasmid DNA, such as with a mammalian expression plasmid.
- the nucleotide sequence encoding the disclosed antibody, or antigen binding fragments thereof can be placed under the control of a promoter to increase expression.
- the methods include liposomal delivery of the nucleic acids. Such methods can be applied to the production of an antibody, or antigen binding fragments thereof.
- a disclosed antibody or antigen binding fragment is expressed in a subject using the pVRC8400 vector (described in Barouch et al., J. Virol., 79(14), 8828-8834, 2005).
- a subject such as a human subject at risk of P. falciparum infection
- the AAV viral vector is designed for expression of the nucleic acid molecules encoding a disclosed antibody or antigen binding fragment, and administration of the effective amount of the AAV viral vector to the subject leads to expression of an effective amount of the antibody or antigen binding fragment in the subject.
- Non-limiting examples of AAV viral vectors that can be used to express a disclosed antibody or antigen binding fragment in a subject include those provided in Johnson et al., Nat. Med., 15(8):901-906, 2009 and Gardner et al., Nature, 519(7541):87-91, 2015.
- a nucleic acid encoding a disclosed antibody, or antigen binding fragment thereof is introduced directly into tissue.
- the nucleic acid can be loaded onto gold microspheres by standard methods and introduced into the skin by a device such as Bio-Rad’s HELIOS ⁇ Gene Gun.
- the nucleic acids can be “naked,” consisting of plasmids under control of a strong promoter.
- the DNA is injected into muscle, although it can also be injected directly into other sites.
- Dosages for injection are usually around 0.5 ⁇ g/kg to about 50 mg/kg, and typically are about 0.005 mg/kg to about 5 mg/kg (see, e.g., U.S. Patent No.5,589,466).
- Single or multiple administrations of a composition including a disclosed PfCSP-specific antibody, antigen binding fragment, conjugate, or nucleic acid molecule encoding such molecules can be administered depending on the dosage and frequency as required and tolerated by the patient.
- the dosage can be administered once, but may be applied periodically until either a desired result is achieved or until side effects warrant discontinuation of therapy. Generally, the dose is sufficient to inhibit P.
- the dosage normally lies within a range of circulating concentrations that include the ED 50 , with little or minimal toxicity.
- the dosage can vary within this range depending upon the dosage form employed and the route of administration utilized.
- the effective dose can be determined from cell culture assays and animal studies.
- the PfCSP-specific antibody, antigen binding fragment, conjugate, or nucleic acid molecule encoding such molecules, or a composition including such molecules can be administered to subjects in various ways, including local and systemic administration, such as, e.g., by injection subcutaneously, intravenously, intra-arterially, intraperitoneally, intramuscularly, intradermally, or intrathecally.
- the antibody, antigen binding fragment, conjugate, or nucleic acid molecule encoding such molecules, or a composition including such molecules is administered by a single subcutaneous, intravenous, intra-arterial, intraperitoneal, intramuscular, intradermal or intrathecal injection once a day.
- the antibody, antigen binding fragment, conjugate, or nucleic acid molecule encoding such molecules, or a composition including such molecules can also be administered by direct injection at or near the site of disease.
- a further method of administration is by osmotic pump (e.g., an Alzet pump) or mini-pump (e.g., an Alzet mini-osmotic pump), which allows for controlled, continuous and/or slow-release delivery of the antibody, antigen binding fragment, conjugate, or nucleic acid molecule encoding such molecules, or a composition including such molecules, over a pre-determined period.
- the osmotic pump or mini-pump can be implanted subcutaneously, or near a target site. 2.
- compositions are provided that include one or more of the PfCSP-specific antibody, antigen binding fragment, conjugate, or nucleic acid molecule encoding such molecules, that are disclosed herein in a pharmaceutically acceptable carrier.
- the composition comprises an antibody as provided herein (such as any one of MAD21-17, MAD21-46, MAD21-53, MAD21-95, MAD21-101, MAD22-17, MAD22-38, MAD22-39, MAD24-01, MAD24-05, or MAD24-52).
- the composition comprises an antibody as provided herein (such as any one of MAD21-17, MAD21-46, MAD21-53, MAD21-95, MAD21-101, MAD22-17, MAD22-38, MAD22-39, MAD24-01, MAD24-05, or MAD24-52) and one or more additional PfCSP-specific antibody, such as L9 or CIS43 or 317.
- the compositions are useful, for example, for example, for the inhibition or detection of a P. falciparum infection.
- the compositions can be prepared in unit dosage forms for administration to a subject. The amount and timing of administration are at the discretion of the administering physician to achieve the desired purposes.
- the PfCSP-specific antibody, antigen binding fragment, conjugate, or nucleic acid molecule encoding such molecules can be formulated for systemic or local administration.
- the PfCSP-specific antibody, antigen binding fragment, conjugate, or nucleic acid molecule encoding such molecules is formulated for parenteral administration, such as intravenous administration.
- the antibody, antigen binding fragment, or conjugate thereof, in the composition is at least 70% (such as at least 75%, at least 80%, at least 85%, at least 90%, at least 95%, at least 96%, at least 97%, at least 98% or at least 99%) pure.
- the composition contains less than 10% (such as less than 5%, less than 4%, less than 3%, less than 2%, less than 1%, less than 0.5%, or even less) of macromolecular contaminants, such as other mammalian (e.g., human) proteins.
- the compositions for administration can include a solution of the PfCSP-specific antibody, antigen binding fragment, conjugate, or nucleic acid molecule encoding such molecules, dissolved in a pharmaceutically acceptable carrier, such as an aqueous carrier.
- a pharmaceutically acceptable carrier such as an aqueous carrier.
- aqueous carriers can be used, for example, buffered saline and the like. These solutions are sterile and generally free of undesirable matter.
- These compositions may be sterilized by any suitable technique.
- compositions may contain pharmaceutically acceptable auxiliary substances as required to approximate physiological conditions such as pH adjusting and buffering agents, toxicity adjusting agents and the like, for example, sodium acetate, sodium chloride, potassium chloride, calcium chloride, sodium lactate and the like.
- concentration of antibody in these formulations can vary widely, and will be selected primarily based on fluid volumes, viscosities, body weight and the like in accordance with the particular mode of administration selected and the subject’s needs.
- a typical composition for intravenous administration comprises about 0.01 to about 30 mg/kg of antibody or antigen binding fragment or conjugate per subject per day (or the corresponding dose of a conjugate including the antibody or antigen binding fragment).
- the composition can be a liquid formulation including one or more antibodies, antigen binding fragments (such as an antibody or antigen binding fragment that specifically binds to PfCSP), in a concentration range from about 0.1 mg/ml to about 20 mg/ml, or from about 0.5 mg/ml to about 20 mg/ml, or from about 1 mg/ml to about 20 mg/ml, or from about 0.1 mg/ml to about 10 mg/ml, or from about 0.5 mg/ml to about 10 mg/ml, or from about 1 mg/ml to about 10 mg/ml.
- antigen binding fragments such as an antibody or antigen binding fragment that specifically binds to PfCSP
- Antibodies, or an antigen binding fragment thereof or a conjugate or a nucleic acid encoding such molecules can be provided in lyophilized form and rehydrated with sterile water before administration, although they are also provided in sterile solutions of known concentration.
- the antibody solution, or an antigen binding fragment or a nucleic acid encoding such antibodies or antigen binding fragments can then be added to an infusion bag containing 0.9% sodium chloride, USP, and typically administered at a dosage of from 0.5 to 15 mg/kg of body weight.
- Antibodies, antigen binding fragments, conjugates, or a nucleic acid encoding such molecules can be administered by slow infusion, rather than in an intravenous push or bolus.
- a higher loading dose is administered, with subsequent, maintenance doses being administered at a lower level.
- an initial loading dose of 4 mg/kg may be infused over a period of some 90 minutes, followed by weekly maintenance doses for 4-8 weeks of 2 mg/kg infused over a 30-minute period if the previous dose was well tolerated.
- Controlled-release parenteral formulations can be made as implants, oily injections, or as particulate systems.
- Particulate systems include microspheres, microparticles, microcapsules, nanocapsules, nanospheres, and nanoparticles.
- Microcapsules contain the active protein agent, such as a cytotoxin or a drug, as a central core. In microspheres, the active protein agent is dispersed throughout the particle. Particles, microspheres, and microcapsules smaller than about 1 ⁇ m are generally referred to as nanoparticles, nanospheres, and nanocapsules, respectively.
- Capillaries have a diameter of approximately 5 ⁇ m so that only nanoparticles are administered intravenously. Microparticles are typically around 100 ⁇ m in diameter and are administered subcutaneously or intramuscularly. See, for example, Kreuter, Colloidal Drug Delivery Systems, J. Kreuter (Ed.), New York, NY: Marcel Dekker, Inc., pp.219-342, 1994; and Tice and Tabibi, Treatise on Controlled Drug Delivery: Fundamentals, Optimization, Applications, A. Kydonieus (Ed.), New York, NY: Marcel Dekker, Inc., pp.315-339, 1992. Polymers can be used for ion-controlled release of the antibody compositions disclosed herein.
- Any suitable polymer may be used, such as a degradable or nondegradable polymeric matrix designed for use in controlled drug delivery.
- hydroxyapatite has been used as a microcarrier for controlled release of proteins.
- liposomes are used for controlled release as well as drug targeting of the lipid-capsulated drug. 3.
- Methods of detection and diagnosis Methods are also provided for the detection of the presence of PfCSP in vitro or in vivo.
- the presence of PfCSP is detected in a biological sample from a subject, and can be used to identify a subject with P. falciparum infection.
- the sample can be any sample, including, but not limited to, tissue from biopsies, autopsies and pathology specimens.
- Biological samples also include sections of tissues, for example, frozen sections taken for histological purposes. Biological samples further include body fluids, such as blood, serum, plasma, sputum, spinal fluid or urine.
- the method of detection can include contacting a cell or sample, with an antibody or antigen binding fragment that specifically binds to PfCSP, or conjugate thereof (e.g., a conjugate including a detectable marker) under conditions sufficient to form an immune complex, and detecting the immune complex (e.g., by detecting a detectable marker conjugated to the antibody or antigen binding fragment.
- the antibody or antigen binding fragment is directly labeled with a detectable marker.
- the antibody that binds P is directly labeled with a detectable marker.
- the primary antibody is unlabeled and a secondary antibody or other molecule that can bind the primary antibody is utilized for detection.
- the secondary antibody is chosen that is able to specifically bind the specific species and class of the first antibody.
- the first antibody is a human IgG
- the secondary antibody may be an anti-human-IgG.
- Other molecules that can bind to antibodies include, without limitation, Protein A and Protein G, both of which are available commercially.
- Suitable labels for the antibody, antigen binding fragment or secondary antibody are known and described above, and include various enzymes, prosthetic groups, fluorescent materials, luminescent materials, magnetic agents and radioactive materials.
- the disclosed antibodies or antigen binding fragments thereof are used to test vaccines.
- a vaccine composition including a PfCSP or fragment thereof assumes a conformation including the epitope of a disclosed antibody.
- the method comprises contacting a sample containing the vaccine, such as a PfCSP immunogen, with a disclosed antibody or antigen binding fragment under conditions sufficient for formation of an immune complex, and detecting the immune complex, to detect the vaccine with an PfCSP immunogen including the epitope in the sample.
- the detection of the immune complex in the sample indicates that vaccine component, such as a PfCSP immunogen assumes a conformation capable of binding the antibody or antigen binding fragment.
- Example 1 Highly Protective Anti-Malarial Antibodies This example illustrates the design and assessment of antibodies to PfCSP with protective potency and that bind to a novel PfCSP epitope. Identification of Pf sporozoite specific mAbs. An antigen-agnostic approach was used to isolate functional monoclonal antibodies (mAbs) that target novel epitopes on the Plasmodium falciparum (Pf) sporozoite.
- mAbs monoclonal antibodies
- Plasma IgG reactivity towards whole Pf sporozoites was assessed in parallel for both the blocked and unblocked plasma samples and is represented as the percentage of IgG positive sporozoites. In total, 4 vaccinees showed high IgG reactivity to sporozoites after blocking of plasma (FIG.1). These individuals were therefore selected as donors of interest for the study. Binding of plasma IgG to sporozoites or PfCSP antigens was measured with the IntelliCyt iQue Screener flow cytometer and FACS data were analyzed with FlowJo (Version 10.8.1. Ashland, OR).
- MBCs memory B cells isolated from the four donors of interest and exported MBCs that secreted mAbs which bound to the surface of Pf sporozoites but not to recombinant, mammalian cell expressed PfCSP.
- the respective antibodies were recombinantly expressed as IgG1 mAbs and titrated against wild-type Pf sporozoites. Binding of recombinant mAbs to sporozoites was measured with the IntelliCyt iQue Screener flow cytometer and FACS data were analysed with FlowJo (Version 10.8.1. Ashland, OR).
- the panel consisted of transgenic Pb sporozoites that express the full PfCSP sequence (Pb PfCSP ); transgenic Pb sporozoites that express PfCSP which lacks the ADGNPDP residues in the junctional region (Pb-PfCSP JRKO); chimeric Pb sporozoites with 12 Pf-NANP repeats inserted into the PbCSP open reading frame (Pb CSP Pf-NANP 12 ); and chimeric Pb sporozoites with 4 Pf-NANP repeats and the ADGNPDP residues from the Pf junctional region inserted into the PbCSP open reading frame (Pb CSP Pf-NANP 4-5 ).
- the eleven mAbs were titrated against recombinant peptides that recapitulate sporozoite-mediated, post- translational modifications present on PfCSP. Binding of recombinant mAbs to the antigen conjugated beads was measured by flow cytometry in a multiplexed bead-based assay. All mAbs bound to the peptide bearing an N-terminal glutamine which represents the proposed PfCSP N-terminus post-cleavage (FIG.10).
Landscapes
- Health & Medical Sciences (AREA)
- Chemical & Material Sciences (AREA)
- Tropical Medicine & Parasitology (AREA)
- Organic Chemistry (AREA)
- Medicinal Chemistry (AREA)
- Veterinary Medicine (AREA)
- Life Sciences & Earth Sciences (AREA)
- General Health & Medical Sciences (AREA)
- Molecular Biology (AREA)
- Genetics & Genomics (AREA)
- Biophysics (AREA)
- Proteomics, Peptides & Aminoacids (AREA)
- Biochemistry (AREA)
- Immunology (AREA)
- Chemical Kinetics & Catalysis (AREA)
- General Chemical & Material Sciences (AREA)
- Nuclear Medicine, Radiotherapy & Molecular Imaging (AREA)
- Pharmacology & Pharmacy (AREA)
- Animal Behavior & Ethology (AREA)
- Public Health (AREA)
- Peptides Or Proteins (AREA)
Abstract
L'invention concerne des anticorps et des fragments de liaison à l'antigène qui se lient spécifiquement à la protéine P. falciparum circumsporozoïte. L'invention concerne également des acides nucléiques codant pour ces anticorps, des vecteurs et des cellules hôtes. Les anticorps, les fragments de liaison à l'antigène, les acides nucléiques et les vecteurs décrits peuvent être utilisés, par exemple, pour inhiber une infection par P. falciparum.
Applications Claiming Priority (2)
Application Number | Priority Date | Filing Date | Title |
---|---|---|---|
US202263409016P | 2022-09-22 | 2022-09-22 | |
US63/409,016 | 2022-09-22 |
Publications (1)
Publication Number | Publication Date |
---|---|
WO2024064826A1 true WO2024064826A1 (fr) | 2024-03-28 |
Family
ID=88505260
Family Applications (1)
Application Number | Title | Priority Date | Filing Date |
---|---|---|---|
PCT/US2023/074791 WO2024064826A1 (fr) | 2022-09-22 | 2023-09-21 | Anticorps neutralisants dirigés contre la protéine plasmodium falciparum circumsporozoïte et leur utilisation |
Country Status (1)
Country | Link |
---|---|
WO (1) | WO2024064826A1 (fr) |
Citations (45)
Publication number | Priority date | Publication date | Assignee | Title |
---|---|---|---|---|
US5589466A (en) | 1989-03-21 | 1996-12-31 | Vical Incorporated | Induction of a protective immune response in a mammal by injecting a DNA sequence |
US5593972A (en) | 1993-01-26 | 1997-01-14 | The Wistar Institute | Genetic immunization |
US5643578A (en) | 1992-03-23 | 1997-07-01 | University Of Massachusetts Medical Center | Immunization by inoculation of DNA transcription unit |
WO1997030087A1 (fr) | 1996-02-16 | 1997-08-21 | Glaxo Group Limited | Preparation d'anticorps glycosyles |
WO1998058964A1 (fr) | 1997-06-24 | 1998-12-30 | Genentech, Inc. | Procedes et compositions concernant des glycoproteines galactosylees |
US5880103A (en) | 1992-08-11 | 1999-03-09 | President And Fellows Of Harvard College | Immunomodulatory peptides |
WO1999022764A1 (fr) | 1997-10-31 | 1999-05-14 | Genentech, Inc. | Compositions renfermant des glycoformes de glycoproteine et methodes afferentes |
WO1999054440A1 (fr) | 1998-04-21 | 1999-10-28 | Micromet Gesellschaft Für Biomedizinische Forschung Mbh | Polypeptides specifiques a cd19 et cd3 et leurs utilisations |
WO2000061739A1 (fr) | 1999-04-09 | 2000-10-19 | Kyowa Hakko Kogyo Co., Ltd. | Methode de regulation de l'activite d'une molecule immunologiquement fonctionnelle |
WO2001029246A1 (fr) | 1999-10-19 | 2001-04-26 | Kyowa Hakko Kogyo Co., Ltd. | Procede de production d'un polypeptide |
WO2002031140A1 (fr) | 2000-10-06 | 2002-04-18 | Kyowa Hakko Kogyo Co., Ltd. | Cellules produisant des compositions d'anticorps |
US20020164328A1 (en) | 2000-10-06 | 2002-11-07 | Toyohide Shinkawa | Process for purifying antibody |
WO2003011878A2 (fr) | 2001-08-03 | 2003-02-13 | Glycart Biotechnology Ag | Variants de glycosylation d'anticorps presentant une cytotoxicite cellulaire accrue dependante des anticorps |
US20030115614A1 (en) | 2000-10-06 | 2003-06-19 | Yutaka Kanda | Antibody composition-producing cell |
US6602684B1 (en) | 1998-04-20 | 2003-08-05 | Glycart Biotechnology Ag | Glycosylation engineering of antibodies for improving antibody-dependent cellular cytotoxicity |
US20030157108A1 (en) | 2001-10-25 | 2003-08-21 | Genentech, Inc. | Glycoprotein compositions |
WO2003084570A1 (fr) | 2002-04-09 | 2003-10-16 | Kyowa Hakko Kogyo Co., Ltd. | Medicament contenant une composition d'anticorps appropriee au patient souffrant de polymorphisme fc$g(g)riiia |
WO2003085107A1 (fr) | 2002-04-09 | 2003-10-16 | Kyowa Hakko Kogyo Co., Ltd. | Cellules à génome modifié |
WO2003085119A1 (fr) | 2002-04-09 | 2003-10-16 | Kyowa Hakko Kogyo Co., Ltd. | Procede d'amelioration de l'activite d'une composition d'anticorps de liaison avec le recepteur fc$g(g) iiia |
US6723538B2 (en) | 1999-03-11 | 2004-04-20 | Micromet Ag | Bispecific antibody and chemokine receptor constructs |
US20040093621A1 (en) | 2001-12-25 | 2004-05-13 | Kyowa Hakko Kogyo Co., Ltd | Antibody composition which specifically binds to CD20 |
US20040109865A1 (en) | 2002-04-09 | 2004-06-10 | Kyowa Hakko Kogyo Co., Ltd. | Antibody composition-containing medicament |
US20040110282A1 (en) | 2002-04-09 | 2004-06-10 | Kyowa Hakko Kogyo Co., Ltd. | Cells in which activity of the protein involved in transportation of GDP-fucose is reduced or lost |
US20040132140A1 (en) | 2002-04-09 | 2004-07-08 | Kyowa Hakko Kogyo Co., Ltd. | Production process for antibody composition |
WO2004056312A2 (fr) | 2002-12-16 | 2004-07-08 | Genentech, Inc. | Variants d'immunoglobuline et utilisations |
WO2005035586A1 (fr) | 2003-10-08 | 2005-04-21 | Kyowa Hakko Kogyo Co., Ltd. | Composition proteique hybride |
WO2005035778A1 (fr) | 2003-10-09 | 2005-04-21 | Kyowa Hakko Kogyo Co., Ltd. | Procede permettant de produire une composition d'anticorps par inhibition par l'arn de la fonction de $g(a)1,6-fucosyltransferase |
US20050123546A1 (en) | 2003-11-05 | 2005-06-09 | Glycart Biotechnology Ag | Antigen binding molecules with increased Fc receptor binding affinity and effector function |
WO2005053742A1 (fr) | 2003-12-04 | 2005-06-16 | Kyowa Hakko Kogyo Co., Ltd. | Medicament contenant une composition a base d'anticorps |
US7229760B2 (en) | 2000-03-24 | 2007-06-12 | Micromet Ag | mRNA amplification |
US7235641B2 (en) | 2003-12-22 | 2007-06-26 | Micromet Ag | Bispecific antibodies |
US7323440B2 (en) | 2002-02-13 | 2008-01-29 | Micromet Ag | De-immunized MOG (poly)peptide constructs |
US7332168B2 (en) | 2000-08-22 | 2008-02-19 | Micromet Ag | Composition for the elimination of autoreactive B-cells |
WO2008077546A1 (fr) | 2006-12-22 | 2008-07-03 | F. Hoffmann-La Roche Ag | Anticorps contre le récepteur du facteur de croissance i de type insuline et leurs utilisations |
US7435549B1 (en) | 1997-11-17 | 2008-10-14 | Micromet Ag | Method of identifying binding site domains that retain the capacity of binding to an epitope |
US7635472B2 (en) | 2003-05-31 | 2009-12-22 | Micromet Ag | Pharmaceutical compositions comprising bispecific anti-cd3, anti-cd19 antibody constructs for the treatment of b-cell related disorders |
US7820166B2 (en) | 2002-10-11 | 2010-10-26 | Micromet Ag | Potent T cell modulating molecules |
US7919089B2 (en) | 2003-05-31 | 2011-04-05 | Micromet Ag | Pharmaceutical composition comprising a bispecific antibody for EpCAM |
US8007796B2 (en) | 2005-12-16 | 2011-08-30 | Micromet Ag | Means and methods for the treatment of tumorous diseases |
US8017748B2 (en) | 2005-04-18 | 2011-09-13 | Micromet Ag | Antibody neutralizers of human granulocyte macrophage colony stimulating factor |
US8076459B2 (en) | 2003-10-16 | 2011-12-13 | Micromet Ag | Multispecfic deimmunized CD3-binders |
WO2013163427A1 (fr) | 2012-04-25 | 2013-10-31 | The United States Of America, As Represented By The Secretary, Department Of Health & Human Services | Anticorps pour traiter les infections par le vih-1 |
WO2018148660A1 (fr) | 2017-02-10 | 2018-08-16 | The United States Of America, As Represented By The Secretary, Department Of Health And Human Services | Anticorps neutralisants dirigés contre la protéine circumsporozoïte de plasmodium falciparum et leur utilisation |
WO2020227228A2 (fr) | 2019-05-03 | 2020-11-12 | The United States Of America, As Represented By The Secretary, Department Of Health And Human Services | Anticorps neutralisants dirigés contre la protéine circumsporozoïte de plasmodium falciparum et leur utilisation |
WO2021257665A1 (fr) * | 2020-06-19 | 2021-12-23 | The United States Of America, As Represented By The Secretary, Department Of Health And Human Services | Anticorps monoclonal humain ciblant un site conservé sur la protéine circumsporozoïte de plasmodium falciparum |
-
2023
- 2023-09-21 WO PCT/US2023/074791 patent/WO2024064826A1/fr unknown
Patent Citations (49)
Publication number | Priority date | Publication date | Assignee | Title |
---|---|---|---|---|
US5589466A (en) | 1989-03-21 | 1996-12-31 | Vical Incorporated | Induction of a protective immune response in a mammal by injecting a DNA sequence |
US5643578A (en) | 1992-03-23 | 1997-07-01 | University Of Massachusetts Medical Center | Immunization by inoculation of DNA transcription unit |
US5880103A (en) | 1992-08-11 | 1999-03-09 | President And Fellows Of Harvard College | Immunomodulatory peptides |
US5593972A (en) | 1993-01-26 | 1997-01-14 | The Wistar Institute | Genetic immunization |
US5817637A (en) | 1993-01-26 | 1998-10-06 | The Trustees Of The University Of Pennsylvania | Genetic immunization |
WO1997030087A1 (fr) | 1996-02-16 | 1997-08-21 | Glaxo Group Limited | Preparation d'anticorps glycosyles |
WO1998058964A1 (fr) | 1997-06-24 | 1998-12-30 | Genentech, Inc. | Procedes et compositions concernant des glycoproteines galactosylees |
WO1999022764A1 (fr) | 1997-10-31 | 1999-05-14 | Genentech, Inc. | Compositions renfermant des glycoformes de glycoproteine et methodes afferentes |
US7435549B1 (en) | 1997-11-17 | 2008-10-14 | Micromet Ag | Method of identifying binding site domains that retain the capacity of binding to an epitope |
US6602684B1 (en) | 1998-04-20 | 2003-08-05 | Glycart Biotechnology Ag | Glycosylation engineering of antibodies for improving antibody-dependent cellular cytotoxicity |
WO1999054440A1 (fr) | 1998-04-21 | 1999-10-28 | Micromet Gesellschaft Für Biomedizinische Forschung Mbh | Polypeptides specifiques a cd19 et cd3 et leurs utilisations |
US7575923B2 (en) | 1998-04-21 | 2009-08-18 | Micromet Ag | CD19xCD3 specific polypeptides and uses thereof |
US7112324B1 (en) | 1998-04-21 | 2006-09-26 | Micromet Ag | CD 19×CD3 specific polypeptides and uses thereof |
US6723538B2 (en) | 1999-03-11 | 2004-04-20 | Micromet Ag | Bispecific antibody and chemokine receptor constructs |
WO2000061739A1 (fr) | 1999-04-09 | 2000-10-19 | Kyowa Hakko Kogyo Co., Ltd. | Methode de regulation de l'activite d'une molecule immunologiquement fonctionnelle |
WO2001029246A1 (fr) | 1999-10-19 | 2001-04-26 | Kyowa Hakko Kogyo Co., Ltd. | Procede de production d'un polypeptide |
US7229760B2 (en) | 2000-03-24 | 2007-06-12 | Micromet Ag | mRNA amplification |
US7332168B2 (en) | 2000-08-22 | 2008-02-19 | Micromet Ag | Composition for the elimination of autoreactive B-cells |
WO2002031140A1 (fr) | 2000-10-06 | 2002-04-18 | Kyowa Hakko Kogyo Co., Ltd. | Cellules produisant des compositions d'anticorps |
US20020164328A1 (en) | 2000-10-06 | 2002-11-07 | Toyohide Shinkawa | Process for purifying antibody |
US20030115614A1 (en) | 2000-10-06 | 2003-06-19 | Yutaka Kanda | Antibody composition-producing cell |
WO2003011878A2 (fr) | 2001-08-03 | 2003-02-13 | Glycart Biotechnology Ag | Variants de glycosylation d'anticorps presentant une cytotoxicite cellulaire accrue dependante des anticorps |
US20030157108A1 (en) | 2001-10-25 | 2003-08-21 | Genentech, Inc. | Glycoprotein compositions |
US20040093621A1 (en) | 2001-12-25 | 2004-05-13 | Kyowa Hakko Kogyo Co., Ltd | Antibody composition which specifically binds to CD20 |
US7323440B2 (en) | 2002-02-13 | 2008-01-29 | Micromet Ag | De-immunized MOG (poly)peptide constructs |
US20040110282A1 (en) | 2002-04-09 | 2004-06-10 | Kyowa Hakko Kogyo Co., Ltd. | Cells in which activity of the protein involved in transportation of GDP-fucose is reduced or lost |
US20040110704A1 (en) | 2002-04-09 | 2004-06-10 | Kyowa Hakko Kogyo Co., Ltd. | Cells of which genome is modified |
WO2003084570A1 (fr) | 2002-04-09 | 2003-10-16 | Kyowa Hakko Kogyo Co., Ltd. | Medicament contenant une composition d'anticorps appropriee au patient souffrant de polymorphisme fc$g(g)riiia |
WO2003085107A1 (fr) | 2002-04-09 | 2003-10-16 | Kyowa Hakko Kogyo Co., Ltd. | Cellules à génome modifié |
US20040132140A1 (en) | 2002-04-09 | 2004-07-08 | Kyowa Hakko Kogyo Co., Ltd. | Production process for antibody composition |
US20040109865A1 (en) | 2002-04-09 | 2004-06-10 | Kyowa Hakko Kogyo Co., Ltd. | Antibody composition-containing medicament |
WO2003085119A1 (fr) | 2002-04-09 | 2003-10-16 | Kyowa Hakko Kogyo Co., Ltd. | Procede d'amelioration de l'activite d'une composition d'anticorps de liaison avec le recepteur fc$g(g) iiia |
US7820166B2 (en) | 2002-10-11 | 2010-10-26 | Micromet Ag | Potent T cell modulating molecules |
WO2004056312A2 (fr) | 2002-12-16 | 2004-07-08 | Genentech, Inc. | Variants d'immunoglobuline et utilisations |
US7919089B2 (en) | 2003-05-31 | 2011-04-05 | Micromet Ag | Pharmaceutical composition comprising a bispecific antibody for EpCAM |
US7635472B2 (en) | 2003-05-31 | 2009-12-22 | Micromet Ag | Pharmaceutical compositions comprising bispecific anti-cd3, anti-cd19 antibody constructs for the treatment of b-cell related disorders |
WO2005035586A1 (fr) | 2003-10-08 | 2005-04-21 | Kyowa Hakko Kogyo Co., Ltd. | Composition proteique hybride |
WO2005035778A1 (fr) | 2003-10-09 | 2005-04-21 | Kyowa Hakko Kogyo Co., Ltd. | Procede permettant de produire une composition d'anticorps par inhibition par l'arn de la fonction de $g(a)1,6-fucosyltransferase |
US8076459B2 (en) | 2003-10-16 | 2011-12-13 | Micromet Ag | Multispecfic deimmunized CD3-binders |
US20050123546A1 (en) | 2003-11-05 | 2005-06-09 | Glycart Biotechnology Ag | Antigen binding molecules with increased Fc receptor binding affinity and effector function |
WO2005053742A1 (fr) | 2003-12-04 | 2005-06-16 | Kyowa Hakko Kogyo Co., Ltd. | Medicament contenant une composition a base d'anticorps |
US7235641B2 (en) | 2003-12-22 | 2007-06-26 | Micromet Ag | Bispecific antibodies |
US8017748B2 (en) | 2005-04-18 | 2011-09-13 | Micromet Ag | Antibody neutralizers of human granulocyte macrophage colony stimulating factor |
US8007796B2 (en) | 2005-12-16 | 2011-08-30 | Micromet Ag | Means and methods for the treatment of tumorous diseases |
WO2008077546A1 (fr) | 2006-12-22 | 2008-07-03 | F. Hoffmann-La Roche Ag | Anticorps contre le récepteur du facteur de croissance i de type insuline et leurs utilisations |
WO2013163427A1 (fr) | 2012-04-25 | 2013-10-31 | The United States Of America, As Represented By The Secretary, Department Of Health & Human Services | Anticorps pour traiter les infections par le vih-1 |
WO2018148660A1 (fr) | 2017-02-10 | 2018-08-16 | The United States Of America, As Represented By The Secretary, Department Of Health And Human Services | Anticorps neutralisants dirigés contre la protéine circumsporozoïte de plasmodium falciparum et leur utilisation |
WO2020227228A2 (fr) | 2019-05-03 | 2020-11-12 | The United States Of America, As Represented By The Secretary, Department Of Health And Human Services | Anticorps neutralisants dirigés contre la protéine circumsporozoïte de plasmodium falciparum et leur utilisation |
WO2021257665A1 (fr) * | 2020-06-19 | 2021-12-23 | The United States Of America, As Represented By The Secretary, Department Of Health And Human Services | Anticorps monoclonal humain ciblant un site conservé sur la protéine circumsporozoïte de plasmodium falciparum |
Non-Patent Citations (57)
Title |
---|
"Antibody Expre sion and Production, Dordrecht", 2011, SPRINGER |
AHMAD ET AL., CLIN. DEV. IMMUNOL., 2012 |
AL-LAZIKANI ET AL.: "Standard conformations for the canonical structures of immunoglobulins", J. MOL. BIO., vol. 273, no. 4, 1997, pages 927 - 948, XP004461383, DOI: 10.1006/jmbi.1997.1354 |
ALTSCHUL ET AL., J. MOL. BIOL., vol. 215, no. 3, 1990, pages 403 - 410 |
BANGA: "Therapeutic Peptides and Proteins: Formulation, Processing, and Deliver-v Systems", 1995, TECHNOMIC PUBLISHING COMPANY, INC. |
BAROUCH ET AL., J. VIROL., vol. 79, no. 14, 2005, pages 8828 - 8834 |
BIRD ET AL., SCIENCE, vol. 242, no. 4877, 1988, pages 423 - 426 |
BRIIHL ET AL., J. IMMUNOL., vol. 166, no. 4, 2001, pages 2420 - 2426 |
CHEN ET AL., J. MOL. BIOL., vol. 293, no. 4, 1999, pages 865 - 881 |
CORPET, NUCLEIC ACIDS RES., vol. 16, no. 22, 1988, pages 10881 - 10890 |
DALL'ACQUA ET AL., J. BIOL. CHEM., vol. 281, no. 33, 2006, pages 23514 - 23524 |
ESPINOSA ET AL., J INFECT DIS, vol. 212, 2015, pages 1111 - 1119 |
GARDNER ET AL., NATURE, vol. 519, no. 7541, 2015, pages 87 - 91 |
HARLOWLANE: "Remington: The Science and Practice of Pharmacy", 2013, COLD SPRING HARBOR PUBLICATIONS |
HIGGINSSHARP, BIOINFORMATICS, vol. 5, no. 2, 1989, pages 151 - 3 |
HIGGINSSHARP, GENE, vol. 73, no. 1, 1988, pages 237 - 244 |
HINTON ET AL., J IMMUNOL., vol. 176, 2006, pages 346 - 356 |
HUANG ET AL., BIOINFORMATICS, vol. 8, no. 2, 1992, pages 155 - 165 |
HUSTON ET AL., PROC. NATL. ACAD. SCI. U.S.A., vol. 85, no. 16, 1988, pages 5879 - 5883 |
JOHNSON ET AL., NAT. MED., vol. 15, no. 8, 2009, pages 901 - 906 |
KABAT ET AL.: "NIH Publication No. 91-3242", 1991, PUBLIC HEALTH SERVICE, NATIONAL INSTITUTES OF HEALTH, article "Sequences of Proteins of Immunological Interest" |
KANDA ET AL., BIOTECHNOL. BIOENG., vol. 94, no. 4, 2006, pages 680 - 688 |
KASTENMULLER ET AL., INFECT IMMUN, vol. 81, 2013, pages 789 - 800 |
KISALU ET AL., NAT MED, vol. 24, 2018, pages 408 - 416 |
KISALU ET AL., NAT. MED., vol. 24, 2018, pages 408 - 416 |
KOLLI ET AL., PROC NATL ACAD SCI U S A, vol. 119, 2022, pages e2209729119 |
KREUTER: "Colloidal Drug Delivery Systems", 1994, MARCEL DEKKER, INC., pages: 219 - 342 |
KUFER ET AL., CANCER IMMUNOL. IMMUNOTHER., vol. 45, no. 3-4, 1997, pages 193 - 197 |
LAZAR ET AL., PROC. NATL., ACAD. SCI. U.S.A., vol. 103, no. 11, 2006, pages 4005 - 4010 |
LEFRANC ET AL.: "IMGT unique numbering for immunoglobulin and T cell receptor variable domains and Ig superfamily V-like domains", DEV. COMP. IMMUNOL., vol. 27, no. 1, 2003, pages 55 - 77, XP055585227, DOI: 10.1016/S0145-305X(02)00039-3 |
LOFFLER ET AL., BLOOD, vol. 95, no. 6, 2000, pages 2098 - 2103 |
LONBERG, NAT. BIOTECH., vol. 23, 2005, pages 1117 - 1125 |
LONENBERG, CURR. OPIN. IMMUNOL., vol. 20, 2008, pages 450 - 459 |
MACK ET AL., J. IMMUNOL., vol. 158, no. 8, 1997, pages 3965 - 3970 |
MACK ET AL., PROC. NATL. ACAD. SCI. U.S.A., vol. 92, no. 15, 1995, pages 7021 - 7025 |
MARBRYSNAVELY, IDRUGS, vol. 1-2, no. 8, 2010, pages 543 - 549 |
MCCAFFERTY ET AL., NATURE, vol. 348, 1990, pages 552 - 554 |
NEEDLEMANWUNSCH, J. MOL. BIOL., vol. 48, no. 3, 1970, pages 443 - 453 |
NEVILLE K KISALU ET AL: "A human monoclonal antibody prevents malaria infection by targeting a new site of vulnerability on the parasite", NATURE MEDICINE, vol. 24, no. 4, 19 March 2018 (2018-03-19), New York, pages 408 - 416, XP055717091, ISSN: 1078-8956, DOI: 10.1038/nm.4512 * |
OKAZAKI ET AL., J. MOL. BIOL., vol. 336, no. 5, 2004, pages 1239 - 1249 |
OYEN ET AL., PROC NATL ACAD SCI U S A, vol. 114, 2017, pages E10438 - E10445 |
OYEN ET AL.: "Structural basis for antibody recognition of the NANP repeats in Plasmodium falciparum circumsporozoite protein", PROC NATL ACAD SCI USA, vol. 114, 2017, pages E10438 - E10445, XP055717496, DOI: 10.1073/pnas.1715812114 |
PEARSON, METHODS MOL. BIOL., vol. 24, 1994, pages 307 - 331 |
PETKOVA ET AL., INT. IMMUNOL., vol. 18, no. 12, 2006, pages 1759 - 1769 |
PRESTA ET AL., CANCER RES., vol. 57, no. 20, 1997, pages 4593 - 4599 |
RAGHUNANDAN ET AL., MALAR J, vol. 19, 2020, pages 113 |
RIPKA ET AL., ARCH. BIOCHEM. BIOPHYS., vol. 249, no. 2, 1986, pages 533 - 545 |
SCHOONJANS ET AL., J. IMMUNOL., vol. 165, no. 12, 2000, pages 7050 - 7057 |
SINGH ET AL., J BIOL CHEM, vol. 295, 2020, pages 403 - 414 |
SMITHWATERMAN, ADV. APPL. MATH., vol. 2, no. 4, 1981, pages 482 - 489 |
TICETABIBI: "Treatise on Controlled Drug Delivery: Fundamentals, Optimization, Applications", 1992, MARCEL DEKKER, INC., pages: 315 - 339 |
WANG ET AL., IMMUNITY, vol. 53, 2020, pages 733 - 744 |
WARD ET AL., NATURE, vol. 341, no. 6242, 1989, pages 544 - 546 |
WILLEMS ET AL., J. CHROMATOGR. B ANALYT. TECHNOL. BIOMED LIFE SCI., vol. 786, no. 1-2, 2003, pages 161 - 176 |
WRIGHT ET AL., TRENDS BIOTECHNOL, vol. 15, no. 1, 1997, pages 26 - 32 |
YAMANE-OHNUKI ET AL., BIOTECHNOL. BIOENG., vol. 87, no. 5, 2004, pages 614 - 622 |
ZALEVSKY ET AL., NATURE BIOTECHNOL., vol. 28, no. 2, 2010, pages 157 - 159 |
Similar Documents
Publication | Publication Date | Title |
---|---|---|
US11760794B2 (en) | Neutralizing antibodies to plasmodium falciparum circumsporozoite protein and their use | |
US20220227853A1 (en) | Neutralizing antibodies to plasmodium falciparum circumsporozoite protein and their use | |
US10273288B2 (en) | Neutralizing antibodies to Ebola virus glycoprotein and their use | |
AU2019226034A1 (en) | Neutralizing antibodies to HIV-1 Env and their use | |
US20220380474A1 (en) | Monoclonal antibodies that bind egfrviii and their use | |
WO2023154824A1 (fr) | Anticorps monoclonaux humains ciblant largement les coronavirus | |
EP3972995A1 (fr) | Anticorps se liant à la protéine de fusion du métapneumovirus humain et leur utilisation | |
US11976109B2 (en) | Neutralizing antibodies to ebola virus glycoprotein and their use | |
WO2021257665A1 (fr) | Anticorps monoclonal humain ciblant un site conservé sur la protéine circumsporozoïte de plasmodium falciparum | |
WO2022132904A1 (fr) | Anticorps monoclonaux humains ciblant le sars-cov-2 | |
WO2024064826A1 (fr) | Anticorps neutralisants dirigés contre la protéine plasmodium falciparum circumsporozoïte et leur utilisation | |
WO2023081851A1 (fr) | Anticorps neutralisants dirigés contre la protéine plasmodium falciparum circumsporozoite et leur utilisation | |
WO2024054822A1 (fr) | Anticorps du sars-cov -2 modifiés ayant une largeur de neutralisation accrue | |
US20230348568A1 (en) | Epstein-barr virus monoclonal antibodies and uses thereof | |
US20240043506A1 (en) | Sars-cov-2 antibodies | |
WO2024137381A1 (fr) | Anticorps monoclonaux pour le traitement d'une infection au sars-cov-2 | |
WO2023240246A1 (fr) | Anticorps monocolonaux modifiés par calcul informatique et fragments de liaison à l'antigène spécifiques de protéines de spicule du sars-cov-2 et leurs utilisations | |
WO2023192881A1 (fr) | Anticorps neutralisants dirigés contre la protéine d'enveloppe (env) du vih-1 et leur utilisation | |
WO2024138151A1 (fr) | Anticorps du virus ebola (soudan et zaïre) issus de primates non humains et de sujets humains vaccinés | |
WO2023172881A1 (fr) | Anticorps anti-hmpv et leur utilisation |
Legal Events
Date | Code | Title | Description |
---|---|---|---|
121 | Ep: the epo has been informed by wipo that ep was designated in this application |
Ref document number: 23793183 Country of ref document: EP Kind code of ref document: A1 |